Subcortical serotonin 5HT2c receptor-containing neurons sex-specifically regulate binge-like alcohol consumption, social, and arousal behaviors in mice.

Binge alcohol consumption induces discrete social and arousal disturbances in human populations that promote increased drinking and accelerate the progression of Alcohol Use Disorder. Here, we show in a mouse model that binge alcohol consumption disrupts social recognition in females and potentiates sensorimotor arousal in males. These negative behavioral outcomes were associated with sex-specific adaptations in serotonergic signaling systems within the lateral habenula (LHb) and the bed nucleus of the stria terminalis (BNST), particularly those related to the receptor 5HT2c. While both BNST and LHb neurons expressing this receptor display potentiated activation following binge alcohol consumption, the primary causal mechanism underlying the effects of alcohol on social and arousal behaviors appears to be excessive activation of LHb5HT2c neurons. These findings may have valuable implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brain's serotonin system.

Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice.

We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 × C57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 × D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression.

Transdisciplinary synthesis for ecosystem science, policy and management: The Australian experience.

Mitigating the environmental effects of global population growth, climatic change and increasing socio-ecological complexity is a daunting challenge. To tackle this requires synthesis: the integration of disparate information to generate novel insights from heterogeneous, complex situations where there are diverse perspectives. Since 1995, a structured approach to inter-, multi- and trans-disciplinary(1) collaboration around big science questions has been supported through synthesis centres around the world. These centres are finding an expanding role due to ever-accumulating data and the need for more and better opportunities to develop transdisciplinary and holistic approaches to solve real-world problems. The Australian Centre for Ecological Analysis and Synthesis (ACEAS ) has been the pioneering ecosystem science synthesis centre in the Southern Hemisphere. Such centres provide analysis and synthesis opportunities for time-pressed scientists, policy-makers and managers. They provide the scientific and organisational environs for virtual and face-to-face engagement, impetus for integration, data and methodological support, and innovative ways to deliver synthesis products. We detail the contribution, role and value of synthesis using ACEAS to exemplify the capacity for synthesis centres to facilitate trans-organisational, transdisciplinary synthesis. We compare ACEAS to other international synthesis centres, and describe how it facilitated project teams and its objective of linking natural resource science to policy to management. Scientists and managers were brought together to actively collaborate in multi-institutional, cross-sectoral and transdisciplinary research on contemporary ecological problems. The teams analysed, integrated and synthesised existing data to co-develop solution-oriented publications and management recommendations that might otherwise not have been produced. We identify key outcomes of some ACEAS working groups which used synthesis to tackle important ecosystem challenges. We also examine the barriers and enablers to synthesis, so that risks can be minimised and successful outcomes maximised. We argue that synthesis centres have a crucial role in developing, communicating and using synthetic transdisciplinary research.

Wistar rats acquire and maintain self-administration of 20 % ethanol without water deprivation, saccharin/sucrose fading, or extended access training.

RATIONALE: Operant self-administration (SA) is an important model of motivation to consume ethanol (EtOH), but low rates of voluntary consumption in rats are thought to necessitate water deprivation and saccharin/sucrose fading for acquisition of responding. OBJECTIVES: Here, we sought to devise an effective model of SA that does not use water deprivation or saccharin/sucrose fading. METHODS: First, we tested if Wistar rats would acquire and maintain SA behavior of 20 % EtOH under two conditions, water deprivation (WD) and non-water deprivation (NWD). Second, we tested the efficacy of our SA procedure by confirming a prior study which found that the NK1 antagonist L822429 specifically blocked stress-induced reinstatement of EtOH seeking but not SA. Finally, we assessed the effect of naltrexone, an FDA-approved medication for alcohol dependence that has been shown to suppress EtOH SA in rodents. RESULTS: Lever presses (LPs) and rewards were consistent with previous reports that utilized WD and saccharin/sucrose fading. Similar to previous findings, we found that L822429 blocked stress-induced reinstatement but not baseline SA of 20 % EtOH. Moreover, naltrexone dose-dependently decreased alcohol intake and motivation to consume alcohol for rats that are self-administering 20 % EtOH. CONCLUSIONS: Our findings provide a method for voluntary oral EtOH SA in rats that is convenient for experimenters and eliminates the potential confound of sweeteners in EtOH-operant SA studies. Unlike models that use intermittent access to 20 % EtOH, this method does not induce escalation, and based on pharmacological experiments, it appears to be driven by the positive reinforcing effects of EtOH.

Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence.

Long-term changes in brain gene expression have been identified in alcohol dependence, but underlying mechanisms remain unknown. Here, we examined the potential role of microRNAs (miRNAs) for persistent gene expression changes in the rat medial prefrontal cortex (mPFC) after a history of alcohol dependence. Two-bottle free-choice alcohol consumption increased following 7-week exposure to intermittent alcohol intoxication. A bioinformatic approach using microarray analysis, quantitative PCR (qPCR), bioinformatic analysis and microRNA-messenger RNA (mRNA) integrative analysis identified expression patterns indicative of a disruption in synaptic processes and neuroplasticity. About 41 rat miRNAs and 165 mRNAs in the mPFC were significantly altered after chronic alcohol exposure. A subset of the miRNAs and mRNAs was confirmed by qPCR. Gene ontology categories of differential expression pointed to functional processes commonly associated with neurotransmission, neuroadaptation and synaptic plasticity. microRNA-mRNA expression pairing identified 33 miRNAs putatively targeting 89 mRNAs suggesting transcriptional networks involved in axonal guidance and neurotransmitter signaling. Our results demonstrate a significant shift in microRNA expression patterns in the mPFC following a history of dependence. Owing to their global regulation of multiple downstream target transcripts, miRNAs may have a pivotal role in the reorganization of synaptic connections and long-term neuroadaptations in alcohol dependence. MicroRNA-mediated alterations of transcriptional networks may be involved in disrupted prefrontal control over alcohol drinking observed in alcoholic patients.

Vasopressin: a look at dialysis hypertension and autonomic dysfunction.

Dialysis hypertension is a complex disorder in which ambient vascular resistance is too high for the blood volume. van der Zee et al. remind us that this is contingent upon the endothelium itself, and that endothelial dysfunction is integral to uremia. Thus, while vasopressin may not abolish dialysis hypotension, its effects highlight the influence of uremia on the autocrine and neuroendocrine control of cardiovascular physiology.

Associations between CMS's Clinical Performance Measures project benchmarks, profit structure, and mortality in dialysis units.

Prior studies observing greater mortality in for-profit dialysis units have not captured information about benchmarks of care. This study was undertaken to examine the association between profit status and mortality while achieving benchmarks. Utilizing data from the US Renal Data System and the Centers for Medicare & Medicaid Services' end-stage renal disease (ESRD) Clinical Performance Measures project, hemodialysis units were categorized as for-profit or not-for-profit. Associations with mortality at 1 year were estimated using Cox regression. Two thousand six hundred and eighty-five dialysis units (31,515 patients) were designated as for-profit and 1018 (15,085 patients) as not-for-profit. Patients in for-profit facilities were more likely to be older, black, female, diabetic, and have higher urea reduction ratio (URR), hematocrit, serum albumin, and transferrin saturation. Patients (19.4 and 18.6%) in for-profit and not-for-profit units died, respectively. In unadjusted analyses, profit status was not associated with mortality (hazard ratio (HR)=1.04, P=0.09). When added to models with profit status, the following resulted in a significant association between profit status (for-profit vs not-for-profit) and increasing mortality risk: URR, hematocrit, albumin, and ESRD Network. In adjusted models, patients in for-profit facilities had a greater death risk (HR 1.09, P=0.004). More patients in for-profit units met clinical benchmarks. Survival among patients in for-profit units was similar to not-for-profit units. This suggests that in the contemporary era, interventions in for-profit dialysis units have not impaired their ability to deliver performance benchmarks and do not affect survival.

Are there gender differences in the prescribing of hypnotic medications for insomnia?

Gender differences in the prescribing patterns of general classes of medications for insomnia were examined. The classes of medications included: zopiclone, antidepressants, benzodiazepines, antihistamines and no medication. The sample comprised a sub-set of respondents from 2620 questionnaires of the Canadian Multicentre Sleep Database. Respondents for this database were contacted through physicians, announcements in the media and local pharmacies. The results indicated that gender alone was not associated with differential prescribing for insomnia, nor was gender associated with patterns of medication use such as frequency of taking medication, length of use, taking more or less medication than prescribed or attempts to stop taking medication. Demographic factors were included in the analysis and age and marital status were associated with different prescribing patterns for men and women with insomnia. It is possible that physicians refer to stereotypic expectations when prescribing hypnotics.

Clinical performance measures: the changing status of peritoneal dialysis.

BACKGROUND: The Peritoneal Dialysis-Clinical Performance Measures Project (PD-CPM) characterizes peritoneal dialysis within the U.S. Current survey results are reported and compared to those of previous years. METHODS: Prevalence data from random national samples of adult peritoneal dialysis (PD) patients participating in the United States End-Stage Renal Disease (ESRD) program have been collected annually since 1995. RESULTS: In 1995, 79% of the respondents used continuous ambulatory peritoneal dialysis (CAPD) rather than automated peritoneal dialysis (APD). The mean hematocrit (Hct) of PD patients was 32% and only 66% of individuals had a measurement of dialysis adequacy reported. The mean weekly Kt/Vurea (wKt/V) and weekly creatinine clearance (wCCr) reported for CAPD patients in 1995 were 1.9 and 67 L/1.73 m2/week, respectively. In 2000 the median age of PD patients was 55 years and 63% were white. The leading cause of ESRD was diabetes mellitus (34%) and 54% of adult PD patients performed some form of APD rather than CAPD. Age, sex, size, hematocrit, peritoneal permeability, dialysis adequacy, residual renal function and nutritional indices did not differ between APD and CAPD patients. The mean hemoglobin (Hb) for the 2000 PD-CPM population was 11.6 +/- 1.4 g/dL (mean +/- 1 SD) and 11% of patients had an average Hb below 10 g/dL. The average serum albumin was 3.5 +/- 0.5 g/dL by the bromcresol green method and 56% of subjects had an average serum albumin equal to or above 3.5 g/dL (or 3.2 g/dL by bromcresol purple). In 2000 85% of patients had a dialysis adequacy measurement reported and the mean calculated wKt/V and wCCr were 2.3 +/- 0.6 and 72.7 +/- 24.9 liters/1.73 m2/week for CAPD patients and 2.3 +/- 0.6 and 71.6 +/- 25.1 L/1.73 m2/week for APD patients. PD subjects had a mean body weight of 76 +/- 19 kg and body mass index (BMI) of 27.5 +/- 6.4 kg/m2. The protein equivalent of nitrogen appearance (nPNA) of these patients was 0.95 +/- 0.31 g/kg/day, their normalized creatinine appearance rate (nCAR) equaled 17 +/- 6.5 mg/kg/day, resulting in a percent lean body mass (%LBM) of 64 +/- 17% of actual body weight. Serum albumin correlated in a positive fashion with BMI, nPNA, nCAR and %LBM, but not with wCCr. CONCLUSIONS: The majority of indicator variables monitored by the PD-CPM have improved since 1995. PD patients have higher hemoglobins and a greater proportion of patients meet the criteria for adequate dialysis. Serum albumin values, however, remain marginal and unchanged over the five-year project. Furthermore, serum albumin values fail to correlate with the intensity of renal replacement therapy and are not strongly correlated with alternative estimates of nutritional status.

Nutritional markers during peritoneal dialysis: data from the 1998 Peritoneal Dialysis Core Indicators Study.

OBJECTIVE: This analysis explores the nutritional status of adult U.S. peritoneal dialysis (PD) patients. DESIGN: The Peritoneal Dialysis Core Indicators Study is a prospective cross-sectional prevalence survey describing the care provided to a random sample of adult U.S. PD patients. METHODS AND POPULATION: Prevalence data were collected from a national random sample of 1381 adult PD patients participating in the United States End Stage Renal Disease (ESRD) program. RESULTS: The median age of these patients was 55 years, 61% were Caucasian; the leading cause of ESRD was diabetes mellitus. Age, sex, size, peritoneal permeability, dialysis adequacy, and nutritional indices did not differ between patients on continuous ambulatory PD and patients on automated PD. The dialysis prescriptions employed achieved mean weekly Kt/V urea (wKt/V) and creatinine clearance (wCCr) values of 2.22 +/- 0.57 and 67.8 +/- 22.5 L/1.73 m2/week, respectively. The PD patients were large, with a mean body weight of 77 +/- 21 kg and body mass index (BMI) of 27 +/- 8.6 kg/m2. The mean serum albumin of these patients was 3.5 +/- 0.51 g/dL, and 43% of values fell below the National Kidney Foundation Dialysis Outcomes Quality Initiative's desired range. The PD patients had a normalized protein equivalent of nitrogen appearance (nPNA) of 1.0 +/- 0.57 g/kg/day, a normalized creatinine appearance rate (nCAR) of 17 +/- 7.3 mg/kg/day, and an estimated lean body mass (%LBM) of 62% +/- 18% of body weight. Serum albumin correlated positively with patient size, nCAR, and nPNA, but negatively with age, the presence of diabetes mellitus, female gender, erythropoietin dose, the creatinine dialysate-to-plasma ratio results of peritoneal equilibration testing, and the dialysis portion of the wCCr. The duration of ESRD experience correlated negatively with both serum albumin and patient size, although these relationships were complex. CONCLUSION: Peritoneal dialysis patients generally have marginal serum albumin levels, a finding incongruent with alternative measures of nutritional status, such as weight, BMI, and creatinine generation. Serum albumin is reduced in patients with high peritoneal permeability (i.e., rapid transporters) and, because these patients generally have higher than average wCCr values, serum albumin is inversely correlated with the dialysis component of the wCCr. The presumptive nutritional indicators (BMI, %LBM, nPNA, and serum albumin) provide disparate estimates, varying from 10% to 50% for the prevalence of nutritionally stressed PD patients.

Design of a compartmentalized shotgun assembler for the human genome.

Two different strategies for determining the human genome are currently being pursued: one is the "clone-by-clone" approach, employed by the publicly funded project, and the other is the "whole genome shotgun assembler" approach, favored by researchers at Celera Genomics. An interim strategy employed at Celera, called compartmentalized shotgun assembly, makes use of preliminary data produced by both approaches. In this paper we describe the design, implementation and operation of the "compartmentalized shotgun assembler".

Protein intake in patients with renal failure: comments on the current NKF-DOQI guidelines for nutrition in chronic renal failure.

The National Kidney Foundation Clinical Practice Dialysis Outcomes Quality Initiative (DOQI) guidelines recently recommended dietary protein intake for patients with chronic renal failure as follows: predialysis patients should receive 0.60 g/kg/day of protein and increase intake to 0.75 g/kg/day for subjects who cannot follow such a diet. For stable maintenance hemodialysis patients, the recommended protein intake is 1.2 g/kg/day, and for chronic peritoneal dialysis patients, 1.2-1.3 g/kg/day. We differ with these recommendations and believe that a dietary protein intake of 0.8 g/kg/day is appropriate for the predialysis population; an intake of 0.9-1.0 g/kg/day and 1.0-1.1 g/kg/day for maintenance hemodialysis patients and peritoneal dialysis patients, respectively, should be adequate. The rationale and the evidence supporting our arguments are outlined and discussed.

Effect of grapefruit juice on pharmacokinetics of microemulsion cyclosporine in African American subjects compared with Caucasian subjects: does ethnic difference matter?

This study aims to determine the effect of grapefruit juice (GJ) on microemulsion cyclosporine (CsA) in 11 African American subjects, and it was compared to those in 11 Caucasian subjects. Each subject received two oral doses of CsA with water (W) or GI as well as i.v. CsA. Regardless of race, GJ significantly increased the peak concentration (Cmax) and area under the time-curve (AUC) of CsA; however, the magnitude of GJ effects was different between African American subjects and Caucasian subjects (p = 0.0003). GJ increased peak concentration of CsA by 39% in African American subjects, while the difference in Caucasian subjects was only 8% (p > 0.05). GJ also increased AUC of CsA in African American subjects by 60%, while GJ increased that in Caucasian subjects by 44% (p = 0.0001). The absolute bioavailability of CsA was 21% lower in African American subjects compared with Caucasian subjects when it was given with water (p = 0.048), but these differences disappeared when it was given with GJ (p = 0.6). These findings suggest that concurrent administration of GJ increases the bioavailability of CsA in African American subjects in greater magnitude compared with Caucasian subjects.

The sequence of the human genome.

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

Gender-dependent racial difference in disposition of cyclosporine among healthy African American and white volunteers.

Pharmacokinetic studies of intravenous and oral cyclosporine (cyclosporin) were performed in 22 healthy African American (n = 11) and white (n = 11) volunteers. Blood cyclosporine concentrations were measured by high performance liquid chromatography. Concentration versus time data were analyzed by noncompartmental models, and statistical analyses were performed by ANOVA. The clearance of intravenous and oral cyclosporine was 4.3 +/- 0.9 mL/min/kg and 13.5 +/- 4.5 mL/min/kg, respectively, in African Americans and 3.7 +/- 0.5 mL/min/kg and 9.6 mL/min/kg, respectively, in the white volunteers (P = .0001). There was a significant race and gender interaction (P = .038). Bioavailability was lower in African Americans (32.8 +/- 6.6%) compared with white volunteers (39.3 +/- 7.1%; P = .049), with a significant race and gender interaction (P = .048). The dose-adjusted area under the curve (AUC) of intravenous and oral cyclosporine was 54.3 +/- 10.6 ng x hr/mL per milligram and 18.1 +/- 4.1 ng x hr/mL per milligram, respectively, in African Americans and 61.9 +/- 6.8 ng x hr/mL per milligram and 24.2 +/- 4.6 ng x hr/mL per milligram, respectively, in white volunteers (P = .023). These findings suggest that disposition of cyclosporine is dependent both on race and on gender.

Role of sodium in hemodialysis.

Sodium chloride is the most abundant salt in extracellular fluid. In normal individuals, the tonicity exerted by dissolved sodium chloride determines plasma osmolality and indirectly determines intracellular tonicity and cell volume. Uremic patients retain nitrogenous wastes and have an elevated plasma osmolality. While urea exhibits osmotic activity in serum, no sustained gradient can be established across cell boundaries because it readily diffuses through cell membranes. Thus, sodium remains the major indicator of body tonicity and determines the distribution of water across the intracellular-extracellular boundary, subsequent cell volume, thirst, and, among patients with renal insufficiency, systemic blood pressure. As a result of highly conserved plasma tonicity control systems, uremic subjects demonstrate remarkable stability of their serum sodium. Dialysate is a synthetic interstitial fluid capable of reconstituting extracellular fluid composition through urea extraction and extremely efficient solute and solvent (salt and water) transfer to the patient. Subtle transdialyzer gradients deliver and remove large quantities of trace elements, solvent, and solute to patients, creating a variety of dialysis "disequilibrium" syndromes manifest as cellular and systemic distress. Every dialysis patient uses dialysate, and the most abundant chemicals in dialysate are salt and water. Despite its universal use, no consensus on dialysate composition or tonicity exists. This can only be explained if we believe that dialysate composition is best determined by matching unique dialysis delivery system characteristics to specific patient requirements. Such a paradigm treats dialysate as a drug and the dialysis system as a delivery device. Understanding the therapeutic and toxic profiles of this drug (dialysate) and its delivery device (the dialyzer) is important to safe, effective, goal-directed modifications of therapy. This article explores some of the historical rationale behind choosing specific dialysate tonicities.

A whole-genome assembly of Drosophila.

We report on the quality of a whole-genome assembly of Drosophila melanogaster and the nature of the computer algorithms that accomplished it. Three independent external data sources essentially agree with and support the assembly's sequence and ordering of contigs across the euchromatic portion of the genome. In addition, there are isolated contigs that we believe represent nonrepetitive pockets within the heterochromatin of the centromeres. Comparison with a previously sequenced 2.9- megabase region indicates that sequencing accuracy within nonrepetitive segments is greater than 99. 99% without manual curation. As such, this initial reconstruction of the Drosophila sequence should be of substantial value to the scientific community.

Resistance to replication of human immunodeficiency virus challenge in SCID-Hu mice engrafted with peripheral blood mononuclear cells of nonprogressors is mediated by CD8(+) T cells and associated with a proliferative response to p24 antigen.

High levels of resistance to challenge with human immunodeficiency virus type 1 SF162 were observed in animals engrafted with peripheral blood mononuclear cells of four long-term nonprogressors (LTNPs). Resistance was abrogated by depletion of CD8(+) T cells in vivo and was observed only in LTNPs with proliferative responses to p24. In a subgroup of nonprogressors, CD8(+) T cells mediated restriction of challenge viruses, and this response was associated with strong proliferative responses to p24 antigen.