2 2017
www.maedica.org
EDITORIAL
• A never ending story...
ORIGINAL PAPERS
• Vitamin D receptor gene haplotype and late-onset obesity in
Iranian Azeri Turkish women
• Evaluation of multidetector computed tomography in haematuria
• Evaluation of the effect of statins on post-surgical patients with acute kidney injury
• Mode of delivery in stillbirth
• Cancer related fatigue in breast cancer survivors: in correlation to demographic factors
STATE-OF-THE-ART
• How feasible is renal transplantation in HIV-infected patients?
CASE REPORT
• The psychological abuse of the elderly – a silent factor of cardiac decompensation
• First report of pachyonychia congenita type PC-K6a in the Romanian population
• Endotracheal intubation in a Down syndrome adult undergoing cataract surgery
– a multidisciplinary approach
• Congenital lobar emphysema in infants
• The autoimmunity’s footprint in pediatrics: type 1 diabetes, coeliac disease, thyroiditis
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Contents
EDITORIAL POINT OF VIEW
Mircea CINTEZA A never ending story... 79
ORIGINAL PAPERS
Morteza BAGHERI, Fatemeh Vitamin D receptor gene haplotype and late-onset 81
BAHADORI, SHahsanam GHEIBI, obesity in Iranian Azeri Turkish women
Tahereh BEHROOZ LAK,
Zahra SAHEBOZAMANI,
Zahra KUSE-LU, Isa ABDI-RAD
STATE-OF-THE-ART
Oana Ramayana AILIOAIE, How feasible is renal transplantation in 112
Gabriel MIRCESCU HIV-infected patients?
CASE REPORTS
Adina Carmen ILIE, Anca Iuliana The psychological abuse of the elderly – a silent 119
PÎSLARU, Adriana PANCU, factor of cardiac decompensation
Ovidiu GAVRILOVICI, Aliona DRONIC,
Ioana Dana ALEXA
Article received on the 29th of June 2017 and accepted for publication on the 30th of June 2017.
(IHEC), that develops reference maps of human sence of poor metabolizers on the CYP2D6 cyto-
epigenome for different cellular states. The epi- chrome means not to cure with tamoxifen (1).
genome is constituted by the chemical com- Or in colon cancer, the KRAS mutation announc-
pounds which surround the DNA and modify es the lack of response to cetuximab or panitu-
genome activity without changing its basic struc- mumab (3). Of course, it would be much better
ture. The complex of macromolecules consisting to have an atlas to show which marker announ-
of DNA + proteins + RNA is called chromatin ces a 100% response to a specific cancer therapy.
and constitues another complex field of research. But this is still a dream.
The main functions of chromatin are to package To resume, genetics, epigenetics, metabolo-
DNA into a compact stage, reinforced for mito- mic and pharmacogenomics may give important
sis, to prevent DNA damage, and to control re- information about the inherrited predisposition
plication. The Human Epigenomic Atlas tries to to a special cancer, to the predisposition of a
identify modifications in this process. For in- poor defence against the aggression of environ-
stance, a bad function of the previously de- mental factors, to bad habits of lifestyle regarding
scribed sequences is accomplished when there is cancer and to the ability to respond or not to
a hypo-methylation of the DNA. Another point respond to a specific cancer therapy. A dramatic
described in such an atlas is the aspect of RNA example in the field was Angelina Jolie’s decision
sequence and especially the small noncoding to surgically remove her ovaries and breasts be-
RNA (miRNA), which in special conditions may cause of a poor genetic heritage predisposing to
lead, however, to cancer development. Another cancer.
database deveolped in this field is NIH Roadmap The complexity of data presented so far
Epigenomics. makes the daily life of an oncologist very hard.
The next „regional” science in the field is That’s why a new synthetic science, called thera-
called metabolomics; it studies all the metabo- nostics, develops. Using nanotechnology, it
lites in the cell – which are generally small mole- brings a single group of information for diagno-
cules with an essential contribution to the under- stic and target therapy.
standing of a cell functional state. They are We may understand why this devastating
studied, for instance, by mass spectrometry or amount of knowledge finally penetrated in the
nuclear magnetic resonance spectometry, which field of politics. In 2015, president Obama had
deployed to date hundreds of thousands of an important talk dedicated to Precision Medi-
chemical entities (1). cine (meaning „personalized medicine”) – as the
The last huge field of research in cancer, and medicine of the future and maybe of the pre-
not only in cancer, is the specific response to sent. He presented the American Governement’s
therapy – pharmacogenomics. This means the decision to provide substantial funds for this
ability of the tumour and/or the host to respond field. Atttracting funds, research and briliant
to a therapy in respect to their gene composi- minds to cancer personalized medicine is the
tion. Because it implies different genetic compo- only way of bringing us today the medicine of
sitions, this is a very complex issue. In the field of tomorrow.
some cancer pharmacogenomics, today we may
affirm that a specific cancer therapy does not Conflicts of interest: none declared.
work. For instance, in breast cancer, the pre- Financial support: none declared.
References
1. Verma M. Personalized medicine and genome”. Nature 2001;6822:860-921. metastatic colorectal cancer: A systematic
cancer. J Pers Med 2012;2:1-14. 3. Therkildsen C, Bergmann TK, Henrich- review and metaanalysis. Acta Oncologica
2. International Human Genome Sequenc- sen-Schnack T, et al. The predictive 2014;53:852-864.
ing Consortium (Feb 2001). “Initial value of KRAS, NRAS, BRAF, PIK3CA
sequencing and analysis of the human and PTEN for anti-EGFR treatment in
O RIGINAL PAPER
ABSTRACT
Introduction: A large body of literature has revealed the association between vitamin D3-VDR complex
and obesity. The aim of the present study was to survey the rate of the VDR polymorphisms in obese women
and to determine whether there may be an association between VDR BsmI and Tru9I haplotypes and obesity
in Iranian Azeri Turkish women.
Material and methods: 65 Iranian Azeri Turkish women were enrolled in the study and PCR
amplification and direct sequencing of PCR products were used for genotypings.
Results: The findings of this study showed that VDR BsmIG allele, VDR BsmI G/G genotype, VDR
BsmI A/A genotype, Tru9IA allele and Tru9I A/A genotype were more frequent in obese women compared
to controls. The frequency of VDR BsmIG/Tru9IA (GA), VDR BsmIG/Tru9IG (GG), VDR BsmIA/Tru9IG
(AG), and VDR BsmIA/Tru9IA (AA) haplotypes were 19.74%, 42.11%, 38.16% and 0% in cases, and
11.11%, 40.74%, 42.59 and 5.56% in controls. Statistically significant differences were found between
cases and controls regarding the VDR AA haplotype (P=0.03).
Conclusions: Our findings demonstrated that the VDR AA haplotype frequency was significantly lower
in subjects with obesity compared with normal controls. This study shows that the VDR AA haplotype is
significantly associated with a decreased risk of obesity in the tested group. This report is the first of its kind
in the West Azerbaijani population.
Keywords: VDR, haplotype, obesity, women
O
besity is known as unwarranted height in meters. A person with a BMI of 30 or
fat amassing that exposes public more is defined as obese (1). Globally, in 2015,
health to numerous risks (1). In a about 2.3 billion people (age 15+) and over 700
population, the body mass index million adults (age 18+) were obese (2). World-
(BMI) is used to measure the se- wide, the prevalence of obesity increased con-
Address for correspondence:
Prof. Isa Abdi Rad, Cellular and Molecular Research Center,
Urmia University of Medical Sciences, Urmia, Iran,
P.O. Box: 5756115111
E-mail: isaabdirad@yahoo.com
Article received on the 25th of November 2016 and accepted for publication on the 14th of March 2017.
siderably in the last decades from 4.2% in 1990 MATERIALS AND METHODS
to 6.7% in 2010, and it is estimated to reach
9.1% in 2020 (3). In Iran, similarly to the other
countries, the prevalence of obesity has been in- T his research project was a case-control study
and conducted at the Maternal and Child-
hood Obesity Research Center, Urmia University
creasing (3). In 2013, the prevalence of over-
weight and obesity among people in Tehran of Medical Sciences, Urmia, Iran. The ethics com-
aged 20–84 was 34.1% (95% CI 32.3–35.9) and mittee of Urmia University of Medical Sciences
15.4% (95% CI 14.0–16.8), respectively (4). The approved this research project prior to the initial
prevalence of overweight in urban population is enrollment of any subject (irumsu.rec.1393.47).
expected to be about 22% and 40% in 15-39 After a full clarification of this investigation, every
and 40-69 year olds, respectively. Relevant va- individual was informed about the contents and
lues in Iranian females seem to be higher (5). In goals of the research project. Individuals who
Tehran, Iran, 40% and 23.1% of the adult study signed the written informed consent were en-
group were overweight (BMI, 25 to 29.9 kg/m2) rolled in investigation. Sixty five Iranian Azeri
and obese (BMI ≥ 30 kg/m2), respectively. Fre- Turkish women were enrolled in the study; 38 of
quency of overweight and obesity was 42.6% them were obese and 27 non-obese (control
versus 38.1%, and 14.4 versus 29.5% in males group). All subjects were genetically unrelated
versus females, respectively (6). This study shows and matched for ethnicity, geographical area and
the impact of gender on increasing incidence age in case and control groups. All subjects were
of obesity and overweight in Iranian popu- examined in Motahari Teaching Hospital (Urmia,
lation (6). Iran), which is an obstetrics and gynecology refer-
Obesity is one of the most important health ral center. Medical history, physical tests, and cli-
problems leading to several diseases such as nical evaluations were performed by the same
diabetes mellitus (7), hypertension (8), specialist for all individuals. Diagnosis of obesity
hyperlipidemia (9), depression (10, 11), and death was based on the finding of the criteria as pro-
(12). Obesity influences the long-term dialysis posed by Pi-Sunyer (2000) (25). Participants with
(13) as well as the function and survival of renal a history of any known disorders including obesity
allograft following transplantation (14). In women, after pregnancy, endocrine abnormalities (such as
obesity results in irregular menstrual cycles and Cushing syndrome, hypothyroidism, hyperthy-
oligo-anovulation as well as infertility (15-17). roidism, parathyroid disease, etc), and chronic
Obese women have poor reproductive outcomes kidney disease were excluded from the study as
in assisted conceptions such as induction of well as those who were taking vitamin D3 or drugs
ovulation in polycystic ovarian syndrome, in vitro which are known to affect calcium metabolism
fertilization (IVF), intracytoplasmic sperm in- and lipid profile (25). The salting out method was
jection (ICSI), and oocyte donation cycles (18). In used to extract genomic DNA from 3-4 mL whole
men, obesity is associated with reduced levels of blood collected with EDTA (26).
testosterone and spermatogenesis and sub-
sequent infertility (18). The prevalence of obesity PCR and sequencing
is regularly increasing in the world because of
several factors such as lifestyle, diet behavior and Optimized primer pairs of 5’-ggcaacctgaaggga-
physical activity (19). Environmental and genetic gacgta-3’ and 5’-ctctttggacctcatcaccgac-3’ were used
factors are the subject of studies in different for PCR amplification and direct sequencing of PCR
ethnic groups (20). Recent findings suggest that products regarding VDR SNPs rs1544410(A/G)
vitamin D and vitamin D (1,25-dihydroxyvita- (BsmI) and rs757343 (G/A)(Tru9I) (27). PCR reac-
min D3) receptor (VDR) polymorphisms play a tions were carried out in 50 L solution including
role in obesity via various mechanisms (21-24). 50 ng of DNA, 1x reaction buffer 5 pmol of each
The aim of the present study was to survey primer, 200 μmol of each dNTPs, 0.3 unit of Taq
the rate of the VDR polymorphisms in obese DNA polymerase, and 1.5 mmol MgCl2. PCR pro-
women and to determine whether there was an gram was 93°C for 45 s, 66°C for 30 s, and 72°C for
association between the VDR BsmI and Tru9I al- 45 s (35 cycles) (27). PCR products were evaluated
leles/genotypes/haplotypes and obesity in Irani- by electrophoresis on 2% agarose gel stained with
an Azeri Turkish women. CinnaGen DNA safe Stain (CinnaGen Co. Tehran,
Allele/Genotype/
Marker Cases F (% F) Controls F (% F) OR (95% CI) P value
Haplotype
G 48(63.16) 29(53.7) 1.478(0.727-3.004) 0.279
A 28(36.84) 25(46.3) 0.677(0.333-1.376) 0.279
rs1544410 GG 14(36.84) 5(18.52) 2.567(0.794-8.3) 0.109
GA 18(47.37) 19(70.37) 0.379(0.134-1.075) 0.064
AA 6(15.79) 3(11.11) 1.5(0.34-6.613) 0.590
G 60(78.95) 45(83.33) 0.75(0.304-1.851) 0.531
rs757343 A 16(21.05) 9(16.67) 1.333(0.54-3.291) 0.531
GG 25(65.79) 18(66.67) 0.962(0.339-2.731) 0.941
GA 10(26.32) 9(33.33) 0.714(0.243-2.099) 0.539
AA 3(7.89) 0(0) - 0.134
rs1544410/ GA 15(19.74) 6(11.11) 1.967(0.71-5.453) 0.187
rs757343 GG 32(42.11) 22(40.74) 1.058(0.521-2.149) 0.876
AG 29(38.16) 23(42.59) 0.832(0.409-1.693) 0.611
AA 0(0) 3(5.56) - 0.037
TABLE 1. Markers, alleles, genotypes and haplotypes in studied groups and analysis of the VDR
polymorphisms data
Iran). Presence or absence of a 461(bp) fragment
was monitored by UV transilluminator. Subse-
quently, direct sequencing of the PCR products
was carried out in an ABI 730XL DNA analyzer (Ap-
plied Biosystems). Chromas Lite version 2.1.1 (2012)
was used for chromatogram visualization of se-
quenced DNA fragments (Chromas Lite version 2.1
(2012), Technelysium Pty Ltd, South Brisbane,
Queensland, Australia). VDR SNPs rs1544410 (A/G)
(BsmI) and rs757343 (G/A)(Tru9I) alleles, genotypes,
and haplotypes were found regarding BsmI and
Tru9I sites on chromatograms.
Statistical analysis
Descriptive statistics were used to report the
frequency of the VDR polymorphisms. P value,
odds ratio (OR), and 95% confidence interval (CI)
have been computed for detection of statistically
significant differences between cases and con-
trols regarding the frequencies in studied mar-
kers. The frequencies of our data were compared
using the chi-square test or the Fisher’s exact test
FIGURE 1. Schematic representation of
chromatography and the VDR SNP rs1544410 (G/A)
(BsmI) polymorphisms that is located in the intron 8
at position 10,583,292 of the chromosome 12q12-q14
in a sample. Black color arrow represents the VDR
BsmI (rs1544410) G allele and green color arrow
represents the VDR BsmI (rs1544410) A allele in
suspected DNA locus. The VDR SNP rs1544410
(A/G)(BsmI) genotypes: a: g/g; b: g/a; c: a/a.
RESULTS
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O RIGINAL PAPER
Evaluation of Multidetector
Computed Tomography in
Haematuria
Ranjan KUMARa, Raj KUMAR AIRONa, Amit MITTALa, Rikki SINGALb,
Kamal SHARMAc, Samita SINGALa
a
Department of Radiodiagnosis and Imaging, M.M.
Institute of Medical Sciences and Research, Mullana (Distt -Ambala), Haryana, India
b
Department of Surgery, M.M. Institute of Medical Sciences and Research,
Mullana (Distt -Ambala), Haryana, India
c
Department of Urology, M.M. Institute of Medical Sciences and Research,
Mullana (Distt -Ambala), Haryana, India
ABSTRACT
Aims and Objectives: (1) To study the role of multidetector computed tomography in patients with
haematuria. (2) To correlate multidetector computed tomography findings with clinical outcome/laboratory
findings/FNAC and/or operative findings (wherever performed).
Materials and Methods: The present study was carried out in the Department of Radiodiagnosis, M.M.
Institute of Medical Sciences and Research, Mullana, Ambala, from April 2014 to 2016. Fifty patients
with complaint of haematuria, referred from various wards and outpatient departments of this institution,
were included. Multidetector computed tomography was performed in ultrasonography positive cases, in
symptomatic patients with negative ultrasonography scans and in those with suboptimal ultrasonography
scans. The equipment used in our study was a HD 11 XE (Philips medical systems) ultrasound unit with
convex and linear probes and a 128 slice Multidetector CT (Philips Ingenuity).
Results: Maximum number of patients (30%) in the 51-60 years age group with a male preponderance.
The prevalence of malignancy in patients with haematuria in this study was 28% which included bladder
urothelial carcinoma (18%), renal cell carcinoma (6%), UTUC (4%), prostatic carcinoma (2%) and one case
of TCC which turned out to be non-Hodgkin’s lymphoma on histopathology. Calculi were more prevalent in
the younger age group and overall constituted 20% of the causes of haematuria. Other causes of haematuria
detected on multidetector computed tomography were pyelonephritis, renal trauma (grade V renal injury),
bladder diverticulum, benign prostatic hyperplasia and cystitis.
Conclusion: Multidetector computed tomography by using its multiplanar and 3D capabilities is highly
accurate and specific in detecting the causes of haematuria. It can demonstrate the exact site of involvement
in very high percent of cases. In addition to haematuria, multidetector computed tomography can detect
various associated and incidental findings which may not be suspected clinically.
Keywords: haematuria, tumours, ultrasonography, computed tomography.
Article received on the 27th of February 2017. Article accepted on the 8th of June 2017.
H
aematuria is one of the most com- lergic to contrast medium were excluded from
mon manifestations of urinary tract the study.
disease, its reported prevalence A complete patient history regarding the chief
ranging from 0.2% to 21%. Multi- complaints was taken and a thorough clinical ex-
detector computed tomography amination was carried out after taking a written
(MDCT) urography (MDCTU) has replaced excre- informed consent. Relevant laboratory investiga-
tory urography as the first imaging test in many tions were done. Patients with haematuria were
institutions. It has the ability to acquire thinly col- evaluated by ultrasonography (US). Plain x-ray
limated data sets which can be used to create ex- KUB was performed in 20 patients. Multidetec-
cellent 3D quality images of the urinary tract (1). tor computed tomography was performed in US
Given a prior low likelihood of cancer in haema- positive cases, in symptomatic patients with neg-
turia, risk categories should be established and ative US scans and in those with suboptimal US
imaging algorithms should be tailored to popula- scans.
tions at low-risk, medium-risk and high risk for
developing urothelial cancer (2). Common ex- Equipment
traurinary findings included diverticular disease • Ultrasonography
(138, 17.7%), adrenal masses (85, 10.9%), lung - HD 11 XE (Philips medical systems) ultra-
abnormalities (67, 8.6%), and gall bladders con- sound unit with convex and linear probes
taining calculi (44, 5.7%), adnexal cysts (7.7% of • Multidetector Computed Tomography (MDCT)
women) and aortic aneurysms (18, 2.3%). - 128 slice Multidetector CT (Philips Inge-
Computed tomography (CT) urography (CTU) nuity)
was associated with a high rate of unsuspected
findings. There was an economic implication to PROCEDURES
performing CT scan in this setting in which unan-
ticipated investigation and treatment cost was Ultrasonography
60 pounds/patient (3). MDCT-VC combined with Overnight fasting was preferred. The patient
urine cytology is a good alternative to conven- was made to lie down on the couch and proper
tional cystoscopy for patients with painless gross exposure of part was ensured. A coupling agent
haematuria. It should be used as a decision ma- was applied liberally to the patient’s skin to act
king aid to identify patients who will benefit from as acoustic window removing the air between
additional cystoscopic examination. Future de- transducer and patient’s skin surface and thus al-
velopments should focus on visibility of sessile lowing swift movement of the transducer. A ge-
and carcinoma in situ lesions (4). A clinically sig- neral abdominal and pelvic survey by using a
nificant source of haematuria was detected in 3.5 MHz convex transducer was done. The pan-
22.1% of CT urograms of young adults. However, creas was visualized by transverse scans in mid-
an unenhanced CT alone may be sufficient in pa- line below the xiphoid process. The adrenal
tients without additional predisposing medical glands were assessed intercostally at the midaxil-
conditions (5). lary line. The liver was assessed by starting with
the left lobe along the midline, followed by the
MATERIALS AND METHODS inferior lobe and intercostally in the end along
the midaxillary line. Kidneys were assessed in
windows. An attempt was made to follow the patients with haematuria. The most frequently
ureters to the bladder maintaining the same ap- encountered symptom was abdominal pain in 24
proach. The urinary bladder was best visualised patients (48%). Anaemia was present in 30 pa-
in distended state and was followed by a post tients (60%). Fever was also observed in 10 pa-
void scan for residual urine. tients (20%). History of diabetes was present in
five cases. Out of these five cases, two belonged
Multidetector Computed Tomography to the inflammatory group. Loss of appetite was
Computed tomography scan was performed another important clinical feature in malignant
on a 128 multidetector CT scanner. Patients cases (30%). One patient presented with history
were placed in the supine position. Oral contrast of road side accident with severe head and ab-
was used depending upon clinical situation. CT dominal injuries (Figure 1). Out of the 30 patients
scans were obtained from diaphragm to the pu- in our study, 14 (28%) presented with haematuria
bic symphysis with a collimation of 64 x 0.625, associated with pain and 36 (72%) with painless
pitch-1.016 and with 259 mAs. Images were re- haematuria (Figure 2).
constructed at a thickness of 0.625 mm. A
3 phase CT examination was performed after
obtaining written consent. The first phase was
the initial non-contrast phase. The second phase
was the nephrographic/venous phase which was
acquired following a delay of 90-100 seconds af-
ter administration of 120 mL of intravenous non-
ionic iodinated contrast to evaluate the renal pa-
renchyma. This was followed by a delayed phase
(after 3-10 mins) from contrast administration to
evaluate the excretory function of the kidneys
and for the visualization of the ureters.
Findings were recorded as per Performa at-
tached. Results of USG and MDCT were evalu-
ated in each case and findings were correlated
with clinical outcome/laboratory findings/FNAC
and /or operative findings (wherever performed).
causes of haematuria. It can demonstrate the and incidental findings which may not be sus-
exact site of involvement in a very high percent pected clinically.
of cases. It is highly sensitive and specific in dia-
gnosing cause of haematuria. In addition to hae- Conflicts of interest: none declared.
maturia, MDCT can detect various associated Financial support: none declared.
References
1. Song JH, et al. Haematuria evaluation J Urol 2012;79:270-276. 9. Kim JY et al MDCT urography for
with MDCT urography. 5. Lokken RP, Sadow CA, Silverman SG. detecting recurrence after transurethral
AJR 2011;197:W84-W89. Diagnostic yield of CT urography in the resection of bladder cancer: comparison
2. Molen AJ, Hovius MC. Haematuria: A evaluation of young adults with of nephrographic phase with pyelo-
problem based imaging algorithm haematuria. Am J Roentgenol graphic phase. AJR Am J Roentgenol
illustrating the recent Dutch guidelines 2012;198:609-615. 2014;203:1021-1027.
on haematuria. AJR 2012;198:1256-1265. 6. Maheshwari E et al. Split bolus MDCT 10. Cha KH. Urinary bladder segmentation
3. Bromage SJ et al The economic urography: upper tract opacification and in CT urography using deep learning
implications of unsuspected findings performance for upper tract in patients convolutional neural network and level
from CT urography performed for with haematuria. AJR 2010;194:453-458. sets. Med Phys 2016;43:1882.
haematuria. Br J Radiol 2012;85:1303-1306. 7. Cowan NC. CT urography for haematu- 11. Singal R et al. Delayed presentation of
4. Kuehass FE et al. Multidetector ria. Nat Rev Urol 2012;13;9:218-226. the traumatic abdominal wall hernia;
computed tomography virtual cystos- 8. Shaaban MS et al. Multidetector CT dilemma in the management – review
copy: an effective diagnostic tool in assessment of traumatic lesions. of literature. Indian J Surg 2012;74:149-156.
patients with haematuria. Alex J Med 2016;52:173-184.
O RIGINAL PAPER
ABSTRACT
Introduction: Acute kidney injury is the sudden and almost complete loss of renal function with reduced
glomerular filtration rate, and it occurs whenever the kidneys are unable to excrete metabolic waste products.
Method: This randomized double-blinded clinical trial was performed in an intensive care unit (ICU) of
a university educational hospital. After randomization with a random assigning table of numbers, patients
were divided into two groups: an intervention group and a control group. The patients’ daily blood urea
nitrogen and creatinine levels were measured and changes were recorded. The statin group received a tablet
of atorvastatin 40 mg daily (Abidi Pharmacy Production). Moreover, patients’ baseline vital signs and
changes in serum blood urea nitrogen, creatinine, mechanical ventilation requirement, need for dialysis,
ICU stays, and mortality were recorded in both groups. SPSS version 20 software was used for data analysis.
P value <0.05 was considered significant.
Results: The mean intubation time for the intervention and control groups was 4.44±1.8 and 3.46±2.02,
respectively, and the mean mechanical ventilation time was 2.14±2.15 and 2.34±2.07 days, respectively.
The mean ICU stay was 4.91±3.3 days for the intervention group and 4.67±2.67 days for the control
group. Throughout the study duration, the mean dialysis requirement frequency was 4.66±1.2 times in
the intervention group and 5.54 ±1.75 times in the control group. Two patients in the intervention group
and three patients in the control group died. There was no statistically significant difference in mortality
between the two groups (P >0.05).
Discussion and conclusion: The effects of statins on the different stages of acute kidney injury and its
outcomes are yet challengeable, so we recommend conducting further studies with larger sample sizes.
Keywords: acute kidney injury, statins, outcome, intensive care unit
Article received on the 17st of December 2016 and accepted for publication on the 30th of March 2017.
INTRODUCTION
METHOD
A
cute kidney injury (AKI) occurs when
the kidneys are unable to excrete
metabolic waste products and do not
have a natural function. Acute kidney
A fter approval by the research committee of
the Medical Faculty and ethical committee
of Urmia University of Medical Sciences, 70 pa-
injury is a sudden and almost com- tients (calculated with power SSC software with
plete loss of renal function with reduced glome- p2=80%, p1= 20%, =0.05 and 1-=0.8) ad-
rular filtration rate. There are three main reasons mitted to a university educational hospital fol-
for AKI, including pre-renal, renal and post-renal lowing non-cardiac surgery (abdominal surgery:
disturbances. Decreased perfusion due to de- cholecystectomy) and diagnosed with AKI with-
creased blood volume or heart failure is one of out need for blood transfusion were included.
the leading causes for pre-renal states. Transfu- After meeting the inclusion criteria and fulfilling
sion reactions, nephrotoxicity, renal tubular in- a written informed consent, the study was star-
jury, and infections are the most common intra- ted. A double-blind randomized controlled trial
renal causes of AKI. Oliguria (urinary volume < (RCT) design was used. The subjects were as-
400 mL/day), hyperkalemia, uremia, and rises in signed to one of two groups – an intervention
creatinine (Cr) level occur in AKI. Several studies group or a control group – using a computer-ge-
have been conducted for finding ways to reduce nerated table of random numbers. All nurses,
mortality and morbidity in acute renal failure pa- residents, patients, and caregivers were blinded
tients, among which the use of statins is note- to treatment during the study. The inclusion cri-
worthy. Cellular injury mechanisms in AKI in- teria were: 1) to be diagnosed with AKI after a
clude cellular adhesion, inflammatory cell non-cardiac surgical intervention; 2) age of 25 <
infiltration, free radicals production and inflam- and ≤70 years old; 3) physical status of <ASA III;
matory cytokines. Statins can completely inhibit 4) lack of using the nephrotoxic drugs; and 5)
the release of inflammatory mediators by macro- absence of significant conditions in patients
phages and monocytes. The outer medulla of the (DIC, thrombosis, etc.). The exclusion criteria
kidney is one of the susceptible areas to hypo- were: 1) patients with renal failure due to urinary
xemia (1). Ischemia is the main reason for AKI in tract obstruction; and 2) presence of liver dys-
major surgeries or kidney transplant operations, function or failure.
in which statins can conserve kidneys by impro- After admission, patients underwent non-car-
ving the perfusion of renal tubular tissue and in- diac surgery in ICU, and routine tests were per-
creasing nitric oxide (2, 3). formed. The intervention group received a daily
Anti-inflammatory, vasodilatation and antico- dose of atorvastatin 40 mg (Abidi Pharmacy Pro-
agulation effects of statins are mediated by re- duction) for two weeks, while the control group
leasing nitric oxide from endothelial cells (4). received a placebo. The patients’ baseline vital
Statins can reduce the incidence of AKI up to 1.3 signs, including systolic and diastolic blood pres-
times (5, 6). A mortality rate for AKI of about 60% sure, heart rate, respiratory rate and body tem-
has been reported (7, 8). This mortality rate re- perature were recorded. Also, serum levels of
quires rapid intervention in these patients. In a BUN and Cr were measured daily. Patients in the
German study in mice, statin treatment led to a two groups were matched by age at the date of
reduction in the incidence of AKI (9). In another admission. Proper Folley catheter was fixed in all
study carried out in the USA on thousands of pa- the patients and the collected data were given to
tients using statins, a reduction in the incidence a relevant nephrologist, who was blinded to the
of AKI in patients who underwent noncardiac patients’ assignment. The pre-provided checklist
surgery was reported (10). In a meta-analysis per- was completed and data were subsequently ana-
formed in Germany, the preventive effects of lyzed with SPSS v.20, while P value <0.05 was
statins have been established for heart diseases considered significant. At first, data were ana-
(11). Taking into account the studies that have es- lyzed for normality via using the Kolmogorov-
Smirnov test. Accordingly, parametric or non-
tablished the effectiveness of statins in improving
parametric tests were recruited for appropriate
the status of these patients, we aimed to conduct
ones. An independent sample t-test was used for
the current study in this framework.
comparing groups based on baseline vital sign pare the groups based on mechanical ventilation
and ICU stays. Once the t-test repeated, Ancova requirement and mortality.
was used for comparing two groups at the start The definition of AKI in this study was accor-
and end of the intervention and before and after ding to at least 25% increase in serum creatinine
the intervention. The 2 test was used to com- from patients’ baseline levels (12).
RESULTS
Control group Measured value P
Variable
Age
(Mean ±SD)
57.08 ± 14
(Mean ±SD)
57.20 ± 12.22
value
0.93
S eventy patients were assessed in this study.
Thirty-five of them received statins (interven-
tion group) and thirty-five (control group) place-
Height 168±3.14 167.78±4.1 0.94 bo. Seventeen patients in the intervention group
Weight 78.19±8.7 80.31±6.9 0.89 were males (48.6%) and the rest were females.
BMI 27.72±2.1 28.47±1.87 0.86 Participants’ demographic and baseline charac-
APACHE ΙΙ score 8.29±2.12 8.34± 2.18 0.91 teristics are shown in Table 1.
Concurrent effect of treatment time and
Blood pressure 114±14.3 109.5±12.8 0.87
group for BUN was not significant according to
Pulse rate 93.7±8.7 95.1±7.4 0.88
the presented means (P=0.15) (Figure 2).
(Number (%) (Number (%) Concurrent effect of treatment time and
Sex Male: 17 (48.6%) Male: 17 (48.6%) 1.00 group for serum creatinine was not significant ac-
Female: 18 (51.4%) Female: 18 (51.4%) cording to the presented means (P=0.07)
Co-morbidities (Figure 3).
Obesity 5 (14.28%) 4 (11.42%) 0.93
The mean intubation time was similar be-
tween the intervention group and the control
Diabetes 8 (22.85%) 9 (25.71%) 0.91
group (P=0.25). Also, there was no significant
Hypertension 14 (40%) 14 (27.45%) 0.88 difference between the two groups regarding the
Hyperlipidemia 8 (22.85%) 8 (22.85%) 0.87 mechanical ventilation time (P=0.69) and the
TABLE 1. The patients’ demographic and baseline characteristics duration of ICU stay (P=0.78) (Table 2).
Control group Measured value P vascular surgery and weaker in those with cardi-
Variable ac surgery. One year before them, Molnar et al.
(Mean ±SD) (Mean ±SD) value
Start GFR (ml/min) 55.81±17.24 60.18±15.23 0.87 (15) published the results of their 14-year study in
Start BUN (mg/dl)
Canada and reported that 32% of their patients
56.32±17.24 60.18±15.23 0.86
used statins before surgery, with 16% of them
Start Cr (mg/dl) 3.82±2.41 3.99±2.58 0.86
having a reduced incidence of AKI, 17% a re-
Time interval for duced emergent dialysis requirement and 21% a
AKI incidence after 3.2±0.87 3.63±0.91 0.79
reduced mortality rate.
undergone surgery
In contrast to the studies of Bruneli (14) and
Average intubation time
4.44 ± 1.8 3.46 ± 2.02 0.25 Molnar et al. (15), our study showed no diffe-
(days)
rence between investigating outcomes of the
Average mechanical
2.14 ± 2.15 2.34 ± 2.07 0.69 two groups. Moreover, our sample size was limi-
ventilation time (days)
ted in comparison with that in their studies, and
Average ICU stay (days) 4.91 ± 3.30 4.67 ± 2.67 0.78
that was one limitation in the current study. Singh
Mean dialysis et al. (16) published a meta-analysis in 2012 in
requirement frequency 4.66 ± 1.2 5.54 ± 1.75 0.22
which they investigated 17 studies with 47,080
(times)
patients and stated that the group who used
TABLE 2. Comparing mean and SD of the intubation period,
mechanical ventilation period, ICU stay, and dialysis requirement
statin before heart surgery, notwithstanding the
frequency in the intervention and control group type, had a lower mortality rate. As compared to
the study of Singh et al. (16), our study was con-
of statins was much more than they expected. In ducted in a shorter time interval (throughout the
their study, they referred to their previous studies year of 2015) on non-cardiac surgery patients.
with some specific inclusion criteria. Their findings This study confirms the results from some studies
showed that the anti-inflammatory effects of (10) in this context and is not in accordance with
statins can be mediated by decreasing the level some others. A notable point in our study is that
of CRP and IL-6. Also, statins can lead to a de- we assessed the effect of post-operative statins
cline in neutrophil adherence to endothelial cells and this is different from previous studies on hu-
and neutrophil apoptosis. For achieving this, they man models since they all investigated the effect
used statins 30 days before surgery, although Ya- of pre-operative statin use.
suda et al. (13) had previously stated, in 2006, Finally, according to the results obtained in
that simvastatin reduced TNF- and improved the previous studies as well as in the current
renal oxygenation, thus leading to a decrease in study (regardless of similarities and differences),
mortality from septic shock with AKI. However, the effect of statins on different stages of AKI and
we found no significant difference between mor- their outcomes is yet debatable and further stu-
tality and expected outcomes in the two groups. dies with larger sample sizes are needed.
In their 10-year longitudinal retrospective
study on 98,939 patients undergoing abdominal, Acknowledgements: The authors wish to
cardiovascular and thoracic surgery, Bruneli et al. appreciate Mr Davoud Vahabzadeh’s help in
(14) evaluated the relation between AKI and coordinating the editing and review of our
statins and reported that the risk of AKI after sur- manuscript before final submission.
gery declined in patients with statin intakes and Conflicts of interest: none declared.
this relationship was stronger in patients with Financial support: none declared.
References
1. Ysebaert DK, De Greef KE, Vercauteren 2. Dragun D, Hoff U, Park JK, Qun Y, Der Internist 2001;3:379-88, 90-402.
SR, Ghielli M, Verpooten GA, Schneider W, Luft FC, et al. Ischemia- 4. Kheterpal S, Tremper KK, Englesbe MJ,
Eyskens EJ, et al. Identification and reperfusion injury in renal transplanta- O’reilly M, Shanks AM, Fetterman DM,
kinetics of leukocytes after severe tion is independent of the immunologic et al. Predictors of postoperative acute
ischaemia/reperfusion renal injury. background. Kidney International renal failure after noncardiac surgery in
Nephrology Dialysis Transplantation 2000;5:2166-2177. patients with previously normal renal
2000;10:1562-1574. 3. Jörres A, Frei U. Acute kidney failure. function. The Journal of the American
Society of Anesthesiologists 2007;6:892-902. surgery: risk factors and prognosis. induced mortality and acute kidney
5. Sharyo S, Yokota-Ikeda N, Mori M, Perfusion 2005;6:317-322. injury via renal vascular effects.
Kumagai K, Uchida K, Ito K, et al. 9. Gueler F, Rong S, Park J-K, Fiebeler A, Kidney International 2006;9:1535-1542.
Pravastatin improves renal ischemia–re- Menne J, Elger M, et al. Postischemic 14. Brunelli SM, Waikar SS, Bateman BT,
perfusion injury by inhibiting the acute renal failure is reduced by Chang TI, Lii J, Garg AX, et al.
mevalonate pathway. short-term statin treatment in a rat Preoperative statin use and postopera-
Kidney International 2008;5:577-584. model. Journal of the American Society of tive acute kidney injury. The American
6. Joyce M, Kelly C, Winter D, Chen G, Nephrology 2002;9:2288-2298. Journal of Medicine 2012;12:1195-1204. e3.
Leahy A, Bouchier-Hayes D. Pravas- 10. Argalious MY, Dalton JE, Sreenivasalu 15. Molnar AO, Coca SG, Devereaux PJ,
tatin, a 3-hydroxy-3-methylglutaryl T, O’Hara J, Sessler DI. The association Jain AK, Kitchlu A, Luo J, et al. Statin
coenzyme A reductase inhibitor, of preoperative statin use and acute use associates with a lower incidence of
attenuates renal injury in an experimen- kidney injury after noncardiac surgery. acute kidney injury after major elective
tal model of ischemia-reperfusion. Anesthesia & Analgesia 2013;4:916-923. surgery. Journal of the American Society of
Journal of Surgical Research 2001;1:79-84. 11. van Lier F, Schouten O, Poldermans D. Nephrology 2011;5:939-946.
7. Katznelson R, Djaiani GN, Borger MA, Statins in Intensive Care Medicine: still 16. Singh I, Rajagopalan S, Srinivasan A,
Friedman Z, Abbey SE, Fedorko L, et al. too early to tell. Netherlands Journal of Achuthan S, Dhamija P, Hota D, et al.
Preoperative use of statins is associated Critical Care 2011;3:137-142. Preoperative statin therapy is associated
with reduced early delirium rates after 12. Macedo E, Castro I, Yu L, Abdulkader with lower requirement of renal
cardiac surgery. The Journal of the RR, Vieira Jr JM. Impact of mild acute replacement therapy in patients
American Society of Anesthesiologists kidney injury (AKI) on outcome after undergoing cardiac surgery: a meta-
2009;1:67-73. open repair of aortic aneurysms. analysis of observational studies.
8. Bahar I, Akgul A, Ozatik MA, Vural Renal failure 2008;3:287-296. Interactive Cardiovascular and Thoracic
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Acute renal failure following open heart Star RA. Simvastatin improves sepsis-
O RIGINAL PAPER
ABSTRACT
Objective: In Romania, a national statistics report on the mode of delivery in pregnancies that ends in
stillbirths has never been conducted. Thus, we decided to analyze the incidence of cesarean section versus
vaginal delivery rate over a 10-year period in Filantropia Clinical Hospital of Bucharest.
Materials and Methods: We conducted a retrospective analysis over a period of 10 years from January
2005 to December 2015. Maternal age, parity, social status, place of origin, educational level, gestational
age, fetal presentation and fetal sex were studied in order to see if there were a scientific correlation with
death in utero.
Results: Between 2005 and 2015, Filantropia Clinical Hospital had a total of 31676 births after the 28th
week of gestation. During this time period, 174 (0.55%) stillbirths were registered. The overall number
of cesarean sections in live-births was 13199 (41.7%) and the rate of cesarean sections calculated for the
stillbirth was 17.24% (30/174).
Conclusion: Our study revealed that the rate of cesarean sections in stillbirth had a dramatic decrease
based on the adoption of guidelines reflecting evidence based medicine. The vast majority of pregnancies
included in our study did not undergo standard perinatal tests and screenings that ensure a healthy and safe
delivery, as it is a known fact that many causes of perinatal deaths can be prevented by health care access and
perinatal regular visits. We suggest that a proper follow up in the last trimester and easy access to health
care facilities can lower the incidence of stillbirths in Romania.
Keywords: stillbirth, cesarean section, vaginal birth, high-risk pregnancies
D
espite the major interest in pre- the weight is unknown, with at least 20 weeks of
venting intrauterine fetal death in gestation completed shall be reported to the Na-
the last decades, a common defi- tional Center of Health Statistics (1). The World
nition of stillbirth is yet to be ac- Health Organization (WHO) recommends the
cepted worldwide. Definitions vary following definition of intrauterine death as an
amongst countries according to their national international consensus: a baby born with no
legislation. In the United States, the American signs of life, at or after 28 weeks of gestation (2).
Address for correspondence:
Nicolae GICA, MD
Department of Obstetrics and Gynecology, Filantropia Clinical Hospital, No 11-13, Ion Mihalache Avenue, 71117, Bucharest, Romania
Tel/Fax: 0040/21318 89 37; 0040/21310 41 74
E-mail: gica.nicolae@gmail.com
Article received on the 13th of February 2017 and accepted for publication on the 8th of June 2017.
In Romania, any baby delivered at the 24th week were registered 31676 births over the 28th week
of gestation with signs of life is registered as a gestation, 174 of which were diagnosed as ante-
living newborn and stillbirths is defined in accor- partum deaths. The diagnosis was established by
dance to the WHO criteria (3). the absence of fetal heartbeat during the ultra-
When an intrauterine fetal death is diagnosed, sound examination performed immediately
termination of pregnancy is recommended. We upon the patient’s arrival. Gestational age was
strongly endorse vaginal birth in these cases ra- established taking into account the patients last
ther than cesarean section (CS), which is still menstrual period as well as ultrasound measure-
popular among Romanian obstetricians. The sur- ments of the fetus, since the majority of the pa-
gical procedure (cesarean section) has high risks tients were at the first presentation at an obstetri-
compared to any other abortion procedure. It cian.
could adversely affect the future fertility of the We tried to notice the mode of delivery in
patient. However, CS should be performed if all stillbirths, the indications for cesarean section
medical procedures have failed or the situation delivery and if there was a higher frequency of
requires it (fetal transverse lie with prior CS or intrauterine fetal death in correlation with socio-
placenta accreta/increta). Individualized clinical economic status, maternal age at conception,
judgment of each case can lead to either expec- parity, gestational age and fetal gender.
ting a spontaneous onset of labor, which usually
occurs within 14 days after the diagnosis (4), or RESULTS
induction of labor can be performed using local
prostaglandins or systemic oxytocin (5).
The aim of this study was to analyze the mode B etween 2005 and 2015, 31676 births were
registered in our database after the 28th week
of gestation, of which 174 were stillbirths (inclu-
of delivery in pregnancies ending with stillbirths.
We also tried to find if there were any patterns in ding 12 tween pregnancies from which only three
stillbirth pregnancies and how the decision to had both fetuses nonviable). The overall number
deliver the patient was founded. of CS performed on live births was 13199 (41.7%)
and 17.24% (30/174) represented the ratio cal-
MATERIALS AND METHODS culated for the stillbirth group (Table 1). During
the study we noticed an increased frequency
have noticed a sharp decrease of cesarean sec- economic level and medical education was lo-
tions in stillbirth group. Despite the high peak in wer than expected as that was their first presen-
2008 when almost half of the stillbirth pregnan- tation to a doctor during the current pregnancy,
cies finalized by cesarean section, in 2015 the despite the fact that access to medical facilities is
rate of vaginal delivery was 90%. available and free of charge for all pregnant pa-
The incidence of stillbirth in our study was tients (Table 5).
found to be 0.55% (174 stillbirths) and in only 30
Environmental Percentage
cases (17.24%) (Table 2) it was decided to per- origin
Number (N)
(%)
form a cesarean section in order to deliver the
Rural 49 28.16
dead fetus. The indications for CS were gesta-
tional hypertension/preeclampsia (16 cases), pla- Urban 125 71.84
cental abruption with massive bleeding (12 ca- TABLE 5. Distribution of stillbirth according to
environmental origin
ses), twin pregnancies with one fetus living and
one death associated with breech/transverse lie Preterm pregnancies prevailed within the
and previous cesarean section (8 cases), breech study group (71.26%) and only few post-term
presentation (1 case), placenta praevia (1 case), pregnancies were noted (10.34%) (Table 6).
leiomyoma praevia (1 case).
Gestational age Number (N) Percentage (%)
Mod of delivery Number (N) Percentage (%)
Preterm
Vaginal delivery 144 82.75 124 71.26
<37 weeks
Cesarean delivery 30 17.25 Term 37-40 weeks 32 18.40
TABLE 2. Distribution of stillbirths according to the
Poste term
mode of delivery 18 10.34
>40weeks
The majority of stillbirths were found in women TABLE 6. Distribution of stillbirth according
in the age group of 25-30 years and not in the gestational age
extreme groups as we expected (Table 3) (6). Al-
most half of them were at first delivery (P 1) About 19% (Table 7) unviable fetuses were in
(52.87%) followed by second delivery (P2) in abnormal presentations and 18 (60%) fetuses
29.31% of cases (7) (Table 4). Thus, parity was had major congenital abnormalities including
not associated with a higher risk of stillbirth, as it corpus callosum agenesis, spina bifida, ventrico-
was reported in a study from Nepal (8). lomegaly, anencefaly, hidrocephalus, fetal hy-
Despite the observation that most women drops, fetal ascites, fetal anasarca and bilateral
came from urban areas (71.83%), their socio- renal agenesis. Only few (12 cases) were noticed
to have intrauterine growth restriction which was
Age (years) Number (N) Percentage (%)
associated with gestational hypertension.
<20 16 9.20
20-25 33 18.96 Presentation Number (N) Percentage (%)
Parity Number (N) Percentage (%) The male gender was found to have a higher
P1 92 52.87 incidence (55.17%) comparing to the female gen-
P2 51 29.31 der (44.83%) (Table 8) (9).
P3 16 9.19 Fetal sex Number (N) Percentage (%)
P4 12 6.89 Male 96 55.17
P5 or more 3 1.74 Female 78 44.83
TABLE 4. Distribution of stillbirths according to TABLE 8. Distribution of stillbirths according to
parity fetal sex
References
1. Centers for Disease Control and Preven- Guidelines. In: Maternal-Fetal Evidence case-control study in Nepal. In BMC
tion/National Center for Health Statistics// Based Guidelines. - 2nd ed. London, UK; 2012. Pregnancy & Childbirth 2015; 15:146.
Model State Vital Statistics Act and 5. ACOG Practice Bulletin No 102: manage- 9. Debapriya G, Trevor C and Fiona M.
Regulations. Hyattsville, Maryland: ment of stillbirth 2009;3:748-761. Elevated risk of stillbirth in males:
February 1994, 1992 revision. Vol. DHHS 6. Canterino J, et al. Maternal age and risk of systematic review and meta-analysis of
Publication No. (PHS) 94-1115. fetal death in singleton gestations: USA, more than 30 million births.
2. World Health Organization. 2016. 1995-2000. In J Matern Fetal Neonatal Med BMC Medicine 2014;12:220.
3. ORDIN nr. 359 din 4 aprilie 2012 2004; 3:193-197. 10. Siassakos D, Fox R, Draycott T, Winter
privind criteriile de înregistrare şi 7. Saurabh K, Patel K. Study of the risk factors RM. Management of late intrauterine fetal
declarare a nou-nascutului. contributing to stillbirths in Central India death and stillbirth. In Royal College of
http://www.monitoruljuridic.ro/act/ 2015;3:13-16. Obstetricians & Gynecologists (RCOG)
ordin-nr-359-din-4-aprilie-2012. 8. Ashish KV, Johan W, Uwe Ewald, et al. October 2010; RCOG Green-top
4. U Reddy Maternal-Fetal Evidence Based Risk factors for antepartum stillbirth: a Guideline No. 55:13.
O RIGINAL PAPER
ABSTRACT
Background: Fatigue is one of the most frequent symptoms in cancer patients. However, its exact causes
are still unknown, and this circumstance makes it complicated to encounter the problem.
Objectives: The current research was carried out to investigate factors associated with fatigue in cancer
patients without other diseases.
Methods: The research was conducted in 2013. A group of 150 randomly selected breast cancer patients
who had successful surgical treatment and attending in oncology ward to receive chemotherapy and
radiotherapy. They completed the Cancer Fatigue Scale; medical information was obtained through patient
recorded files and demographic questions obtained by self-reported data. Then, univariate analysis between
the CFS scores and the investigated factors was used to assess the potential fatigue associated factors; related
factors (P<0.05) were retained.
Results: The mean age of the subjects was 47.9 (SD=11.4), ranging from 25 to 72 years old. Among
demographic factors, age (0.30, p= 0.006) and employment status (0.35, p=0.009) were correlated with
physical aspects, whereas marital status (-4.0, p=0.001) and educational status (-0.59, p=0.005) were
correlated with affective and cognitive aspects of fatigue scores, respectively. Among factors concerned with
cancer and treatment such as disease stage, number of days since surgery, past intravenous chemotherapy,
radiotherapy was not correlated with any aspects of fatigue. In this section, only the types of surgery (3.01,
p=0.06) were correlated to the affective aspect of fatigue.
Conclusions: The results suggest that fatigue in this population is determined by demographic factors
rather than by cancer itself and prior cancer treatments, and that the modifying demographic situation,
such as work time and supporting group arrangement as a self-help group as a social support for unmarried
patients who live alone, might be essential clues in reducing fatigue in this population.
Keywords: breast cancer, fatigue, demographic
Article received on the 13th of January 2017 and accepted for publication on the 8th of June 2017.
C
ancer-related fatigue (CRF) is a tioned studies, we hypothesized that fatigue in
symptom commonly experienced this group of patients might be related to demo-
by patients during the course of can- graphic and clinical factors. Therefore, we inves-
cer and its treatment (1). It is de- tigated factors correlated with both the total
scribed as a distressing permanent score and each subscale.
feeling of tiredness or exhaustion concerned to
cancer that is not related to recent activity and PURPOSE
interferes with common functioning (2). It can be
defined in terms of perceived energy, mental ca-
pacity, and psychological situation (3, 4). Patients
describe it as one of their most troublesome
T he aim of this study was to evaluate demo-
graphic and treatment factors in relation to
physical, affective and cognitive aspects of can-
symptoms, not least because it causes distress cer related fatigue scores in breast cancer survi-
and greatly influences quality of life (5). Histori- vors.
cally, fatigue has been poorly managed in this
patient group (6). While it is increasingly recog- RESEARCH DESIGN
nized as a common problem, many health care
professionals still hesitate to treat it (7). It is per-
ceived as an unavoidable result of the disease
I n the current reserach, a prospective study was
used to evaluate the cancer related fatigue in
physical, affective and cognitive domains of fa-
and its treatment that patients have to tolerate
tigue scale in breast cancer survivors hospitalized
(8). The prevalence of cancer-related fatigue
in an oncology ward. The study was conducted
ranged from 4% to 91%, depending on the stu-
in Omid Research and Treatment Center (affili-
died population and the evaluation methods
ated to Urmia Medical Sciences University). In-
(9-11). It is found that fatigue conflicts with quali-
dividuals who were beginning CTX, radiotherapy
ty of life regardless of diagnosis, treatment, or
(RT), or concurrent therapy for cancer were se-
prognosis (12).
lected by convenience method (n = 150).
There are expanding documents to suggest
that fatigue may remain for months or even years
Inclusion and exclusion criteria
after completion of breast cancer treatment, es-
pecially among patients who have received adju- Subjects were eligible if they were presently
vant chemotherapy (13). The prevalence of fa- starting treatment for breast cancer. Individuals
tigue beyond the acute phase of treatment was were excluded if they had chronic fatigue syn-
first highlighted in studies evaluating the long- drome and were registered in other research that
term quality of life of breast cancer survivors, engaged a psychoeducational intervention or if
which established that many women continued they had obvious declaration of somatic or psy-
to perceive a sense of fatigue, diminished energy, chiatric disorder. Another exclusion criterion was
and distraction in their activity level years after the beginning of treatment for anemia or depres-
diagnosis and treatment (14). sion during the previous three weeks, since these
Fatigue is a comprehensive, multifaceted conformable causes of fatigue (16, 17) may have
compound that is commonly thought to affect been overlapped by perceived fatigue.
subjective feelings of tiredness, weakness, and/or
lack of energy (15). A large number of factors can Procedure
provoke fatigue, including physical or mental ac- After the study was approved by the ethics
tivity, medical situations, psychological variables committee of Urmia University of Medical Sci-
and demographic factors that can influence the ences, informed consent was obtained from all
patient’s life style. participants. A researcher was attending at che-
The purpose of this study was to investigate motherapy ward to meet potential participants.
the demographic and clinical factors correlated Data on fatigue were obtained when they were
with fatigue in breast cancer survivors who were applied for the treatment. Medical information
not suffering from other diseases. Recognizing was provided by patient recorded files and de-
these variables may generate suggestions on how mographic as well as several new questions that
shown in Table 2, which means that older wo- king after young children or marital stress, which
men were at risk to increase the fatigue score. may contribute to fatigue, but receiving support
Therefore, health professionals should be alert to from the family motivated them and diminished
the possibility of greater fatigue in older survi- their fatigue. It would seem that having a spouse/
vors. children may lessen the feeling of loneliness and
In general, aging results in deterioration of depression causing achieve family support and
physiological systems. While there is no known consequently experiencing less fatigue. Cognitive
threshold age, it is considered that the deteriora- fatigue may interfere with the use of social sup-
tion of biological systems begins from about the port, but this finding is also difficult to explain.
age of 45–50 years (20). Alteration of the circa- Further research is needed to explore this issue.
dian time-keeping system and physiology of There was a significant association between
sleep homeostasis often results in fatigue (21). affective aspects of fatigue in patients who had a
Aging is related to a more difficult adaptation of partial resection and those who had a mastec-
circadian rhythms, changes in the sleep/wake tomy. Tong et al. (2012) revealed the social out-
cycle, and heightened sleep disorders (22). So, comes of breast-conserving surgery versus mast-
decreased sleep quality stimulates higher fatigue. ectomy and found psychological benefits in
Aging also results in changes to the construction breast-conserving surgery (30). Our results indi-
and formation of sleep. In a metaanalysis, Ohay- cate that the psychological impact of mastecto-
on et al. (2004) found that aging was related to a my might be positively associated with affective
reduction in slow wave (deep) sleep, an increase aspects of fatigue. Fung et al. (2001) found that
in stages 1 and 2 of sleep, and a larger number of patients who received breast conserving therapy
awakenings. In addition, heigher age seems to were less concerned about their appearance and
result in shorter sleep duration and inferior sleep more freely selected clothing than those who re-
quality (23). Shortened and poorer sleep quality ceived mastectomies. They also found better
commonly results in increased sleepiness and fa- psychological adjustment in patients with breast
tigue during the waking hours (24). In the present conserving therapy (31).
study, being employed was associated with fa- Neither the number of days after surgery nor
tigue. In this line, other studies showed that lon- past chemotherapy or radiotherapy was signifi-
ger working hours have also been associated cantly correlated to fatigue scores. According to
with elevated patients’ complaints of fatigue (25). these results, we assume that fatigue might not
Similarly, Mehnert et al. (2011) reported a signifi- be simply the consequence of aggressive cancer
cantly larger likelihood of ‘general fatigue’ and treatment, and therefore, it might not decrease
‘chronic tiredness’ among employees working a with time, but is was caused by concurrent phy-
longer (26) than shorter week. It seems that inter- sical and psychosocial factors at the time.
acting psychosocial work characteristics associ- Limitations of the present study were related
ated to the nature of work and work environ- to the study design (cross-sectional). The study
ment plays important roles in increasing fatigue. was conducted in a single medical center; also,
Education and income have been reported to the findings cannot be generalized. Despite limi-
be weekly associated with intention to sleep (27). tations, this study may contribute to the manage-
In particular, people with higher incomes and ment of fatigue in breast cancer survivors, direc-
higher level of education spent less time in bed, ting innovative interventions to prevent and treat
while pthose with lower incomes showed longer fatigue. The strengths of this study were its focus
sleep latency and slept less, even though time in on fatigue in Iranian non-depressive breast can-
bed was similar. cer survivors and the use of one standardized
In the present study, marital status is signifi- and internationally validated cancer-specific
cantly associated with cognitive subscale of fa- questionnaire to evaluate fatigue.
tigue. Studies suggest being married reduces fa- Iranian breast cancer survivors who suffer
tigue. On the other hand, studies showed that from fatigue have a higher age, live alone and are
employees who lived alone had significantly employed. Thus, for breast cancer survivors,
higher fatigue (28, 29). However, being married health care professionals should pay more atten-
was linked to an additional set of demands that tion to the possibility of fatigue in older, unmar-
stemmed from family related issues such as loo- ried and employed women. Also, our results sug-
gest that fatigue in this population is determined Acknowledgements: The authors wish to thank
by demographic factors rather than cancer itself Mrs Shoori, the head of oncology ward, for her
and prior cancer treatments, and that the modi- help to invite participants, as well as all participants
fying demographic situation, such as shortening who accepted to attend the study.
work time and supporting group arrangement as Ethical statement: The research project has
a self help group for social support in unmarried received the confirmation of the Institution’s Ethics
patients who live alone, might be an essential Committee.
clue in reducing fatigue in this population. Future This research project was conducted during
research should evaluate additional variables re- 2014 as a master’s degree thesis for midwifery
lated to fatigue following breast cancer treatment consultation student.
and their impact on quality of life over time.
References
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Cancer-Related Fatigue, Springer, 2015, promotion practices in women with 23. Ohayon MM, et al. Meta-analysis of
pp. 1-10. multiple sclerosis: increasing quality and quantitative sleep parameters from child-
2. Harris SR, et al. Clinical practice years of healthy life. Physical medicine and hood to old age in healthy individuals:
guidelines for breast cancer rehabilita- rehabilitation clinics of North America developing normative sleep values
tion. Cancer 2012;118(S8):2312-2324. 2001;1:9-22. across the human lifespan. SLEEP-NEW
3. Cella D, et al. Cancer-related fatigue: 13. Ewertz M, Jensen AB. Late effects of YORK THEN WESTCHESTER
prevalence of proposed diagnostic breast cancer treatment and potentials 2004;27:1255-1274.
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compared with fatigue in the general living with cancer as a chronic illness. 25. Di Milia L, et al. Shift work disorder in a
United States population. Cancer CA: A Cancer Journal for Clinicians random population sample–prevalence
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8. Takeuchi EE, et al. Impact of patient- 18. Okuyama T, et al. Development and logical distress in the working popula-
reported outcomes in oncology: a validation of the cancer fatigue scale: a tion: psychometrics, prevalence, and
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ABSTRACT
HIV infection has been considered for a long time an absolute contraindication to transplantation. The
introduction of highly active antiretroviral therapy has led to improved immunovirological control and in-
creased survival in HIV-infected patients. Renal transplantation can now be performed if these patients are
on stable highly active antiretroviral therapy and achieve undetectable viral load and a sufficient CD4 level,
in the absence of untreatable infections and cancers. Highly active antiretroviral therapy and immunosup-
pressive medication should be maintained for life in these patients, raising the problem of multiple drug-
drug interactions. Thus, an increased rate of rejection was attributed to the difficulty of achieving sufficient
immunosuppressive levels but also to the intrinsic immune system activation despite suppressed HIV RNA
levels. HIV infection of the kidney allograft could constitute a renal viral reservoir that impacts long term
graft survival. Future options are developing, such as transplanting organs from HIV-infected donors. With
highly active antiretroviral therapy, patient and graft survival in HIV-infected kidney transplant recipients
are improving and approaching that of non-infected controls.
Keywords: kidney transplant, HIV infection, highly active antiretroviral therapy,
infection, rejection
H
uman immunodeficiency infection tunistic infections has decreased. As HIV-infec-
virus (HIV) is one of the major in- ted patients live longer, chronic complications
fectious diseases of our time. Since have increased, leading to terminal cardiac, liver
the introduction of highly active and renal failure in these patients (1, 2). Accor-
antiretroviral therapy (HAART) in dingly, the need for renal replacement therapy –
1996, HIV-infected patients have better control dialysis and renal transplantation – is continu-
of viral replication, and the mortality secondary ously increasing.
Address for correspondence:
Oana Ailioaie,
“Dr. Carol Davila” Clinical Hospital of Nephrology, Calea Grivitei Nr. 4, District 1, Bucharest
Phone: 0744328506; E-mail: nephromed01@gmail.com
Article received on the 14h of March 2017 and accepted for publication on the 19th of March 2017.
Transplant recipient selection criteria Newer antiretrovirals that do not interact with
CYP450 have been developed, such as integrase
HIV-infected ESRD patients have been for a
inhibitors raltegravir and dolutegravir. Raltegravir
long time excluded from transplantation (21).
is increasingly being used in HIV–infected KT re-
However, with better antiretroviral therapy
cipients and is associated with good antiretroviral
HIV-infected patients can achieve today a suffi-
efficacy (26).
cient viral and immunological control that allows
Doses of antiretrovirals have to be adapted in
them to receive transplants and immunosuppres-
KT recipients, as most of them have a degree of
sion therapy. Nevertheless, renal transplantation
residual renal failure. Tenofovir is contraindica-
in HIV-infected patients is challenging, because of
ted in patients with creatinine clearance under
problems related to immunosuppression in pa-
60 mL/min and should be avoided in KT re-
tients with ongoing HIV infection, drug-to-drug
cipients, due to its potential of nephrotoxicity
interactions (antiretrovirals and immunosuppres-
(27).
sors) and the additional risk of infection and cancer.
Inclusion criteria for renal transplantation in
Immunosuppresion and rejection
HIV-infected patients comprise undetectable vi-
ral load under stable antiretroviral therapy, a mi- It has been believed that immunosuppression
nimal level of CD4 lymphocytes of 200 cells/mL may accelerate HIV progression in kidney trans-
and absence of untreatable opportunistic infec- plant recipients. Therefore, minimal immuno-
tions and cancers (22). All patients should un- suppression was traditionally used in HIV-infec-
dergo a psychiatric evaluation. Patients that con- ted KT recipients. Transplant immunosuppression
sume alcohol should become abstinent for is composed of an initial induction treatment
six months before transplantation. For drug us- with potent immunosuppressors, followed by a
ers, a drug-free period of at least two years is maintenance treatment. Studies that did not use
recommended (23). Medical treatment inobser- induction therapy at all in HIV-infected KT re-
vance is a contraindication to transplantation. cipients were faced with an increased rate of
acute rejection that imposed later the intensifica-
Interactions between immunosuppressors tion of immunosuppression (28). Current British
and antiretroviral therapy guidelines (22) recommend induction with an
anti-interleukin-2 (anti-IL-2) antibody basilixi-
There are multiple drug-drug interactions be-
mab. Maintenance immunosuppressive treat-
tween HAART and immunosuppressive therapy.
ment should be comprised by calcineurin inhibi-
The main drugs used post transplantation are
tors (CNI), mycophenolate mofetil (MMF) and
calcineurin inhibitors (CNI) – tacrolimus (TAC)
tapering corticosteroids.
and cyclosporine A (CSA) – and mammalian tar-
Induction with anti thymocyte globulins
get of rapamycin inhibitors (mTOR) – sirolimus
(ATG) is generally avoided in HIV-infected KT re-
and everolimus. These drugs are metabolized in
cipients, due to the risk of depleting CD4 lym-
the liver by cytochrome P (CYP) 450 and also by
phocytes and developing secondary infections.
the system of P-glycoprotein. Protease inhibitors
In a study of 150 HIV-infected KT recipients,
(PIs), especially ritonavir, and also cobicistat, in-
Stock et al found that ATG induction is associa-
hibit CYP450, causing large variations in through
ted with a double incidence of infections (0.9 vs
levels, potentially causing nephrotoxicity (24).
0.4, p=0.002) (29).
Immunosuppressor doses have to be lowered
A recent study on 830 HIV-infected KT re-
and intervals between doses have to be increased
cipients challenges this opinion. Anti thymocyte
(e.g., from twice a day to once a week), poten-
globulins, that are potent agents, were associated
tially causing rejection. Also, rejection episodes
with lower rates of infections than the lighter
can be induced in HIV-infected kidney trans-
agent anti-IL-2 antibody. This was explained by
plant (KT) recipients if PIs are withheld and im-
the fact that patients receiving initially induction
munosuppresor concentrations are steeply mo-
with the less potent anti-IL-2 antibody had hi-
dified. Non-nucleoside reverse transcriptase
gher rates of acute rejection (AR), consequently
inhibitors (NNRTIs) are inducers of CYP450 and
needing subsequent heavy immunosuppression
decrease CNI levels, potentially causing rejection
(30). Another study of 516 HIV-infected KT re-
(25).
cipients found a 2.6 fold reduction in AR at one- (40). They have particularly worse outcomes
year with ATG induction (31). post transplantation, with lower patient and graft
Acute rejection rates in HIV infected KT re- survival that non-coinfected controls. In a study
cipients are 3-5 fold higher that in non-infected of 510 KT recipients, coinfected HIV/HCV pa-
controls, being as high as 50%. (29-30, 32-33). tients had worse graft survival at 5-years (52%
Causes are multifactorial – racial, pharmacologic versus 64%, p=0.02) and at 10 years (27% vs
and immunologic – and not completely under- 36.2%, p=0.004) compared with HCV monoin-
stood. Black race (30), use of cyclosporine (29), fected controls. Patient survival was also lower
sirolimus (30) and kidney grafts from deceased among coinfected HIV/HCV patients at five
donors have been associated with increased rates years (66.3% vs 78.6%, p<0.01) and at 10 years
of AR among HIV-infected KT recipients. (29.3% vs 56.23%, p=0.002). Risk of death was
Drug-drug interactions between HAART and CNI 2.85 higher among coinfected HIV/HCV KT re-
leading to insufficient immunosuppression in pa- cipients (p<0.001) (41).
tients taking PIs have been associated with AR. Treatment of HIV/HCV coinfection post
HIV infection itself is associated with immune transplantation was particularly difficult in the
system dysregulation, despite good viral control period when only pegylated interferon and riba-
with HAART. There is T cell activation despite virin were available, as interferon was contrain-
suppressed viral loads (35). Markers of inflam- dicated due to the increased risk of graft rejec-
mation such as IL-1beta, IL-6, and hs-CRP are tion and ribavirin alone had a low response rate
persistently elevated (36-37). A period of six (42). The new direct acting antiviral agents
months of negative viral loads under stable (DAAs) have revolutionized the treatment of
HAART is mandatory before transplantation in HCV infection due to their high rate of virologic
HIV-infected patients. A prolonged period of vi- response of 90-95% (43). However, there are
ral suppression before transplantation was re- multiple drug-drug interactions between DAAs,
cently proved to reduce post transplant rejec- HAART and immunosuppressants that compli-
tion. In the study of Husson et al., it was found cate the use of these agents post transplantation.
that, if the period of viral suppression was pro-
longed to two years, there was a 2.48-fold re- Cancers
duction in the post transplant AR rate (38).
HIV-infected patients are frequently coinfec-
ted with oncogenic viruses. Human papilloma
Post transplant infections
virus (HPV) is associated with cervical and anal
Incidence of post transplant infectious com- cancers. Ebstein-Barr virus (EBV) leads to non-
plications in HIV-infected KT recipients is similar Hodgkin lymphomas. Human Kaposi’s herpes
to that of non-infected controls, ranging from 38 virus 8 (HHV8) is associated with Kaposi’s sar-
to 55% (29, 39). Bacterial infections are domi- coma, especially in black race and Mediterra-
nant (69%), followed by fungal (9%), viral (6%) nean patients. Treatment with HAART improves
and protozoal (1%) infections. The majority immunovirological control in HIV-infected pa-
(60%) of infections occur in the first six months tients and is associated with a decrease in the
post transplantation, which is the period of most incidence of Kaposi’s sarcoma and EBV-associa-
intense immunosuppression (29). The etiology of ted non-Hodgkin lymphoma (44).
opportunistic infections is similar to that seen in
non-transplanted HIV-infected patients. Lifelong Kidney as a HIV reservoir
prophylaxis against Pneumocystis sp. is manda-
At the moment of transplantation, all HIV-in-
tory in all HIV-infected KT recipients. Depending
fected KT recipients must have undetectable
on CD4 levels, prophylaxis may be necessary
HIV viral loads (<50 copies/mL). However, even
against other pathogens such as Histoplasma,
in the presence of undetectable viral loads, HIV
Coccidioides, Cryptoccocus and Mycobacterium
still can infect renal allografts. In the study of
avium complex.
Canaud et al, (45) in patients with undetectable
Viral hepatitis coinfection is frequent among
HIV RNA in the blood, HIV-1 infected 68% of
HIV-infected KT recipients mostly because of
renal allografts. Two patterns of HIV-1 infection
history of intravenous drugs use in these patients
in renal allografts were described. The most se-
vere form was the infection of podocytes, with of Stock et al, patient survival rates were 94.6%
loss of differentiation markers and development at one year and 88.2% at three years. Graft sur-
of podocyte apoptosis and progressive renal fo- vival rates were 90.4% and 73.7%, respectively.
cal segmental glomerulosclerosis (FSGS). This These results were comparable to that of older
was associated clinically with nephrotic protein- (>65 years) non-infected KT recipients from the
uria and renal graft failure. The second form was large database of Scientific Registry of Transplant
the infection by HIV-1 of renal tubular cells. This Recipients (SRTR) (29). In another recent study of
was more frequent than the glomerular form SRTR database, 10 year outcomes were reported.
(62% vs 38%) and was associated with better HIV-infected KT recipients had similar outcomes
graft outcomes. The mechanisms of this are not to that of non-infected controls, but HIV/HCV
completely understood. One explanation is that, coinfected KT recipients had worse outcomes
even with good viral control, transient episodes (41). In European studies from France (51), Spain
of viremia can arise (HIV blips).46 Other hy- (52) and United Kingdom (53), patient survival of
pothesis is the transfection of HIV from HIV-in- HIV-infected KT recipients was excellent, ranging
fected T-cells of the recipient to the naïve renal from 91.3 to 100% at one and three years. Graft
cells of the kidney allograft (47). HIV infection of survival at one year ranged from 85 to 98% and at
the renal epithelial cells constitutes a viral reser- three years from 74 to 84.7%. These results were
voir and has adverse consequences on renal al- similar to HIV-negative controls.
lograft function (45).
Multidisciplinary approach
HIV–to–HIV transplantation
Management of HIV-infected KT recipients
A solution to donor shortage in HIV-infected needs a multidisciplinary approach. The ne-
population could be the use of organs from phrologist has to deal with multiple post trans-
HIV-infected donors. The first four cases of renal plant issues such as impaired renal function, hy-
transplantation from HIV-infected donors have droelectrolytic disturbances, hypertension, acute
been performed by Muller et al in 2010 in South and chronic rejection, etc. The surgeon has to
Africa, with 100% graft and patient survival at one manage post transplant urologic complications.
year (48). In 2015, the same author reported a Specific HIV complications and opportunistic in-
series of 27 HIV-to-HIV transplantations (49). Pa- fections have to be managed by a HIV-experi-
tient survival rates at one, three and five years enced infectionist. Complex drug-drug interac-
post transplantation were 84%, 84% and 74%, tions between HAART and immunosuppressors
respectively. Graft survival rates were 93%, 84% need the advice of a pharmacist with experience
and 84%, respectively. The median serum creati- in HIV care. A social assistant has to deal with
nine at one year was 1.3 mg/dL (IQR 1.2-1.3). specific social issues in these patients.
The allograft rejection rate was 8% at one year
and 22% at three years. Post transplantation pa- CONCLUSIONS
tients had good immunovirological control and
did not develop opportunistic infections. Overall, Renal transplantation in HIV-infected patients is
HIV-to-HIV transplantation seems to have favo- a viable option in patients treated with HAART
rable results. Issues may be represented by the and with good immunovirological control. Some
possibility of acquiring a more virulent strain of issues remain to be resolved, such as the multiple
HIV and the development of viral resistance. In- drug-drug interactions between HAART and im-
fection of medical personnel while manipulating munosuppressors and the increased rates of re-
HIV-infected organs is another potential concern. jection and infections. Patient and graft survival
are somewhat lower than in non-infected KT re-
Patient and graft survival cipients, but significantly higher than before the
HAART era. A multidisciplinary approach of the
Before the HAART era, patient and graft sur- management of these patients is mandatory for
vival in HIV-infected KT recipients were inferior their care.
to that of HIV-negative controls (50). Introduc-
tion of HAART improved post transplant out- Conflicts of interests: none declared.
comes in HIV-infected KT recipients. In the study Financial support: none declared.
References
1. Palella FJ Jr, Delaney KM, Moorman AC, 15. Lang S, Mary-Krause M, Simon A, et al. A, Sanz AB, et al. Tenofovir
et al. Declining morbidity and mortality HIV replication and immune status are Nephrotoxicity: 2011 Update.
among patients with advanced human independent predictors of the risk of AIDS Res Treat 2011 (2011):354908.
immunodeficiency virus infection. HIV myocardial infarction in HIV-infected 28. Kumar MS, Sierka DR, Damask AM,
Outpatient Study Investigators. individuals. Clin Infect Dis et al. Safety and success of kidney
N Engl J Med 1998;338:853-860. 2012;55:600-607. transplantation and concomitant
2. May MT, Sterne JA, Costagliola D, et al. 16. Rasch MG, Helleberg M, Feldt-Rasmus- immunosuppression in HIV-positive
HIV treatment response and prognosis in sen B, et al. Increased risk of dialysis and patients.Kidney Int 2005;67:1622-1629.
Europe and North America in the first end-stage renal disease among HIV 29. Stock PG, Barin B, Murphy B, et al.
decade of highly active antiretroviral patients in Denmark compared with the Outcomes of kidney transplantation in
therapy: a collaborative analysis. background population. Nephrol Dial HIV-infected recipients.
Lancet 2006;368:451-458. Transplant 2014;6:1232-1238. N Engl J Med 2010;363:2004-2014.
3. Ahuja TS, Borucki M, Funtanilla M, et 17. Trullas JC, Barril G, Cofan F, et al. 30. Kucirka LM, Durand CM, Bae S, et al.
al. Is the prevalence of HIV-associated Prevalence and clinical characteristics of Induction immunosuppression and
nephropathy decreasing? HIV type 1-infected patients receiving clinical outcomes in kidney transplant
Am J Nephrol 1999;19:655-659. dialysis in Spain: result of a Spanish recipients infected with human immuno-
4. Cohen AH, Sun NC, Shapshak P, et al. survey in 2006: GESIDA 48/05 study. deficiency virus. Am J Transplant
Demonstration of human immunodefi- AIDS Res Hum Retroviruses 2016;16:2368-2376.
ciency virus in renal epithelium in 2008;24:1229-1235. 31. Locke JE, James NT, Mannon RB, et al.
HIV-associated nephropathy. 18. Jotwani V, Li Y, Grunfeld C, et al. Risk Immunosuppression regimen and the risk
Mod Pathol 1989;2:125-128. factors for ESRD in HIV-infected of acute rejection in HIV- infected kidney
5. Atta MG, Gallant JE, Rahman MH, et al. individuals: traditional and HIV-related transplant recipients.
Antiretroviral therapy in the treatment of factors. Am J Kidney Dis 2012;59:628-635. Transplantation 2014;97:446-450.
HIV-associated nephropathy. 19. Tourret J, Tostivint I, Tezenas du 32. Malat GE, Ranganna KM, Sikalas N,
Nephrol Dial Transplant 2006;21:2809-2813. Montcel S, et al. Outcome and prognosis et al. High frequency of rejections in
6. Moir S, Fauci AS. B cells in HIV infection factors in HIV-infected hemodialysis HIV-positive recipients of kidney
and disease. Nat Rev Immunol patients. Clin J Am Soc Nephrol transplantation: a single center
2009;9:235-245. 2006;6:1241-1247. prospective trial.
7. Kimmel PL, Phillips TM, 20. Schwartz EJ, Szczech LA, Ross MJ, et al. Transplantation 2012;94:1020-1024.
Ferreira-Centeno A, et al. HIV-associated Highly Active Antiretroviral Therapy and 33. Qui J, Therasaki PI, Kayo W, et al.
immune-mediated renal disease. the epidemic of HIV+ end-stage renal HIV-positive renal transplant recipients
Kidney Int 1993;44:1327-1340. disease. J Am Soc Nephrol can achieve survival rates similar to those
8. Berliner AR, Fine DM, Lucas GM, et al. 2005;16:2412-2420. of HIV-negative patients.
Observations on a cohort of HIV-infected 21. Spital A. Should all human immunodefi- Transplantation 2006;81:1658-1661.
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Am J Nephrol 2008;28:478-486. end-stage renal disease be excluded from Kidney and liver transplantation in
9. Daugas É, Deroure B. Nouveaux aspects transplantation? The views of U.S. human immunodeficiency virus–infected
des atteintes rénales de l’infection par le transplant centers. patients: a pilot safety and efficacy study.
VIH. Flammarion Médecine-Sciences. Transplantation 1998;65:1187-1191. Transplantation 2003;76:370-375.
Actualités Néphrologiques 2008;75-85. 22. Working Party of the British Transplan- 35. Hunt PW, Martin JN, Sinclair E, et al.
10. Rosenberg AZ, Naicker S, Winkler CA, tation Society. UK Guidelines for kidney T cell activation is associated with lower
et al. HIV-associated nephropathies: and pancreas transplantation in patients CD4+ T cell gains in human immunodefi-
epidemiology, pathology, mechanisms with HIV 2015. http://www.bhiva.org/ ciency virus-infected patients with
and treatment. Nat Rev Nephrol kidney-transplantation-guidelines.aspx. sustained viral suppression during
2015;11:150-160. 23. Miro JM, Torre-Cisnero J, Moreno A, et antiretroviral therapy.
11. Currier JS, Taylor A, Boyd F, et al. al. GESIDA/GESITRA–SEIMC, PNS and J Infect Dis 2003;187:1534-1543.
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individuals. J Acquir Immune Defic Syndr transplant in HIV infected patients in Markers of inflammation, coagulation
2003;33:506-512. Spain . Enferm Infecc Microbiol Clin and renal function are elevated in adults
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13. DAD Study Group. Friis-Møller N, Ann Intern Med 1998;129:914-915. suppression on circulating markers of
Reiss P, Sabin CA, et al. Class of 25. Tseng A, Nguyen ME, Cardella C, et al. inflammation and immune activation.
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N Engl J Med 2007;356:1723-1735. 26. Tricot L, Teicher E, Peytavin G, et al. Association between duration of HIV-1
14. Kuller LH, Tracy R, Belloso W, et al. Safety and efficacy of raltegravir in viral suppression prior to renal transplan-
INSIGHT SMART Study Group. HIV-infected transplant patients cotreated tation and acute cellular rejection.
Inflammatory and coagulation biomark- with immunosuppressive drugs. Am J Transplant 2016;20:1-6.
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infection.PLoS Med 2008; 5(10):e203. 27. Fernandez-Fernandez B, Montoya–Ferrer HIV-infected liver and kidney transplant
C ASE REPORTS
ABSTRACT
Abuse of the elderly is a major issue debated worldwide. The most commonly identified form of abuse is the physical
abuse. It is also the most frequently studied in the medical literature. However, at least six types of elder abuse are identified,
and physical abuse is found in a small proportion of the cases. The consequences of abuse are frequent and, by prolonging
hospitalizations, they will be associated with high costs of medical services, and patient’s lack of self-confidence which, in time,
may lead to social isolation, somatization, anxiety, depression, and suicide attempts. In this context, the identification and
correction of psychological abuse becomes a desideratum of utmost importance for ensuring an optimal therapeutic response.
This should be done by using a simple method that does not require qualified personnel, but allows the patient to be guided
towards psychological consultation; this study was carried out with the help of the EASI EASI (The Elder Abuse Suspicion
Index) questionnaire.
We present the case of an 80-year old patient in a rural area, who has been hospitalized several times, admitted for numerous
episodes of global cardiac decompensation (about four over the last year). The causes of cardiac decompensation were,
systematically, non-compliance with treatment, regardless of all attempts to readjust and simplify the therapeutic schemes.
The dynamic geriatric assessment showed a deterioration of the patient’s mental and nutritional status and an accentuation
of depression. The EASI questionnaire used during the last admission corroborated with the psychological consultation and
detected several types of abuse: abandonment, negligence and financial abuse. Given that the complexity of care, the frequency
of hospitalizations and the length of stay were reduced, therapeutic compliance increased and the mental and nutritional
status improved after correcting the abuse.
Keywords: abuse, elder, geriatric assessment
Article received on the 12th of March 2017 and accepted for publication on the 15th of June 2017.
E
lder abuse is a significant phenomenon, ischemic heart disease, permanent atrial fibrilla-
with a major impact and an increasing tion, CEAP class 4 chronic venous insufficiency),
incidence. World Health Organization metabolic (type 2 diabetes, insulin-dependent),
defines elder abuse as “a single, or re- neurological (stroke sequelae, diabetic sensori-
peated act, or lack of appropriate ac- motor polyneuropathy, vertiginous syndrome),
tion, occurring within any relationship where hepatic (chronic hepatitis with C virus), and os-
there is an expectation of trust and care, which teoarticular (chronic degenerative rheumatism),
causes harm or distress to an older person”, as well as presbyopia and presbyacusis.
while negligence is defined as “the lack of action The clinical examination reveals a conscious,
of the person involved in a relationship of trust, cooperative, cleanly dressed patient, but with a
which leads to the same result” (1). In literature, psycho-emotional liability and easy cry. From the
the most commonly mentioned form of abuse is history of the disease (and the medical records)
the physical abuse, which accounts, however, for we identified non-compliance to treatment as the
only 15% of the elder abuse cases. The other main cause of cardiac decompensations. Nume-
types of abuse are abandonment, psychological rous therapeutic alternatives aimed at simplifying
and emotional abuse, financial/material exploi- treatment schemes and lowering prescription
tation, negligence, and sexual abuse (2). Derived costs were carried out, but with no result. Subjec-
from these, there are also some particular forms tive complaints were increasing from one admis-
of abuse: medical abuse, legal abuse, spiritual sion to another, concerning mainly the aggrava-
abuse, cultural abuse, systemic abuse, persona- tion of pain, either osteoarticular, neurological or
lity abuse, “invisible” abuse – the older person due to complications of diabetes, but with no cor-
having limited access to healthcare and treat- relation of the reported pain intensity with possi-
ments, to spirituality or in relation to his religious ble organic changes on a pain intensity visual
or cultural needs and limited access to state insti- scale. The evolution of geriatric assessment pa-
tutions due to system deficiencies. rameters from one admission to another shows:
The consequences of elder abuse are multiple aggravation of the depressive status (initial GDS =
and of various types, mainly depending on the 8/15, on the third admission GDS = 12/15), de-
type of abuse to which the person is subject to. preciation of the nutritional status (MNA = 24,
Among all forms of abuse, the psychological and corresponding to a normal nutritional status, on
emotional abuse is most frequently associated the third admission MNA = 19, corresponding to
with a high risk of morbidity and mortality as well malnutrition), deterioration of the cognitive status
as an increased rate of healthcare services use, (from a normal cognitive status with a MMSE
thus increasing the costs in the medical system score of 25/30, corroborated with an average
and significantly decreasing the response to treat- educational level, to a mild neurocognitive disor-
ment. Also, this type of abuse has an increased der with MMSE = 20/30) and a deterioration of
risk of depression, suicide, dementia, malnutri- the independence degree, which started from the
tion, somatization, and chronic pathological dete- preservation of the independence degree at the
rioration, leading to enhanced fragility. In addition initial assessment (ADL = 5/6, IADL = 8/8) and
to organic damage, there is also an increased reached the need for assistance in carrying out
anxiety, with a tendency towards social isolation daily activities (ADL = 3/6, IADL = 5/8). These
and, of course, towards poorer quality of life (3-5). changes have raised the suspicion of a psycho-
logical component, and the application of the
CASE REPORT EASI (The Elder Abuse Suspicion Index) question-
naire has confirmed the presence of financial and
nutritional assistance), has included psychological ding also to institutionalisation. Thus, elder abuse
consultation and counselling. Subsequently, pro- is considered an issue specific to gerontology, and
cedures for social and psychological support at it must be identified, prevented and treated ac-
home (including spiritual support and legal assis- cordingly, in order to minimize the impact on el-
tance) were initiated. The types of abuse identi- ders’ health condition (6, 7).
fied were: financial, by negligence and abandon- Non-adherence to treatment is one of the
ment, the abuser being her own daughter. After many causes of chronic pathology decompensa-
the initiation of the measures for fighting and pre- tion in older persons – in our case, cardiac patho-
venting the abuse, the clinical state of the patient logy. There are multiple factors leading to non-a-
showed significant improvement. She presented dherence, and their identification is mainly related
no more episodes of cardiac decompensation and not only to the doctor’s ability to conduct an
both the balance degree of the diabetes and the anamnesis of both the patient and his/her caregi-
geriatric assessment scores have improved: the in- vers, but also to the accuracy of the geriatric as-
dependence degree has increased, the depres- sessment, because the latter can detect neurocog-
sion degree has decreased, and the nutritional nitive disorders, malnutrition, deterioration of the
status has improved (with transition from the mal- degree of independence related to carrying out
nutrition stage to the stage of malnutrition risk). activities of daily living, depression, sensorial defi-
Cognitive function was the only stationary ele- ciencies, and marks of an abuse, all of these being
ment. Follow-up was performed in ambulatory potential causes for therapeutic non-compliance.
care, hospitalization being no longer needed, and Geriatric assessment requires a specialty exam
the patient reported that she felt better, having a which is currently available only in Geriatric de-
more “tranquil” mental state, with considerable partments. Abuse was identified for the first time
improvement of all symptoms. in a Romanian study by using the EASI question-
naire (8).
DISCUSSION For the presented case, the application of the
questionnaire enabled us to identify the main fac-
The presented case emphasizes the impor- tify and fight both the abuse and its
tance of introducing geriatric assessment and the consequences.
EASI questionnaire in current practice. These will
make it easier to identify the problems specific to Acknowledgements: This research is part of
older people, will increase and render more effec- the project “I refuse silent abuse” and partially
tive provision of medical services customized ac- founded by EEA Grants, project no RO09-0342.
cording to the needs of the elderly, and will iden- Conflicts of interest: none declared.
References
1. World Health Organization/INPEA. 4. Lachs MS, Pillemer K. Elder abuse. disability. J Forensic Leg Med
Missing voices: Views of older persons on Lancet 2004;364:1263-1272. 2014;28:19-24.
elder abuse. Geneva, 5. Dong X, Simon M, Evans D. Elder 8. Yaffe MJ, Wolfson C, Lithwick M, et al.
World Health Organization 2002. self-neglect is associated with increased Development and validation of a tool to
2. Anthony EK, Lehning A, Austin MJ, risk for elder abuse in a community- improve physician identification of elder
et al. Assessing elder mistreatment: dwelling population: findings from the abuse: the Elder Abuse Suspicion Index
Instrument development and implications Chicago Health and Aging Project. (EASI). J Elder Abuse Negl 2008;3:276-300.
for adult protective services, J Aging Health 2013;1:80-96. 9. Calero-García MJ, Ortega AR, Navarro E,
Journal of Gerontological Social Work 2009; 6. Reske-Nielsen C, Medzon R. Geriatric et al. Relationship betweenhospitalization
52:815-836. Trauma. Emerg Med Clin North Am and functional and cognitive impairment
3. Dong, XQ. Elder Abuse: Systematic 2016;3:483-500. in hospitalized older adults patients.
Review and Implications for Practice. 7. Frazão SL, Silva MS, Norton P, et al. Aging Ment Health 2016;6:1-7.
J Am Geriatr Soc 2015; 6:1214-1238. Domestic violence against elderly with
C ASE REPORTS
ABSTRACT
Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder, with unknown prevalence, although it is estimated
there are between 2,000 and 10,000 cases of PC worldwide. The International PC Research Registry (IPCRR) has currently
identified (as of November 2016) 746 individuals (in 403 families) with genetically confirmed PC. Heterozygous mutations,
predominantly missense mutations, in any one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17 cause PC.
The predominant clinical findings include plantar keratoderma, plantar pain and variable dystrophy of some or all toenails and/
or fingernails. Oral leukokeratosis, follicular hyperkeratosis, cysts of various types and natal teeth may also be present. We report
the first case of genetically confirmed PC from Romania due to a mutation in KRT6A, p.Arg466Pro.
Keywords: pachyonychia congenita, oral leukokeratosis, nail dystrophy, palmoplantar keratoderma,
plantar pain, keratin mutation
P
achyonychia congenita (PC; MIM
luses develop in early childhood as children start
#615726, #615728, #615735, #167200,
#167210) is a rare autosomal domi- walking and the subsequent excruciating plantar
nant genodermatosis that typically pain that develops by the second decade of life
presents with plantar keratoderma, is the most problematic complaint (2). This great-
plantar pain and variable nail dystrophy (1). Oral ly affects their quality of life and they may re-
leukokeratosis, follicular hyperkeratosis and cysts quire the use of canes, crutches or wheelchairs
Address for correspondence:
Anca Chiriac MD, PhD, Centrul Medical Nicolina, Str. Hatman Sendrea, Nr 2, Iasi, Romania
E-mail: ancachiriac@yahoo.com
Phone: 004072134999
Article received on the 8th of May 201x and accepted for publication on the 18th of May 2017.
CASE REPORT
mutations in PC-K6a form the largest group with- feature. Nail dystrophy is frequently observed
in the IPCRR (38%) and typically present with since birth or early childhood. Follicular
severe, painful plantar keratoderma, nail dystro- hyperkeratosis also occurs. PC-K17 individuals
phy and oral leukokeratosis. Plantar keratoder- exhibit variable expression of plantar keratoderma
ma usually occurs before the age of 5 and is ex- and highly variable pain levels; oral leukokeratosis
tremely painful, having a negative impact on is present in a small number of cases.
quality of life. Palmar keratoderma may also be Due to the rarity of PC gaining, a correct clini-
present. Thickening of the fingernails and toe- cal diagnosis can be difficult. In this case, several
nails is characteristic; often all 20 nails are af- previous visits to clinic had pointed towards al-
fected since birth or early childhood and may be ternative diagnoses. The oral leukokeratosis was
either extremely thickened or terminate prema- thought to be chronic oral candidiasis, for which
turely. Follicular hyperkeratosis may be present he was treated but with no effect; this diagnosis
on elbows, knees or other sites of friction espe- was later excluded following laboratory investi-
cially in children and lessens with time. A num- gations, including direct microscopic examina-
ber of patients have various types of cysts. Some tion and culturing a scraping from a lesion. His
children (4-12 years of age) experience extreme nail dystrophy was diagnosed as onychomycosis
pain with the first bite or first swallow that lasts and subsequently treated by systemic and local
for approximately 15-25 seconds and lessens aggressive antifungal therapy. Although nail in-
with age. fections are sometimes a problem, they are not
PC-K6b affects a much smaller group of pa- the cause of his hypertrophic nail dystrophy. The
tients than PC-K6a (9%) and is generally consi- hoarseness of his voice was misdiagnosed as
dered milder than PC-K6a. It is often not evident chronic laryngitis. Although these are not un-
at birth but shows signs in childhood. The most common misdiagnoses in babies and young chil-
consistent and challenging feature is the painful dren with nail, oral and/or plantar keratoderma
plantar keratoderma. The number of toenails involvement, a diagnosis of PC should be consi-
and fingernails affected is variable, with less than dered (2).
50% of individuals having any fingernail dystro- Confirmation of a clinical diagnosis by genetic
phy. Cysts and follicular hyperkeratosis are re- testing is important to ensure appropriate care
ported in many cases; oral leukokeratosis is pre- and genetic counseling. Other rare skin disor-
sent in a small number of cases. The mildest form ders can be confused with/appear like PC due to
of PC is due to mutations in KRT6C, but those similarity of some clinical features (3). These in-
with PC-K6c are also by far the smallest subgroup clude autosomal dominant disorders; Clouston
of patients within the IPCRR (only 3%); there- syndrome/hidrotic ectodermal dysplasia, which
fore, there are very few data available. presents with hypertrophic nail dystrophy; pal-
For those diagnosed with PC-K16 (33%), moplantar keratoderma and variable hypotri-
painful plantar keratoderma is the most challeng- chosis (due to mutations in the gap junction
ing feature. PC-K16 is not usually present at birth beta-6 gene (GJB6), which encodes connexin
but it is evident before the age of 14. More than 30, Cx30); Olmsted syndrome, characterized by
50% have constant palmar keratoderma with fis- painful palmoplantar keratoderma with/without
sures and associated pain. Nail dystrophy pre- periorificial hyperkeratosis; pseudoainhum and
sents as very thickened nails or, in the case of alopecia (caused by mutations in the transient
some specific mutations, with little/no nail dys- receptor potential cation channel subfamily V,
trophy (6). Oral leukokeratosis, cysts and follicu- member 3, TRPV3); and striate palmoplantar
lar hyperkeratosis occur in a small number of keratoderma (due to mutations in desmoglein 1,
cases. DSG1, a calcium-binding transmembrane glyco-
To date, approximately 17% of PC patients protein).
within the IPCRR have mutations in KRT17. Natal Detailed information on management and
teeth are a key feature of PC-K17 (though not caring for PC are available on the PC Project
present in all cases of PC-K17). Cysts (steatocysts) website (www.pachyonychia.org). Patients care
occur in almost all individuals with PC-K17. They for their main complaints themselves by regularly
develop around puberty, continuing during trimming/filing/grinding and paring calluses and
adulthood and are often the most troublesome by filing/grinding/clipping nails (7). Pain medica-
tion may be necessary to deal with the plantar for this rare disorder. Here we report the first
pain. Although at present there is no specific case of PC-K6a from Romania and add it to
treatment for PC, a number of ongoing research the IPCRR.
projects develop an effective therapy. Identifying
and documenting further cases of PC will aid Conflicts of interests: none declared
and promote the planning of future clinical trials Financial support: none declared
References
1. Eliason MJ, Leachman SA, Feng BJ, et al. The molecular genetic analysis of the features of pachyonychia congenita.
A review of the clinical phenotype of 254 expanding pachyonychia congenita case J Invest Dermatol 2011;131 1015-1017.
patients with genetically confirmed collection. Br J Dermatol 6 Fu T, Leachman SA, Wilson NJ, et al.
pachyonychia congenita. 2014;171:343-355. Genotype-phenotype correlations among
J Am Acad Dermatol 2012;67:680-686. 4 Tiwary AK, Wilson NJ, Schwartz ME, et al. pachyonychia congenita patients with
2 Shah S, Boen M, Kenner-Bell B et al. A novel KRT6A mutation in a case of K16 mutations. J Invest Dermatol
Pachyonychia congenita in pediatric pachyonychia congenita from India. 2011;131:1025-1028.
patients: natural history, features, and Indian J Dermatol Venereol Leprol 7 Goldberg I, Fruchter D, Meilick A, et al.
impact. JAMA Dermatol 2017;83:95-98. Best treatment practices for pachyonychia
2014;150:146-153. 5 McLean WH, Hansen CD, Eliason MJ, et al. congenita. J Eur Acad Dermatol Venereol
3 Wilson NJ, O’Toole EA, Milstone LM, et al. The phenotypic and molecular genetic 2014;28:279-285..
C ASE REPORTS
Endotracheal Intubation in a
Down Syndrome Adult Undergoing
Cataract Surgery – a
Multidisciplinary Approach
George Gabriel MOLDOVEANUa, Emilia SEVERINb, Andreea PAUNc
a
Department of Anesthesiology and Intensive Care, “Elias” Emergency University
Hospital, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
b
Department of Genetics, Faculty of Dentistry, “Carol Davila” University of Medicine and
Pharmacy, Bucharest, Romania
c
Orthodontic Specialist, “Carol Davila” University of Medicine and Pharmacy,
Bucharest, Romania
ABSTRACT
The present case report aims to describe and discuss the approach for the management of difficult endotracheal intubation in an
adult with Down syndrome undergoing cataract surgery. A 26-year-old female with Down syndrome and a validated diagnosis
of cataract requiring surgery was examined in order to assess the degree of difficulty of endotracheal intubation. Patients with
Down syndrome have characteristic craniofacial abnormalities which require a thorough pre-operative assessment to anticipate
and prepare for a difficult endotracheal intubation. Before the surgery, a series of clinical and paraclinical examinations were
conducted. Although cataract surgery generally requires loco-regional anesthesia, in our case it was performed under general
anesthesia. Indicators of potentially difficult intubation were macroglossia, prognathism, short neck, limited degree of head
extension and obesity. The pre-operative examinations, which revealed a high degree of endotracheal intubation, allowed the
anesthetist to achieve a better peri- and intra-operative management of the patient.
Keywords: endotracheal intubation, Down syndrome, lateral cephalogram
T
risomy 21, meaning an extra copy of
blood disorders, hypotonia, sleep disorders, gum
human chromosome 21, gives rise to a
characteristic physical and cognitive and dental problems or epilepsy (1). Therefore,
phenotype. In terms of medical patho- they have particular medical needs and require a
logy, individuals with Down syndrome special care. The preliminary anesthetic exami-
have an increased risk of developing several nation should involve careful evaluation of these
medical conditions. Some of the diseases that patients for achieving a safe surgery (2).
Address for correspondence:
George Gabriel Moldoveanu, MD, PhD Student
Phone: 0754 759 859
E-mail: gabrielmoldoveanu12@gmail.com
Article received on the 8th of December 2016 and accepted for publication on the 20th of June 2017.
The aim of this case report is to evaluate the The Ethics Committee of “Carol Davila” Uni-
type of anesthesia required in an adult patient versity approved the clinical protocol and the
with Down syndrome (DS) undergoing cataract informed consent form for this study. The re-
surgery. Furthermore, the elements necessary for search has been conducted in full accordance
assessing the degree of difficulty of endotracheal with the World Medical Association Declaration
intubation were evaluated through a multidisci- of Helsinki. The written informed consent was
plinary approach. obtained from the patient’s parents.
The pre-anesthetic examination included
CASE REPORT taking the family and medical history of the pa-
tient, which was correlated with a series of clini-
sternomental distance (Savva test) were recor- of 6 cm was another important risk factor for in-
ded, and the Mallampati score was assessed. tubation, given the fact that values of <6.5 cm
The clinical evaluation began by measuring were shown to predict a difficult intubation (8, 9).
the patient’s height and weight in order to calcu- Sternomental distance (Savva test) was appre-
late the BMI (Table 2). So, the patient was in- ciated between the sternal notch and the Men-
cluded in the third class of obesity (5), which in- talis point, also with the head in full extension
creased the difficulty of intubation by altering (7). Considering that the measured distance was
the position of the glottis and limiting the mobi- 12 cm and values less than 12.5 cm increase the
lity of the cervical spine. difficulty of endotracheal intubation (9, 10), this
The neck circumference measured below the parameter is another indicator of a potential
laryngeal protrusion and perpendicular to the complicated procedure.
long axis of the neck (6) was 43 cm. This parame- Intraorally, the maximum mouth opening was
ter is an indicator for the limited mobility of the measured between the incisal edges of the up-
neck, which is a predictive element for a difficult per and lower canines. A mouth opening under
intubation by reducing the head extension. 30 mm is a predictor of difficult intubation (9). It
Furthermore, the thyromental distance was was observed that in this case, the distance was
measured (Patil test) between the top of the thy- 38 mm.
roid cartilage and the Mentalis point with the Tooth mobility was also evaluated according
head in full extension (7). The measured distance to Miller’s classification, which comprises four
classes (11): (0) no movement detected; (1) the
Anthropometric point Location tooth may be moved less than 1 mm in buccolin-
Mentalis (Me)
The most inferior point of the mandibular gual or mesiodistal direction; (2) the tooth may
symphysis be moved 1 mm or more in buccolingual or me-
The point built at the intersection between siodistal direction; (3) the tooth may be moved
the tangent to the posterior side of the 1 mm or more in buccolingual or mesiodistal di-
Condilion (Co) condyle and the mandibular angle with rection, but mobility in the occluso-apical direc-
the tangent to the most upper point of the
condyle
tion is also present. Dental problems involved
both upper and lower arches. The upper incisors
The lowest and most posterior point of the
Gnation (Gn) were missing and the upper left canine fitted into
mandibular symphysis
class 3 mobility. In the lower arch, the incisors
Anterior nasal spine
The top of the anterior nasal spine belong to class 1 mobility.
(ANS)
The patient was assigned to class IV Mallam-
Posterior nasal spine
The top of the posterior nasal spine pati due to the lack of visibility of the soft palate
(PNS)
(Figure 3).
TABLE 1. Antropometric points used for clinical examination and for
tracing the lateral skull radiograph
Reference Measured
Parameters Unit
values value
Weight - 92 Kg
Height - 147 m
BMI (5) 20 – 24.9 46,2 kg/m² FIGURE 3. Examining the Mallampati score with
Neck circumference (13) <43 43 cm the mouth opened and tongue maximally protruded.
Class IV was assigned for the DS patient.
Thyromental distance (8, 9) >6 6 cm
Sternomental distance (9,10) >12,5 12 cm
Maximum mouth opening (9) >30 38 mm Also, the Cormack-Lehane score was deter-
mined by visualizing the appearance of the la-
Dental mobility (11) 0 3 class
rynx through direct laryngoscopy. It designates
Mallampati score - IV class
four grades of difficulty, with the same signifi-
Cormack Lehane - 4 grade cance to the previous score (8). The patient was
TABLE 2. Parameters measured during the clinical examination and classified into grade 4 of difficulty due to the lack
the results obtained for the DS patient of visibility of the epiglottis.
The results obtained for the parameters eva- the most superior and posterior point of the spi-
luated during the clinical examination are sum- nous process of axis (15). The measured distance
marized in Table 2. was 6 mm, representing an average value for this
Moreover, a series of parameters on the late- parameter.
ral cephalogram radiograph were evaluated, Maxillo-pharyngeal angle (Delegue) is the
whilst maintaining the subject’s head in the na- angle between maxillary axis (MA) and pharyn-
tural head position. The radiographs were traced geal axis (PA). MA (16) is the line passing be-
on acetate paper, using conventional antropo- tween anterior and posterior nasal spine points
metric landmarks and measurements were car- (ANS, PNS), while PA is the line passing through
ried out with a Cephalometric Protractor from the anterior part of the first and second cervical
3M Unitek (Figure 4, Table 1). vertebrae (10). The value obtained for this pa-
rameter was 92°, which was predictive for diffi-
cult intubation, an angle smaller than 90° being
associated with an impossible laryngoscopy.
The results obtained from the lateral cephalo-
gram tracing are shown in Table 3.
Normal Measured
Parameters Landmarks Unit
value value
Mandibular effective
length
Kdl–Gn 120 190 mm
FIGURE 4. Cephalometric analysis showing
increased mandibular effective length, normal Atlanto-occipital gap C0-C1 4-9 9 mm
values for C0-C1 and C1-C2 gaps and the low Atlas-axis gap C1-C2 4-9 6 mm
maxillo-pharyngeal angle. Maxilo-pharyngeal de-
MA–PA 100 92
angle gree
TABLE 3. Parameters analyzed on skull radiograph and the measured
The mandibular effective length from McNa-
values
mara analysis was measured between Condylion
and Gnathion (Co-Gn). Normal average values
are 120.2 ± 5.3 mm for females and 134 ± 6.8 mm Following the clinical and paraclinical exami-
for males (14). For the referred patient, the mea- nations performed, it can be assumed that for
sured distance was 190 mm, which denoted an this patient, endotracheal intubation presented a
increased mandible and a potential difficult intu- high degree of difficulty. For this reason, we
bation (8). chose the video laryngoscope (C-MAC, Macin-
Furthermore, the atlanto-occipital gap be- tosh laryngoscope blade, size 3) to achieve the
tween C0-C1 vertebrae was appreciated by intubation.
drawing a perpendicular line from the base of During induction of general anesthesia, the
the occipital bone to the most posterior and su- patient received Fentanil 2 microg/kg-body
perior point of the first cervical vertebra. For this weight, Propofol 2 mg/kg-body weight, Succinyl-
parameter, normal values are between 4-9 mm choline 1 mg/kg-body weight and adequate
(15). C0-C1 gap is a major factor that influences mask ventilation. The endotracheal tube, size
the extension of head because the greater the 7.0, was advanced without difficulty after identi-
distance, the more space is available for the mo- fying the anatomic landmarks (the tongue, the
bility of the head, which ensures a favorable axis uvula, the epiglottis, the arytenoid cartilages and
for laryngoscopy and endotracheal intubation the vocal cords). Capnography and auscultation
(8). In this case, the value obtained for C0-C1 confirmed the correct placement of the tube
gap was 9 mm, meaning that from this point of into the trachea.
view there was a favorable circumstance for in- In this case, intubation was performed with
tubation. video laryngoscopy, which allowed us to achieve
C1-C2 gap (atlas-axis) represents the perpen- a detailed examination of the larynx in order to
dicular distance between the lowest and most attain a better management in a difficult airway
posterior point of the posterior arch of atlas and situation.
References
1. Palmer TC, Torres GD, Derrick KN. Down’s Syndrome with Achalasia Cardia. practica nr. 4. In: Genetica umana. Concepte
Anesthetic Management of Pediatric J Clin Diagn Res 2016;10:UD03-UD05. şi aplicaţii practice. Ediţia a 2-a. Severin E,
Patients with Down Syndrome. In: 3. Li EY, Chan TC, Lam NM, Jhanji V. Albu C, Albu FD. Bucureşti, Editura
Down Syndrome, Palmer TC, SMGE Books, Cataract Surgery Outcomes in Adult Medicala. 2004:55-56.
2016:1-6. Patients with Down’s Syndrome. 5. Nuttall FQ. Body Mass Index: Obesity,
2. Santha N, Upadya M, Vishwanatham S. Br J Ophthalmol 2014;9:1273-1276. BMI, and Health: A Critical Review.
Anaesthetic Management of a Case of 4. Severin E, Albu C, Albu FD. Lucrarea Nutr Today 2015;3:117-128.
6. Joshipura K, Muñoz-Torres F, Vergara J, Elsevier Health Sciences. 2014:98-99. Paris: Société Nouvelle de Publications
Palacios C, Pérez CM. Neck Circumfe- 12. Huang H-H, Lee M-S, Shih Y-L, Médicales et Dentaires. 1979:40-51.
rence May Be a Better Alternative to Chu H-C, Huang T-Y, Hsieh T-Y. 17. Haddadi S, Marzban S, Fazeli B, et al.
Standard Anthropometric Measures. Modified Mallampati Classification as a Comparing the Effect of Topical
J Diabetes Res 2016;2016:1-8. Clinical Predictor of Peroral Esophago- Anesthesia and Retrobulbar Block with
7. Patel B, Khandekar R, Diwan R, Shah A. gastroduodenoscopy Tolerance. Intravenous Sedation on Hemodynamic
Validation of Modified Mallampati Test BMC Gastroenterol 2011;12:1-7. Changes and Satisfaction in Patients
with Addition of Thyromental Distance 13. Budde AO, Desciak M, Reddy V, Undergoing Cataract Surgery (Phaco
and Sternomental Distance to Predict Falcucci OA, Vaida SJ, Pott LM. The Method). Anesthesiol Pain Med 2015;2:1-6.
Difficult Endotracheal Intubation in Prediction of Difficult Intubation in Obese 18. Shott SR. Down Syndrome: Analysis of
Adults. Indian J Anaesth 2014;2:171-175. Patients Using Mirror Indirect Laryngos- Airway Size and A Guide for Appropriate
8. Sunanda G, Rajesh SK, Dimpel J. copy: A Prospective Pilot Study. Intubation. The Laryngoscope
Airway Assessment: Predictors of Diffcult J Anaesthesiol Clin Pharmacol 2013;2:183-186. 2000;4:585-592.
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preoperatorie şi premedicaţia. In: Orthodontic Cephalometry, 1st Ed. Endotracheal tube selection in children: a
Anestezie clinică, ediţia a 3-a. Acalovschi I. Athanasiou AE. London: Mosby. comparison of four methods.
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10. Gupta K, Gupta PK. Assessment of 15. Matheus RA, Ramos-Perez FM de M, 20. Nakazawa K, Ikeda D, Ishikawa S,
Difficult Laryngoscopy by Electronically Menezes AV, et al. The Relationship Makita K. A Case of Difficult Airway Due
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Lateral Cervical Radiograph: A prospec- tion and Head and Cervical Posture. Patient with Down’s Syndrome.
tive Study. Saudi J Anaesth 2010;3:158-162. J Appl Oral Sci 2009;3:204-208. Anesth Analg 2003;3:704-705.
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Endodontic Problems. In: Endodontics. Céphalométrie et Orthodontie. Muller L.
C ASE REPORTS
ABSTRACT
Congenital lobar emphysema in infants is a disorder that is detected most often in newborns or young infants. We report here
the case of a 4-month-old infant who at two months suddenly presented upper respiratory infections, treated symptomatically,
but evolution showed shortness of breath, wheezing, weight deficit. Thoracic ultrasound revealed left upper lobe hyperinflation
causing mediastinal displacement to the right, a slightly reduced blood supply at this level, and a lobar emphysema appearance.
Bronchoscopy evidenced a thickening in the left bronchial tree, due to left upper lobe emphysema.
Keywords: congenital lobar emphysema, congenital lobar emphysema in infants, infant
C A
ongenital lobar emphysema (CLE) is 4-month-old male infant was admitted for
a congenital anomaly of the lung, respiratory disstress, wheezing and failure to
with a prevalence of 1 in 20,000 to thrive. Personal physiological history showed
1 in 30,000 (1). Most of the cases that he was the first child from a physiological
present in the neonatal period, with pregnancy, born at term by C-section, with a
a male to female ratio of 3:1 (2, 3). CLE has also birth weight of 2850 g, an Apgar score 8/9, and
been reported with other associated anomalies a normal psychosomatic development. Family
with double superior vena cava and horse shoe history was not significant, and personal patho-
kidney (4). One case is reported with polysple- logical history included a congenital infection of
nia, a syndrome characterized by bilateral bi- undetermined etiology.
lobed lungs and bilateral pulmonary atria along The clinical onset of the disease was two
with liver, which is symmetrically placed in the months before admission, on the occasion of an
midline and multiple nodules of spleen (5). acute upper airway infection episode, which was
Article received on the 23d of May 2017 and accepted for publication on the 9th of June 2017.
treated by the family doctor with symptomatic Bronchoscopy evidenced omega-shaped epi-
drugs, but evolution showed persistent breathing glottis, short paramedian aryepiglottic folds, an-
difficulty, wheezing, and weight deficit. Objec- teriorly displaced arytenoids; during inspiration,
tive examination at admission evidenced a pa- aryepiglottic folds and arytenoids made contact
tient with a weight of 4650 g (< 5th percentile), a on the median line, starting to vibrate. The tra-
length of 63 cm (75th percentile), weight index = chea and the right bronchial tree were com-
0.77, afebrile, with pale skin, reduced subcuta- pletely permeable, without pathological chan-
neous cellular tissue, laryngeal stridor, pulmo- ges, and the left bronchial tree was permeable at
nary hypersonority in the left hemithorax, vesicu- the level of the tertiary carinae of the lingular
lar murmur with prolonged expiration, bilateral bronchus. In the superior branch of the left up-
sibilant rales, more frequent in the right hemi- per lobe bronchus, a thickening due to left upper
thorax, mild intercostal and subcostal retractions, lobe emphysema, without pathological secre-
respiratory rate 42 breaths/min, heart rate tions, was found.
166/min, SaO2=95-96%. Regarding differential diagnosis, cystic fibrosis
Laboratory investigations detected no patho- was excluded based on two negative sweat tests,
logical changes, and echocardiography excluded and cystic adenomatoid malformation was also
congenital cardiac malformations. Chest X-ray excluded by chest computed tomography.
showed left upper lobe hyperinflation causing
mediastinal displacement to the right, with a DISCUSSION
slightly reduced blood supply at this level
(Figure 1).
Chest computed tomography detected left C ongenital lobar emphysema (CLE) is a rare
congenital malformation, characterized by
alveolar distension and pulmonary hyperinfla-
upper lobe hyperinflation causing mediastinal
displacement to the right, with a slightly reduced tion, with contralateral pulmonary atelectasis (3).
blood supply at this level and a lobar emphyse- CLE is most frequently diagnosed in the neonatal
ma appearance (Figure 2). period, 5% of patients being diagnosed around
the age of six months. Diagnosis can also be es-
tablished prenatally by ultrasound, as well as at
school age (6, 7). Familial CLE cases have also
been reported (8). The incidence of left lung
lobe involvement is 43% of all cases, our infant
belonging to this group; the middle right lobe is
affected in 32% of cases, the upper right lobe in
28% of cases, while bilateral involvement occurs
in 20% of cases (9).
The cause of congenital lobar emphysema
FIGURE 1. AP and LL chest X-ray
can be identified in 50% of patients and can be
attributed to a congenital bronchial cartilage de-
fect, extrinsic compression of aberrant vessels,
bronchial stenosis, viscous bronchial mucus, and
mediastinal displacement to the opposite side of
bronchial obstruction (10). In 10% of cases, con-
genital lobar emphysema can be associated with
congenital cardiac malformations, which are ex-
cluded by echocardiography (11).
Patients frequently present tachycardia,
tachypnea, costal retraction, with progressive ac-
cumulation of carbon dioxide in the affected
lobe, and evolution towards respiratory failure.
The pulmonary expansion of the two hemithora-
ces is asymmetrical, with the presence of bron-
FIGURE 2. Chest CT chi, pulmonary hypersonority in the affected
lobe, and diminished respiratory and cardiac Conservative treatment is used in asymptom-
sounds. The infant had polypnea, tachycardia, atic patients with minimal respiratory manifesta-
pulmonary sonority was detected by percussion; tions. Children over the age of two years with
auscultation revealed vesicular murmur with moderate respiratory symptoms and normal bron-
prolonged expiration and bilateral sibilant rales, choscopy can also be treated conservatively. In
intercostal and subcostal retractions; respiratory patients with severe respiratory manifestations,
failure was not associated, SaO2 values being resection of the affected lobe segment is per-
higher than 92%. formed as an alternative to lobectomy (14). The
Chest X-ray describes hyperinflation of the af- case was interpreted as congenital lobar emphy-
fected lobe, with pulmonary atelectasis and con- sema with mild/moderate respiratory manifesta-
tralateral mediastinal displacement, and bron- tions, and was treated by conservative therapy,
choscopy can be normal or changed. The with a good clinical evolution of symptomatology.
suspicion of congenital lobar emphysema re-
quires additional imaging investigations such as TAKE-HOME MESSAGE
CT/MRI, which allow diagnosis and initiation of
early treatment for a favorable prognosis (11-14).
In order to diagnose the infant, chest X-ray and U nilateral clinical findings in a bronchiolitis-
like young infant should point to a congeni-
tal lung malformation.
CT were performed, which evidenced left upper
lobe hyperinflation causing mediastinal displace-
ment to the right, with a slightly reduced blood Conflicts of interest: none declared.
supply at this level, and bronchoscopy detected Financial support: none declared.
a minimal thickening in the upper branch of the
left lobe bronchus.
References
1. Thakral CL, Maji DC, Sajwani MJ. Pulmonary Malformations: Predictors of 2000;35:792-795.
Congenital lobar emphysema: experience Neonatal Respiratory Distress and Early 11. Prabhu M, Joseph TT. Congenital lobar
with 21 cases. Pediatr Surg Int Surgery. J. Neonatal Surg 2016;5:27. emphysema: Challanges in diagnosis and
2001;17:88-91. 7. Karnak I, Senocak ME, Ciftci AO, ventilation. Anesth Essays Res
2. Cay A, Sarihan H. Congenital malforma- Buyukpamukcu N. Congenital lobar 2012;6:203-206.
tion of the lung. J Cardiovasc Surg (Torino) emphysema: diagnostic and therapeutic 12. Tempe DK, Virmani S, Banerjee A, Puri
2000;41:507-510. considerations. J Pediatr Surg SK, Datt V. Congenital lobar emphysema:
3. Al-Salem AH, Gyamfi YA, Grant CS. 1999;34:1347-1351. Pitfalls and management.
Congenital lobar emphysema. 8. Berlinger NT, Porto DP, Thompson TR. Ann Cardiac Anesth 2010;13:53-58.
Can J. Anaesth 1990;37:377-379. Infantile lobar emphysema. Ann Otol 13. Nath MP, Gupta, S, Kumar A, Chakrab-
4. Ogul H, Sevketbeyoglu H, Ozgokce M, Rhinol Laryngol 1987;96:106-111. arty A. Congenital lobar emphysema in
Alper F. Congenital lobar emphysema 9. Stocker JT, Drake RM, Madewell JE. neonates: Anaesthetic challengers.
association with double superior vena Cystic and congenital lung disease in Indian J Anaesth 2011;55:280-283.
cava and horseshoe kidney. newborn. Prespect Pediatr Pathol 14. Rocha G, Azevedo I, Pinto JC, Moura
Ann Thorac Surg. 2012;94:2131. 1978;4:93-154. CS, Guimaraes H. Congenital lobar
5. Choh NA, Choh SA, Jehangir M, et al. 10. Center for fetal Diagnosis and Treat- emphysema of the newborn. Report of
Congenital lobar emphysema associated ment, The Children’ s Hospital of four clinical cases. Rev Port Pneumol
with polysplenia syndrome. Philadelphia, PA, USA. Prenatal diagnosis 2010;16:849-857.
Ann Saudi Med 2010;30:482–484 and management of congenital lobar
6. Costanzo S, Filisetti C, Vella C, et al. emphysema. J Pediatr Surg
C ASE REPORTS
ABSTRACT
The present case report aims to describe and discuss the approach for the management of difficult endotracheal intubation in an
adult with Down syndrome undergoing cataract surgery. A 26-year-old female with Down syndrome and a validated diagnosis
of cataract requiring surgery was examined in order to assess the degree of difficulty of endotracheal intubation. Patients with
Down syndrome have characteristic craniofacial abnormalities which require a thorough pre-operative assessment to anticipate
and prepare for a difficult endotracheal intubation. Before the surgery, a series of clinical and paraclinical examinations were
conducted. Although cataract surgery generally requires loco-regional anesthesia, in our case it was performed under general
anesthesia. Indicators of potentially difficult intubation were macroglossia, prognathism, short neck, limited degree of head
extension and obesity. The pre-operative examinations, which revealed a high degree of endotracheal intubation, allowed the
anesthetist to achieve a better peri- and intra-operative management of the patient.
Keywords: children, type 1 diabetes, autoimmunity, coeliac disease, thyroiditis
P
ediatric autoimmune diseases are ge- are quoted by specialized publications, but the
nerally rare and when they occur, they precise cause of autoimmune disorders is still
might represent a diagnosis and treat- unknown (1). They may occur more frequently
ment challenge. Many pediatric sys- in people who have a genetic predisposition to
temic autoimmune diseases are diffe- autoimmune diseases. An autoimmune disorder
rent from adults’ diseases, thus turning into a might affect one or several types of organs or tis-
special problem for the physicians and resear- sues, which means that a person/patient may
chers attending the children affected by these suffer from several autoimmune diseases at the
diseases. same time (2).
Address for correspondence:
Anca Andreea Orzan, 20th Constantin Brancoveanu Boulevard, 4th District, Bucharest, Romania
E-mail: anca.orzan@gmail.com
Phone: 0729805497
Article received on the 16th of June 2017 and accepted for publication on the 3rd of July 2017.
Type 1 diabetes mellitus is the most frequent antigens as well as a series of other genes whose
endocrine-metabolic disease of children and products might influence susceptibility. Gene
teenagers. Its incidence is increasing annually for polymorphisms besides those within the HLA
each population, regardless of race and nationa- area, especially genes for insulin and PTPN22
lity. Type 1 diabetes mellitus results from the au- genes (protein tyrosine phosphatase gene), also
toimmune destruction of insulin-producing beta influence susceptibility for type 1 diabetes but in
cells at the pancreas level; this disease is basi- a smaller percent than the classical HLA loci.
cally a complex genetic disorder expressed by an Thus, the genes known to be affecting T1D sus-
increased frequency in families where there are ceptibility may be grouped in three general cate-
relatives suffering from type 1 diabetes mellitus gories: immune function, insulin expression and
and other autoimmune diseases (3, 4). The in- -cellular function. Besides HLA, the locus with
heritance of this genetic tare in the presence of the highest susceptibility is the insulin gene itself,
certain environment triggers leads to the identifi- when insulin expression levels are affected.
cation of insulin producing cells (pancreatic B) as Other loci are involved in the cell function (3).
“non-self” and then to their destruction by auto- It is a known fact that type 1 diabetes mellitus
antibodies. The most frequent autoantibodies is associated with a series of other autoimmune
associated to diabetes mellitus are the islet cell diseases; the strongest association is with celiac
antibodies (ICA), insulin autoantibodies (IAA), disease; hypothyroidism or Hashimoto disease;
glutamic acid decarboxylase (GAD65), mole- Graves disease or hyperthyroidism; Addison di-
cules associated to protein tyrosine phosphatase sease or adrenal insufficiency and pernicious
IA-2 (ICA 512) and IA-2SS (phogrin) and/or Zinc anemia, and rheumatoid arthritis (4).
transporter 8 (ZnT 8) (50). GAD and ZnT8A anti- The celiac disease is associated to type 1 dia-
bodies are associated to thyroid autoimmunity betes mellitus in 4 up to 9% of all cases, but for
(52). The family members of children with dia- 60-70% of asymptomatic cases (“Silent celiac
betes are more likely to be susceptible of having disease”). Children with type 1 diabetes mellitus
antibodies and manifestations of certain autoi- have an increased risk of celiac disease in the
mmune diseases compared to general popula- first 10 years of diabetes evolution (14). Both ce-
tion (54-56). liac disease and type 1 diabetes are two genetic
Studies reported in the specialized literature disorders based on similar genes (DQ2 and
show that the risk of pediatric patients develo- DQ8). Both of them are immuno-regulated and
ping diabetes mellitus is 5 to 6% when the father associated to other autoimmune diseases of au-
has type 1 diabetes and 3 to 4% when the mother toimmune thyroid and rheumatoid arthritis type.
has it (3). It is considered that a part of the Approximately 3.5–10% of people suffering from
mother’s chromosomal material or the DNA be- celiac disease develop type 1 diabetes mellitus
comes inactivated when passed to the children, and vice versa. Celiac disease or type 1 diabetes
thus leading to the risk’s percentage difference of mellitus screening is recommended for persons
acquiring the disease for the child. In case a already diagnosed with one of the two autoi-
brother has type 1 diabetes, the risk is 5–6%; mmune disorders. When individuals suffer from
however, the risk increases when the brother both diseases, type 1 diabetes mellitus is most
shows major complex of histocompatibility commonly diagnosed first; the speculated moti-
(MHC) identical haplotypes. In case of monozy- vation is that the diabetes symptoms are more
gotes where one suffers from type 1 diabetes obvious and therefore it is easier to be diagnosed
mellitus, the other one’s risk to develop the di- than celiac disease (5-13).
sease is considered to be of approximately 40%, Patients with type 1 diabetes mellitus and un-
but recent research suggests that the percentage diagnosed celiac disease may present unstable
could be much higher (3, 4). glucose values, reduced need of insulin, delayed
After decades of research and thousands of gastric emptying, weight loss, growth retardation
reports, HLA remains by far the strongest predic- (for children) and reduced bone density. Some
tor of type 1 diabetes risk. “HLA” does not refer diabetic patients with newly diagnosed celiac
to one single genetic locus, but to an area of the disease may present different symptoms: hypo-
genome which includes genes codifying three glycemic disorders, increased need of insulin
classical HLA II antigens and three classical HLA I and hemoglobin A1C increased values (glycosyla-
ted hemoglobin) even after a gluten free diet is diabetes (58, 60). Hypothyroidism is accompa-
initiated by increasing intestinal absorption asso- nied by a series of anomalies in plasma lipid me-
ciated with the gastro-intestinal tract healing but tabolism, triglycerides, low density lipoproteins
also on the type and density of carbohydrates, (LDL), cholesterol presenting high values. The
which are found in gluten free foods (5-13, 31). clinical features may include the presence of a
Both celiac disease and type 1 diabetes pre- painless goiter, weight gain, delayed growth, fa-
sent the same genetic background and an abnor- tigue, lethargy, cold intolerance, bradycardia
mal immune response at the small intestine level (57) and a poor glycemic control. Hypothyroi-
manifested by an inflammation process and a dism is confirmed by demonstrating a low free
variable degree of enteropathy. The serological thyroxine and a high concentration of TSH. The
screening for the celiac disease by dosing Ig A presence of compensated hypothyroidism may
antitransglutaminase tissue antibodies should be be detected in a person with a moderately in-
performed on all patients with type 1 diabetes creased TSH but a normal level of free thyroxine.
mellitus even from the onset and then on an an- Hyperthyroidism within autoimmune thy-
nual basis, especially in the first years of evolu- roiditis is usually associated with exacerbation of
tion. In order to confirm the diagnosis, an intes- glucose control and increase of insulin necessary
tinal biopsy and immunohistochemical studies by gluconeogenesis increase at hepatic level, fast
should be performed. The certainly diagnosed glucose absorption at gastro-intestinal level and
celiac disease shall be treated with a gluten-free increase of insulin resistance until occurrence of
diet (14-35). diabetic ketoacidosis. Hyperthyroidism is less
The autoimmune thyroid disease is frequent in frequent than hypothyroidism in association with
the general population and its prevalence increa- type 1 diabetes mellitus, with a prevalence of
ses with age. In children with type 1 diabetes mel- 3-6% in diabetic children (58), and remaining
litus, autoimmune thyroid disease is one of the more frequent than in general population. Hy-
most frequent associations of autoimmune di- perthyroidism should be considered in case
seases. Autoimmune thyroiditis associated to type there is an unexplained difficulty in maintaining
1 diabetes mellitus is also clinically silent but it glycemic control, weight loss despite a normal
may progress either as thyroid disease with obvi- appetite, agitation, tachycardia, tremor, heat in-
ous or subclinical hypothyroidism, or with hyper- tolerance, thyroid enlargement or specific eye
thyroidism (44). Thyroid dysfunction may affect symptoms. The diagnosis of autoimmune thy-
the control of diabetes mellitus. Autoimmune thy- roiditis with hyperthyroidism is established based
roid disease is easier detected by measuring the on anti-receptor TSH antibodies (TR Ab), TSH
circulating antibodies against thyroid peroxidase dosage when it is low and increased T3.
(anti-TPO Ab) and thyroglobulin (anti-Tg Ab) (36). Considering the high prevalence of autoi-
Autoimmune thyroiditis associated to type 1 dia- mmune thyroiditis, the thyroid dysfunction in
betes mellitus may have two clinical forms: hypo- patients with type 1 DZ and the effects of thyroid
thyroidism and hyperthyroidism. disorders on their metabolic control, there is a
The primary or subclinical hypothyroidism general agreement regarding the diabetic pa-
due to autoimmune thyroiditis occurs in appro- tients’ screening for thyroid antibodies and dys-
ximately 3-8% of the young adults with type 1 function. Despite this fact, there is still no con-
diabetes mellitus (57, 58), with an incidence be- sensus regarding the screening of autoimmune
tween 0.3 and 1.1 in 100 children and teenagers thyroiditis and thyroid function in patients with
with diabetes per year (44, 45). type 1 DZ (49).
Anti-thyroid antibodies may be detected in
up to 29% of all patients with type 1 diabetes CASE 1
mellitus throughout the first years of illness (51,
58), and they are highly predictive for the hypo-
thyroidism development, with a risk of approxi-
mately 25% (58, 60). Anti-thyroid antibodies are
P atient S. A.-M. diagnosed with type 1 diabe-
tes mellitus at the age of 1 year and 3 months.
The onset included the diabetic ketoacidosis
more frequent in girls than in boys, most of the (pH 7.22; bicarbonate 6 mmol/L; base excess
times during pubertal maturation (58), and they (BE) 21.9 mmol/L), glycemia 566 mg/dL, glycos-
can be associated to aging and long duration of uria, ketonuria, HbA1c 12.5%. The patient’s
evolution in the following eight years was favo- diagnosis indicated Marsh III stage celiac disease.
rable, with an average HbA1c of 8% in this pe- Initially, the gluten-free diet was not fully ob-
riod. At the age of nine, upon the annual evalu- served, the glycemic balance continued to be
ation, the patient presents Ig A type Ac unstable with high daily hypo/hyperglycemic
anti-transglutaminase 150 U/mL (normal values values, which led to the occurrence of a signifi-
< 10 U/mL) and Ig A anti-gliadin antibody cant microalbuminuria (287 microg/dL) for an
30 U/mL (normal values 0-20 U/mL); this is the early diabetic nephropathy at the age of 10. At
reason why a duodenal biopsy is decided. The the same age, the ATPO,TSH and f T4 values
histopathological result indicated Marsh III stage lead to the Hashimoto autoimmune thyroiditis
celiac disease. Gluten-free diet is initiated (par- diagnosis confirmed by thyroid ultrasound,
tially observed by the patient) for two years, lea- which describds a thyroid with a reduced echo-
ding to a poor glycemic balance (HbA1c 9-10%). genicity, several homogeneous nodular hy-
Also at that time (at the age of 11), the appea- poechoic images with dimensions of up to 4 mm
rance of vitiligo areas is noted, especially on the and hypoechoic layers disposed throughout the
neck and dorsum of the hands, and the evalua- entire thyroid.
tion of thyroid function – TSH 9,9 μUI/mL (nor- Within the evolution, gluten-free diet is initi-
mal values: 0,6–4,84 μUI/mL), FT4 18.9 (normal ated, which is fully observed this time, the treat-
values 12.5–21.5 pmol/L), ATPO 496 UI/mL – ment of thyroid dysfunction with L–thyroxine as
showed significant values for an autoimmune thy- well as of early diabetic nephropathy with Cap-
roiditis in the subclinical hypothyroidism stage. topril leading to the normalization of glycemic
Thus, within 10 years from diabetes onset, balance, weight status and microalbuminuria
the patient presents the association of three au- negativity.
toimmune diseases: celiac disease, vitiligo, and
thyroiditis. CASE 3
The family medical history is very important:
the father was diagnosed with type 1 diabetes
mellitus, two years before the little girl’s diagno- C .A. diagnosed with type 1diabetes at the age
of 10, ketoacidosis onset, good glycemic
control until the age of 14 years (6–6.5%), after
sis (at the age of 26), by associating the same
autoimmune diseases as his daughter, namely that followed by cognitive disorders with ex-
vitiligo, celiac disease, fast onset thyroiditis and tremely poor school results, behavioral (agita-
unfavorable evolution of the diabetes mellitus, tion, nervousness, smoking) and dietary disor-
which led to the occurrence of diabetes mellitus ders (alcohol consumption and failure in
major complications; therefore, at the age of 42 observing the carbohydrate quantity and quality)
he is a candidate for kidney transplant. with the occurrence of frequent, medium and
severe hypoglycemia (3–4 episodes per year)
CASE 2 that required hospitalization. During these ho-
spitalizations, significant weight loss and unre-
population, thus providing a wide subject for the might be an obstacle, given that many gluten-
future scientific researches concerning the dis- free foods provide a high glycemic index. There-
covery of methods by which these diseases may fore, the association of celiac disease in a person
be detected, prevented and even healed. An with diabetes may influence the prognostic of a
equally well known fact until now is that certain diabetic patient regarding the onset of long term
autoimmune diseases do not “appear” alone but complications (see the presentation of the first
in association with others; in this regard, the case – the rapid onset of severe chronic compli-
most common combination is of type 1 diabetes cations in the patient’s father).
mellitus with thyroid diseases, followed by the The relation between thyroid disorders and
association of type 1 diabetes with celiac di- diabetes mellitus is characterized by a complex
sease. interaction. Hyperthyroidism modifies the glyce-
Patients diagnosed with celiac disease require mic control in diabetic subjects; also, it may in-
the observance of a strict free gluten diet crease and accelerate diabetic retinopathy, while
throughout their entire lives in order to prevent hypothyroidism may increase susceptibility to
acute (malabsorption, diarrhea, folic acid defi- severe hypoglycemia, complicating diabetes
ciency, iron deficiency, growth retardation) and mellitus management with the early occurrence
chronic complications (intestinal lymphoma, os- of neuropsychiatric complications (see the pre-
teoporosis, autoimmune diseases, infertility, sentation of the third case).
death) (61-63). Gluten exclusion associated to a
diet imposed by diabetes mellitus lead to an un- CONCLUSION
stable/poor glycemic balance, with an accele-
rated onset of diabetes mellitus chronic compli-
cations (see the presentation of the second case T ype 1 diabetes as an autoimmune disease as-
sociated with other autoimmune diseases.
The early determination of associated autoi-
complicated with diabetic nephropathy). Thus,
unfortunately, failure to observe a gluten-free mmune diseases in the absence of clinical symp-
diet in a patient with diabetes mellitus and celiac toms requires regular screening (annually), star-
disease is a very common situation. The purpose ting with the first year after diabetes onset.
of a gluten-free is to achieve and maintain a Family aggregation of autoimmune diseases re-
proper glycemic balance, normal blood pres- quires the examination of all family members.
sure, normal lipid profile and a proper body Type 1 diabetes and management of its compli-
weight. The maintenance of a constant glycemic cation for short and long term depends on early
control is essential to reduce both micro- and diagnosis and treatment of the associated autoi-
macro-vascular complications of type 1 diabetes mmune diseases.
mellitus (64, 65). This is why patients’ counseling
and education on carbohydrate quantity and Financial support: none declared.
quality is important (66). But gluten-free diet Conflicts of interest: none declared.
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1. The ereditary origin of cancer is present in a d. A baby with no signs of life born after at least
proportion of: 20 weeks of gestation
a. Zero e. A baby of at least 1000 g born after at least
b. 0.1% 30 weeks of gestation
c. 1%
d. 10% 7. The prevalence of cancer related fatigue is situated
e. 20% between:
a. 1 and 3%
2. Chromatin is a complex of macromolecules consisting b. 11 and 13%
exactly of: c. 22 and 34%
a. DNA d. 52 and 64%
b. RNA e. 92 and 100%
c. Proteins
d. DNA + RNA 8. Mechanisms of renal disease in HIV patients include:
e. DNA + RNA + proteins a. Direct HIV infection of glomerular cells
b. Direct HIV infection of tubular cells
3. In 2010 he prevalence of obesity worldwide was c. Collapsing focal segmental glomerulosclerosis
between: d. Increased secretion of autoantibodies by
a. 1-2% B lymphocytes
b. 5-6% e. Coinfection with B and C hepatitis viruses
c. 9-10%
d. 15-16% 9. The risk of a child to develop type 1 diabetes is:
e. 20-21% a. 5% when the father has type 1 diabetes
b. 3% when the mother has type 1 diabete
4. Tests performed to elucidate the cause of haematuria c. 6% when a brother has type 1 diabetes
include: d. 10% when a sister has type 1 diabetes
a. Multidetector computed tomography e. 40% when the homozygotic twin has
b. Multidetector computed tomographic urography type 1 diabetes
c. Urine cytology
d. Cystoscopy 10. In trisomy 21, the following ilnesses are more often
e. Bone densitometry associated:
a. Hearing loss
5. Cellular and intercellular mechanisms in an acute b. Hypotonia
kidney injury include: c. Epilepsy
a. Inflammatory cell infiltration d. Dental problems
b. Free radical production e. Sleep disorders
c. Inflammatory cytokines
d. Reduction of nitric oxide
e. Reduction of perfusion in renal tubular tissue
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