Hemodialysis-related headaches

BACKGROUND/AIM: Hemodialysis (HD) is a therapeutic procedure used to partially correct homeostatic disorders and prevent complications of uremia to appear in the terminal stage of renal insufficiency. The aim of this study was to evaluate and analyze the incidence and features of haedaches in patients undergoing hemodialysis. METHODS: A total of 143 patients, 50 women and 93 men, undergoing hemodialysis, were questionned about their problems with headache using a questionnary designend according to the diagnostic criteria of the Intemational Headache Classification of Headache Disorders from 2004. The patients were separated into two groups: the patients without headache and the patients with repeated headaches. Afterwards, the patients with headaches were further divided into subgroups: the patients who had the headaches before the beginning of HD and patients who experienced repeated headaches with the beginning of HD headache (HDH). In the group of patients with headaches we analyzed characteristics of headache according to which diagnoses of headaches were made, as well as the effects of HD on headaches. We also analyzed features of HDH. The patients with headache were compared to the patients without haedache regarding sex, age, duration of HD, causes of end-stage renal disease, arterial diastolic and systolic blood pressure and serum concentration of hemoglobin, urea nitrogen, creatinine, sodium and potassium. The results were statistically compared. RESULTS: In the group of 143 patients examined, 27 (18.9%) patients had headaches. There were no statistically significant differences between the group of patients with headaches and those without headache regarding to sex, age, duration of HD, causes of end-stage renal disease, serum concentration of hemoglobin, urea nitrogen, creatinine, sodium and potassium. The patients with headaches showed significantlly higher mean values of systolic blood pressure during HD in comparison to the patients without headaches (p = 0.029). There was no statistically significant difference between the two groups regarding the mean values of diastolic blood pressure. Nineteen (13.3%) patients had had headache before starting HD. HD did not have any effect on the characteristics of headaches in more than a half of these patients. In 8 (5.6%) patients we diagnozed HDH using the diagnostic criteria of the International Headache Classification of Headache Disorders from 2004. HDH showed similar caracteristics in all the patients: it appeared mostly in men, during the 4th hour of HD, lasted less than four hours, it was localized bilaterally in the frontal parts of the head, strong in intensity, throbbing and without the associated symptoms. CONCLUSION: The results of our study clearly showed that HDH was a particular entity of headache, not only because of its connenction with HD, but because it had similar characteristics in all the patients in wich it had appeared. Finding out the pathophysiological mechanisms of their occurrence would significantly improve the quality of life style of patients on hemodialysis.     

Expression of nuclear Ki-67 antigen in prostatic high grade intraepithelial neoplasia and prostatic carcinoma

BACKGROUND/AIM: Prostatic intraepithelial high grade neoplasia (PINHG) is accepted as preneoplastic lesion in prostatic carcinoma. One of the fundamental events in early oncogenesis is the disruption of proliferative activity. One of the numerous regulatory proteins is Ki-67 expressed in all proliferating cells. Index Ki-67 is considered to have prognostic significance. The aim of the study was to compare the level of proliferation in hyperplastic epithelium, prostatic carcinoma (Gleason score > 6) and PINHG. METHODS: Micromorphological examination was done in 85 patients. Pathohistological analysis was performed on standard histologic specimens with the estimation of Gleason score and the presence of PINHG in its surroundings. Nuclear proliferative activity was analyzed immunohistochemically in 19 cases, using a monoclonal anti-Ki-67 antibody. RESULTS: PINHG was found in prostatic carcinoma surrounding in 30% of the patients. In hyperplastic epithelia Ki-67 proliferative activity was 1,08, in PINHG 2,25 (p < 0,05), while in prostatic cancer, Ki-67 index was 17,64. Proliferative activity in prostatic carcinoma was significantly higher than in PINHG (p < 0,001) and hyperplasia (p < 0,001). CONCLUSION: This study confirmed that high grade PIN lesion predominately appears in the surrounding of poor or moderately differentiated prostate carcinoma, and that it represents progressive disorder of proliferation in preneoplastic and neoplastic prostatic epithelium.     

Damage of tubule cells in diabetic nephropathy type 2: urinary N-acetyl-beta-D-glucosaminidasis and gamma-glutamil-transferasis

BACKGROUND/AIM: A damage of tubular epithelial cells is followed by the release of cell enzymes and production of proinflammatory compounds, which lead to the tubulointerstitial damage. The aim of this study was to examine the function of renal tubules in the patients with diabetes mellitus type 2 (DM type 2) and the various proteinuria degrees, to establish the damage of the proximal tubule cells caused by DM type 2 by determining urinary N-acetyl-beta-D-glucosaminidasis (beta-NAG) and gamma-glutamil-transferasis (gamma-GT) activity in urine, as well as to compare the obtained results in the examined groups of patients with the values in the healthy examinees. METHODS: A complete examination of renal function and selective enzymuria was performed in 37 patients with DM type 2, and 14 healthy examinees as the controls. The patients were divided in three groups according to the degree of proteinuria. The first group consisted of the patients with diabetes without microalbuminuria; the second one consisted of the patients with proteinuria of < 300 mg/24 h, and microalbuminuria of > 20 mg/24 h, while the third one included the patients with proteinuria of > 300 mg/24 h. RESULTS: In the patients with DM type 2 and the preserved global renal function, fractional excretion of sodium, potassium and phosphates, as well as renal threshold of phosphates concentration, were not sensitive parameters for discovering the damage of the renal tubule function. The determination of beta-NAG activity proved to be the most sensitive parameter for early discovering of tubule cells damages. The difference among the examined groups was statistically highly significant. CONCLUSION: The increased presence of beta-NAG in the urine of DM type 2 patients, pointed out an early tubular disorder and damage of cells, while gamma-GT was a less sensitive indicator of this damage.     

Divergent Squamous Differentiation in Upper Urothelial Carcinoma—Comparative Clinicopathological and Molecular Study

Upper urothelial carcinoma (UUC) has a plasticity to demonstrate divergent differentiation with squamous metaplastic elements. There was no previous study exploring profiling of molecular markers in metaplastic squamous upper urothelial carcinoma (SUUC) and conventional upper urothelial carcinoma (CUUC). The aims of this study was to compare expression of the phenotypic characteristics of tumors and molecular markers (p53, p16, cyclin D1, E-cadherin, HER-2, Ki-67, Bcl-2, Bax) in SUUC and CUUC. SUUC was detected in 20% of 44 patients. There was significant difference between SUUC and CUUC in the pathological stage, grade, growth and presence of lymphovasular invasion (p < 0.05; 0.05; 0.05; 0.01 respectively). The mean Ki-67 and p53 labeling index was significantly higher in SUUC than in CUUC (p < 0.05; 0.05). There was no significant difference in the expression of p16, cyclin D1, E-cadherin, HER-2, Bcl-2 and Bax between SUUC and CUUC. Univariant model showed that SUUC was significantly associated with lymphovascular invasion (p = 0.007), Ki-67 activity (p = 0.016) and growth (p = 0.026). Exploration of UUC with squamous divergent differentiation showed changes in phenotypic characteristics and Ki-67, as well as similar molecular profile with CUUC.     

Relationship between fluoride intake in Serbian children living in two areas with different natural levels of fluorides and occurrence of dental fluorosis

The amount of fluoride present naturally in drinking water is highly variable, being dependent upon the individual geological environment from which the water is obtained. Chronic exposure to exceeding fluoride doses induces set of toxic effects, i.e. fluorosis. The aim of this study was to examine fluoride content in water and in the most frequently used vegetables, potato and bean, grown in two different Serbian regions, i.e. control region (Valjevo) and high naturally occurring fluoride region (Vranjska Banja), and moreover, to correlate estimated daily intake with dental fluorosis occurrence as an adverse effect of fluoride exposure of schoolchildren in Serbia. Study confirmed significant difference in fluoride content in water, potato and bean, consumed by 12-year-old children in two investigated municipalities. Results of the study indicated positive and statistically significant correlation between daily intake of fluoride and dental fluorosis level in the fluorotic municipality of Vranjska Banja (r = 0.61; p = 0.000017). Obtained relationship could be evaluated by means of binary logistic regression analysis, whereas probability for fluorosis occurrence could be predicted using the following equation: fluorosis occurence (%) = (34.852 × C_water − 12.644 × C_potato − 9.362 × C_bean − 7.673) × 100 (Chi-Square (3) = 33.033; p < 0.001).     

The expression of Ki-67 and Bcl-2 in hodgkin’s lymphoma: Correlation with the international prognostic score and bulky disease

The prognosis of Hodgkin’s lymphoma has been improved over last 10 yr due to identification of prognostic parameters. These factors may predict the clinical outcome and therefore may have influence on the selection of appropriate treatment. In a cohort of 40 patients with Hodgkin’s lymphoma of nodular sclerosis subtype, treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen, we analyzed prognostic relevance of the expression of Ki-67 and Bcl-2 at diagnosis as well as other clinical parameters: International Prognostic Score, bulky disease, tissue eosinophilia, and high erythrocyte sedimentation rate. Significance was tested according to response rate and overall survival. Patients with a high proliferative fraction (Ki-67 > 50%) had worse overall survival compared with those with low proliferation, 56% vs 91%. There was a correlation between Ki-67 positivity and the achievement of complete remission. Cox’s multivariate model revealed that Ki-67 positivity at threshold of 50% was a significant independent prognostic factor. The Bcl-2 expression in less than 50% of tumor cells was detected in 65.5% of patients, and in a majority of cases it was associated with complete remission. Patients with high IPS had more progressive disease and shorter survival. Bulky disease, tissue eosinophilia, and high erythrocyte sedimentation rate had no significant influence on complete remission and survival. However, there was a marked divergence in survival curves after 4 yr follow-up for each of these parameters. Patients with high Ki-67, IPS > 3, bulky disease, tissue eosinophilia, and high sedimentation rate are at a higher risk of treatment failure and relapse and therefore might be eligible for other aggressive therapeutic approach.     

Adverse Events During Immunotherapy in Slovenian Patients with Metastatic Melanoma Reveal a Positive Correlation with Better Treatment Outcomes

BackgroundImmunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy.Patients and methodsA retrospective analysis of patients with metastatic melanoma treated with immunotherapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups.ResultsAmong the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE cohort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.ConclusionsPatients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall response rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.Key words: immune related adverse events, immunotherapy, melanoma, metastases, response, survival     

FK506 neuroprotection after cavernous nerve injury is mediated by thioredoxin and glutathione redox systems

IntroductionImmunophilin ligands such as FK506 (FK) preserve erectile function (EF) following cavernous nerve injury (CNI), although the precise mechanisms are unclear. We examined whether the thioredoxin (Trx) and glutathione (GSH) redox systems mediate this effect after CNI.AimTo investigate the roles of Trx reductase 2 (TrxR2) and S‐Nitrosoglutathione reductase (GSNOR) as antioxidative/nitrosative and antiapoptotic mediators of the neuroprotective effect of FK in the penis after CNI.MethodsAdult male rats, wild‐type (WT) mice, and GSNOR deficient (GSNOR ‐/‐) mice were divided into four groups: sham surgery (CN [cavernous nerves] exposure only) + vehicle; sham surgery + FK (5 mg/kg/day/rat or 2 mg/kg/day/mouse, for 2 days, subcutaneous); CNI + vehicle; and CNI + FK. At day 4 after injury, electrically stimulated changes in intracavernosal pressure (ICP) were measured. Penises were collected for Western blot analysis of TrxR2, GSNOR, and Bcl‐2, and for immunolocalization of TrxR2 and GSNOR.Main Outcome MeasuresEF assessment represented by maximal ICP and total ICP in response to electrical stimulation. Evaluation of protein expression levels and distribution patterns of antioxidative/nitrosative and antiapoptotic factors in penile tissue.ResultsEF decreased after CNI compared with sham surgery values in both rats (P < 0.01) and WT and GSNOR ‐/‐ mice (P < 0.05). FK treatment preserved EF after CNI compared with vehicle treatment in rats (P < 0.01) and WT mice (P < 0.05) but not in GSNOR ‐/‐ mice. In rats, GSNOR (P < 0.01) and Bcl‐2 (P < 0.05) expressions were significantly decreased after CNI. FK treatment in CN‐injured rats restored expression of GSNOR and upregulated TrxR2 (P < 0.001) and Bcl‐2 (P < 0.001) expressions compared with vehicle treatment. Localizations of proteins in the penis were observed for TrxR2 (endothelium, smooth muscle) and for GSNOR (nerves, endothelium, smooth muscle).ConclusionsThe neuroprotective effect of FK in preserving EF after CNI involves antioxidative/nitrosative and antiapoptotic mechanisms mediated, to some extent, by Trx and GSH systems. Lagoda G, Xie Y, Sezen SF, Hurt KJ, Liu L, Musicki B, and Burnett AL. FK506 neuroprotection after cavernous nerve injury is mediated by thioredoxin and glutathione redox systems. J Sex Med **;**:**–**.