Biologic Therapy in Inflammatory Bowel Disease - Results from a Single Tertiary Care Center in North Macedonia.

Medical therapies used for Inflammatory Bowel Disease (IBD) include conventional (e.g. 5-aminosalicylates, steroids, immunomodulators) and biologic (e.g. inhibitors of tumor necrosis factor - alpha, integrin inhibitors, interleukin inhibitors) medications. Biologics, due to their high cost, were unfortunately not covered by the public health insurance system in North Macedonia until 2019 and, therefore, not widely utilized for our IBD patients. In 2019, the University Clinic of Gastroenterology and Hepatology in Skopje developed a biologic therapy supply, provided by the National Health Insurance Fund, making this therapy available for a larger number of patients. This report presents the initial results of our prospective, single tertiary-care center study on the effects of biologic therapy in patients with IBD in North Macedonia. The study is focused on the evaluation of clinical outcomes after anti-tumor necrosis factor alpha (anti TNF-alpha) therapy in IBD patients with prior inadequate response to conventional medications.

Prevalence and Predictors of Impaired Glucose Tolerance and Diabetes Mellitus Type 2 in Patients with Polycystic Ovary Syndrome.

Aim: To estimate the prevalence of impaired glucose tolerance (IGT) and diabetes mellitus type 2 (DMT2), as well as the predictors for glucose abnormalities in women with polycystic ovary syndrome (PCOS). Material and methods: A cross-sectional study with 80 consecutive patients with newly diagnosed PCOS who underwent the standard 75g oral glucose tolerance test (OGTT) and the measurement of sex steroid hormone and lipid profile. Results: According to the results from the OGTT, 63% had a normal test (NT), 23% had IGT, and 9% had DMT2. The NT group was younger with lower BMI than IGT and DMT2 groups (25.1 ± 7.3, 31.5 ± 6.5, 37.4 ± 4.0 years, and 29.1 ± 8.3 kg/m2, 31.7 ± 4.6 kg/m2, and 34.5 ± 5.6 kg/m2, respectively). The testosterone levels were highest in the group with a normal test (2.7 ± 0.8 nmol/l) and lowest in the DMT2 group (1.9 ± 0.8 nmol/L), with statistical significance. The sex hormone bounding globulin (SHBG) levels were low in all three groups, with statistically significant differences between NG and IGT, and the NT and DMT2 groups. The multivariate linear regression model identified age, BMI, SHBG and testosterone as major independent predictors for abnormal glucose metabolism. Conclusion: It seems that the prevalence of IGT and DMT2 among PCOS women in our country is not as high as in Western countries. Age, BMI, and SHBG increase the risk for the development of IGT and DMT2. Thus, close monitoring of older, obese women with low SHBG is needed because of the higher risk for the development of IGT and DMT2 in such patients.

Remission of Late-Onset Post-Liver Transplantation Non-Hodgkin Lymphoma.

We describe the clinical course of a patient who developed high-grade lymphoma during immunosuppression treatment with cyclosporine A, following liver transplantation. After anti-neoplastic polychemotherapy treatment, the remission of lymphoma was confirmed and maintained for over four years. The patient, a 27 year old female had liver transplantation at the age of 17, due to acute liver failure, caused by non-diagnosed Wilson disease. Nearly seven years post-transplantation, the patient was diagnosed with non-Hodgkin B-cell lymphoma (NHBCL), potentially induced by Cephalosporin A therapy. After the treatment with rituximab and CHOP therapy (r-CHOP protocol), remission was determined using computer tomography. Remission is maintained to date. A review of reported cases of post-transplant lymphoproliferative disorders (PTLDs) in liver transplanted (LT) patients showed that the onset of PTLDs is the highest in the first year after transplantation. In addition, remission rates of NHBCL in LT patients are not much elaborated in the literature. It is our opinion that the presented case is rare, both from the aspect of timeline of occurrence of the PTLD and the achieved remission, using r-CHOP protocol.

Comparison of Argon Plasma Coagulation and Injection Therapy with Adrenalin and Polidocanol in the Management of Bleeding Angiodysplasia in Upper Gastrointestinal Tract.

INTRODUCTION: The term angiodysplasia (AD) refers to acquired malformation of the blood vessels (communications between veins and capillaries), frequently found within the gastrointestinal mucosa and submucosa. AD of stomach and duodenum are cause of upper gastrointestinal bleeding in 4%-7% of patients. The means of treatment are usually endoscopic, including argon plasma coagulation (APC), electrocoagulation, mechanical hemostasis by clippsing, laser photo-coagulation and injection therapy. AIM: To compare the success rate, and adverse events (ulcer lesions, perforations) of APC and injection therapy in the treatment of bleeding angiodysplasia in the upper gastrointestinal tract (GIT). MATERIAL AND METHODS: In a prospective study including 50 patients with bleeding angiodysplasia of the upper GIT, 35 patients were treated with APC, and remaining 15 with injection therapy using adrenaline and 1.5% solution of polidocanol. Follow-up period was 6 months. RESULTS: A total of 50 patients aged 18 to 64 years, 64% male and 36% female, have been treated during 2 years period. The rate of recurrent bleeding and side effects was significantly higher in the adrenaline group (p <0.01). Blood transfusion was required in 68% during the first hospital admission. Angiodysplasia of the stomach was present in 66%, versus 34% in duodenum. CONCLUSION: Endoscopy is "gold standard" for diagnosis and treatment of AD in the gastrointestinal tract. The study unveiled APC as more effective treatment option with lower degree of complications and adverse events in comparison to injection therapy in patients with bleeding AD.

Correlation Between Microvessel Density and Morphological Features in Skin Squamous Cell Carcinoma.

INTRODUCTION: Abnormal angiogenesis is described in tumor growth and it facilitates its metastatic spread. Tumors with high angiogenic activity belong to the category of aggressive tumors with poor prognosis for patients. The aim of this study was to determine the blood vessels density (BVD), i.e. neovascularization at the tumor invasive front in skin squamous cell carcinoma (SCC) in order to determine its possible role in the tumor progression, and to correlate it to the blood vessels density of healthy skin and with the prognostic parameters of the TNM classification: T status, depth of tumor invasion (DI) and tumor histological grade (G), which were also correlated between each other. MATERIAL AND METHODS: The material consisted of surgical specimens obtained from 30 patients with skin SCC, who underwent surgery. Tissue samples were routinely processed by standard paraffin technique stained by Hematoxilin-Eosin and immunohistochemically with antibodies against smooth muscle actin (SMA) and CD34. The BVD in the invasive front of the neoplasms was correlated to the healthy skin, tumor status (pT), depth of invasion and grade of histological differentiation (pG). RESULTS: The histological analysis has shown a high statistical difference in the density of blood vessels in SCC compared to the healthy skin and statistical difference in BVD in neoplasms with different depth of invasion and different grade of differentiation. The density of neovascularzation increased with the deeper invasion and the worse differentiation. CONCLUSION: The increased vascularization at the invasive front of SCC with deeper invasion and worse differentiation has pointed out to its possible role in neoplasm progression.

Factors That Influence the Virological Response in Patients with Chronic Hepatitis C Treated with Pegylated Interferon and Ribavirin.

INTRODUCTION: The success of the antiviral treatment in patients with chronic hepatitis C depends on the factors related to the virus and the host. The aim of the study is the analysis of the antiviral therapy which is a combination of pegylated interferon and ribavirin, considering various factors that will identify the predictors of the sustained virological response. MATERIAL AND METHODS: This retrospective study included 226 patients, divided in two groups. Patients with sustained virological response and patients without sustained virological response were compared in terms of the following factors: genotype, viral load, gender, age, inflammatory and fibrotic changes in the liver, metabolic abnormalities, obesity and fatty liver. RESULTS: The rate of the sustained virological response is 83.6%, more frequently in patients with genotype 3, with evidenced statistical significance (90.54%). The factors that significantly contribute to sustained virological response are related to the age (p = 0.0001), genotype (p = 0.002), mode of transmission (p = 0.005), inflammatory changes in the liver (p = 0.028), body mass index (p = 0.022) and insulin resistance (p = 0.039). The high rate of sustained virological response is related to the younger age of the patients which indirectly means short Hepatitis C Virus infection duration, absence of advanced liver disease and lack of significant co-morbid conditions. Single confirmed independent predictors of sustained virological response are the age (OR 0.928, p = 0.0001) and genotype (OR 3.134, p = 0.005). CONCLUSIONS: Factors that are related to the virological response are the age, genotype, mode of transmission, inflammatory changes in the liver, body mass index and insulin resistance, but still, independent predictors of sustained virologic response are the age and the genotype.

Evaluation of the Role of ABCB1gene Polymorphic Variants on Psychiatric Disorders Predisposition in Macedonian Population.

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.

Maternal Lipids May Predict Fetal Growth in Type 2 Diabetes Mellitus and Gestational Diabetes Mellitus Pregnancies.

AIM: During diabetic pregnancy, complex metabolic changes occur in the lipid profile. The aim of the study was to determine the predictive values of maternal serum lipid levels on large-for-gestational age newborns during the third trimester in pregnancies of women with type 2 diabetes mellitus (DM2) and gestational diabetes mellitus (GDM). MATERIAL AND METHODS: Data of forty three pregnancies of women with DM2 and two hundred women with GDM were analyzed. The analysis encompassed the following parameters: age, body mass index (BMI), lipid parameters, HbA1c in first, second and third trimester of pregnancy, preeclampsia and baby birth weight. RESULTS: DM2 and GDM groups showed statistically significant differences in the following variables: total lipids, triglycerides, total cholesterol, BMI, age, baby birth weight, incidence of SGA and preterm delivery (9.4 ± 2.3 vs. 11.0 ± 2.3 mmol/L, 2.4 ± 1.4 vs. 3.4 ± 1.6 mmol/L, 5.5 ± 1.2 vs. 6.4 ± 1.4 mmol/L, 30.6 ± 5.4 vs. 26.9 ± 5.2 kg/m2, 34 ± 7.8 vs. 31.5 ± 5.6 years, 3183 ± 972 vs. 3533 ± 699 g., 20% vs. 7.5%, 27.9 vs. 14%, respectively, p < 0.05). Linear multiple regression analysis demonstrated that triglycerides, LDL-C and total cholesterol were independent predictors of LGA (p < 0.05). CONCLUSION: Triglycerides and LDL-C in the third trimester of pregnancy are independent predictors for fetal macrosomia in DM2 and GDM pregnancies. Thus, the maternal serum triglycerides and LDL-C levels determined in the maternal blood taken in the third trimester of pregnancy may indentify women who will give birth to LGA newborns.

Contribution of Academician Momir Polenakovic to the Development of Nephrology in the Republic of Macedonia.

Academician Momir H. Polenakovic, MD, Ph.D. is an outstanding researcher, educator and scientist, one of the founders of the nephrology in the Republic of Macedonia. With more than 500 published papers in national and international journals, of which more than 189 are on the PubMed, he is one of the most fruitful medical worker in our country. With his participation in national and international congresses he has contributed to the transfer of the world nephrology in Macedonia, as well as, to the dissemination of the reputation of the Macedonian nephrology and science in the world. He has educated a number of specialists in internal medicine and subspecialists in nephrology. He has introduced new tests and methods in diagnosis and treatment of renal disease, which was a basis for his research and publication. Analyzing the life opus of Academician Momir Polenakovic we can say that he has dedicated his life and work to the research, diagnosis and treatment of kidney patients.

Effect of lipid parameters on foetal growth in gestational diabetes mellitus pregnancies.

INTRODUCTION: Women with gestational diabetes mellitus (GDM) often deliver newborns large for their gestational age (LGA). The aim of the study was to evaluate the effect of lipid parameters in the second half of pregnancy on foetal growth in GDM pregnancies. MATERIAL AND METHODS: In two hundred consecutive women with GDM the age, body mass index before pregnancy, body mass index before delivery, gestational week of GDM diagnosis, lipid parameters after 24 weeks of pregnancy, fasting glycaemia, HbA1c in the second and third trimester of pregnancy, gestational age at delivery, mode of delivery, and baby birth weight were analyzed. RESULTS: Of the 200 GDM pregnancies, 50 (25%) women delivered LGA newborns, 135 (67.5%) women delivered newborns appropriate for gestational age (AGA), and 15 (7.5%) women delivered newborns small for gestational age (SGA). Maternal triglyceride levels and HbA1c in the second trimester were higher, and HDL-C was significantly lower, in the LGA group than in the AGA group (3.8 ± 1.8 vs. 3.1 ± 1.1 mmol/L, 6.1 ± 1.1 vs. 5.5 ± 0.8%, and 1.3 ± 0.4 vs. 1.6 ± 0.4 mmol/L, p < 0.05). Also, maternal triglyceride levels and HbA1c in the second trimester were significantly higher in the SGA group than in the AGA group (3.8 ± 1.9 vs. 3.1 ± 1.1 mmol/L and 6.8 ± 0.8 vs. 5.5 ± 0.8%, p < 0.05). Maternal triglycerides were independent predictors for delivering LGA newborns in GDM women. CONCLUSION: In GDM pregnancies, maternal triglycerides in the second half of pregnancy may indentify women who will deliver LGA newborns. Thus, with good regulation of lipid profile, we can avoid macrosomia from GDM pregnancies.

Pulp stones can help in detection of calculus in the kidneys and/or in the bile--fact or fiction?

BACKGROUND: Pulp stones or denticles are frequently found in the dental pulp; there is, however, scarce evidence about this phenomenon. Regardless of the obvious endodontic problem of inhibiting access to the canals and their further treatment, they have not been given great importance. The latest experiences of scientific and practical research, including examinations of dental calcifications and their association with calcifications/calculi in the organism, have not been included in the literature. AIM: To investigate the possible association between dental calcifications and calculi in the kidney and/or bile. METHODS: The study group included 200 patients diagnosed with pulptits chronica. All patients underwent dental and systematic examinations. Dental examination included x-rays, which detected the presence of calcifications in the dental pulps. Histopathological analysis of extirpated pulps was also made. Clinical examination comprised ultrasound that detected calculi. RESULTS: The results of the histopathological analysis of the extirpated pulps from the group of patients without denticles, but with calculi in their kidneys, bile and/or other organs, showed a regular presence of "sand" in large quantities in dental pulps. The presence of "sand" was depicted as presence of dystrophic calcifications. There was a percentage difference between the two groups: calculi in the organism (kidney and bile) and denticles--70% and calculi in the organism without denticles--30%. The Student's t-test showed a statistically significant difference for P=0.0000. This study defines the association between the calculi in the organism and the presence of dental calcifications, as well as their possible bacterial association.

Short and medium-term therapeutic effects of pneumatic dilatation for achalasia: a 15-year tertiary centre experience.

BACKGROUND: Pneumatic dilatation (PD) is a commonly used endoscopic technique to weaken the lower oesophageal sphincter in patients with achalasia. It is considered as the most effective non-surgical therapeutic option for achalasia, but further data on the overall effectiveness and rate of complications is needed. AIMS: To determine the short- and medium-term therapeutic effectiveness of PD for achalasia and estimate the cumulative probability of remaining in remission over one year after a single treatment. The study also aimed to identify clinical predictors of therapeutic outcome achieved by PD and assess for PD-related complications. METHODS: A total of 26 patients with achalasia who were treated with PD between 1997 and 2011 at a tertiary care centre were followed for up to 1 year. Data related to demographics, clinical symptoms and PD-related complications were collected. Short (1 and 3 months) and medium (1 year) term therapeutic effectiveness of PD was assessed with the use of the Eckhart scoring system for evaluation of clinical symptoms. The probability of staying in remission one year after a single PD was determined by using a Kaplan-Meier estimator. In order to prevent major complications, limited maximal pressure of no more than 11 PSI was used during PD. RESULTS: Twenty-six patients with symptomatic achalasia (mean age 47.1±18.5 years, 82% males) underwent 44 PD procedures (mean 1.7/patient). Thirteen patients (50%) had a single PD, 10 patients (38%) had two dilatations, and 3 patients (12%) had three or more dilatations over one year. Nineteen out of the 26 patients (73%) were in remission at one and three months each, following the initial PD. Seventeen out of the 26 patients (65%) remained in remission after one year. A total of 5 patients (19%) were referred for surgery over 1 year due to lack of success of the endoscopic treatment. The mean Eckhart symptom scores, at 1 month (3.2±1.2), 3 months (3.5±1.3) and 1 year (1.8±0.6) after the initial PD, were significantly lower when compared to the mean initial Eckhart symptom score (9.7±4.4, P<0.05). Using a symptom score above 3 as a cutoff value for treatment failure, the probability of remaining in remission (relapse-free) after a single dilatation was 35% at one year. Patient gender appeared as an important treatment outcome predictor. Namely, 4 of the 5 patients (80%) with PD treatment failure were males. There were no major complications from the 44 PDs. One patient (3.8%) developed significant heartburn. The majority of PDs (33/44, 75%) were followed with minor, subclinical oesophageal mucosal bleeding from the dilation site as seen on post-dilation oesophagoscopy. CONCLUSION: Pneumatic dilatation is an effective short and medium term treatment option for the majority of patients with achalasia without significant related complications. Further studies are warranted to assess the possible role of limited maximal pressure use of no more than 11 PSI during PD in preventing oesophageal perforations.

Total parenteral nutrition in treatment of patients with inflammatory bowel disease.

Patients with Inflammatory Bowel Disease (IBD) are exposed to nutritional risk. Malnutrition in Crohn's Disease (CD) and to a somewhat lesser in Ulcerative Colitis (UC) is very frequent. Depending on the severity of the disease, weight loss has been reported in 65% to 76% of those with CD and in 18% to 62% of those with UC. The role of Total Parenteral Nutrition (TPN) is essential in very severe cases where enteral nutrition is not tolerated or standard drug therapy is not effective. Nutritional therapy is important for the correction of nutritional deficiency, especially in cases where elective surgical treatment is required. This study examined the effects of preoperative TPN administration in patients with IBD. Since 1990, 29 pts, 13 (44.8%) male and 16 (55.2%) female with severe IBD; 16 (55.2%) with UC and 13 (44.8%) with CD were treated with TPN in our department in the preoperative period. Evaluation of this group was compared with a group which was not treated with TPN preoperatively: 61 pts, 34 (55.7%) male, 27 (44.3%) female; 50 (82%) with CD, 11 (18%) with UC. Evaluation of this group was compared with the group of patients who were subjected to surgical procedure without prior TPN administration, in total a number of 61, of whom 34 (55.7%) were male and 27 (44.3%) female patients. In this group, the number of patients with CD and UC was 50 (82%) and 11(18%) respectively. During the course of the study, the following parameters were examined: Body mass index (BMI), Disease Activity Index (CDAI/AI), laboratory parameters and the number of hospital days. The parameters were analysed before the surgical intervention, and one week and six months after the surgical intervention. The duration of the application of TPN was 12.5 +/- 5 days. The analysis of these parameters has shown that there is no statistically significant difference in the number of hospital days in both groups, which was 18.9 +/- 8.9 in the intervention group and 18.9 +/- 6.5 days in the control group, p = 0.9808, but analysis of the Disease Activity (CDAI/AI) has shown that patients who were on TPN were in a more severe stage of the disease. In the TPN treated group of patients none, 0 pts (0%), of the pts had no Index of Activity, 1.7 pts (24.1%) had Index 2 and 22 (75.9%) had Index 3. In the other group 3 pts (4.9%) had Index 1; 39 pts (63.9%) had Index 2 and 19 pts (31.2%) had Index of Activity 3. During the monitoring period of six months the activity of the disease was lower in patients treated with TPN. The BMI in the group of patients treated with TPN was lower in both sexes. It was lower than 18.4 in 7 males and 5 females; between 18.4 and 19.9 in 2 males and 4 females; between 19.9 and 25 in 3 males and 6 females; between 25 and 19.9 in 1 male and 1 female; there were no pts with BMI higher than 29.9. In the control non-TPN group, 5 males and 3 females had BMI < or = 18.4; 2 males and 5 females had between 18.4 and 19.9; 23 males and 13 females had between 19.9 and 25; 3 males and 5 females had between 25 and 29.9 and 1 male and 1 female had BMI higher than 29.9. The BMI had an increasing trend in the postoperative period in both groups. The laboratory parameters that we examined were: number of erythrocytes and sedimentation, number of leukocytes, haemoglobin levels, total number of lymphocytes, albumin level, C-reactive protein, orosomucoid, electrolytes; sodium, potassium, calcium and serum iron, the enzymes (AP, AST and ALT); level of bilirubin and urea and creatinine. The results were analysed using the Tukey honest significant difference test (HSD), ANOVA and Student t-test. Statistically significant differences were observed between preoperative and postoperative period in both groups. The intergroup comparison showed significant differences in the level of albumin, AST, ALT and bilirubin.

Henoch-Schönlein purpura in an adult patient: extragastric, cutaneous manifestation of helicobacter pylori infection.

Today there is evidence that Helicobacter pylori has a critical role in different extragastric diseases. The discovery of a number of other new Helicobacter species has stimulated research into different extragastric diseases, in which an infectious hypothesis is plausible. Enterohepatic Helicobacter species have been hypothesized to play a role in different disorders including the extragastric manifestations of H. pylori infection. The authors present a case of Henoch-Schönlein purpura in an adult patient with Helicobacter pylori infection and disease regression after triple anti-Helicobacter eradication therapy. The patient was monitored, over a follow-up period of almost 9 years after eradication of Helicobacter pylori presence, by clinical examination as well as serological findings. There was no disease reccurence during the follow-up period and no markers of Helicobacter pylori reinfection. Since disease recurrence occurs throughout weeks to months, the authors conclude that Henoch-Schonlein purpura is a possible extragastric, cutaneous manifestation of Helicobacter pylori infection.

Contrast-enhanced power doppler sonography in detection and differentiation of focal liver lesions.

The aim of the study is to evaluate the contrast enhanced power doppler technique as a method to detect and differentiate vascular patterns of focal liver lesions. Fourty-nine patients with focal liver lesions were included in the study, twenty-nine of them with malignant liver lesions (9 HCC, 20 metastatic), twenty patients with benign lesions (12 haemangiomas, 5 focal nodular hyperplasia, 3 focal steatosis). In all patients classic B-mode and power doppler sonography was performed prior to administration of the contrast medium Levovist (300 mg/ml) and a power doppler examination subsequent to medium administration. Contrast administration led to lowering the number of "no-flow" lesions from 19 to 11. Postcontrast scan analysis revealed markedly enhanced flow in 15 cases in comparison to only 4 in pre-contrast examinations. The pre-contrast power doppler showed central flow in 7, and peripheral in 26 focal liver lesions. On the other hand, the postcontrast study revealed a central flow in 14, and peripheral in 34 focal liver lesions. Statistical significance between pre- and post-contrast power doppler detection of vascularization existed in malignant focal liver lesions and haemangiomas. The same pre- and post-contrast evaluation proved to be statistically non-significant in the focal nodular hyperplasia and focal steatosis groups. Administration of contrast medium enables a better visualization of intratumor blood vessels in focal liver lesions. This, in combination with the power doppler technique, brings such scans close to angiographic findings.