Volume 38 (2017): Edizione 3 (December 2017)

Papers on medical subjects have been published since the first issue of the journal Prilozi in 1969, totalling a number of of 957 (nine hundred and fifty seven) papers have been published in Prilozi. Two hundred and twenty nine cover subjects on natural sciences and mathematics, and 728 (seven hundred and twenty eight) subjects on medical sciences. So far, 2017 No. XXXVIII-2, 622 (six hundred and twenty two) papers published in Prilozi are in Pubmed. Prilozi is published three times a year and it is covered by the following services: Baidu Scholar, Case, Celdes, CNKI Scholar (China National Knowledge Infrastructure), CNPIEC, DOAJ (Directory of Open Access Journals), EBSCO (relevant databases), EBSCO Discovery Service, Elsevier – SCOPUS, Google Scholar, J-Gate, JournalTOCs, KESLI-NDSL (Korean National Discovery for Science Leaders), Naviga (Softweco), Primo Central (ExLibris), Publons, PubMed, ReadCube, ResearchGate, SCImago (SJR), Summon (Serials Solutions/ProQuest), TDNet, Ulrich’s Periodicals Directory/ulrichsweb WanFang Data, WorldCat (OCLC).

In this review we present some data about the use of mobile phones in medical practice. The results of over hundred studies cited in PubMed during the last few years have been discussed. The article gives background connected with a project in the Macedonian Academy of Sciences and Arts referring to a personal mobile phone application named “Neurogame” which is currently constructed to evaluate motor skills related to attention and concentration in different samples of people.

There is scarce data in the contemporary literature regarding the correlation of the microanatomy of the perforating arteries, their atherosclerosis, and the ischemia in their territory. In order to examine, at least partially, those parameters, the perforating arteries of 12 brains were microdissected or their vascular casts were obtained. In addition, 30 specimens of the perforators were used for a histological and immunohistochemical study. Finally, radiological images of 14 patients with deep cerebral infarcts were examined following a selection among 62 subjects. It was found out that certain groups of the perforators ranged in number between 0 to 11 (1.1-8.4 on average). In addition to the origin from the parent vessels, some of the perforators also arose from the leptomeningeal branches. Occlusion of such a branch may result in both a superficial and a deep ischemic lesion. Besides, the common stems of certain perforators supplied both right and left portions of the corresponding brain regions. Occlusion of such a common trunk leads to bilateral infarction. The atherosclerosis of the perforating vessels, which was found in one third of the specimens, is the basis for the ischemic lesions development on their territory. Among the 62 patients with ischemic lesions, 14 had a deep cerebral infarcts, most often within the thalamus, as well as on the territory of the middle cerebral and the anterior choroidal artery perforators of the hemispheres. Our study showed that a strong correlation exists between certain microanatomical features, atherosclerosis, and region of supply of the perforating arteries, on the one hand, and location of the ischemic lesions on the other hand.

Purposes:Bone tumours have been a tragedy for the patient in any time period. In the majority of the cases it occurs in children or young adults. In the past the affected limbs could not be spared and the overall prognosis was poor.

Methods:Chemotherapy successfully introduced for the purpose of overcoming the poor overall prognosis (Rosen and Jaffe) and tumour prostheses were invented for the purpose of salvaging the affected limbs (Marcove, Scales, Campanacci, Sivas, Salzer).

According to the Vienna Tumour Registry in 1968, the first custom-made Vitallium prosthesis for the proximal femur was implanted in a parosteal osteosarcoma.

Results: In Vienna, as a result of the successful chemotherapy the surgical methods for bone tumours changed to limb sparing methods also. A modular ceramic prosthesis for the proximal humerus was introduced by Salzer. From 1975 -1982 16 custom-made endoprosthesis (1) for the knee region were implanted which were replaced by the KMFTR in 1982 (2, Kotz modular femur tibia reconstruction system) which was introduced at the “2nd ISOLS” to an international group of experts. The successful system was followed by the HMRS (Howmedica modular resection system) in 1988. At that time, especially in children, the rotation-plasty of Borgreve was adopted for tumours of the knee region (2). A scientific survey of 70 patients with rotation-plasty until 1991 showed excellent clinical and oncologic results. Later a similar approach was used in upper extremity tumours as “resection replantation” with surprisingly good results. Sophisticated technologies with growing mechanisms allowed the use of endoprostheses even in children (3) for the purpose of substitution since the mutilating rotation-plasty in 1996.

Conclusion: For almost 100 years efforts have been undertaken to improve the treatment of bone tumours. Surgery was aiming to keep the function of the limbs by tumour resection instead of amputation. Together with successful chemotherapy, which saves lives, an adequate surgery could stepwise salvage the function of the limb. Body integrity was the final aim for the diseased. Finally, by the effort of the International Societies like ISOLS and EMSOS the survival of malignant bone tumour patients improved from 20% to 80 % with good function quality by sophisticated operative techniques and improved tumour prostheses.

Proteome analysis has been applied in multiple studies in the context of chronic kidney disease, aiming at improving our knowledge on the molecular pathophysiology of the disease. The approach is generally based on the hypothesis that proteins are key in maintaining kidney function, and disease is a clinical consequence of a significant change of the protein level. Knowledge on critical proteins and their alteration in disease should in turn enable identification of ideal biomarkers that could guide patient management. In addition, all drugs currently employed target proteins. Hence, proteome analysis also promises to enable identifying the best suited therapeutic target, and, in combination with biomarkers, could be used as the rationale basis for personalized intervention. To assess the current status of proteome analysis in the context of CKD, we present the results of a systematic review, of up-to-date scientific research, and give an outlook on the developments that can be expected in near future. Based on the current literature, proteome analysis has already seen implementation in the management of CKD patients, and it is expected that this approach, also supported by the positive results generated to date, will see advanced high-throughput application.

Smartphones are ubiquitous, but it is still unknown what physiological functions can be monitored at clinical quality. In medicine their use is cited in many fields (cardiology, pulmology, endocrinology, rheumatology, pediatrics as well as in the field of mental health).

The aim of this paper is to explain how the use of mobile application can help clients to improve the index of their focus, concentration and motor skills. Our original developed application on Android operating system, named “neurogame” is based on an open source platform to enable assessment and therapeutic stimulation, focus and concentration with the ability to monitor the progress of the results obtained in a larger number of participants (normal subjects as well as patients with different disorders) over a period of time.

Whilst nowadays the predominant focus is on the pharmacological treatments, there is a rapidly growing interest in research on alternative options that will offer help in many cases of disorder management in terms of mobile application games.

In order to have some kind of “norms”, we evaluated a group of healthy population. Obtained results will serve as a database for comparison the future results. This article displays the results obtained as database.

Rare renal diseases (RRD) are an important category of rare disease (RD) as they can do great damage to the patients, families and society. The patient may undergo years even decades of numerous investigations including invasive procedures and yet not have definitive and precise diagnose and therefore, no opportunity for appropriate treatment. The great progress in molecular genetic techniques characterized many Mendelian diseases on molecular level. This gave the possibility for appropriate prevention and treatment interventions, genetic counseling and prenatal diagnosis. Herein, we summarize the current status of RRD in Macedonia. The research interest of Macedonian clinicians and scientists is focused on the genetics of congenital anomalies of the kidney and urinary tract (CAKUT), steroid resistant nephrotic syndrome, nephrolithiasis and nephrocalcinosis, cystic diseases and cilliopathies with collaborations with eminent laboratories in Unites States and Europe. This collaboration resulted in detection of new genes and pathophysiological pathways published in The New England Journal of Medicine and in other high impact journals. Macedonian health professionals have knowledge and equipment for diagnosis of RRD. Unfortunately the lack of finances is great obstacle for early and appropriate diagnosis. Participation in the international registries, studies and trials should be encouraged. This would result in significant benefit for the patients, health professionals and science.

The psychiatric and other CNS disorders are characterized with unregulated neuro-inflammatory processes and chronic microglia cell activation resulting with detrimental effect. ABCB1gene polymorphismsC1236T, G2677T/Aand C3435T are associated with P-glycoprotein expression and function andare linked with predisposition to psychiatric disorders such as schizophrenia and bipolar disorders. The relationship between mood disorders and glucocorticoids has been confirmed and ABCB1 SNPs influence the glucocorticoids access to the brain.

The aim of the study is evaluation of the influence of the three most common ABCB1SNPs on predisposition to psychiatric disorders in Macedonian population.

In the study 107 unrelated healthy Macedonians of both sexes were enrolled as a control group and patient population of 54 patients (22 to 65 years old) diagnosed with schizophrenia or bipolar disorder. ABCB1 for three polymorphisms were analyzed by Real-Time PCR in both groups.

The results have confirmed the role of the ABCB1 gene in predisposition to psychiatric disorders and increased risk of developing bipolar disorder in carriers of the heterozygotes and mutant homozygotes for polymorphic variations in 1236 and 2677 in comparison to the normal genotype carriers. Three-fold higher risk was estimated for psychiatric illness in women that are 1236 and 2677 heterozygous carrier (heterozygous and mutant homozygous) compared to healthy control (men and women) population and four-fold higher risk in comparison only to healthy women population. Mutant allele carriers for 1236 and 2677 polymorphisms that are 35 years and below in patients population have almost three-fold higher risk for development of psychiatric illness.

Herein, we present a simple and rapid high performance liquid chromatographic (HPLC) method with UV-detection for the direct determination of diazepam in whole blood and serum that can be used for monitoring diazepam levels in clinical samples analysis. The isolation of diazepam and the internal standard bromazepam from serum and whole blood samples was performed using solid phase extraction method with RP select B cartridges. The analytes were separated employing a reversed phase C8 column with a mobile phase composed of 0.1 % (V/V) triethylamine in water (pH 3.5) and acetonitrile (63:37, V/V). UV detection was carried out at 240 nm. Linearity was achieved in the range from 10.0-1000.0 ng/ml for serum and whole blood. The method was applied to spiked and real biological samples after an oral administration of 10 mg diazepam. In conclusion, the proposed method is simple, rapid and provides efficient clean-up of the complex biological matrix and high recovery of diazepam.

Herein synchronous occurrence of Hodgkin lymphoma and secondary myelodysplastic syndrome in a 60 year old male patient with small cell lung cancer treated with combined chemotherapy (carboplatin and paclitaxel) and radiotherapy is presented. The objective of this report is to stress the importance of documenting and monitoring adverse drug reactions that arise from chemotherapy.

After four years of treatment with the combined chemotherapy, the patient presented inguinal lymphadenopathy and enlarged lymph nodes and histopathology rapport was suggestive for plasmacytoid variant of Castleman disease. Three years later, biopsy of lymph node was performed and diagnosis of Hodgkin lymphoma – mixed cellularity has been established. Molecular analyses revealed presence of dominant monoclonal population of the immunoglobulin genes in the oligo/monoclonal background. Bone marrow biopsy findings suggested secondary myelodysplasia and revealed signs of hematopoietic cells dismaturation with signs of megaloblastic maturation of the erytropoetic lineage, appearance of ALIP (abnormal localization of immature precursors) in the myeloid lineage and dysplastic megakaryocytes. In addition, an increased level of polyclonal plasmacytes (lambda vs kappa was 60%:40%) was found.

Hodgkin lymphoma and MDS occurring after 4 years of carboplatin/paclitaxel therapy might be contributed to the accumulation of alkylator-related DNA damage. This emphasize the need of outlining a monitoring plan regarding development of secondary leukemia and other malignant hematological proliferations should be outlined in the protocols.

Introduction: Left ventricle (LV) volumes and ejection fraction (EF) determined with two-dimensional echocardiography (2DE) and three-dimensional echocardiography (3DE) show significant differences.The aim of this study is to determine the agreement of the measurements of LV volumes and EF with 2DE and 3DE in the general adult population, with preserved LV systolic function.

Material and methods: In 52 subjects, older than 65 years, LV end-diastolic volume index (EDVi), end-systolic volume index (ESVi) and EF were measured with 2DE and 3DE according to the official recommendations, and reproducibility of both methods and their agreement were determined.

Results: Intraclass correlation coefficient for intra-observer reproducibility in the measurement of EDVi, ESVi and EF with 2DE was 0.861, 0.891 and 0.917 respectively, whereas with 3DE 0.854, 0.893 and 0.913, respectively. The difference in the measurement of EDVi and ESVi was significant (p<0.001) whereas the measurement of EF was insignificant (p=0.153). The mean difference value EDVi and ESVi determined with 2DE and 3DE was 5.6+/-5.21 and 3.01+/-2.69 ml/m2 (p<0.001), and of EF 0.306+/-1.475%. Spearman’s correlation coefficient for EDV was 0.693, for ESV 0.763 and for EF 0.97.

Conclusion: Larger LV volumes were measured in the adult population using 3DE compared to 2DE, but identical values for EF were obtained. This difference in the measured values could not be attributed to the largeness of the LV volume and EF itself.. 3DE demonstrated better intra-observer reproducibility for LV volumes and EF as a major parameter in many clinical decisions.

Aim: To evaluate the factors that influence the surgical margin state in patients undergoing cold knife conization at the University Clinic of Gynecology and Obstetrics in Skopje, Republic of Macedonia

Materials and methods: We have retrospectively analyzed the medical records of all patients that underwent a cold knife conization at our Clinic in 2015. We cross-referenced the surgical margin state with the histopathological diagnosis (LSIL, HSIL or micro-invasive/invasive cancer), menopausal status of the patients, number of pregnancies, surgeon experience, operating time and cone depth. The data was analyzed with the Chi square test, Fisher’s exact test for categorical data and Student’s T test for continuous data and univariate and multivariate logistical regressions were performed.

Results: A total of 246 medical records have neen analyzed, out of which 29 (11.79%) patients had LSIL, 194 (78.86%) had HSIL and 23 (9.34%) patients suffered micro-invasive/invasive cervical cancer. The surgical margins were positive in 78 (31.7%) of the patients. The average age of the patients was 41.13 and 35 (14.23%) of the patients were menopausal. The multivariate logistic regression identified preoperative forceps biopsy of micro-invasive SCC, HSIL or higher cone specimen histology and shorter cone depth as independent predictors of surgical margin involvement in patients undergoing cold knife conization.

Conclusion: In the current study, we have found no association between the inherent characteristics of the patient and the surgeon and the surgical margin state after a CKC. The most important predictors for positive margins were the severity of the lesion and the cone depth.

Obesity and excess weight are a pandemic phenomenon in the modern world. Childhood and adolescent obesity often ends up in obesity in adults. The costs of obesity and its consequences are staggering for any society, crippling for countries in development. Childhood obesity is also widespread in Macedonia. Metabolic syndrome, dyslipidemia and carbohydrate intolerance are found in significant numbers. Parents and grandparents are often obese. Some of the children are either dysmorphic, or slightly retarded. We have already described patients with Prader-Willi syndrome, Bardet-Biedl syndrome or WAGR syndrome. A genetic screening for mutations in monogenic obesity in children with early, rapid-onset or severe obesity, severe hyperphagia, hypogonadism, intestinal dysfunction, hypopigmentation of hair and skin, postprandial hypoglycaemia, diabetes insipidus, abnormal leptin level and coexistence of lean and obese siblings in the family discovers many genetic forms of obesity. There are about 30 monogenic forms of obesity. In addition, obesity is different in ethnic groups, and the types of monogenic obesity differ. In brief, an increasing number of genes and genetic mechanisms in children continue to be discovered. This sheds new light on the molecular mechanisms of obesity and potentially gives a target for new forms of treatment.

Background: Ultrasound guided rectus sheath block can block the ventral rami of the 7th to 12th thoracolumbar nerves by injection of local anesthetic into the space between the rectus muscle and posterior rectus sheath. The aim of this randomized double-blind study was to evaluate the analgesic effect of the bilateral ultrasound guided rectus sheath block as supplement of general anesthesia on patents undergoing elective umbilical hernia repair.

Methods: After the hospital ethics committee approval, 60 (ASA I–II) adult patients scheduled for umbilical hernia repair were included in this study. The group I (n=30) patents received only general anesthesia. In the group II (n = 30) patents after induction of general anesthesia received a bilateral ultrasound guided rectus sheath block with 40 ml of 0.25% bupivacaine. In this study we assessed demographic and clinical characteristics, pain score - VAS at rest at 2, 4, 6, 12 and 24 hours after operation and total analgesic consumption of morphine dose over 24-hours.

Results: There were statistically significant differences in VAS scores between the groups I and II at all postoperative time points - 2hr, 4 hr, 6 hr, 12 hr and 24 hr. (P < 0.00001). The cumulative 24 hours morphine consumption after the operation was significantly lower in the group II (mean = 3.73 ± 1. 41) than the group I (mean = 8.76 ± 2.41). This difference was statistically significant (p = 0.00076).

Conclusion: The ultrasound guided rectus sheath block used for umbilical hernia repair could reduce postoperative pain scores and the amount of morphine consumption in 24 hours postoperative period.

Telomerase Reverse Transcriptase (TERT) is the main catalytic sub-unit of telomerase, a reverse transcriptase enzyme. Telomerase expression is regulated at many levels, with numerous studies suggesting that up-regulation of human TERT gene (hTERT) at transcriptional level results in immortal cell phenotype associated with cancer. The aim of this study is to determine the correlation between hTERT expression and different cervical precursor lesions, as well as with cervical cancer in patients with confirmed Human papillomavirus (HPV) infection.

The study included molecular analyzes on cervical samples from 214 women and matched Papanicolaou (Pap) test results. HPV detection and genotyping was performed by polymerase chain reaction (PCR) and genotyping. Quantitative real-time PCR (qRT-PCR) was performed using TaqMan probes and were calculated relative to the reference gene.

Results showed significantly increased hTERT mRNA expression levels in high-grade and low-grade lesions compared to normal control samples (p<0.01) associated with 6.31 fold higher risk for developing ASC-US and 9.20 for LSIL. Strong correlation between HPV infection and hTERT expression in the high-grade lesions and cervical cancer was also observed. hTERT relative expression values showed 98% specificity and 100 % sensitivity as indicator of cervical lesions particularly for the ACS-H, HSIL and cervical cancer. In conclusion, hTERT expression correlate with the cytological grade of the cervical lesions and HPV infection and has a potential to be used as a diagnostic and prognostic marker.

We report a 10 days old newborn with brachycephaly, midfacial hypoplasia, syndactyly and broad distal phalanx of thumb and big toe. At the 20th gestational weeks an enlargement of the left cerebral ventricle and malformation of the fingers of the hands and toes were noticed on a regular ultrasound examination. The aforementioned malformations were observed at birth and at the age of 11 months. The large fontal was closed; the small one was palpable at the tip of the finger. Brachycephaly was evident with high full forehead, flat occiput, and irregular craniosynostosis especially at the coronal suture. Cutaneous syndactyly was present at both hands (fingers II-V), with almost complete fusion of the second, third and fourth fingers. Distal phalanges of the thumbs were broad as well as distal hallux. There was cutaneous syndactyly of the feet. Mental development at the age of 11 months was normal.

Apert syndrome is a sporadic disorder. Rarely, inheritance is autosomal dominant. Appropriate management includes surgical treatment of the syndactylies, follow up of the eventual airway compromise and hearing difficulties. This is a report of a patient identified as a newborn.

Myelodysplastic syndrome (MDS) is a diverse group of clonal hematologic neoplasms. The only curative treatment for MDS is allogeneic stem cell transplantation (SCT). Epigenetic changes play an important role in the pathogenesis of MDS and treatment with DNA methyl transferase inhibitors, Azacitidine, significantly prolong the survival of high-risk MDS patients. Here we report a case of a 58-year-old male presented with pancytopenia, macrocytosis, and hyperplastic bone marrow with 3-lineage dysplasia with ~14% of myeloid blasts. Cytogenetic studies with G banding showed normal karyotype. Multiplex ligation-dependent probe amplification (MLPA) screening for most predictive cytogenetic abnormalities of MDS showed loss of the Y chromosome. Those findings later were confirmed with Quantitative Fluorescent (QF)-PCR and specific MLPA for Y chromosome, showing loss of the Y chromosome in >80% of cells. He was diagnosed with MDS-RAEB2 according to 2008 WHO classification and stratified into high risk group (IPSS score 5). Unrelated allogeneic SCT was planed and bridging treatment with Azacitidine at a dose of 75mg/m2/daily subcutaneously for 7 days every 28 days was initiated. Hematologic improvements, according to the International Working Group 2006 criteria, were observed after 4 cycles of Azacitidine treatment. After 6 cycles, complete hematological remission was achieved. Interestingly, molecular analysis performed after the 8th cycle showed normal presence of Y chromosome indicating a cytogenetic remission, molecularly confirmed. Maintenance treatment with Azacitidine was assigned, and the scheduled SCT was postponed. Experience from our case showed that the loss of the Y chromosome was related to the disease onset, and indicated that Azacitidine might be consider as effective treatment for MDS cases associated with good cytogenetic

The sixth SEE meeting on rare diseases (RDs) was held in MASA the November 10th, 2017. A block of lectures on rare renal diseases started the meeting: nephrotic syndrome, Alport syndrome, atypical HUS, hypophosphatemic rickets, CAKUT were presented in all complexities. Their molecular and genetic mechanisms were discussed. The discovery of a dozen of newly genes in CAKUT, congenital overgrowth, spodilocostal dysplasia, precocious puberty has been done with collaboration of Macedonian and foreign researchers. NGS and other molecular methods in diagnosis of RDs have been presented by several presenters. The mitochondrial diseases, the novelties and importance of early discovery were comprehensively presented and discussed. The genetics and treatment of persistent neonatal hypoglcaemia were of special interest. Dysmorphic syndromes (Klippel Feil) were also presented. A session of oral electronic posters was reach and inspiring. Several lectures dealt with mucopolisaccaridoses, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatement (ERT), its availability, effects (or the lack of it on the brain), intratecal ERT administration and further prospects of eventual gene treatment were comprehensively exposed and discussed. The main purposes of this traditional meeting are hopefully fulfilled: increased number of patients with RDs treated and cutting edge presentations got.