Synthesis and biological evaluation of new β,β′-disubstituted 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl ethylamido melatoninergic ligands

Tricyclic analogs of melatonin with alkyl and cycloalkyl moieties in the β position of the ethylamido chain have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores. The introduction of two methyl groups in the β position of the side-chain of the methoxyl-substituted ligands induces a synergistic effect in agonist potency, which, importantly, is maintained after the methoxyl substituent is removed. The presence of more bulky β-substituents, regardless of the size of the R group, seems to lead to antagonism.     

Cultural affiliation and self-esteem as predictors of internalizing symptoms among mexican american adolescents.

We investigated the relations between affiliation with Mexican culture and self-esteem at baseline (Time 1 [T1]), and internalizing symptoms 2 years later (Time 2 [T2]) among a sample of high-risk Mexican American adolescents. Results indicated that T1 affiliation with Mexican culture was not related to T2 internalizing symptoms, controlling for T1 internalizing symptoms. The relation between T1 self-esteem and T2 internalizing symptoms was significant, controlling for T1 internalizing symptoms. Regression analyses revealed, for girls only, a significant interaction between affiliation with Mexican culture and self-esteem in the prediction of T2 internalizing symptoms. Specifically, low self-esteem was a risk factor for internalizing symptoms only among those girls minimally affiliated with Mexican culture. There was no significant interaction between cultural affiliation and self-esteem among Mexican American boys. Findings highlight the importance of gender and culture in risk processes for internalizing symptoms.     

Influences on venom yield in Australian tigersnakes (Notechis scutatus) and brownsnakes (Pseudonaja textilis: Elapidae, Serpentes).

The rates at which venomous animals produce venoms are of obvious biological and medical importance, but factors influencing those rates remain poorly understood. We gathered data on venom yield (wet mass of venom) and percentage solids (dry mass of the venom divided by wet mass) for 53 eastern brownsnakes (Pseudonaja textilis) and 36 mainland tigersnakes (Notechis scutatus) over a 4-year period at Venom Supplies Pty. Ltd, a commercial venom production facility in South Australia. Tigersnakes yielded about threefold more venom (by wet mass) than brownsnakes, but with slightly lower percentage solids. Both species showed significant geographic variation in percentage solids. Venom yields varied as a function of the snake's sex and geographic origin, but these effects were secondary consequences of geographic and sex-based differences in body size. Relative head size affected venom yield in brownsnakes but not tigersnakes. Overall, the amount of venom that a snake produced during milking was affected by its species, its geographic origin, its body size and relative head size, and by the time of year that it was milked, as well as by interactions among these factors. Body size was the most important effect on venom yield, with yields increasing more rapidly with size in brownsnakes than in tigersnakes. Research at the intersection of snake ecology and venom characteristics has great potential, but will require a genuinely interdisciplinary approach.     

Differences in clinical features and mental health service use in bipolar disorder across the lifespan.

OBJECTIVE: Because of the scarcity of research in geriatric bipolar disorder, the authors examined the prevalence, clinical features, and service use of persons with bipolar disorder among older adults treated in a large public mental health system. METHODS: From San Diego County's Adult and Older-Adult Mental Health Services database (N=34,970, fiscal year 2002-2003), the authors selected patients with bipolar disorder, divided them into three age-groups (young: age 18-39, middle-aged: age 40-59, and elderly: age 60+) and compared them on demographic, clinical, and mental health service use characteristics. RESULTS: The authors identified 2,903 patients who received services for bipolar disorder at least once during the fiscal year, accounting for a slightly lower proportion of diagnosis among elderly patients (7.0%) than middle-aged (8.7%) or younger groups (8.3%). Elderly patients were less likely to have substance use disorder comorbidity, but more likely to have a cognitive disorder diagnosis and lower global functioning scores than their younger counterparts. Elderly bipolar patients were less likely than younger groups to use inpatient, outpatient, and emergency room psychiatric care, but more likely to use case-management and conservator services. DISCUSSION: Bipolar disorder was only slightly less common among elderly patients in a large, public mental health system, compared to younger age-groups. Available clinical data revealed a mixed picture of bipolar disorder in late life, with more functional and cognitive impairment and less substance use disorder comorbidity and use of acute psychiatric services. Our findings suggest that older adults with bipolar disorder have unique mental health service needs.     

Factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia A mice

Summary.  Background : Adenoviral-based methods of gene therapy have been ineffective at providing sustained factor (F)VIII expression in outbred populations of large animal hemophilic models primarily due to the immunogenicity of these vectors. Improvements have been made in vector design leading to the development of the helper-dependent adenoviral (HD) system. Unfortunately, it remains unclear whether these modifications are sufficient to circumvent the induction of inhibitor formation associated with adenoviral gene transfer. Objective : To develop an HD vector capable of mediating sustained FVIII expression and to determine the variables that influence inhibitor development. Methods : HD vectors were constructed encoding the canine FVIII B-domain deleted transgene under the control of either the cytomegalovirus (CMV) promoter or a tissue-restricted hybrid element consisting of five HNF-1 binding sites, located upstream of the human FVIII proximal promoter. Inbred and outbred populations of hemophilic mice were treated, and monitored for vector-induced toxicity, therapeutic efficacy, and inhibitor formation. Results : When HD vectors utilizing the CMV promoter were administered, all hemophilic mice developed high levels of FVIII inhibitors. In contrast, vectors under the control of the HNF/FVIII element were capable of achieving sustained elevations of FVIII for over 6 months. Strain-specific differences were also observed, with outbred animals showing a greater propensity towards inhibitor development in response to treatment. Conclusions : HD vectors can be used to provide long-term FVIII expression in hemophilic animals, but treatment outcome and the induction of inhibitors is dependent on a number of variables including the transgene promoter, the vector dose, and the genetic background of the host.