NF-κB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in this study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter (NET) system, considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was performed on three different stable PHEO cell lines. We found that blocking NF-κB with TTL or capsaicin increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, in vivo treatment with TTL significantly reduced metastatic burden in an animal model of metastatic PHEO. The present study for the first time shows how NF-κB inhibitors could be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis.     

Investigating the spectral features of the brain meso‐scale structure at rest

Recent studies provide novel insights into the meso‐scale organization of the brain, highlighting the co‐occurrence of different structures: classic assortative (modular), disassortative, and core‐periphery. However, the spectral properties of the brain meso‐scale remain mostly unexplored. To fill this knowledge gap, we investigated how the meso‐scale structure is organized across the frequency domain. We analyzed the resting state activity of healthy participants with source‐localized high‐density electroencephalography signals. Then, we inferred the community structure using weighted stochastic block‐model (WSBM) to capture the landscape of meso‐scale structures across the frequency domain. We found that different meso‐scale modalities co‐exist and are diversely organized over the frequency spectrum. Specifically, we found a core‐periphery structure dominance, but we also highlighted a selective increase of disassortativity in the low frequency bands (<8 Hz), and of assortativity in the high frequency band (30–50 Hz). We further described other features of the meso‐scale organization by identifying those brain regions which, at the same time, (a) exhibited the highest degree of assortativity, disassortativity, and core‐peripheriness (i.e., participation) and (b) were consistently assigned to the same community, irrespective from the granularity imposed by WSBM (i.e., granularity‐invariance). In conclusion, we observed that the brain spontaneous activity shows frequency‐specific meso‐scale organization, which may support spatially distributed and local information processing.     

Hearing rehabilitation with single-stage bilateral vibroplasty in a child with Franceschetti syndrome

Hearing is of utmost importance for normal speech and social development. Even children who have mild or unilateral permanent hearing loss may experience difficulties with understanding speech, as well as problems with educational and psycho-social development. The increasing advantages of middle-ear implant technologies are opening new perspectives for restoring hearing. Active middle-ear implants can be used in children and adolescents with hearing loss. In addition to the well-documented results for improving speech intelligibility and quality of hearing in sensorineural hearing loss active middle-ear implants are now successfully used in patients with conductive and mixed hearing loss. In this article we present a case of successful, single-stage vibroplasty, on the right side with the fixation of the FMT on the stapes and PORP CLiP vibroplasty on the left side in a 6-year-old girl with bilateral mixed hearing loss and multiple dyslalia associated with Franceschetti syndrome (mandibulofacial dysostosis). CT revealed bilateral middle-ear malformations as well as an atretic right and stenotic left external auditory canal. Due to craniofacial dysmorphia airway and (post)operative, management is significantly more difficult in patients with a Franceschetti syndrome which in this case favoured a single-stage bilateral procedure. No intra- or postoperative surgical complications were reported. The middle-ear implants were activated 4 weeks after surgery. In the audiological examination 6 months after surgery, the child showed 100 % speech intelligibility with activated implants on each side.     

Region-specific maturation of cerebral cortex in human fetal brain: diffusion tensor imaging and histology

Introduction  In this study, diffusion tensor imaging (DTI) and glial fibrillary acidic protein (GFAP) immunohistochemical analysis in different cortical regions in fetal brains at different gestational age (GA) were performed. Methods  DTI was performed on 50 freshly aborted fetal brains with GA ranging from 12 to 42 weeks to compare age-related fractional anisotropy (FA) changes in different cerebral cortical regions that include frontal, parietal, occipital, and temporal lobes at the level of thalami. GFAP immunostaining was performed and the percentage of GFAP-positive areas was quantified. Results  The cortical FA values in the frontal lobe peaked at around 26 weeks of GA, occipital and temporal lobes at around 20 weeks, and parietal lobe at around 23 weeks. A significant, but modest, positive correlation (r = 0.31, p = 0.02) was observed between cortical FA values and percentage area of GFAP expression in cortical region around the time period during which the migrational events are at its peak, i.e., GA ≤ 28 weeks for frontal cortical region and GA ≤ 22 weeks for rest of the lobes. Conclusions  The DTI-derived FA quantification with its GFAP immunohistologic correlation in cortical regions of the various lobes of the cerebral hemispheres supports region-specific migrational and maturational events in human fetal brain.     

Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis

Aim: Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane transporters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xenobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases. Methods: Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains transgenic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyping was performed to rule out individuals predisposed to hyperbilirubinemia. Results: The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross-reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B proteins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009). Conclusions: Down-regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.     

Suicide attempters in Abu Dhabi: Is criminal prosecution associated with patients’ guardedness?

The objective of this study was to examine the relationship between legal status and guardedness in patients who attempted suicide in Abu Dhabi, United Arab Emirates. The consultation-liaison team assessed 355 patients admitted for suicidal/self-injurious behavior, recording their guardedness before knowing whether they were legally charged. Patients who were legally charged for the suicidal act (n?=?139) were 1.6 times (p?=?.03) more guarded in volunteering information than patients who were not legally charged. Legally charging suicide attempters might have a negative impact on risk assessment and psychiatric care.     

Lovastatin raises serum osteoprotegerin level in people with type 2 diabetic nephropathy

ObjectivesOsteoprotegerin (OPG), a glycoprotein, is a member of the tumor necrotizing factor alpha receptor super-family. By considering the possible role of OPG in cardiovascular disease (CVD), higher incidence of CVD in people with type 2 diabetic nephropathy (T2DN), and anti-atherosclerotic effects of statins, the present study aimed to investigate the effects of lovastatin on serum levels of OPG and soluble receptor activator of nuclear factor-κB ligand (sRANKL) in people with T2DN.Design and methodsThirty patients completed the study course, out of 38 adult male patients with T2DN who were initially enrolled. Lovastatin, 20 mg/d, was administered for 90 days. Afterwards, lovastatin was withdrawn for the next 30 days. Serum levels of OPG and sRANKL were measured using commercial ELISA kits at baseline, after 90 days of intervention, and after 30 days of withdrawal of lovastatin.ResultsSerum level of OPG was significantly increased (10.76 ± 16.44) and decreased (?7.38 ± 11.98) during 90 days of intervention and 30 days of withdrawal periods, respectively, while, sRANKL level was significantly decreased (?1192.08 ± 578.20) and increased (4418.67 ± 2124.66) during the same periods, respectively.ConclusionsLovastatin therapy increased serum OPG level and decreased sRANKL level in people with T2DN. The withdrawal of lovastatin decreased serum OPG level, while sRANKL level was extensively increased.