Initiating acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence

ObjectivesThis trial compared the efficacy of acamprosate, started at the beginning of detoxification, to acamprosate started at the completion of detoxification, in the treatment of alcohol dependence.MethodsThis biphasic clinical trial consisted of a randomized, double-blind, placebo-controlled Detoxification Phase (DP), followed by a 10-week open-label Rehabilitation Phase (RP). Forty alcohol dependent patients were randomly assigned to receive either 1998 mg of acamprosate daily, or matching placebo, during the DP (5–14 days). After completing detoxification, all patients received open label acamprosate (1998 mg daily) in the RP. Outcome measures during the DP included: treatment retention, alcohol withdrawal, alcohol consumption, and oxazepam used. Outcome measures during the RP included: treatment retention and alcohol consumption.ResultsThere were no significant outcome differences between acamprosate and placebo-treated patients during the DP. Patients given acamprosate, compared to placebo, during the DP drank more alcohol in the RP.ConclusionsStarting acamprosate at the beginning of detoxification did not improve DP outcomes. Starting acamprosate after detoxification was completed was associated with better drinking outcomes during subsequent alcohol rehabilitation treatment.     

In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: microbiology profiling studies with staphylococci and streptococci

We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC(90)s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 mug/ml. Against Staphylococcus aureus, CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and >8.5 h determined for the PAE (3x MIC), SME (0.12x MIC), and PAE-SME (3x MIC/0.12x MIC) periods, respectively. Studies of genetically defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 mug/ml and a resistance frequency of <10(-12) determined at 1 mug/ml in agar for S. aureus. Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of S. aureus, CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.     

The potential and the pitfalls of beta-adrenoceptor agonists for the management of skeletal muscle wasting

The beta-adrenergic signaling pathway represents a novel therapeutic target for skeletal muscle wasting and weakness due to its role in the mechanisms controlling protein synthesis and degradation and in modulating fiber type. Stimulation of the pathway with beta-adrenoceptor agonists (beta-agonists) has therapeutic potential for muscle wasting disorders including: sarcopenia, cancer cachexia, disuse and inactivity, unloading or microgravity, sepsis and other metabolic disorders, denervation, burns, HIV-AIDS, chronic kidney or heart failure, and neuromuscular diseases. However, there are also pitfalls associated with beta-agonist administration and clinical applications have so far been limited, largely because of cardiovascular side effects. In rats and mice, newer generation beta-agonists (such as formoterol) can elicit an anabolic response in skeletal muscle even at very low doses, with reduced effects on the heart and cardiovascular system compared with older generation beta-agonists (such as fenoterol and clenbuterol). However, the potentially deleterious cardiovascular side effects of beta-agonists have not been obviated completely and so it is important to refine their development and therapeutic approach in order to overcome these obstacles. This review describes the therapeutic potential of stimulating the beta-adrenergic signaling pathway with beta-agonists, highlighting the beneficial effects on skeletal muscle structure and function and identifying some of the pitfalls associated with short- and long-term beta-agonist administration. The review also identifies some important, but as yet unanswered questions, regarding the importance of beta-adrenoceptor signaling in muscle health and disease and the strategies needed to improve the efficacy and safety of beta-agonists for muscle wasting disorders.     

Convergence of body mass index of immigrants to the Canadian-born population: evidence from the National Population Health Survey (1994–2006)

Recent immigrants typically have better physical health than the native born population. However, this ‘healthy immigrant effect’ tends to gradually wane over time, with increasing length of residence in the host country. To assess whether the body mass index (BMI) of different immigrant groups converged to the Canadian population’s levels, we estimated 12-year trajectories of changes in BMI (accounting for socio-demographic changes). Using data from seven longitudinal waves of the National Population Health Survey (1994 through 2006), we compared the changes in BMI (kg/m²) among three groups: white immigrants, non-white immigrants and Canadian born, aged 18–54 at baseline. We applied linear random effects models to evaluate these BMI separately in 2,504 males and 2,960 females. BMI increased in Canadian born, white immigrants, and non-white immigrants over the 12-year period. However, non-white immigrants (males and females) had a lower mean BMI than Canadian born individuals during this period [Males: −2.27, 95% Confidence interval (CI) −3.02 to −1.53; Females: −1.84, 95% CI −2.79 to −0.90]. In contrast, the mean BMI in white male immigrants and Canadian born individuals were similar (−0.32, 95% CI −0.91 to 0.27). Even after adjusting for time since immigration, non-white immigrants had lower BMI than white immigrants. White male immigrants were the only sub-group to converge to the BMI of the Canadian born population. These results indicate that the loss of ‘healthy immigrant effect’ with regard to convergence of BMI to Canadian levels may not be experienced equally by all immigrants in Canada.     

Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

Integrins regulate cytoplasmic calcium levels ([Ca²⁺]i) in various cell types but information on activities in neurons is limited. The issue is of current interest because of the evidence that both integrins and changes in [Ca²⁺]i are required for Long-Term Potentiation. Accordingly, the present studies evaluated integrin ligand effects in cortical neurons. Integrin ligands or α5β1 integrin activating antisera rapidly increased [Ca²⁺]i with effects greater in glutamatergic than GABAergic neurons, absent in astroglia, and blocked by β1 integrin neutralizing antisera and the tyrosine kinase antagonist genistein. Increases depended upon extracellular calcium and intracellular store release. Ligand-induced effects were reduced by voltage-sensitive calcium channel and NMDA receptor antagonists, but blocked by tetrodotoxin or AMPA receptor antagonists. These results indicate that integrin ligation triggers AMPA receptor/depolarization-dependent calcium influx followed by intracellular store release and suggest the possibility that integrin modulation of activity-induced changes in [Ca²⁺]i contributes importantly to lasting synaptic plasticity in forebrain neurons.     

Emotion regulation skills mediate the effects of shame on eating disorder symptoms in women

We examined the impact of negative affectivity, chronic shame, and emotion regulation skills on eating disorder symptoms in undergraduate women (N = 154). We hypothesized that self-reported emotion regulation skills would mediate the well-documented relationship between chronic shame and eating disorder symptoms. Results revealed that chronic shame predicted eating disorder symptoms over and above general negative affectivity. Further, difficulties with emotion regulation mediated the relationship between chronic shame and ED symptoms. These findings suggest that chronic shame's role in eating disorder symptoms can be ameliorated by skillful emotion regulation.     

Differences in emotional experience and emotion regulation as a function of age and psychiatric condition

In this study, self-reported experiences of negative affectivity and emotional regulation in a sample of older and younger adults with and without psychiatric co-morbidity were evaluated. Study participants were divided into four separate groups (younger nonpsychiatric = YN; younger psychiatric = YP; older non-psychiatric = ON; and older psychiatric = OP). Findings indicated that, as hypothesized, individuals in the OP and YP groups reported more negative affect intensity and reactivity and more maladaptive emotion regulation than individuals in the ON and YN groups. Contrary to hypotheses, when collapsed across psychiatric conditions, older adults did not report significantly less negative affect intensity and reactivity than younger adults. A significant age by psychiatric group interaction effect on negative affect intensity occurred such that individuals in YN and ON groups reported similar levels of negative affect intensity and individuals in the YP group reported more negative affect intensity than individuals in the OP group. The finding that older adults with Axis I and Axis II diagnoses differ in their symptom reports from younger adults with similar diagnoses suggests there may be important assessment and intervention issues related to the interaction of aging and psychopathology. Clinical implications and directions for future studies are discussed.     

A multimodal assessment of the relationship between emotion dysregulation and borderline personality disorder among inner-city substance users in residential treatment

The concept of emotion dysregulation has been integrated into theory and treatment for borderline personality disorder (BPD), despite limited empirical support. Expanding upon existing research on the relationship between emotion dysregulation and BPD, the present study utilized a multimodal approach to the assessment of emotion dysregulation (including two behavioral measures of the willingness to tolerate emotional distress, and a self-report measure of emotion dysregulation broadly defined) to examine the relationship between emotion dysregulation and BPD among inner-city substance users in residential treatment (n = 76, with 25 meeting criteria for BPD). Results provide laboratory-based evidence for heightened emotion dysregulation in BPD, extending extant research on BPD to underserved clinical populations. Specifically, the presence of a BPD diagnosis among a sample of inner-city inpatient substance users was associated with both higher scores on the self-report measure of emotion dysregulation and less willingness to tolerate emotional distress on the behavioral measures of emotion dysregulation. Moreover, both self-report and behavioral measures of emotion dysregulation accounted for unique variance in BPD status, suggesting the importance of utilizing comprehensive assessments of emotion dysregulation within studies of BPD. Findings suggest the need to further explore the role of emotion dysregulation in the development and maintenance of BPD among inner-city substance users in residential treatment.     

Neurokinin-1 receptor mRNA expression differences in brains of HIV-infected individuals

The neurokinin-1 receptor, a G-protein coupled receptor, is present in cells of the nervous system and the immune system. Utilizing our recently developed SYBR green-based RT-PCR, we quantified full-length and truncated NK1R mRNA expression in the cingulate cortex and cerebellum of autopsy brains from HIV-negative and -positive individuals. In the cingulate cortex, the expression of the full-length NK1R was greater in HIV-negative individuals (n=3) in comparison to HIV-positive individuals (n=21; p-value=0.026). There were no observed differences in expression of the truncated NK1R in the cingulate cortex between HIV-positive and -negative individuals. The expression of NK1R isoforms, both truncated and full-length, was similar between HIV-negative and -positive individuals in the cerebellum. It was not possible to directly relate the magnitude of NK1R expression to impairment in neuropsychological impairment in this small cohort and none of the subjects had HIV encephalopathy. These preliminary data support the concept that the full-length form of NK1R may have important significance in cognitive functions and deficiency of this isoform may be relevant in neurologic and psychiatric manifestations of neuroAIDS.