A single cocaine administration alters dendritic spine morphology and impairs glutamate receptor synaptic retention in the medial prefrontal cortex of adolescent rats

The brain is still maturing during adolescence and interfering with such a vulnerable period may lead to structural and functional consequences. We investigated the effect of a single cocaine exposure on dendritic spine structure and glutamate dynamics in the medial prefrontal cortex (mPFC) of adolescent rats 7 days after a single cocaine administration. We found a reduced number of dendritic spines, suggesting that cocaine lowers the density of dendritic spines in the mPFC of adolescent rats. Since dendritic spines are postsynaptic glutamatergic protrusions, we investigated the main determinants of glutamate postsynaptic responsiveness. In the postsynaptic density, cocaine reduced the expression of the NMDA receptor subunits GluN1, GluN2A and GluN2B as well as of the AMPA GluA1 and GluA2 subunits. Cocaine also impaired their synaptic stability since the expression of the scaffolding proteins SAP102 and SAP97, critical for the anchoring of such receptors at the postsynaptic membrane, was reduced as well. The expression of PSD-95 and Arc/Arg3.1, which play structural and functional roles in glutamate neurons, was also similarly reduced. Such changes were not found in the whole homogenate, ruling out a translational effect of cocaine and implying, rather, an impaired synaptic retention at the active zones of the synapse. Notably, neither these critical glutamate determinants nor the density and morphology of the dendritic spines were altered in the mPFC of adult animals, suggesting that a single cocaine exposure selectively impairs the developmental trajectory of the glutamate synapse. These results indicate a dynamic impairment of mPFC glutamate homeostasis during a critical developmental window that persists for at least one week after a single cocaine administration. Our results identify dysfunctional glutamate synapse as a major contributor to the mechanisms that distinguish adolescent vs. adult outcomes of a single cocaine exposure

HBV vaccination with Fendrix is effective and safe in pre-dialysis CKD population

Background: Patients with chronic kidney disease have a poor response to hepatitis B vaccine due to the immunodeficiency conferred from chronic uremia. A recombinant HB vaccine containing an improved adjuvant system AS04 (HBV-AS04) has been manufactured but scarce evidence exists on HBV-AS04 use among patients with CKD. Aim: To assess efficacy and safety of an adjuvanted recombinant vaccine (HBV-AS04) in a large cohort of CKD patients at pre-dialysis stage (with susceptibility to HBV infection). Methods: Patients were prospectively enrolled to receive four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle) at months 1, 2, 3, and 4. Anti-HBs surface antibody concentrations were tested at intervals of 1, 2, 3, 4, and 12 months. Multivariate analyses were performed to assess the parameters, which predicted immunologic response to HBV-AS04 vaccine. Results: One hundred and seven patients were included and 102 completed the study. At completion of vaccine schedule, the frequency of responders (anti-HBs titers 65 10 mIU/mL) was 95% (97/102) (mean anti-HBs antibody titers, 688.9 \ub1 385 mIU/mL), according to per-protocol analysis. Serum haemoglobin levels were greater in responder than non- or low-responder patients to HBV-AS04 (P = 0.04) and this was confirmed by multivariate analysis. The seroprotection rate at month 50 was 88% (30/34) with lower anti-HBs antibody titers (218.5 \ub1 269.6 mIU/mL, P = 0.001). No major side effects were observed. Conclusions: Our prospective study performed in a real-world setting showed a high immunogenicity and safety of HBV-AS04 vaccine in patients with CKD not yet on maintenance dialysis. Studies provided with longer follow-ups are under way to assess the durability of seroprotection in responders

An unusual cause of gross hematuria, improved by recumbency

n/

Nuove terapie per l’epatite C nei pazienti nefropatici cronici

Gli studi effettuati nell\u2019ultima decade hanno evidenziato il ruolo sfavorevole che svolge l\u2019infezione da virus dell\u2019epatite C sulla sopravvivenza dei pazienti nefropatici (particolarmente i pazienti in dialisi ed i portatori di trapianto renale). In aggiunta, l\u2019infezione da virus dell\u2019epatite C sembra essere associata ad un aumentato rischio di nefropatia cronica nella popolazione adulta generale. Pertanto, c\u2019\ue8 urgente bisogno di terapie antivirali efficaci e sicure in questi pazienti. Recenti studi randomizzati e controllati hanno mostrato che la terapia antivirale basata su interferone peghilato e ribavirina pu\uf2 essere efficace (frequenza della risposta virale protratta, circa il 70%), e ben tollerata quando \ue8 usata da medici esperti in pazienti appropriati. Da qualche anno \ue8 iniziata la commercializzazione dei farmaci ad azione anti-virale diretta nella popolazione adulta con funzione renale normale, ma l\u2019uso di questi farmaci nei nefropatici cronici \ue8 ancora allo stato iniziale. Sono stati negli ultimi mesi pubblicati alcuni studi; il primo ha riguardato il trattamento antivirale di HCV nei pazienti (n=224) con malattia renale cronica (CKD stadio 4/ 5) che hanno ricevuto terapia con grazoprevir (inibitore di HCV NS3/4A) ed elbasvir (inibitore di HCV NS5A) per 12 settimane. La frequenza di SVR12 \ue8 stata pari a 94.3% (115/122); nessuno dei pazienti del gruppo di studio ha interrotto precocemente la terapia antivirale per eventi avversi. Il secondo studio riguarda la combinazione antivirale 3D (ombitasvir/paritaprevir/ritonavir/dasabuvir con e senza ribavirina) che \ue8 stata somministrata a 20 pazienti con malattia renale cronica (CKD, stadio 4/5, genotipo 1), la frequenza di SVR12 era 90% (18/20). Non sono stati riportati eventi avversi che hanno necessitato un\u2019interruzione precoce della terapia antivirale. Esistono inoltre alcuni studi preliminari riguardo la terapia antivirale sofosbuvir/simeprevir (n=38) in pazienti con malattia renale cronica di stadio 4/5; la frequenza di SVR12 era 89% (34/38). Altri studi clinici, di fase 2 o 3, basati sui farmaci ad azione antivirale diretta sono in corso. In conclusione, i nuovi farmaci ad azione anti-virale diretta promettono di eradicare l\u2019infezione da virus dell\u2019epatite C nei pazienti con insufficienza renale. Restano da chiarire alcuni punti cruciali quali il costo dei nuovi farmaci, che \ue8 un problema non trascurabile anche per i paesi industrializzati. Anche le interazioni tra farmaci sono un argomento di rilevanza clinica visto che i pazienti nefropatici cronici hanno una frequenza elevata di co-morbilit\ue0.Recent evidence has been accumulated showing a negative impact of chronic hepatitis C virus infection on survival in patients with chronic kidney disease. Moreover, it appears that anti-HCV positive status has been associated with an increased risk of developing chronic kidney disease in the adult general population. These reports have emphasized the need for safe and effective therapies for hepatitis C virus infection in the chronic kidney disease population. Treatment of HCV has made considerable progress with the approval of interferon-free, direct-acting antiviral drug-based combination therapies among patients with intact kidneys; but a paucity of information exists regarding chronic kidney disease patients. The first published report on the antiviral treatment of hepatitis C among patients with chronic kidney disease (stage 4-5) and HCV genotype 1 concerns the combination of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor); excellent safety and efficacy (sustained viral response, 94.3% 115/122) have been reached. In another study, the 3-D regimen (ombitasvir/ paritaprevir/ ritonavir/ dasabuvir with or without ribavirin) has been administered to CKD (stage 4-5) patients with genotype 1 (n=20); the rate of sustained viral response was excellent (90%, 18/20) and no patients discontinued treatment due to adverse events. Preliminary data on the combined treatment of sofosbuvir (NS5B inhibitor) and simeprevir (NS3/4A inhibitor) has given a viral response of 89% (34/38), but the size of the study group (n=38 patients with end-stage renal disease) was small. Thus, the evidence in the medical literature concerning use of DAAs in CKD population is encouraging even if it has a preliminary nature. Also, several points need to be addressed regarding the use of DAAs in CKD population including their impact on survival, costs, and drug-drug interactions

Progressive Dysphasic Dementia with Bucco-Facial Apraxia: A Case Report

A patient with progressive dementia, prominent non-fluent aphasia and signs of frontal lobe involvement, was evaluated by neuropsychological testing, magnetic resonance imaging (MRI) and high resolution single photon emission tomography (SPET). The presence of severe bucco-facial apraxia, associated with spared imitation of limb movements, correlated well with a marked reduction of cerebral perfusion in the left fronto-temporal cortex. This case emphasizes the usefulness of SPET as a valuable alternative to PET for the diagnosis of conditions, such as progressive neuropsychological syndromes, where a coupled reduction of metabolism and blood flow can be expected

Novel evidence on hepatitis C virus-associated glomerular disease

A large spectrum of renal pathology is associated with hepatitis C virus (HCV). According to novel evidence, occult HCV infection (HCV-RNA in peripheral blood mononuclear cells or in serum after ultracentrifugation) could be involved in the pathogenesis of glomerular nephropathy among patients negative for conventional markers of HCV. Additional studies with appropriate size and technology are in progress to confirm the relationship between occult HCV and glomerular disease, which has multiple implications from the clinical standpoint

Gut microbiota composition and frailty in elderly patients with Chronic Kidney Disease

Background Frailty is common in older patients affected by chronic kidney disease (CKD). Since gut microbiota (gMB) may contribute to frailty, we explored possible associations between gMB and frailty in CKD. Methods We studied 64 CKD patients (stage 3b-4), categorized as frail (F, 38) and not frail (NF, 26) according to Fried criteria, and 15 controls (C), all older than 65 years. In CKD we assessed serum C-reactive protein, blood neutrophil/lymphocyte ratio, Malnutrition-inflammation Score (MIS); gMB was studied by denaturing gel gradient electrophoresis (DGGE), high-throughput sequencing (16S r-RNA gene), and quantitative real-time PCR (RT-PCR). Results No differences in alpha diversity between CKD and C and between F and NF patients emerged, but high-throughput sequencing showed significantly higher abundance of potentially noxious bacteria (Citrobacter, Coprobacillus, etc) and lower abundance of saccharolytic and butyrate-producing bacteria (Prevotella spp., Faecalibacterium prausnitzii, Roseburia spp.), in CKD respect to C. Mogibacteriaceae family and Oscillospira genus abundance was positively related to inflammatory indices in the whole CKD cohort, while that of Akkermansia, Ruminococcus and Eubacterium genera was negatively related. Compared with NF, in F there was a higher abundance of some bacteria (Mogibacteriacee, Coriobacteriacee, Eggerthella, etc), many of which have been described as more abundant in other diseases. Conclusions These results suggest that inflammation and frailty could be associated to gMB modifications in CKD

Caveolin-1, breast cancer and ionizing radiation

Breast cancer (BC) recovery has increased in recent years thanks to efforts of Omics-based research in this field. However, despite the important results obtained, BC remains a complex multifactorial pathology that is difficult to treat appropriately. Caveolin-1 (CAV1), the basic constituent protein of specialized plasma membrane invaginations called caveolae, is emerging as a potential therapeutic biomarker in BC. This factor may modulate BC response to chemotherapy and radiation therapy. In addition, recent reports describe the key role of CAV1 during cell response to oxidative stress. The aim of the present review was to describe the biological roles of CAV1 in BC considering its contrasting dual functions as an oncogene and as a tumor suppressor. In addition, we report on how CAV1 may contribute to tumor cell response to ionizing radiation treatment. Finally, new roles of CAV1 in BC both on epithelium and stroma may be useful as prognostic indicators for patient treatment and help clinicians in the selection of the best personalized therapy

Hepatorenal syndrome and novel advances in its management

Hepatorenal syndrome is a complication of end stage liver disease. It is a unique form of functional renal failure related to kidney vasoconstriction in the absence of underlying kidney pathology. Hepatorenal syndrome is classified into 2 types: type-1 HRS shows a rapid and progressive decline in renal function with a very poor prognosis (median survival of about 2 weeks); type-2 HRS has a more stable kidney failure, with a median survival of 6 months; its main clinical manifestation is refractory ascites. The most appropriate therapy for HRS is liver transplantation but only a minority of HRS patients undergo the procedure due to the high mortality; survival among liver transplant recipients is lower in HRS than among their counterparts without HRS. A large body of evidence, based on observational studies and randomized controlled trials, has been accumulated in the last decade showing that terlipressin represents a milestone in the management of HRS. According to our meta-analysis of randomized trials comparing terlipressin vs. placebo (five trials, n=243 patients), the pooled rate of patients who reversed HRS by terlipressin was 8.09 (95% CI, 3.52; 18.59) (P<0.001). Among vasoconstrictors, terlipressin (a V1 vasopressin agonist) is the most widely used; however, noradrenaline is another good choice. Vasoconstrictor drugs alone or with albumin reduce mortality compared with no intervention or albumin (RR of mortality, 0.82; 95% Confidence Intervals, 0.70; 0.96) (P<0.01). Two series of patients with HRS recurrence after the first treatment have recently shown that long-term therapy with terlipressin and albumin is beneficial as a bridge to liver transplant. Nevertheless, recovery of renal function can be achieved in less than 50% of patients with HRS after terlipressin use and the recovery of renal function may also be partial in patients who are defined full responders. Renal replacement therapy should not be considered a first-line therapy for HRS Clinical trials are under way in order to assess efficacy and safety of novel therapeutic agents for the treatment of type-1 and type-2 HRS