Modulation by chronic stress and ketamine of ionotropic AMPA/NMDA and metabotropic glutamate receptors in the rat hippocampus

Converging clinical and preclinical evidence has shown that dysfunction of the glutamate system is a core feature of major depressive disorder. In this context, the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has raised growing interest as fast acting antidepressant. Using the chronic mild stress (CMS) rat model of depression, performed in male rats, we aimed at analyzing whether hippocampal specific changes in subunit expression and regulation of \u3b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or NMDA ionotropic receptors and in metabotropic glutamate receptors could be associated with behavioral vulnerability/resilience to CMS. We also assessed whether acute ketamine (10 mg/kg) was able to dampen the alterations in CMS vulnerable animals. Although chronic stress and ketamine had no effect on ionotropic glutamate receptors mRNAs (expression, RNA editing and splicing), we found selective modulations in their protein expression, phosphorylation and localization at synaptic membranes. AMPA GluA2 expression at synaptic membranes was significantly increased only in CMS resilient rats (although a trend was found also in vulnerable animals), while its phosphorylation at Ser880 was higher in both CMS resilient and vulnerable rats, a change partially dampened by ketamine. In the hippocampus from all stressed groups, despite NMDA receptor expression levels were reduced in total extract, the levels of GluN2B-containing NMDA receptors were remarkably increased in synaptic membranes. Finally, mGlu2 underwent a selective downregulation in stress vulnerable animals, which was completely restored by acute ketamine. Overall, these results are in line with a hypofunction of activity-dependent glutamatergic synaptic transmission induced by chronic stress exposure in all the animals, as suggested by the alterations of ionotropic glutamate receptors expression and localization at synaptic level. At the same time, the selective modulation of mGlu2 receptor, confirms its previously hypothesized functional role in regulating stress vulnerability and, for the first time here, suggests a mGlu2 involvement in the fast antidepressant effect of ketamine

Dopamine-dependent ketamine modulation of glutamatergic synaptic plasticity in the prelimbic cortex of adult rats exposed to acute stress

Traumatic stress is the main environmental risk factor for the development of psychiatric disorders. We have previously shown that acute footshock (FS) stress in male rats induces rapid and long-lasting functional and structural changes in the prefrontal cortex (PFC), which are partly reversed by acute subanesthetic ketamine. Here, we asked if acute FS may also induce any changes in glutamatergic synaptic plasticity in the PFC 24 h after stress exposure and whether ketamine administration 6 h after stress may have any effect. We found that the induction of long-term potentiation (LTP) in PFC slices of both control and FS animals is dependent on dopamine and that dopamine-dependent LTP is reduced by ketamine. We also found selective changes in ionotropic glutamate receptor subunit expression, phosphorylation, and localization at synaptic membranes induced by both acute stress and ketamine. Although more studies are needed to understand the effects of acute stress and ketamine on PFC glutamatergic plasticity, this first report suggests a restoring effect of acute ketamine, supporting the potential benefit of ketamine in limiting the impact of acute traumatic stress

Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study

Background. Extending the administration interval of erythropoiesis-stimulating agents (ESAs) represents an opportunity to improve the efficiency of anaemia management in patients with chronic kidney disease (CKD). However, effective haemoglobin (Hb) maintenance can be challenging with epoetin alfa and epoetin beta administered at extended intervals. C.E.R.A., a continuous erythropoietin receptor activator, has a unique pharmacologic profile and long half-life (∼130 h), allowing administration at extended intervals. Phase III results have demonstrated that C.E.R.A. administered once every 4 weeks effectively maintains stable Hb levels in patients with CKD on dialysis

Functional and Molecular Changes in the Prefrontal Cortex of the Chronic Mild Stress Rat Model of Depression and Modulation by Acute Ketamine

Stress is a primary risk factor in the onset of neuropsychiatric disorders, including major depressive disorder (MDD). We have previously used the chronic mild stress (CMS) model of depression in male rats to show that CMS induces morphological, functional, and molecular changes in the hippocampus of vulnerable animals, the majority of which were recovered using acute subanesthetic ketamine in just 24 h. Here, we focused our attention on the medial prefrontal cortex (mPFC), a brain area regulating emotional and cognitive functions, and asked whether vulnerability/resilience to CMS and ketamine antidepressant effects were associated with molecular and functional changes in the mPFC of rats. We found that most alterations induced by CMS in the mPFC were selectively observed in stress-vulnerable animals and were rescued by acute subanesthetic ketamine, while others were found only in resilient animals or were induced by ketamine treatment. Importantly, only a few of these modifications were also previously demonstrated in the hippocampus, while most are specific to mPFC. Overall, our results suggest that acute antidepressant ketamine rescues brain-area-specific glutamatergic changes induced by chronic stress

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of na\uefve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites

Comparison of quality of life and causes of hospitalization between hemodialysis and peritoneal dialysis patients in China

<p>Abstract</p> <p>Background</p> <p>Hemodialysis (HD) and peritoneal dialysis (PD) are important renal replacement treatment in end stage renal disease (ESRD), but the comparison of quality of life (QOL) and causes of hospitalisation between the two modalities in China is lacking. In the present study, we compared the two modalities in a multi-center study.</p> <p>Subjects and methods</p> <p>Six hundred and fifty four HD and 408 PD patients were investigated from 10 hospitals in China from Sept, 2004 to Jan, 2005. Among the HD patients, there were 360 males and 294 females with a mean age of 57.22 ± 12.49 years (18–88 y). Among PD patients, there were 165 males and 243 females, with a mean age of 61.59 ± 12.65 years (22–89 y). Health related 36 items short form questionnaires (SF-36) were used to assess the quality of life. Hospitalisation data were collected and analyzed.</p> <p>Results</p> <p>SF-36 domains of Body Pain (BP), General Health (GH), Role-Emotional (RE), Social Functioning (SF), Vitality (VT) and Mental Health (MH) were all significantly higher in the PD patients as compared to the HD patients although there was no significant difference in Physical Functioning (PF) and Role-Physical (RP) between the two groups. The two most common causes of hospitalisation in HD patients were cardiovascular disease (39.8%) and pulmonary infection (21.3%), while they were infectious peritonitis (47.6%) and cardiovascular disease (31.9%) in PD patients. The ever hospitalised patients had lower SF-36 scores in the domains of PF, BP, GH, RE, SF, VT and MH as compared to those of non-hospitalised patients.</p> <p>Conclusion</p> <p>Our study indicated that with the current practice in China, PD patients may enjoy better quality of life than their HD counterparts. Our results also showed that the most common cause of hospitalisation was cardiovascular disease in HD patients and peritonitis in PD patients.</p

Criminalidade organizada nas prisões e os ataques do PCC

The advent of organized crime in Brazilian prisons, especially in the state of São Paulo, constitutes the object of this article. The waves of attack unleashed by the Capital's First Command (PCC - Primeiro Comando da Capital), in May 2006, which resulted in countless deaths, brought cities to a halt, and cornered authorities in charge preventing them from applying law and order are the starting as well as reference points taken. The advent of organized criminality is analyzed under the light of determined axes: the international scenario and the Brazilian context, the historical antecedents, the taking root of crime in society and the role of penitentiary public policies.A emergência da criminalidade organizada nas prisões brasileiras, em especial no Estado de São Paulo, constitui objeto deste artigo. Tomam-se como ponto de partida e referência para análise as ondas de ataques desencadeadas pelo Primeiro Comando da Capital (PCC), de maio a agosto de 2006, que resultaram em inúmeros mortos, paralisaram cidades e acuaram as autoridades encarregadas de aplicar lei e ordem. A emergência da criminalidade organizada é analisada sob eixos determinados: cenário internacional e contexto brasileiro, antecedentes históricos, enraizamento do crime na sociedade e papel das políticas públicas penitenciárias

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening