Dichotomous regulation of striatal plasticity by dynorphin.

Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) is regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bi-directionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) signaling in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin in D1 neurons show comparable motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bi-directionally modulate synaptic plasticity and behavior in the direct pathway.

Locomotion activates PKA through dopamine and adenosine in striatal neurons.

The canonical model of striatal function predicts that animal locomotion is associated with the opposing regulation of protein kinase A (PKA) in direct and indirect pathway striatal spiny projection neurons (SPNs) by dopamine1-7. However, the precise dynamics of PKA in dorsolateral SPNs during locomotion remain to be determined. It is also unclear whether other neuromodulators are involved. Here we show that PKA activity in both types of SPNs is essential for normal locomotion. Using two-photon fluorescence lifetime imaging8-10 of a PKA sensor10 through gradient index lenses, we measured PKA activity within individual SPNs of the mouse dorsolateral striatum during locomotion. Consistent with the canonical view, dopamine activated PKA activity in direct pathway SPNs during locomotion through the dopamine D1 receptor. However, indirect pathway SPNs exhibited a greater increase in PKA activity, which was largely abolished through the blockade of adenosine A2A receptors. In agreement with these results, fibre photometry measurements of an adenosine sensor11 revealed an acute increase in extracellular adenosine during locomotion. Functionally, antagonism of dopamine or adenosine receptors resulted in distinct changes in SPN PKA activity, neuronal activity and locomotion. Together, our results suggest that acute adenosine accumulation interplays with dopamine release to orchestrate PKA activity in SPNs and proper striatal function during animal locomotion.

Radiological evaluation of temporal bone surgical landmarks for a transcanal transpromontorial approach to the internal auditory canal using three-dimensional computed tomography.

OBJECTIVE: This study aimed to analyse a three-dimensional transcanal transpromontorial approach to the internal auditory canal using three-dimensional computed tomography. METHOD: This study was a retrospective investigation of 48 ears of 24 patients using three-dimensional reconstruction data from normal temporal bone computed tomography. The inner structures of the temporal bone were three-dimensionally reconstructed. Eight points were marked in the three-dimensional object with reference to the axial, coronal and sagittal plane images of the computed tomography scans. Distances and angles to each point were measured from the oval and round windows. RESULTS: The point of the facial nerve from the internal auditory canal to the labyrinthine segment could be traced between the cochlear apex and the geniculate ganglion based on the oval window. CONCLUSION: This technique helps with identifying the locations of important surgical landmarks using three-dimensional reconstructions of pre-operative computed tomography scans and to identify the facial nerve from the internal auditory canal during surgery.

Identification of cis-regulatory modules for adeno-associated virus-based cell-type-specific targeting in the retina and brain.

Adeno-associated viruses (AAVs) targeting specific cell types are powerful tools for studying distinct cell types in the central nervous system (CNS). Cis-regulatory modules (CRMs), e.g., enhancers, are highly cell-type-specific and can be integrated into AAVs to render cell type specificity. Chromatin accessibility has been commonly used to nominate CRMs, which have then been incorporated into AAVs and tested for cell type specificity in the CNS. However, chromatin accessibility data alone cannot accurately annotate active CRMs, as many chromatin-accessible CRMs are not active and fail to drive gene expression in vivo. Using available large-scale datasets on chromatin accessibility, such as those published by the ENCODE project, here we explored strategies to increase efficiency in identifying active CRMs for AAV-based cell-type-specific labeling and manipulation. We found that prescreening of chromatin-accessible putative CRMs based on the density of cell-type-specific transcription factor binding sites (TFBSs) can significantly increase efficiency in identifying active CRMs. In addition, generation of synthetic CRMs by stitching chromatin-accessible regions flanking cell-type-specific genes can render cell type specificity in many cases. Using these straightforward strategies, we generated AAVs that can target the extensively studied interneuron and glial cell types in the retina and brain. Both strategies utilize available genomic datasets and can be employed to generate AAVs targeting specific cell types in CNS without conducting comprehensive screening and sequencing experiments, making a step forward in cell-type-specific research.

Safety and metabolic advantages of steroid withdrawal after 6 months posttransplant in de novo kidney transplantation: A 1-year prospective cohort study.

INTRODUCTION: This prospective multicenter study aimed at investigating the safety and metabolic advantages of steroid withdrawal (SW) therapy in kidney transplant recipients with tacrolimus-mycophenolate mofetil-based immunosuppression. METHODS: We analyzed 179 recipients who received kidney transplantation from March 2016 and September 2018. In 179 recipients, 114 patients maintained an immunosuppressive regimen including steroids (steroid continuation [SC] group). The remaining 65 patients were determined to withdraw steroid therapy after 6 months posttransplant (SW group). Metabolic parameters and graft functions of the two groups were evaluated. RESULTS: The estimated glomerular filtration rates at 12 months posttransplant were 67.29 ± 20.29 ml/min/1.73 m2 in SC group and 73.72 ± 17.57 ml/min/1.73 m2 in SW group (p < .001). The acute rejection occurred to four recipients in the SC group (3.5%) and no acute rejection occurred to SW group recipients during the 6-2 months posttransplant period. Oral glucose tolerance tests revealed that recipients in the SW group were more improved in glucose metabolism than the SC group during 6-12 months posttransplant. In addition, cholesterol levels and blood pressure decreased after the withdrawal of steroids in the SW group. CONCLUSION: In conclusion, a 6-month withdrawal of steroids in recipients with low immunological risk and stable graft function can be safely conducted and result in improvement of metabolic profiles. Stable recipients without biopsy-proven acute rejection and proteinuria can safely withdraw from steroids out of a maintenance immunosuppressive regimen 6-months posttransplant. A long-term follow-up study is needed to verify our results.

Validation of a noninvasive prognostic signature for allograft failure following BK virus associated nephropathy.

Identifying kidney transplant recipients at risk for graft failure following BK virus nephropathy (BKVN) may allow personalization of therapy. We have reported that a noninvasive composite signature of urinary cell level of plasminogen activator inhibitor-1(PAI-1) mRNA and serum creatinine level, measured at the time of BKVN diagnosis, is prognostic of graft failure. In this investigation, we determined whether the composite signature is prognostic of graft failure in an independent cohort of 25 patients with BKVN. Of the 25 patients, 8 developed graft failure and 17 did not. We measured urinary cell levels of PAI-1 mRNA, 18S rRNA, and BKV VP1 mRNA at the time of BKVN diagnosis and evaluated clinical parameters including Banff pathology scores, acute rejection, and graft function. The area under the receiver operating characteristic curve for the noninvasive composite signature was 0.95 (P < .001) for prognosticating graft failure. The previously reported threshold of -0.858 predicted graft failure with a sensitivity of 75% and a specificity of 94%. Our current study validates the use of composite signature and the threshold of -0.858 to identify those at risk for graft failure following BKVN diagnosis, and supports future studies utilizing the composite signature score to personalize treatment of BKVN.

Risk factors of COVID-19 mortality: a systematic review of current literature and lessons from recent retracted articles.

OBJECTIVE: Recently, two influential articles that reported the association of (hydroxy)chloroquine or angiotensin converting enzyme (ACE) inhibitors and coronavirus disease 2019 (COVID-19) mortality were retracted due to significant methodological issues. Therefore, we aimed to analyze the same clinical issues through an improved research method and to find out the differences from the retracted papers. We systematically reviewed pre-existing literature, and compared the results with those of the retracted papers to gain a novel insight. MATERIALS AND METHODS: We extracted common risk factors identified in two retracted papers, and conducted relevant publication search until June 26, 2020 in PubMed. Then, we analyzed the risk factors for COVID-19 mortality and compared them to those of the retracted papers. RESULTS: Our systematic review demonstrated that most demographic and clinical risk factors for COVID-19 mortality were similar to those of the retracted papers. However, while the retracted paper indicated that both (hydroxy)chloroquine monotherapy and combination therapy with macrolide were associated with higher risk of mortality, our study showed that only combination therapy of hydroxychloroquine and macrolide was associated with higher risk of mortality (odds ratio 2.33; 95% confidence interval 1.63-3.34). In addition, our study demonstrated that use of ACE inhibitors or angiotensin receptor blockers (ARBs) was associated with reduced risk of mortality (0.77; 0.65-0.91). CONCLUSIONS: When analyzing the same clinical issues with the two retracted papers through a systematic review of randomized controlled trials and relevant cohort studies, we found out that (hydroxy)chloroquine monotherapy was not associated with higher risk of mortality, and that the use of ACE inhibitors or ARBs was associated with reduced risk of mortality in COVID-19 patients.

Effective inhibition of tumor in vivo with a novel DNA vaccine targeting chimeric G250.

OBJECTIVE: To develop a promising approach for tumor immunotherapy with G250 antigen-based DNA vaccine and to investigate its anti-tumor response in mice with renal cell carcinoma. MATERIALS AND METHODS: G250 derived from human, monkey and mouse were prepared by PCR. The heterogeneous chimeric G250 gene was obtained by integrating different gene fragments of three species. Then, the chimeric G250 was inserted into a eukaryotic expression plasmid pVAX1-IRES-GM/B7 to obtain DNA vaccine (named pVAX1-tG250-GM/B7) which could express chimeric G250 antigen and immune adjuvants simultaneously. By transfecting into Cos7 cells, the expression of chimeric G250 antigen was tested using flow cytometry and immunofluorescence assay. The immunological response and protection against tumor were evaluated in vivo. RESULTS: Recombinant plasmid DNA vaccine was constructed successfully through identification of PCR and gene sequencing. The chimeric G250 antigen was well expressed in Cos7 cells. A strong immune response can be detected through ELISPOT and ELISA induced by pVAX1-tG250-GM/B7. The mice vaccinated with pVAX1-tG250-GM/B7, balb/c showed significant inhibition of tumor and a longer time of survival compared with control group. CONCLUSIONS: The experimental results of this study exhibited that the DNA vaccine based on heterogeneous chimeric antigen can produce efficient anti-tumor effect in vivo and they represent a promising strategy for tumor immunotherapy.

Retinol-binding protein 2 (RBP2) binds monoacylglycerols and modulates gut endocrine signaling and body weight.

Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. Rbp2-deficient (Rbp2-/- ) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young Rbp2-/- mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, Rbp2-/- mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance.

Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior.

Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with ∼3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.

Clinical and pathological comparisons of adnexal torsion between pregnant and non-pregnant women.

AIM: We evaluated and compared the clinical and pathological differences between pregnant and non-pregnant women with adnexal torsion. METHODS: We retrospectively reviewed 239 women with adnexal torsion from January 2006 to December 2015 in a tertiary hospital. The clinical and pathological differences between pregnant and non-pregnant women who underwent surgery for adnexal torsion were analyzed. RESULTS: The most common pathologies were corpus luteum cysts in pregnant women and dermoid cysts in non-pregnant women. Eight of the pregnant women (24.2%) had a history of exogenous ovarian stimulation, and their episodes were only caused by corpus luteum or a stimulated ovary. In pregnant women, 72.7% of the torsion occurred before the 14th week of gestation. CONCLUSION: The common pathology causing adnexal torsion was different, depending on the pregnancy status. Exogenous ovarian stimulation increases the risk of adnexal torsion, and the majority of episodes occurred in the first trimester in pregnant women.

Kidney allograft failure in the steroid-free immunosuppression era: A matched case-control study.

We studied the causes and predictors of death-censored kidney allograft failure among 1670 kidney recipients transplanted at our center in the corticosteroid-free maintenance immunosuppression era. As of January 1, 2012, we identified 137 recipients with allograft failure; 130 of them (cases) were matched 1-1 for recipient age, calendar year of transplant, and donor type with 130 recipients with functioning grafts (controls). Median time to allograft failure was 29 months (interquartile range: 18-51). Physician-validated and biopsy-confirmed categories of allograft failure were as follows: acute rejection (21%), glomerular disease (19%), transplant glomerulopathy (13%), interstitial fibrosis tubular atrophy (10%), and polyomavirus-associated nephropathy (7%). Graft failures were attributed to medical conditions in 21% and remained unresolved in 9%. Donor race, donor age, human leukocyte antigen mismatches, serum creatinine, urinary protein, acute cellular rejection, acute antibody-mediated rejection, BK viremia, and CMV viremia were associated with allograft failure. Independent predictors of allograft failure were acute cellular rejection (odds ratio: 18.31, 95% confidence interval: 5.28-63.45) and urine protein ≥1 g/d within the first year post-transplantation (5.85, 2.37-14.45). Serum creatinine ≤1.5 mg/dL within the first year post-transplantation reduced the odds (0.29, 0.13-0.64) of allograft failure. Our study has identified modifiable risk factors to reduce the burden of allograft failure.

Catheter probe endoscopic ultrasonography by using cold lubricating jelly-filled method for esophageal subepithelial tumors.

Catheter probe endoscopic ultrasonography (C-EUS) by ultrasonographic jelly-filled method has been used to evaluate esophageal subepithelial tumors (SETs). Ultrasonographic jelly is safe on the skin, but its internal safety has not been demonstrated. The jelly stored at room temperature is easily injected into the esophagus through the instrument channel of the endoscope. However, using jelly stored at room temperature remains problematic because the jelly is drained rapidly. We used cold lubricating jelly and an intravenous extension tube to resolve these problems. In this study, we evaluated the safety and efficacy of cold lubricating jelly-filled method. The medical records of patients who underwent C-EUS by using water or cold lubricating jelly-filled method for esophageal SETs from March 2013 to September 2016 in Gangneung Asan hospital were reviewed. Clinical characteristics and EUS findings were evaluated retrospectively. Image quality and procedure time between water and cold lubricating jelly-filled method were compared retrospectively. This study included 138 patients (74 males, 64 females) with esophageal SET with a mean age of 57.1 ± 11.1 years. Thirty-four patients had lesions in the upper esophagus, 58 patients had lesions in the middle esophagus, and 46 patients had lesions in the lower esophagus. The EUS diagnoses were leiomyoma (82.6%), hemangioma (4.3%), extrinsic compressive lesion (3.6%), granulosa cell tumor (2.9%), ectopic calcification (1.4%), cyst (1.4%), lipoma (0.7%), varix (0.7%), and inconclusive lesion (2.2%). The mean image score in the cold lubricating jelly filled-method group was higher than that in the water-filled method group (3.2 ± 0.7 vs. 2.8 ± 0.7, P = 0.002). The procedure time in the cold lubricating jelly filled-method group was shorter than that in the water-filled method group (10 minutes 27 seconds ± 4 minutes 22 seconds versus 13 minutes 20 seconds ± 6 minutes 20 seconds, P = 0.045). No procedure-related complication was observed. C-EUS using the cold lubricating jelly-filled method seems to provide better image quality and shorter procedure time compared with C-EUS using the water-filled method.

NPD1-mediated stereoselective regulation of BIRC3 expression through cREL is decisive for neural cell survival.

Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress (OS), neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We report here that, in retinal pigment epithelial cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-κB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-κB pathways. RelB expression follows a similar pattern as BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. BIRC3 silencing prevents NPD1 induction of survival against OS. Moreover, brain NPD1 biosynthesis and selective neuronal BIRC3 abundance are increased by DHA after experimental ischemic stroke followed by remarkable neurological recovery. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription decisive for retinal and brain neural cell integrity when confronted with potential disruptions of homeostasis.

Dopamine D1-like receptors regulate the α1A-adrenergic receptor in human renal proximal tubule cells and D1-like dopamine receptor knockout mice.

The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D1-like dopamine receptors [dopamine D1 and D5 receptors (D1Rs and D5Rs, respectively)] and the α1A-adrenergic receptor (α1A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na(+) transport, i.e., natriuresis (via D1Rs and D5Rs) or antinatriuresis (via α1A-ARs). We tested the hypothesis that the D1R/D5R regulates the α1A-AR. D1-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with α1A-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D1R/D5R agonist fenoldopam resulted in decreased D1R and D5R expression but increased α1A-AR abundance in the plasma membrane. Short-term fenoldopam treatment stimulated the translocation of Na(+)-K(+)-ATPase from the plasma membrane to the cytosol that was partially reversed by an α1A-AR agonist, which by itself induced Na(+)-K(+)-ATPase translocation from the cytosol to the plasma membrane. The α1A-AR-specific agonist A610603 also minimized the ability of fenoldopam to inhibit Na(+)-K(+)-ATPase activity. To determine the interaction among D1Rs, D5Rs, and α1A-ARs in vivo, we used phenylephrine and A610603 to decrease Na(+) excretion in several D1-like dopamine receptor knockout mouse strains. Phenylephrine and A61603 treatment resulted in a partial reduction of urinary Na(+) excretion in wild-type mice and its abolition in D1R knockout, D5R knockout, and D1R-D5R double-knockout mice. Our results demonstrate the ability of the D1-like dopamine receptors to regulate the expression and activity of α1A-AR. Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti- and pro-hypertensive systems.

Circulating levels of 25-hydroxyvitamin D and acute cellular rejection in kidney allograft recipients.

BACKGROUND: Vitamin D, in addition to its established role in bone metabolism, may regulate the immune system and affect the outcome of allografts. METHODS: We identified 351 kidney allograft recipients who had serum levels of 25-hydroxyvitamin D (25[OH]D) measured within the first 30 days of transplantation. We evaluated the relationship between the circulating levels of 25(OH)D and acute cellular rejection (ACR), cytomegalovirus (CMV) disease, BK virus nephropathy, and kidney graft function. RESULTS: Vitamin D deficiency (circulating levels of 25[OH]D ≤20 ng/mL, defined using The Endocrine Society Clinical Practice 2011 Guideline) was observed in 216 (61.5%) of 351 kidney graft recipients. Vitamin D deficiency was more frequent in female recipients (P=0.007, Fisher exact test) and African American recipients (P<0.001) and was less frequent in preemptive kidney graft recipients (P=0.002). Biopsy-confirmed ACR was more frequent in the vitamin D-deficient group than in the sufficient group (10.2% vs. 3.7%, P=0.04). By multivariable Cox regression analysis, vitamin D deficiency was an independent risk factor for ACR (hazard ratio=3.3, P=0.02). Vitamin D deficiency was not associated with CMV disease, BK virus nephropathy, or kidney allograft function at 1 year. 1,25-Dihydroxyvitamin D3 supplementation initiated within the first 90 days of transplantation was associated with a lesser incidence of ACR compared to no treatment with 1,25-dihydroxyvitamin D3 (5.1% vs. 13.0%, P=0.099). CONCLUSIONS: Vitamin D deficiency is an independent risk factor for development of ACR within the first year of kidney transplantation and 1,25-dihydroxyvitamin D3 supplementation may help reduce the occurrence of ACR in the vitamin D-deficient group.

Clinical Feasibility of Multiplanar Reconstruction Images of Temporal Bone CT in the Diagnosis of Temporal Bone Fracture with Otic-Capsule-Sparing Facial Nerve Paralysis.

The aim of this study is to evaluate the feasibility of multiplanar reconstructive (MPR) imaging of temporal bone CT in the diagnosis of temporal bone fracture with oticcapsule-sparing facial nerve paralysis. Twelve patients with traumatic facial nerve paralysis with otic-capsule sparing and temporal bone fractures were selected. Multiplanar reconstruction images were obtained with the V-works 4.0 software program (Cybermed, Seoul, Korea) using axial scanning of high-resolution temporal bone CT of the fracture line. The clinical profiles of the patients displaying temporal bone fractures were examined in relation to the findings. Multiplanar images of the fracture line provided information regarding the direction of the external force that fractured the temporal bone. The fracture line was more continuous in the MPR images than in the axial view. All patients showed an imaginary extended fracture line directed toward the otic capsule. The direction of the fracture line toward the middle ear cavity is important, as it may suggest insult to the otic capsule. The MPR image parallel to the fracture line of the temporal bone provides a guideline for the vector of the force that induced the fracture. Thorough investigation of the critical organs during surgical exploration is recommended if the direction of the fracture in the MPR image points toward the otic capsule in the middle ear even if the fracture line relative to the otic capsule is not well defined in the axial or CT view.

Structure elucidation and characterization of microbial 2-tridecyl sophorosides (biosurfactants).

To produce novel types of sophorose lipids containing an odd number of carbon atoms in the lipophilic moiety, Candida bombicola ATCC 22214 was grown in 500-ml flask cultures with glucose as main carbon source, and additionally, 2-tridecanone as co-substrate. After solvent extraction, the crude product mixture was separated into pure fractions, and each fraction was analysed via NMR and mass spectroscopy. This effective strategy generated five new glycolipids, 2-tridecyl sophorosides, which differed in the number of glucose units, and acetyl and hydroxy groups, respectively. Based on these compounds, a proposal for the possible biosynthetic pathway was deduced. Two compounds of the mixture, mono- and diacetylated 2-tridecyl sophorosides, respectively, were able to lower the surface tension of water from 72 mN m(-1) to 32 mN m(-1) and the interfacial tension between water and n-hexadecane from 43 mN m(-1) down to 4 and 3 mN m(-1). Thus, both compounds possess a very good surfactant behaviour. Moreover, it was observed that the new products inhibit the growth of particular Gram-positive bacteria, and they indicate potential for antitumour-promoting activity.

Early corticosteroid withdrawal in recipients of renal allografts: a single-center report of ethnically diverse recipients and recipients of marginal deceased-donor kidneys.

BACKGROUND: Candidacy for kidney transplantation is being progressively liberalized, and the safety and efficacy of early withdrawal of corticosteroids in high-risk patients have not been fully characterized. METHODS: We analyzed the safety and efficacy of an early corticosteroid withdrawal regimen of rabbit antithymocyte globulin induction, tacrolimus, mycophenolate mofetil, and steroid withdrawal by day 5 after transplantation in our study cohort of 634 kidney transplant recipients that included 27% African American and 18% Hispanic recipients. Fifty-five percent of the recipients were recipients of deceased-donor kidneys, and 46% of deceased-donor kidneys were kidneys from expanded criteria donors. RESULTS: Kaplan-Meier patient survival at 1, 3, and 5 years after transplantation was 98.6%, 94.6%, and 90.2%, and death-censored graft survival was 96.2%, 91.9%, and 87.6%, respectively. During a mean follow-up of 57 months, 89.3% of patients remained off of corticosteroids, and the incidence of acute rejection including subclinical rejection identified by protocol biopsy was 12.0%. Multivariable analysis identified age older than 60 years as protective against (P=0.01) and the African American ethnicity as a risk factor for (P=0.03) rejection. Delayed graft function (P<0.0001), rejection (P<0.0001), and transplant panel reactive antibody 20% or more (P=0.03) were risk factors for graft loss. Opportunistic infections included viral in 15.3%, fungal in 1.6%, and parasitic in 0.6% of the patients. Posttransplantation malignancy occurred in 9.1% of patients. CONCLUSIONS: An early corticosteroid withdrawal regimen of rabbit antithymocyte globulin induction, tacrolimus, and mycophenolate mofetil is associated with excellent patient and kidney graft survival in an ethnically diverse population with risk factors for poor outcomes.

Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone.

AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.