Effects of a compound from the group of substituted thiadiazines with hypothermia inducing properties on brain metabolism in rats, a study in vivo and in vitro.

The aim of the present study was to examine how administration of a compound of 1,3,4- thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17) with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/kg and 760 mg/kg). Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 µM, 30 min). Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5°C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism.

Reproduction, aging and mortality rate in social subterranean mole voles (Ellobius talpinus Pall.).

Eusocial subterranean rodents of the Bathyergidae family have enormous longevity. The long lifespan of these species is associated with negligible senescence, that is, an absence of the signs of age-related deterioration in physical condition. The question arises as to whether these features are unique to eusocial Bathyergids or typical of other social subterranean rodents as well. In the present study, we analysed data from observations of a social subterranean Microtinae rodent, the northern mole vole (Ellobius talpinus Pall.), which, like mole-rats, has reproductive skew. Among the individuals captured in the wild and maintained in captivity, females that reproduced lived significantly longer than non-breeding females. We did not find any changes in muscle strength with age in any of the demographic groups studied. Faecal glucocorticoid concentrations before death were significantly higher in non-breeding females than in breeding females and males. Increased adrenocortical activity may be one mechanism responsible for the decreased lifespan of non-reproducing individuals of social subterranean rodents. We conclude that the patterns of aging, although different in some respects, are generally common for social subterranean rodents of different taxonomic groups.

Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers, Ellobius talpinus.

Inhalation of air-dispersed sub-micrometre and nano-sized particles presents a risk factor for animal and human health. Here, we show that nasal aerodynamics plays a pivotal role in the protection of the subterranean mole vole Ellobius talpinus from an increased exposure to nano-aerosols. Quantitative simulation of particle flow has shown that their deposition on the total surface of the nasal cavity is higher in the mole vole than in a terrestrial rodent Mus musculus (mouse), but lower on the olfactory epithelium. In agreement with simulation results, we found a reduced accumulation of manganese in olfactory bulbs of mole voles in comparison with mice after the inhalation of nano-sized MnCl2 aerosols. We ruled out the possibility that this reduction is owing to a lower transportation from epithelium to brain in the mole vole as intranasal instillations of MnCl2 solution and hydrated nanoparticles of manganese oxide MnO · (H2O)x revealed similar uptake rates for both species. Together, we conclude that nasal geometry contributes to the protection of brain and lung from accumulation of air-dispersed particles in mole voles.

CAG Repeat Number in the Androgen Receptor Gene and Prostate Cancer.

Prostate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 ± 2.65, in controls 22.28 ± 2.86 (p = 0.009) and in BPH patients 22.1 ± 2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men.

Does prostate specific antigen density correlates with aggressiveness of the prostate cancer?

BACKGROUND: As already documented, a high prostate specific antigen in men with normal size of prostate gland is more likely to be associated with an aggressive cancer as compared to others with the same prostate specific antigen and a large gland size. In this retrospective study we tested the association between Prostate Specific Antigen Density (PSAD) and tumor aggressiveness in patients with clinically localized Prostate Cancer (PCa) surgically treated by radical prostatectomy. METHODS: We evaluated data from patients records in a cohort of 72 patients who underwent radical prostatectomy between January 2000 and June 2007. PSAD was calculated as ratio between the preoperative total prostatic specific antigen (PSA) in nanograms per milliliter with the prostate weight (PW) of prostatectomized specimen in grams or prostate volume measured with ultrasound (US). The patients were stratified into four PSAD categories: 0.1-0.15, 0.16- 0.20, 0.21-0.5 and greater than 0.51 ng/ml/gr. Parameters that were included into analysis were: PSA, measurement of the prostate volume by ultrasound (preoperatively) and prostate weight, pathological tumor stage, Gleason sum, Gleason grade, metastatic lymph nodes, seminal vesicle involvement and organ confine disease (postoperatively). Worsening of the clinicopathological properties was defined as aggressiveness. RESULTS: There was a significant correlation between US-PSAD and PW-PSAD (p<0.001). In US-PSAD categories the statistic tests found significant correlation with the primary tumor (R=0.303, p<0.01), metastatic lymph nodes (R=0.331, p<0.01), and the organ confine disease (R=0.296, p<0.05). The PW-PSAD categories correlated significantly with the pathologic findings from other parameters. Hence, a statistically significant correlation was found with Gleason sum (R=0.246, p<0.05), Gleason grade (R=0.234, p<0.05), primary tumor (R=0.285, p<0.05), metastatic lymph node (R=0.287, p<0.05) and organ confine disease (R=0.303, p<0.01). CONCLUSIONS: Prostate specific antigen density measurement is useful tool for the assessment of the degree of aggressiveness in clinically localized prostate cancer, and further investigation regarding its possible use as a prediction marker is justified.

Lower urinary tract reconstruction following a cystectomy: experience and results in 20 patients using the "Studer" orthotopic ileal bladder substitution.

INTRODUCTION AND OBJECTIVE: To analyze the outcome, complications and functional results in patients undergoing bladder substitution with the Studer continent urinary pouch. MATERIALS AND METHODS: At our Clinic, between January 2005 and December 2006, 20 male patients underwent a radical cystoprostatectomy followed by the Studer orthotopic bladder substitution. RESULTS: The transitional cell carcinoma was found to be the most frequent histopathological type. The distribution by grade and pathological stage showed all were high grade infiltrating tumors localized in the bladder. We observed 3 patients with neobladder-unrelated complications: one patient with a wound infection and 2 patients with a prolonged ileus. CONCLUSION: In conclusion, our results with urinary diversion are promising in patients recquiring a radical cystoprostatectomy. We believe that the Studer's orthotopic neobladder is an excellent alternative for patients suffering a radical cystectomy and offers a sufficient protection of the upper urinary tract with a low complication rate, good voiding function and continence (Tab. 1, Ref. 25). Full Text (Free, PDF) www.bmj.sk.

Isolated malignant peripheral nerve sheath tumor of kidney capsule.

The occurrence of an isolated malignant peripheral nerve sheath tumor (MPNST) of the kidney capsule is extremely rare and its presence may only be expressed by an insidious onset of non-specific and misleading symptoms with a predominance of lower back pain. A computer tomography (CT) scan (as the imaging procedure of choice) will demonstrate the tumor location and its relation to the surrounding structures. Tumor excision in toto is considered the treatment of choice, but it can be hazardous, especially if the tumor is adhering to the surrounding structures. Severe bleeding complications due to the damage of venous structures have to be considered, and establishing hemostasis may pose considerable difficulties. Therefore surgery should be attempted with full precautions and the patient must receive preoperative counseling. If malignancy can safely be excluded, a laparoscopic excision should be considered as an alternative treatment as recurrence is unlikely. Definition of the originating nerve might not always be possible, and a minor degree of neurological impairment has therefore to be anticipated. A case of an isolated MPNST of the kidney capsule without neurofibromatosis is presented. The tumor was located in the fatty and fibrous capsule. It was surgically removed. The patient was further managed with radiotherapy and chemotherapy. An MPNST in such a location is very unusual.

De novo malignancies after renal transplantation--a single-center experience in the Balkans.

The occurrence of malignancies is a well-known serious complication after organ transplantation. Despite the fact that many factors may be involved, the pathogenesis is still unclear. The aim of the present study was to examine the incidence and clinical characteristics of de novo malignancies that arise after renal transplantation over a 13-year experience in a single center in the Balkan Peninsula. During this period, 185 renal transplantations (139 living related and 46 cadaveric) were followed in our department. Overall, 19 malignancies (9.78%) were observed in 15 patients (7.8%). The mean age of these patients was 45 years (range, 21-53 years). Ten patients (55%) developed skin cancers: 8 squamous and 2 basal cell. Kaposi's sarcomas were found in 3 patients (16.6%, 1 visceral form). We also detected 1 breast cancer, 1 seminoma, 1 colon cancer, 1 urogenital-transitional cell-like cancer, 1 renal cell carcinoma, 1 plasmacytoma, and 1 retroperitoneal sarcoma after an ABO incompatible transplantation. All cancers were de novo malignancies that presented at a mean time of 21 months (range, 2-52 months) after surgery. In conclusion, the incidence of malignancy in the present series was similar to that reported elsewhere. The predominance of skin cancers was understandable bearing in mind the sunshine. The appearance of skin malignancies in our group of patients was earlier, more severe, and multiple sites. No cases of posttransplantation lymphoproliferative disorders were observed. Careful clinical examination and long-term screening protocols are needed for early detection and treatment of this life-threatening complication among the transplant population.

Epidemiology of severe poisonings caused by ingestion of caustic substances.

Acute poisoning with corrosive substances can cause severe chemical injuries of the upper part of the gastrointestinal tract. They are most frequently localized in the oesophagus and stomach. If the patient survives the acute phase of poisoning, the regenerative response can result in oesophageal and/or gastric stenosis and a higher risk of oesophageal and stomach cancer. Seven-years clinical material was evaluated for this study (2000-2006) with a total number of 517 patients, hospitalized and treated at the Urgent Internal Medicine and Toxicology Clinic, University Clinical Centre, Skopje, Republic of Macedonia. The evaluation of the caustic poisonings was followed on the basis of anamnesis and hetero-anamnesis, physical examination of the patient, and status of the local changes to the oral mucosae, tongue, palate, and pharynx. The patients were assessed by the following techniques of visualization: urgent oesophagoduodenoscopy in the first 24 hours after the ingestion, control oesophagoduodenoscopy (15 and 25 days after ingestion), X-ray of oesophagus, gaster and duodenum with gastrograph (25-30 days after the ingestion), as well as a routine laboratory examination (blood count, urea, creatinine, enzyme, protein and lipid status, serum transferin, etc), following also the actual body mass index (BMI). The presented results show that the dominating patients were female [n = 368 patients (71.79 %), p < 0.001] and Christian by religion [n = 263 (50.87 %), p > 0.05], with the majority having had secondary education [n = 322 (62.28 %), p = 0.001]. The most frequently misused substance was chlorine hydrogen acid [n = 245 patients (47.38%)]., At the first urgent oesophagoduodenoscopy examination the majority of patients had II A (n = 190) and II B (n = 136) grade damage (x(2) = 44.0; p < 0.05). One hundred patients, or 19.34 %, were dismissed from the hospital with stenosis of the oesophagus and stomach. The high percentage of stenosis was the major factor in the invalidity of these patients. A high mortality of 8.69 % (p > 0.05) was also stated. Of 517 patients, 62 (11.99 %) were poisoned with concentrated acetic acid. In 37 patients (59.67 %) acute renal failure developed as an acute complication and four patients (6.5 %) died as a consequence of the disordered renal function and the need for active dialysis treatment. Recovery of the renal function was established in 93.5 % of the patients. A total number of 138 haemodialyses (3.7/patients) were performed. Acute corrosive poisonings represent a serious socio-economic problem, as well as a diagnostic and therapeutic problem. They appear most frequently in a population that is in a period of life when the person is most creative and efficient in terms of working capacity. The treatment is expensive and is an economic burden on the social community. Despite all the current therapeutic treatments and efforts made to decrease the mortality and late morbidity, intoxication with corrosive substances remains a difficult medical problem.

Urinary diversion: 30 years experience of a single centre in Republic of Macedonia.

OBJECTIVES: The aim of this report is to present our 30 years experience with various types of urinary diversions, in particular the Bricker and Studer techniques for the management of muscle invasive bladder cancer at our institution. Perioperative, early and late complications are also evaluated. MATERIAL AND METHODS: Between 1977 and 2007, 186 male and 15 female patients underwent combined radical cystectomy, pelvic lymphadenectomy and urinary diversion. In two subgroups of patients we evaluated the complications, divided as early and late, and subdivided as those related or unrelated to the neobladder. Mean follow up time was 28 months (range 12-60 months). RESULTS: Two main types of urinary diversion were performed: the ileal conduit diversion using a technique previously described by Bricker and the ileal neobladder diversion using a technique previously described by a Studer. The ages at surgery ranged from 40 to 82 years with a mean age of 60 years. Histopathologically, transitional cell carcinoma was the most common tumor cell type (93,7%), followed by difuse papilomatosis (5.5%) and adenocarcinoma (0.7%). The pathological tumor stage was pT1 (4.7%), pT2 (31.4%), pT3 (50.3 %) and pT4a (13,3%). Histological evidence of regional lymph node involvement was seen in 25% of the cases. From 52 patients from the Studer subgroup perioperative complications were found in 16 patients (30.7%). Specific early complications directly related to the neobladder occurred in 14 (26.9%) patients. Prolonged ileus in 2 patient (3.8%), ureteral leakage in 9 patients (17.3%), mucous buildup within the diversion in 3 patients (5.7%). Late complications occurred in 10 patients (19.2%): retention of the urine in 4 patients (7.6%) (stricture of the urethra-pouch anastomosis in one 1 patient) and to big reservoir in 3 patients. One patient (1.9%) developed prolonged metabolic acidosis. Stone formation was observed in one patient, two years postoperatively. Unilateral hydroureteronephrosis was observed in 2 patients whereas bilateral hydroureteronephrosis was observed in one patients at one year postoperatively. Perioperative and late complications were similar in the 32 patients from the Bricker subgroup. CONCLUSION: We show that our results with urinary diversion are promising in patients requiring radical cystoprostatectomy. The two methods preferred in our institution offer a sufficient protection of the upper urinary tract with a low complication rate, good voiding function and continence.

Radical retropubic prostatectomy for prostate carcinoma; first results of the Clinic of Urology in Skopje.

OBJECTIVES: The aim of this retrospective study is to present our experience and results in the management of prostate carcinoma, with radical retropubic prostatectomy, for a period of seven years. MATERIAL AND METHODS: From December 1997 to April 2005, 61 radical retropubic prostatectomies for prostate carcinoma were performed at the Clinic of Urology in Skopje. Mean age of the treated patients was 66.4 years. Mean serum PSA level was 32.75 ng/ml. None of the patients had distant or bone metastases. Mean operative time was 160 minutes and from 2 to 4 units of blood were transfused intra and postoperatively. Mean follow up time was 39 months. RESULTS: In all of 61 patients, the RRP was performed for adenocarcinoma of the prostate. The pathological findings postoperatively showed the following pTNM grade: pT2a in 8, pT2b in 10, pT3a in 10, pT3b in 27and pT4 in 6 patients. Positive lymph nodes were found in 14 cases. Intraoperative complications occurred in 6 patients. Early postoperative complications were seen in 12 patients. Urine leakage was seen in 2 patients, incontinence (day and night) in 8 and pulmonary embolia in 2 patients. Late postoperative complications occurred in 11 patients. Stenosis of the vesicourethral anasthomosis was seen in 3 patients and incontinence (during the night only) in 8 patients. The rate of potency was not evaluated but in the last 30 cases we insisted on preservation of the neurovascular bundles in the cases that it was possible. CONCLUSION: Radical retropubic prostatectomy is the method of choice and the golden standard for treatment of organ confined prostate carcinoma in patients with long life expectancy, no neither local nor distant metastases and good overall status. With this technique complication rates are minimal, the cure rate is very big and the patients have high quality of life. The experience of the surgeon is very important since the learning curve is crucial for diminishing operative time, postoperative complications and blood transfusions.

Seasonal changes of thermoregulation in the mole vole Ellobius talpinus.

Seasonal changes of thermoregulation were studied in mole voles (Ellobius talpinus Pall.) from southern Siberia. Spontaneous fluctuations of body temperature were significantly higher in summer than in autumn. Standard deviations from average daily temperature of individuals were 0.95 (N=212) in summer and 0.57 (N=248) in autumn. Thermoregulatory response to cold exposure and to norepinephrine injection varied in different seasons of the year. In cold seasons, mole voles are able to maintain temperature homeostasis in a wide range of environmental conditions. This ability declined only in summer. Hence, the mole vole's adaptation to the continental climate is based on distinct seasonal variations of thermoregulation. In summer, thermoregulatory mechanisms are similar to those of desert eusocial fossorial species, but in spring and autumn, mole voles share the thermoregulatory strategies of boreal terrestrial rodents.

[Living donors: immunologic factors]. / Donneurs vivants: aspects immunologiques.

Transplantations using grafts from living donors were performed on 70 patients with chronic kidney failure, 66 of them involved matching recipients-donors and four involved non-matching recipients-donors. Immunological data were analyzed in 56 pairs of recipients and patients. Of these pairs, one was identical, seven had three identical antigens, 46 were haploidentical at A and B loci, one pair was identical in one antigen and one pair was completely incompatible. The survival of transplanted kidneys largely depended on the degree of histocompatibility. In 33 (59%) transplantations kidneys are functioning from more than 36 months. In the group of seven transplanted pairs with three identical antigens kidneys are functioning in six cases, with four of them functioning from more than 72 months. In the remaining patients (41 patients [73%]) kidneys are functioning, with 8 of them functioning from more than 10 years. The existence of HLA antibodies was investigated. Preimmunization was found in 18 (32%) patients and correlated with the number of blood transfusions. Rejection crises were observed in 12 (21%) patients. As the number of blood transfusions per patient increased the number of rejection crises decreased. Rejection crises were also observed in haploidentical pairs, with a relative risk > 30%. They occurred in the first 2 weeks following transplantation.

[Postoperative complications following kidney transplantation]. / Complications chirurgicales après la transplantation rénale.

Despite the remarkable development of kidney transplantation techniques, surgical complications are still a very important factor affecting the final outcome of kidney transplantation. After 92 kidney transplantations (22 from cadaver donors and 70 from living donors) performed at Skopje hospital (Macedonia), we observed the following complications: nine (10%) urinary fistula, five (5%) graft ruptures, seven (8%) lymphoceles, two (2%) urinary calculosis, two (2%) intestinal perforations, four (4%) renal artery stenoses, one (1%) renal artery thrombosis, and seven (8%) early complications following surgical incision. Complications were detected by either ultrasonography, intravenous pyelography, percutaneous nephrostomy with anterograde pyelography, computerized tomography, and intravenous digital angiography. They were subsequently treated by application of modern surgical procedures: use of the ureter (termino-terminal or uretero-pyelic anastomosis) for treatment of urinary fistulas; conservative surgery using tissue glue and external compression with polyglactin 910 (Vicryl) mesh for graft ruptures; drainage and application of sclerosants under ultrasound control and intraperitoneal marsupialization for the clinically relevant lymphoceles; transluminal angioplasty with balloon dilatation in case of significant arterial stenosis; extracorporeal shock wave lithotripsy and surgery for urinary calculi. Intestinal perforations and problems relating to parietal tissue were quickly solved using standard surgical techniques. On total, rejection of the graft occurred in four (4%) cases following surgical complications, while one death was encountered due to septic peritonitis. We consider the percentage of surgical complications acceptable, as this work consists of a pioneering effort in this Balkan region.