No modulatory effect of neurokinin-1 receptor antagonists on serotonin uptake in human and rat brain synaptosomes

Some studies have demonstrated antidepressant activity of neurokinin-1-receptor antagonists (NK-1-RA) in major depressive disorder. However, the underlying mechanisms of this antidepressant effect are largely unknown. Preclinical studies in rats and mice have suggested that NK-1-RA do increase the neuronal release of serotonin (5-HT). This, however, seems to be compensated by an increased 5-HT reuptake, indicating that NK-1-RA have no inhibitory effect on the 5-HT transporter in rodents. Given the possibility that modulation of neurotransmitter release and reuptake may differ between species, with major differences found between rodents and humans, we investigated for the first time the possible modulatory effect of NK-1-RA on 5-HT uptake in human brain synaptosomes and compared it with the situation in rat cortex. We found that the specific human NK-1-RA L-733060, in contrast to the SSRI fluvoxamine (IC₅₀ = 10^− 7.96 M) did not inhibit 5-HT uptake in human brain synaptosomes and did not modulate fluvoxamine-induced 5-HT uptake inhibition at 1 μM. Furthermore, substance P as well as Sar⁹Met(O₂)¹¹SP, as the major agonists at the NK-1-R, did not modulate 5-HT uptake in human brain synaptosomes. Similar results were found in rat cortex synaptosomes by using the rat-specific NK-1-RA WIN51708. These results show that in humans, as in rodents, inhibition of the 5-HT transporter is probably not the underlying mechanism of the assumed antidepressant activity of NK-1-RA.     

Impact of treatment on survival of patients with secondary glioblastoma

Data concerning treatment of secondary glioblastoma evolving from previously treated WHO II or III grade tumors are very scarce. The aim of this study was to evaluate the impact of surgical resection and adjuvant treatment on survival in patients with secondary glioblastoma. Thirty-nine patients with secondary glioblastoma evolving from previously treated lower grade gliomas between 2004 and 2015 were included. We evaluated the extent of resection, pathological parameters, adjuvant treatment, as well as survival after malignant transformation. The primary tumor grade was WHO II in 16 (41.0%) and WHO III in 23 (59.0%) patients. Median age was 43 years (range 23–67). Median KPS was 80 (range 60–100) before surgery, and 70 (range 50–100) after surgery. Gross total resection (GTR) of contrast-enhancing disease was achieved in 19 (48.7%) patients. Adjuvant treatment was radio-chemotherapy in 23 (59.0%), radiotherapy in three (7.7%), chemotherapy in five (12.8%) and none in eight (20.5%) patients. Median survival was 11 months (range 1–35) in the entire group. Time since initial diagnosis and previous treatment did not correlate with survival after glioblastoma. Failed GTR, poor KPS after surgery, and no adjuvant treatment were prognostic factors for shorter survival in univariate analysis (p?<?0.0001, p?=?0.028 and p?=?0.003). In selected patients, complete resection and adjuvant treatment may prolong survival in spite of multiple previous therapies.     

Subcellular and regional location of “brain” proteins BASP1 and MARCKS in kidney and testis

Proteins BASP1 and MARCKS are abundant in axonal endings of neurons. Similarly to brain-specific protein GAP-43, BASP1 and MARCKS are reversibly bound to the plasma membrane. These proteins control both actin polymerization and actin cytoskeleton binding to the membrane. Performing these functions, BASP1 and MARCKS take part in growth cone guidance during development and in neurotransmitter secretion in adults. These activities predetermine the pivotal role of BASP1 and MARCKS in learning and memory. BASP1 and MARCKS were also found in non-nerve tissues, in particular, in the kidney and testis. Evidently, the physiological roles of these proteins differ in different tissues. Correspondingly, their intracellular location and activities may not be similar to those in neurons. In this paper, we analyze subcellular fractions (cytoplasm and nuclei) of rat kidney and testis with the purpose of determining the intracellular location of BASP1 and MARCKS. Western blots demonstrated that in these tissues, as in the brain, both proteins are present in the cytoplasm of the cell. According to our immunohistochemical study, BASP1 and MARCKS are specifically distributed in the tissues studied. In kidney, both proteins are present in cells located in glomeruli. In the testicular tubules, BASP1 is mainly expressed at the late stage of spermatogenesis (in spermatids) and is preserved in mature spermatozoa, while MARCKS appears equally during all stages of spermatogenesis. MARCKS is not found in mature spermatozoa. The results indicate that study of functions of BASP1 and MARCKS in the kidney and in the reproduction system holds much promise.     

Results of single‐center screening for chronic hepatitis E in children after liver transplantation and report on successful treatment with ribavirin

RNA screening for HEV in 22 liver‐transplanted children with chronic graft hepatitis out of a cohort of 267 liver‐transplanted children detected a single patient with chronic HEV infection. Although this patient remained viremic for 33 months, anti‐HEV‐IgG was not detectable with MP assay but with Wantai assay. We present the first case of successful ribavirin therapy in an immunosuppressed child with chronic HEV infection. In conclusion, chronic HEV infection in immunosuppressed children may not be detectable employing serological assays. Therefore, the most reliably screening method is screening for HEV‐RNA. Chronic HEV infection in children can successfully be treated with ribavirin.     

Helicobacter pylori infection in laryngeal diseases

Clinical studies have shown that Helicobacter pylori can be found not only in the mucosa of the stomach, but in the pharyngeal and laryngeal regions as well. The aim of this prospective case-control study was to identify H. pylori infection in the biopsy material from the larynx of the patients suffering from benign laryngeal diseases (vocal fold polyps, laryngitis) and laryngeal cancer and to investigate the possible relationships between the laryngeal H. pylori and patients’ socio-demographic data and laryngopharyngeal reflux. The results of the biopsy material from 67 adult patients treated for benign laryngeal diseases and laryngeal cancer and 11 individuals of the control group revealed that H. pylori infection could be identified in more than one-third of the patients. In the majority of cases H. pylori was found in the patients with chronic laryngitis (45.5 %) and laryngeal cancer (46.2 %). The findings of these sub-groups significantly differed from those of the control group (9.1 %) (p < 0.05). No significant relationships between H. pylori infection found in the laryngeal region and patients’ demographic data, their unhealthy habits and reflux-related symptoms or signs were obtained. It could be concluded that H. pylori can colonize in the larynx of patients with benign laryngeal diseases and laryngeal cancer. To clarify the role of H. pylori as a risk factor for laryngeal diseases further research is needed.     

The role of histone demethylases in cancer therapy

Reversible histone methylation has emerged in the last few years as an important mechanism of epigenetic regulation. Histone methyltransferases and demethylases have been identified as contributing factors in the development of several diseases, especially cancer. Therefore, they have been postulated to be new drug targets with high therapeutic potential. Here, we review histone demethylases with a special focus on their potential role in oncology drug discovery. We present an overview over the different classes of enzymes, their biochemistry, selected data on their role in physiology and already available inhibitors.