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Major depression is a multifactorial disease, involving both environmental and genetic risk factors. Recently,SLC6A15– a neutral amino acid transporter mainly expressed in neurons – was proposed as a new candidate gene for major depression and stress vulnerability. Risk allele carriers for a single nucleotide polymorphism (SNP) in aSLC6A15regulatory region display altered hippocampal volume, glutamate levels, and hypothalamus-pituitary-adrenal axis activity, all markers associated with major depression. Despite this genetic link betweenSLC6A15and depression, its functional role with regard to the development and maintenance of depressive disorder is still unclear. The aim of the current study was therefore to characterize the role of mouseslc6a15in modulating brain function and behavior, especially in relation to stress as a key risk factor for the development of mood disorders. We investigated the effects ofslc6a15manipulation using two mouse models, a conventionalslc6a15knock-out mouse line (SLC-KO) and a virus-mediated hippocampalslc6a15overexpression (SLC-OE) model. Mice were tested under basal conditions and following chronic social stress. We found that SLC-KO animals displayed a similar behavioral profile to wild-type littermates (SLC-WT) under basal conditions. Interestingly, following chronic social stress SLC-KO animals showed lower levels of anxiety- and depressive-like behavior compared to stressed WT littermates. In support of these findings, SLC-OE animals displayed increased anxiety-like behavior already under basal condition. We also provide evidence that GluR1 expression in the dentate gyrus, but not GluR2 or NR1, are regulated byslc6a15expression, and may contribute to the difference in stress responsiveness observed between SLC-KO and SLC-WT animals. Taken together, our data demonstrate thatslc6a15plays a role in modulating emotional behavior, possibly mediated by its impact on glutamatergic neurotransmission. [ABSTRACT FROM PUBLISHER]

This narrative review aims to describe the current status of contrast-enhanced ultrasound (CEUS) in characterizing renal cystic lesion. The imaging techniques usually performed for their evaluation are ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) with different criteria of application based on the individual case and the purpose of the examination. Generally, US, as a non-ionizing examination, is the first imaging modality performed and therefore the one that incidentally detects cystic lesions. CT is the most performed imaging modality for cystic lesion assessment before MRI evaluation. It provides better characterization and management and has been introduced into the Bosniak classification. In this context, CEUS is making its way for its characteristics and represents the emerging technique in this field. With these premises, the authors analyze the role of CEUS in the evaluation of renal cysts, starting with an explanation of the technique, describe its main advantages and limitations, and end with a discussion of its application in the Bosniak classification and management, following the current major guidelines., (© 2024. The Author(s).)

The procedure of peritoneal dialysis (PD) catheter placement is of utmost importance for a good outcome of peritoneal dialysis. Currently, catheters are mainly placed by surgeons and interventional nephrologists. Still, there is a lack of trained personnel in many dialysis units, which can impair the efficiency of PD units and reduce the patients' possibility to enter a PD programme. The Italian Society of Nephrology has endorsed a practical core curriculum for interventional nephrology in PD available on the Society website, which is here reported for the wider nephrology community. The topics addressed are the hernias of the abdominal wall, catheter placement with standard surgical open technique, basic video-laparoscopy, advanced video-laparoscopy, video-laparoscopic cholecystectomy and catheter placement, cuff-shaving and video-laparoscopy in catheter malfunction., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives : To define if the use of proton pump inhibitors (PPI) is associated with PDF prevalence and characteristics and with time of recovery after dialysis in patients on maintenance hemodialysis. Methods : Patients were defined as experiencing PDF if they spontaneously offered this complaint when asked the open-ended question: "Do you feel fatigued after dialysis?". Time of recovery after dialysis (TIRD) was also assessed for each patient. Each patient was invited to rate the intensity, duration and frequency of PDF from 1 to 5. We defined if patients used PPI (no PPI use or PPI use), the type of used PPI, the dose of used PPI, and the duration of the use of PPI (<1 year or ≥1 year). Results : A total of 346 patients were studied: 259 used PPI (55 used omeprazole, 63 esomeprazole, 54 pantoprazole, 87 lansoprazole, and 7 rabeprazole) and 87 did not. Two hundred and thirty-two patients declared PDF and 114 did not. The median [min-max] TIRD was 210 min [0-1440]. The prevalence of PDF in PPI users and PPI non-users was 67% and 68%, respectively ( p = 0.878). The median [min-max] TIRD did not differ significantly between PPI users and PPI non-users (180 [0-1440] and 240 [0-1440], respectively; p = 0.871). Median PDF intensity, duration, frequency, and severity did not differ significantly between PPI use and no use. The prevalence of PDF was similar among the different types of PPI use and did not differ with respect to PPI non-users. Duration of PPI exposure was <1 year in 40 patients and ≥1 year in 219 patients. The prevalence of PDF did not differ between the two exposures. The correlation matrix between PPI equivalent dose, PPI treatment duration and PDF frequency, PDF characteristics, and TIRD showed whether there was statistical significance. Conclusions : The use of PPI is not associated with PDF and time of recovery after dialysis in patients on maintenance hemodialysis.

Purpose: Little is known about the relationships between apathy, depressive symptoms and interdialytic weight gain (IDWG) in patients on chronic hemodialysis. Aim of the present study is to investigate the association between IDWG and symptoms of depression and apathy in hemodialysis patients., Methods: A total of 139 chronic patients of the HD units between January 2020 and December 2021 were included in the present cross-sectional study. IDWG was calculated as the difference between the pre-HD weight and the weight registered after the previous session; the average of the sessions in a month was registered. Apathy Evaluation Scale (AES) was adopted to evaluate apathy. Depression was assessed by Beck Depression Inventory (BDI)., Results: Ninety-three patients had IDWG% ≤ 4 and 46 had an IDWG% > 4. Correlation between IDWG% and BDI as well that between IDWG% and AES were not statistically significant. Median BDI and mean AES did not differ significantly between the groups. In addition, 104 patients had a BDI < 16 and 35 had a BDI ≥ 6. Seventy-five patients had an AES score ≤ 35 and 63 had a AES score > 35. The IDWG (kg) and the IDWG% did not differ significantly between the two groups., Conclusion: IDWG is not associated with symptoms of depression or apathy in hemodialysis patients. Thus, these results may question if the use of behavioral intervention aimed at improving motivation is warranted in the hemodialysis population to reduce the IDWG., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington's disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer's disease (APP, Tau) Parkinson's disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Santarelli, Londero, Soldano, Candelaresi, Todeschini, Vernizzi and Bellosta.)

Introduction: The present cross-sectional study aimed to compare the prevalence, the characteristics of post-dialysis fatigue and the length of recovery time after hemodialysis in prevalent end-stage renal disease patients (ESRD) receiving bicarbonate hemodialysis (HD) or hemodiafiltration (HDF)., Methods: Patients were suffering from post-dialysis fatigue if they spontaneously offered this complaint when asked the open-ended question: "Do you feel fatigued after dialysis?". Moreover, each patient was invited to rate the intensity, duration, and frequency of post-dialysis fatigue from 1 to 5. In order to assess RECOVERY TIME AFTER DIALYSIS, patients were invited to answer to the following single open-ended question: "How long does it take you to recover from a dialysis session?", Findings: We included 335 patients: 252 received HD and 83 received HDF. Post-dialysis fatigue was present in 204 patients (60.9%). Prevalence of post-dialysis fatigue did not differ significantly between patients on HD (62.3%) and on HDF (56.6%; p = 0.430). Median recovery time after dialysis was 180 min [180-240] and did not differ significantly between the two subgroups (180 min [130-240] and 240 min [120-332] p = 0.671, respectively). Median post-dialysis fatigue intensity, duration, and frequency were 3 [1-5], 3 [1-5], and 4 [1-5] and did not differ significantly between patients on HD and on HDF. At the multivariate analysis, age, ADL and hemoglobin levels were the independent predictors of the HDF treatment., Discussion: Prevalence and characteristics of post-dialysis fatigue do not differ significantly between patients receiving bicarbonate HD or HDF., (© 2022 The Authors. Hemodialysis International published by Wiley Periodicals LLC on behalf of International Society for Hemodialysis.)

NOC1 is a nucleolar protein necessary in yeast for both transport and maturation of ribosomal subunits. Here, we show that Drosophila NOC1 (annotated CG7839) is necessary for rRNAs maturation and for a correct animal development. Its ubiquitous downregulation results in a dramatic decrease in polysome level and of protein synthesis. NOC1 expression in multiple organs, such as the prothoracic gland and the fat body, is necessary for their proper functioning. Reduction of NOC1 in epithelial cells from the imaginal discs results in clones that die by apoptosis, an event that is partially rescued in a Minute/+ background, suggesting that reduction of NOC1 induces the cells to become less fit and to acquire a 'loser' state. NOC1 downregulation activates the pro-apoptotic Eiger-JNK pathway and leads to an increase of Xrp1, which results in the upregulation of DILP8, a member of the insulin/relaxin-like family known to coordinate organ growth with animal development. Our data underline NOC1 as an essential gene in ribosome biogenesis and highlight its novel functions in the control of growth and cell competition., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Introduction: This study explores the link between fatigue and apathy in patients on chronic hemodialysis (HD)., Methods: One hundred thirty-nine chronic HD patients underwent the assessment of fatigue, apathy, depression, and their functional status, with the fatigue severity scale (FSS), the Apathy Evaluation Scale (AES), the beck depression inventory (BDI), the activity of daily living (ADL), and instrumental activity of daily living (IADL)., Results: Patients with high FSS had a significantly lower ADL and IADL score, higher BDI, Charlson Comorbidity Index, and AES score, and lower serum levels of creatinine, compared to low FSS patients. FSS was highly correlated with the AES, as well as with the BDI and the AES correlates with the BDI. At multiple regression analyses, only apathy and IADL were independent predictor variables of fatigue in HD population., Conclusion: Future longitudinal studies could determine if apathy is a causative factor for fatigue manifestation and development in HD patients., (© 2021 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

A gastrosplenic fistula is a rare complication of primary splenic lymphoma and a rare cause of massive upper gastrointestinal haemorrhage. We report a case of a spontaneous gastrosplenic fistula secondary to splenic large B-cell lymphoma. The patient was admitted to the emergency department with haematemesis. Oesophagogastroduodenoscopy showed a deep gastric ulcer, and a subsequent CT scan revealed a gastrosplenic fistula. Gastric biopsy demonstrated gastric mucosa with infiltration by large lymphoid cells. A multidisciplinary discussion on the management of this case was conducted. Primary surgical treatment of the fistula was not deemed indicated because the bleeding had stopped. The patient was stabilized, transfused, and then transferred to the oncology unit for chemotherapy. During hospitalization, lung metastases were found but the progressive worsening of the patient's general condition contraindicated chemotherapy. She was transferred to a hospice and died 2 months later of neoplastic cachexia. Gastrosplenic fistula is a rare condition. Prompt recognition of the underlying pathology can save the patient's life. We aim to highlight this rare complication of splenic lymphoma, discuss the presenting signs and symptoms, and explore the management options., Learning Points: A gastrosplenic fistula is a rare complication of primary splenic lymphoma.It can cause massive upper gastrointestinal haemorrhage.Our patient was managed without surgery but died 2 months later from neoplastic cachexia., Competing Interests: Conflicts of Interests: The authors declare there are no competing interests., (© EFIM 2022.)

Introduction: Penile traction therapy (PTT) and vacuum erection devices (VED) are nonsurgical conservative treatment options that have been used in the treatment of various urologic and sexual disorders such as Peyronie's Disease (PD) and Erectile Dysfunction (ED). Recently expanded uses for these therapies now include penile lengthening and with surgical interventions such as penile prosthesis surgery (PPS) and radical prostatectomy (RP). These devices can be used as both monotherapy or combination therapy., Objectives: To review the indications and clinical studies for PTT and VED., Methods: A literature search was conducted using PubMed to identify relevant studies addressing PTT, VED, and their indications. Searched terms included penile traction therapy, penile traction device, vacuum erection device, Peyronie's disease, penile prosthesis, radical prostatectomy, subjectively small penis, penile lengthening, erectile dysfunction., Results: PTT with dynamic traction devices has shown favorable benefits for PD in many studies. The benefits of VED for PD cannot be confirmed due to limited studies with poor quality. In posterior urethroplasty, VED shows promise postoperatively, with additional trials also needed. In PPS, both PTT and VED have had positive findings in pre- and postoperative treatment. In RP patients, VED use has had positive outcomes while new literature shows beneficial effects of dynamic PTT and provides a basis for future studies. VED use does not show great benefit in patients with small penis, however PTT does have some positive findings. In ED, VED has a history of successful use and PTT has promising new data available., Conclusion: PTT and VED have been utilized in urologic and sexual conditions with various success. Several promising areas utilizing both PTT and VED are being studied, however, more research needs to be done in these areas prior to becoming a standard treatment. Mehr J, Santarelli S, Green TP, et al. Emerging Roles of Penile Traction Therapy and Vacuum Erectile Devices. Sex Med Rev 2022;10:414-426., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Unplanned readmission/bounceback to the intensive care unit (ICUBB) is a prevalent issue in the medical community. The geriatric population is incompletely studied in regard to ICUBB. We sought to determine if ICUBB in older patients was associated with higher risk of mortality. We hypothesized that, of those who were older, those with ICUBB would have higher mortality compared to those with no ICUBB. Further, we hypothesized that of those with ICUBB, older age would lead to higher mortality., Methods: The Pennsylvania Trauma Outcome Study database was retrospectively queried from 2003 to 2018 for all trauma patients of age ≥40 years. Those with advance directives were excluded. Adjusted analysis in the form of logistic regressions controlling for demographic and injury covariates and clustering by facility were used to assess the adjusted impact of ICUBB and age on mortality., Results: 363,778 patients were aged ≥40 years. When comparing mortalities between the age 40 and 49 years group and those in older groups, a dramatic increase in mortality was observed between those in each respective age category with ICUBB vs non-ICUBB. This trend was most prominent in those in the 90+ years age group (ICUBB: AOR: 34.78, P < .001; non-ICUBB: AOR: 9.08, P < .001). A second model only including patients who had ICUBB found that patients of age ≥65 years had significantly higher odds of mortality (AOR: 4.10, P < .001) when compared to their younger counterparts (age <65 years)., Discussion: An ICUBB seems to exacerbate mortality rates as age increases. This profound increase in mortality calls for strategies to be developed, especially in the older population, to attempt to mitigate the factors leading to ICUBB.

Background: The approach to peritoneal catheter malfunction consists usually in a diagnostic and therapeutic sequence of laxative prescription, abdominal radiography, brushing of the catheter, guide-wire manipulation or fluoroscopy and in the end of a videolaparoscopy (VLS) rescue intervention. Ultrasound (US) is able to find out major causes of peritoneal catheter malfunction, however without a clearly defined diagnostic value. The aim of the study was to validate the diagnostic capability of US in catheter malfunction compared to the diagnostic reference of VLS., Methods: US scans of the subcutaneous and intraperitoneal segment of the catheter were performed prior to a VLS intervention in 40 adult patients presenting persistent catheter malfunction within a prospective multicentre study. Laxative prescription and brushing of the catheter lumen were undertaken prior to US scan. US diagnosis was compared to the corresponding at VLS, kappa coefficient calculated and the causes of mismatch analysed., Results: In US, causes of persistent malfunction were catheter dislocation combined with omental wrapping in 21 cases, omental wrapping without dislocation in 11 cases, dislocation only in 4 cases, adherences to non-omental structures in 3 cases and entrapment in the lateral inguinal fossa in 1 case. The US diagnosis corresponded to the respective at VLS in 36 of 40 cases, resulting in a kappa coefficient of 0.89 (95% CI: 0.78-1.00). The discrepancies were due to improper visualization of the catheter between omentum and intestinal loops, resulting in an erroneous US diagnosis of omental wrapping., Conclusions: This study suggests that US might have a pivotal role in the diagnostic approach to peritoneal catheter dysfunction.

Prostate cancer (PCa), in particular, is known to cause significant psychosocial distress during the duration of a patient's treatment due to its uncertainty and demasculinizing side effects. Prostate cancer support groups (PCSGs) have been proven to be beneficial, yet are underutilized by the majority of PCa patients and physicians. A thorough review of the literature was performed for articles pertaining to prostate cancer support groups. We sought to identify factors contributing to the psychological burden of the disease, factors that influenced patients to join, and barriers to participation in a PCSG. Additionally, the characteristics and format of PCSGs, as well as outcomes (i.e. quality of life), were evaluated., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Santarelli et al.)

Background: Although frequent and debilitating, little is known about the characteristics of post-dialysis fatigue (PDF)., Objective: To characterise the intensity, duration and frequency of PDF and the associated variables in patients on chronic haemodialyses., Design: Prospective, observational and multicenter study., Patients: We studied 271 patients., Measurements: Patients were considered to be suffering from PDF if they spontaneously offered this complaint when asked the open-ended question: "Do you feel fatigued after dialysis? Then, each patient was invited to rate the intensity, duration and frequency of PDF from 1 to 5., Results: One hundred sixty-four patients (60.5%) had PDF. The median [95% confidence interval (CI)] scores of PDF intensity, duration and frequency were 3 (3-4), 3 (3-4) and 4 (4-4), respectively. The median (95% CI) of the sum of the scores (Sum Score) of PDF intensity, duration and frequency was 11 (10-12). Seventy four patients had a Sum Score ≥ 12. Using multiple regression analysis, PDF intensity was associated with dialytic age and ultrafiltration rate (UFR), PDF duration with dialytic age, while PDF fatigue frequency was associated with height. The Sum Score was associated with dialytic age and recovery time and negatively associated with daily activity, height and UFR (ml/kg/h)., Conclusion: The intensity, duration and frequency of PDF are high in a large percentage of patients, suggesting that PDF is an intense event in terms of quantity and quality. Understanding the relationship between the variables associated with PDF and its intensity, duration and frequency may help better understand the underlying mechanisms of this burdensome condition., (© 2020 European Dialysis and Transplant Nurses Association/European Renal Care Association.)

Background : To measure daily sodium intake in patients on chronic hemodialysis and to compare the intake of nutrients, minerals, trace elements, and vitamins in patients who had a daily sodium intake below or above the value of 1500 mg recommended by the American Heart Association. Methods : Dietary intake was recorded for 3 days by means of 3-day diet diaries in prevalent patients on chronic hemodialysis. Each patient was instructed by a dietitian on how to fill the diary, which was subsequently signed by a next of kin. Results : We studied 127 patients. Mean sodium intake (mg) was 1295.9 ± 812.3. Eighty-seven (68.5%) patients had a daily sodium intake < 1500 mg (group 1) and 40 (31.5%) ≥ 1500 mg (group 2). Correlation between daily sodium intake and daily calorie intake was significant ( r = 0.474 [0.327 to 0.599]; p < 0.0001). Daily calorie intake (kcal/kg/day) was lower in group 1 (21.1 ± 6.6; p = 0.0001) than in group 2 (27.1 ± 10.4). Correlation between daily sodium intake and daily protein intake was significant (r = 0.530[0.392 to 0.644]; p < 0.0001). The daily protein intake (grams/kg/day) was lower in group 1 (0.823 ± 0.275; p = 0.0003) than in group 2 (1.061 ± 0.419). Daily intake of magnesium, copper, iron, zinc, and selenium was significantly lower in group 1 than in group 2. Daily intake of vitamin A, B2, B3, and C did not differ significantly between group 1 and group 2. Daily intake of vitamin B1 was significantly lower in group 1 than in group 2. Significantly lower was, in group 1 than in group 2, the percentage of patients within the target value with regard to intake of calories (11.5% vs. 37.5%; p = 0.001) and proteins (9.2% vs. 27.5%; p = 0.015) as well as of iron (23% vs. 45%; p = 0.020), zinc (13.8% vs. 53.8%; p = 0.008) and vitamin B1 (8.1% vs. 50%; p < 0.001). Conclusion : A low daily intake of sodium is associated with an inadequately low intake of calorie, proteins, minerals, trace elements, and vitamin B1. Nutritional counselling aimed to reduce the intake of sodium in patients on chronic hemodialysis should not disregard an adequate intake of macro- and micronutrients, otherwise the risk of malnutrition is high., Competing Interests: The authors declare no conflict of interest.

Glutamine Synthetase 1 (GS1) is a key enzyme that catalyzes the ATP-dependent synthesis of l-glutamine from l-glutamate and is also member of the Glutamate Glutamine Cycle, a complex physiological process between glia and neurons that controls glutamate homeostasis and is often found compromised in neurodegenerative diseases including Huntington's disease (HD). Here we report that the expression of GS1 in neurons ameliorates the motility defects induced by the expression of the mutant Htt, using a Drosophila model for HD. This phenotype is associated with the ability of GS1 to favor the autophagy that we associate with the presence of reduced Htt toxic protein aggregates in neurons expressing mutant Htt. Expression of GS1 prevents the TOR activation and phosphorylation of S6K, a mechanism that we associate with the reduced levels of essential amino acids, particularly of arginine and asparagine important for TOR activation. This study reveals a novel function for GS1 to ameliorate neuronal survival by changing amino acids' levels that induce a "starvation-like" condition responsible to induce autophagy. The identification of novel targets that inhibit TOR in neurons is of particular interest for the beneficial role that autophagy has in preserving physiological neuronal health and in the mechanisms that eliminate the formation of toxic aggregates in proteinopathies.

The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2 +/- mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2 +/- mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2 +/- mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes. Autism Research 2019, 12: 732-743. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

Early-life adversity is an important risk factor for major depressive disorder (MDD) and schizophrenia (SCZ) that interacts with genetic factors to confer disease risk through mechanisms that are still insufficiently understood. One downstream effect of early-life adversity is the activation of glucocorticoid receptor (GR)-dependent gene networks that drive acute and long-term adaptive behavioral and cellular responses to stress. We have previously shown that genetic variants that moderate GR-induced gene transcription (GR-response eSNPs) are significantly enriched among risk variants from genome-wide association studies (GWASs) for MDD and SCZ. Here, we show that the 63 transcripts regulated by these disease-associated functional genetic variants form a tight glucocorticoid-responsive co-expression network (termed GCN). We hypothesized that changes in the correlation structure of this GCN may contribute to early-life adversity-associated disease risk. Therefore, we analyzed the effects of different qualities of social support and stress throughout life on GCN formation across distinct brain regions using a translational mouse model. We observed that different qualities of social experience substantially affect GCN structure in a highly brain region-specific manner. GCN changes were predominantly found in two functionally interconnected regions, the ventral hippocampus and the hypothalamus, two brain regions previously shown to be of relevance for the stress response, as well as psychiatric disorders. Overall, our results support the hypothesis that a subset of genetic variants may contribute to risk for MDD and SCZ by altering circuit-level effects of early and adult social experiences on GCN formation and structure.

Introduction: The present study aimed to determine the variables that are associated with a longer dialysis recovery time (DRT) and to define the relationship that exists between DRT and the ultrafiltration rate (UFR) in prevalent chronic hemodialysis (CHD) patients., Methods: We studied 210 prevalent CHD of 5 hemodialysis units in Central Italy. Patients were invited to answer to the question: "How long does it take you to recover from a dialysis session?" Answers to this question were subsequently converted into minutes. Demographic, clinical and laboratory parameters were recorded for each patient as well as the UFR (mL/kg/h), the dialysate sodium concentration and temperature., Results: Median DRT was 180 min (60-420). Ninety five (45%) patients had a DRT ≥ the median value. Mean UFR was 9.2 ± 3.0 mL/kg/h. Patients with a lower DRT had a less prevalent disability in the instrumental activities daily living, had a higher UFR, and a lower dialysate temperature, as compared with subjects with higher DRT. According to the logistic regression model, UFR was associated with a DRT below the median (i.e., 180) in the unadjusted model (OR 1.12; 95% CI 1.02-1.23; p = 0.019), after adjusting for age and sex (OR 1.11; 95% CI 1.01-1.22; p = 0.025), and in the fully adjusted model (OR 1.11; 95% CI 1.04-1.22; p = 0.040). UFR increase was associated with increasing probability of DRT below the median (p for trend = 0.035). The highest tertile of DRT was associated with UFR below the mean value (i.e., 9.2 mL/kg/h) in multinomial logistic regression having the lowest DRT tertile as reference. DRT was significantly lower in patients with UFR > 13 mL/kg/h than in patients with UFR 10-13 or < 10 mL/kg/h., Conclusion: DRT is inversely associated with UFR in CHD patients. Whether a high UFR should be recommended to reduce the DRT needs to be elucidated through an adequate prospective randomized study., (© 2018 S. Karger AG, Basel.)

Identifying molecular targets that are able to buffer the consequences of stress and therefore restore brain homeostasis is essential to develop treatments for stress-related disorders. Down-regulated in renal cell carcinoma 1 (DRR1) is a unique stress-induced protein in the brain and has been recently proposed to modulate stress resilience. Interestingly, DRR1 shows a prominent expression in the limbic system of the adult mouse. Here, we analyzed the neuroanatomical and cellular expression patterns of DRR1 in the adult mouse brain using in situ hybridization, immunofluorescence and Western blot. Abundant expression of DRR1 mRNA and protein was confirmed in the adult mouse brain with pronounced differences between distinct brain regions. The strongest DRR1 signal was detected in the neocortex, the CA3 region of the hippocampus, the lateral septum and the cerebellum. DRR1 was also present in circumventricular organs and its connecting regions. Additionally, DRR1 was present in non-neuronal tissues like the choroid plexus and ependyma. Within cells, DRR1 protein was distributed in a punctate pattern in several subcellular compartments including cytosol, nucleus as well as some pre- and postsynaptic specializations. Glucocorticoid receptor activation (dexamethasone 10 mg/kg s.c.) induced DRR1 expression throughout the brain, with particularly strong induction in white matter and fiber tracts and in membrane-rich structures. This specific expression pattern and stress modulation of DRR1 point to a role of DRR1 in regulating how cells sense and integrate signals from the environment and thus in restoring brain homeostasis after stressful challenges.

The aim of the present study was to determine the intensity, duration, frequency and prevalence of postdialysis fatigue (PDF) in patients on chronic hemodialysis (PCD) with and without functional disability. Patients underwent assessment of functional ability by the Katz ADL (activity daily living) questionnaire and the Lawton and Brody scale for the instrumental activity daily living (IADL) fatigue using the SF-36 Vitality Subscale, comorbidity through the Charlson comorbidity score index (CDI), and time of recovery after hemodialysis (TIRD). We studied 271 PCD. ADL and IADL disabilities were present in 75 (27.6%) and 168 (62%) patients, respectively. Patients with ADL disability were significantly older and showed higher CDI scores, and lower levels of serum albumin and Kt/V. Prevalence of PDF was significantly higher in patients with ADL disability as well as its severity, intensity, duration and frequency. Patients with IADL disability were significantly older, had a higher CCI score, had lower levels of serum albumin and Kt/V, and had a higher severity, intensity, duration and frequency of PDF. At multivariate regression analysis, ADL disability was positively associated with age, prevalence and severity of PDF, and dialysate temperature and inversely associated with serum albumin levels. IADL disability was instead positively associated with age and dialysate temperature and inversely associated with serum albumin levels. In conclusion, prevalence and severity of PDF are significantly higher in PCD with ADL disability than in those without it. This knowledge may have important implications for the development of interventions to reduce PDF in PCD., (© 2018 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Aim: The study aims to determine prevalence and severity of PDF and to define its associated variables., Methods: In five haemodialysis units of northern-centre Italy, patients were regarded to suffer from PDF if they spontaneously offered this complaint when asked the open-ended question: Do you feel better or worse after dialysis? If worse, please specify in which way. A complaint of fatigue would be probed further with questions directed at its duration, frequency and intensity, allowing creation of a fatigue index of severity (one third of the sum of these three parameters, each rated from 1 to 5). Patients were stratified into three groups according the severity of PDF: 1) score = 0; 2) score = 1-3; 3) score > 3., Results: We studied 271 patients: 164 had PDF and 107 did not. PDF patients had significantly longer time of recovery after dialysis (TIRD). TIRD was significantly associated with PDF duration, intensity, and frequency. Patients with PDF were older and had a lower ADL score. At multivariate analysis, PDF was significantly associated with TIRD. In a multivariate model that did not include TIRD, PDF was independently associated with age and ADL. Sixty patients had moderate PDF and 104 had severe PDF. In patients with severe PDF, age and dialytic age were higher, ADL and IADL scores were lower, TIRD was longer and the ultrafiltration rate was lower. At multivariate analysis, PDF severity was independently associated with TIRD. In the model without TIRD, PDF severity was associated with ADL only., Conclusion: Post-dialysis fatigue is frequent and associated with age and ADL. Dialytic variables seem unrelated to PDF., (© 2017 Asian Pacific Society of Nephrology.)

Response to antidepressant treatment in major depressive disorder (MDD) cannot be predicted currently, leading to uncertainty in medication selection, increasing costs, and prolonged suffering for many patients. Despite tremendous efforts in identifying response-associated genes in large genome-wide association studies, the results have been fairly modest, underlining the need to establish conceptually novel strategies. For the identification of transcriptome signatures that can distinguish between treatment responders and nonresponders, we herein submit a novel animal experimental approach focusing on extreme phenotypes. We utilized the large variance in response to antidepressant treatment occurring in DBA/2J mice, enabling sample stratification into subpopulations of good and poor treatment responders to delineate response-associated signature transcript profiles in peripheral blood samples. As a proof of concept, we translated our murine data to the transcriptome data of a clinically relevant human cohort. A cluster of 259 differentially regulated genes was identified when peripheral transcriptome profiles of good and poor treatment responders were compared in the murine model. Differences in expression profiles from baseline to week 12 of the human orthologues selected on the basis of the murine transcript signature allowed prediction of response status with an accuracy of 76% in the patient population. Finally, we show that glucocorticoid receptor (GR)-regulated genes are significantly enriched in this cluster of antidepressant-response genes. Our findings point to the involvement of GR sensitivity as a potential key mechanism shaping response to antidepressant treatment and support the hypothesis that antidepressants could stimulate resilience-promoting molecular mechanisms. Our data highlight the suitability of an appropriate animal experimental approach for the discovery of treatment response-associated pathways across species.

The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.

Background  Malfunction of the peritoneal dialysis catheter is frequently caused by dislocation. The diagnostic approach is classically based on abdomen X-ray together with detailed case history and physical examination. Despite being rarely applied in clinical practice to evaluate catheter misplacement, ultrasound is a noninvasive, radiation-free technique that is potentially useful also to explore reasons for catheter malfunction. Consequently, we aimed to evaluate the diagnostic accuracy of ultrasound to identify peritoneal catheter misplacement. Methods  In a multicenter observational blinded study, we compared ultrasound to abdomen X-ray for catheter localization in 93 consecutive peritoneal dialysis patients with dialysate outflow problems enrolled in two nephrology and dialysis units. The position of the catheter was annotated on a standard scheme of nine abdominopelvic regions. The sensitivity, specificity, positive and negative predictive value and Kappa coefficient were calculated. Results  Dislocation out of the inferior abdominopelvic regions was present in 19 patients (20 %) at X-ray and 23 patients (25 %) at ultrasound. Correct determination of the position of the catheter in the lower abdomen by ultrasound had a sensitivity of 93 % (95 % CI 84 - 97 %), specificity of 95 % (95 % CI 72 - 100 %), positive predictive value of 99 % (95 % CI 91 - 100 %), negative predictive value of 78 % (95 %CI 56 - 92 %) and Kappa coefficient of 0.82 (95 % CI 0.67 - 0.96). In 10 out of 93 patients (11 %), there was a position mismatch between X-ray and ultrasound in an adjacent abdominopelvic region. Conclusion  Our results suggest that abdomen X-ray for the evaluation of peritoneal catheter position can be replaced by ultrasound in experienced hands. This bedside diagnostic procedure might reduce costs, the time necessary for diagnosis and lifetime radiation exposure., Competing Interests: Conflict of Interest: No conflict if interest has been declared by the author(s)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: The objective of this study was to investigate the prognostic role of quantitative reduction of congestion during hospitalization assessed by Bioelectrical Impedance Vector Analysis (BIVA) serial evaluations in patients admitted for acute heart failure (AHF)., Background: AHF is a frequent reason for patients to be admitted. Exacerbation of chronic heart failure is linked with a progressive worsening of the disease with increased incidence of death. Fluid overload is the main mechanism underlying acute decompensation in these patients. BIVA is a validated technique able to quantify fluid overload., Methods: a prospective, multicentre, observational study in AHF and no AHF patients in three Emergency Departments centres in Italy. Clinical data and BIVA evaluations were performed at admission (t0) and discharge (tdis). A follow-up phone call was carried out at 90 days., Results: Three hundred and thirty-six patients were enrolled (221 AHF and 115 no AHF patients). We found that clinical signs showed the most powerful prognostic relevance. In particular the presence of rales and lower limb oedema at tdis were linked with events relapse at 90 days. At t0, congestion detected by BIVA was observed only in the AHF group, and significantly decreased at tdis. An increase of resistance variation (dR/H) >11 Ω/m during hospitalization was associated with survival. BIVA showed significant results in predicting total events, both at t0 (area under the curve (AUC) 0.56, p<0.04) and at tdis (AUC 0.57, p<0.03). When combined with clinical signs, BIVA showed a very good predictive value for cardiovascular events at 90 days (AUC 0.97, p<0.0001)., Conclusions: In AHF patients, an accurate physical examination evaluating the presence of rales and lower limbs oedema remains the cornerstone in the management of patients with AHF. A congestion reduction, obtained as a consequence of therapies and detected through BIVA analysis, with an increase of dR/H >11 Ω/m during hospitalization seems to be associated with increased 90 day survival in patients admitted for AHF.

Heart failure is a disease characterized by high prevalence and mortality, and frequent rehospitalizations. The aim of this study is to investigate the prognostic power of combining brain natriuretic peptide (BNP) and congestion status detected by bioelectrical impedance vector analysis (BIVA) in acute heart failure patients. This is an observational, prospective, and a multicentre study. BNP assessment was measured upon hospital arrival, while BIVA analysis was obtained at the time of discharge. Cardiovascular deaths were evaluated at 90 days by a follow up phone call. 292 patients were enrolled. Compared to survivors, BNP was higher in the non-survivors group (mean value 838 vs 515 pg/ml, p < 0.001). At discharge, BIVA shows a statistically significant difference in hydration status between survivors and non-survivors [respectively, hydration index (HI) 85 vs 74, p < 0.001; reactance (Xc) 26.7 vs 37, p < 0.001; resistance (R) 445 vs 503, p < 0.01)]. Discharge BIVA shows a prognostic value in predicting cardiovascular death [HI: area under the curve (AUC) 0.715, 95% confidence interval (95% CI) 0.65-0.76; p < 0.004; Xc: AUC 0.712, 95% CI 0.655-0.76, p < 0.007; R: AUC 0.65, 95% CI 0.29-0.706, p < 0.0247]. The combination of BIVA with BNP gives a greater prognostic power for cardiovascular mortality [combined receiving operating characteristic (ROC): AUC 0.74; 95% CI 0.68-0.79; p < 0.001]. In acute heart failure patients, higher BNP levels upon hospital admission, and congestion detected by BIVA at discharge have a significant predictive value for 90 days cardiovascular mortality. The combined use of admission BNP and BIVA discharge seems to be a useful tool for increasing prognostic power in these patients.

Chronic stress is a major risk factor for depression. Interestingly, not all individuals develop psychopathology after chronic stress exposure. In contrast to the prevailing view that stress effects are cumulative and increase stress vulnerability throughout life, the match/mismatch hypothesis of psychiatric disorders. The match/mismatch hypothesis proposes that individuals who experience moderate levels of early life psychosocial stress can acquire resilience to renewed stress exposure later in life. Here, we have tested this hypothesis by comparing the developmental effects of 2 opposite early life conditions, when followed by 2 opposite adult environments. Male Balb/c mice were exposed to either adverse early life conditions (limited nesting and bedding material) or a supportive rearing environment (early handling). At adulthood, the animals of each group were either housed with an ovariectomized female (supportive environment) or underwent chronic social defeat stress (socially adverse environment) for 3 weeks. At the end of the adult manipulations, all of the animals were returned to standard housing conditions. Then, we compared the neuroendocrine, behavioral and molecular effects of the interaction between early and adult environment. Our study shows that early life adversity does not necessarily result in increased vulnerability to stress. Specific endophenotypes, like hypothalamic-pituitary-adrenal axis activity, anxiety-related behavior and glucocorticoid receptor expression levels in the hippocampus were not significantly altered when adversity is experienced during early life and in adulthood, and are mainly affected by either early life or adult life adversity alone. Overall our data support the notion that being raised in a stressful environment prepares the offspring to better cope with a challenging adult environment and emphasize the role of early life experiences in shaping adult responsiveness to stress., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A total of 162 samples of bivalve molluscs (45 mussels and 117 clams) collected between December 2012 and 2014 from harvesting areas of the Central Adriatic were analysed by a culturing method for the presence of Arcobacter spp. Species identification was performed by PCR and sequencing analysis of a fragment of the rpoB gene. Overall, Arcobacter species were detected in 30% of samples, specifically 33% clams and 22% mussels. A. butzleri was the most common species (20% of the samples), followed by A. cryaerophilus (9%) and A. skirrowii (1%). A seasonal association of A. butzleri contamination was detected. A. butzleri was significantly more commonly recovered from samples collected during the winter-spring period (29%) than from those of the summer-autumn (8%). A. cryaerophilus was cultured from 6% to 11% of the samples collected in summer-autumn and winter-spring, respectively, but these differences were not statistically significant. A. skirrowii was recovered from a sample of mussels harvested in May 2014. To identify associations between the occurrence of Arcobacter spp. and E. coli levels, samples were divided into groups generating results with E. coli at >230MPN/100g and E. coli at ≤230MPN/100g, the latter corresponding to EU microbiological criteria allowed for live bivalve molluscs at retail level. A. butzleri was significantly more commonly detected in samples with higher E. coli levels (48%) than in those with lower levels of E. coli (10%), providing evidence for considering E. coli as an index organism for A. butzleri contamination in bivalve molluscs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

During the recent years, immigration in Italy has increased. There are few data on the health status of immigrants and there is a need to improve their healthcare. Cardiovascular disorders account for 7.6% of immigrants' diseases and cause 3.6% of the total deaths. Lack of healthcare services to general medicine support and prescriptions leads immigrants to contact the Emergency Department (ED) to receive medical assistance. Primary endpoints of this study were to assess the use of national healthcare system by immigrants and to determine the incidence of cardiovascular diseases, and the frequency and type of risk factors for cardiovascular diseases in these patients. A no-profit, observational, multicentre study was conducted from April to September 2012. We studied 642 foreign patients referring to the ED for various symptoms/signs. One hundred and fourteen patients referred for suspected cardiovascular disease and 105 had a confirmed final diagnosis of cardiovascular disease. The more represented ethnic origin was Caucasian (59%), whereas the most represented country was Romania (24%). The main symptom recorded at ED arrival was chest pain (37.1%). Final cardiovascular diagnoses were represented by: hypertensive crisis (28.5%), acute coronary syndrome (20%), acute heart failure (12.3%), atrial fibrillation (10.4%) and chest pain (10.4%). Past medical history of cardiovascular disease, hypertension, obesity and male sex showed independent significant predictive value for cardiovascular disease diagnosis.Our study provides support for the development of specific primary prevention of cardiovascular risk factors in immigrants with the important role of culturally competent education of individuals and families. Better outpatient management seems to be needed in order to limit the need for emergency room referral.

Background: The medial prefrontal cortex (mPFC) subserves complex cognition and is impaired by stress. Corticotropin-releasing factor (CRF), through CRF receptor 1 (CRFR1), constitutes a key element of the stress response. However, its contribution to the effects of stress in the mPFC remains unclear., Methods: Mice were exposed to acute social defeat stress and subsequently to either the temporal order memory (n = 11-12) or reversal learning (n = 9-11) behavioral test. Changes in mPFC Crhr1 messenger RNA levels were measured in acutely stressed mice (n = 12). Crhr1 loxP/loxP mice received either intra-mPFC adeno-associated virus-Cre or empty microinjections (n = 17-20) and then were submitted to acute stress and later to the behavioral tests. Co-immunoprecipitation was used to detect activation of the protein kinase A (PKA) signaling pathway in the mPFC of acutely stressed mice (n = 8) or intra-mPFC CRF injected mice (n = 7). Finally, mice received intra-mPFC CRF (n = 11) and/or Rp-isomer cyclic adenosine 3',5' monophosphorothioate (Rp-cAMPS) (n = 12) microinjections and underwent behavioral testing., Results: We report acute stress-induced effects on mPFC-mediated cognition, identify CRF-CRFR1-containing microcircuits within the mPFC, and demonstrate stress-induced changes in Crhr1 messenger RNA expression. Importantly, intra-mPFC CRFR1 deletion abolishes acute stress-induced executive dysfunction, whereas intra-mPFC CRF mimics acute stress-induced mPFC dysfunction. Acute stress and intra-mPFC CRF activate the PKA signaling pathway in the mPFC, leading to cyclic AMP response element binding protein phosphorylation in intra-mPFC CRFR1-expressing neurons. Finally, PKA blockade reverses the intra-mPFC CRF-induced executive dysfunction., Conclusions: Taken together, these results unravel a molecular mechanism linking acute stress to executive dysfunction via CRFR1. This will aid in the development of novel therapeutic targets for stress-induced cognitive dysfunction., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)