Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents.

Plasmodium falciparum thioredoxin reductase (PfTrxR: NADPH+Trx(S)2+H+<-->NADP++Trx(SH)2) is a high Mr flavin-dependent TrxR that reduces thioredoxin (Trx) via a CysXXXXCys pair located penultimately to the C-terminal Gly. In this respect, PfTrxR differs significantly from its human counterpart which bears a Cys-Sec redox pair at the same position. PfTrxR is essentially involved in antioxidant defense and redox regulation of the parasite and has been previously validated by knock-out studies as a potential drug target for malaria chemotherapy. Moreover, human TrxR is present in most cancer cells at levels tenfold higher than in normal cells. Here we report the discovery of a series of potent inhibitors of PfTrxR. The three most promising inhibitors, 3(IC50(PfTrxR)=2 microM and IC50(hTrxR)=50 microM), 7(IC50(PfTrxR)=2 microM and IC50(hTrxR)=140 microM), and 11(IC50(PfTrxR)=0.5 microM and IC50(hTrxR)=4 microM) were selective for the parasite enzyme. Detailed mechanistic characterization of the effects of these compounds on the PfTrxR-catalyzed reaction showed clear uncompetitive inhibition with respect to both substrate and cofactor. For the most specific PfTrxR inhibitor 7, an alkylation mechanism study based on a thiol conjugation model was performed. Furthermore, all three compounds were active in the lower micromolar range on the chloroquine-resistant P. falciparum strain K1 in vitro.

Antinociceptive properties of the methanolic extract obtained from Ipomoea pes-caprae (L.) R. Br.

Ipomoea pes-caprae is a medicinal plant used in many countries for the treatment of several ailments, including inflammatory and algesic processes. The present study describes the antinociceptive effects of the methanolic extract and two fractions obtained from aerial parts of this plant. The results indicated that both methanolic extract and two fractions (ethyl acetate and aqueous) exhibited considerable antinociceptive activity against two classical models of pain in mice. Methanolic extract presented a calculated ID50 value of 33.8 mg/kg, i.p. against writhing test and also inhibited both phases of pain (neurogenic and inflammatory) of the formalin test with ID50 of 37.7 and 12.5 mg/kg, i.p. for the first and second phase, respectively. Preliminary phytochemical analysis suggested the presence of steroids, terpenoids, alkaloids and flavonoids. These findings support, at least in part, the popular use of I. pes-caprae to treat dolorous processes.

Structure-activity relationships for the analgesic activity of gallic acid derivatives.

Values of ID50 for a collection of structurally-related gallic acid derivatives have been employed to create a predictive quantitative structure-activity relationship (QSAR) which links structure to values of analgesic activity. The QSAR model developed has substantial predictive power for the design of novel gallic acid derivatives having improved analgesic potency.

Isolation and identification of compounds with antinociceptive action from Ipomoea pes-caprae (L.) R. Br.

This study describes the isolation and identification of several constituents from Ipomoea pes-caprae (L.) R. Br., a medicinal plant frequently employed in folk medicine of many countries as a remedy against several diseases, including inflammation and pain. Our results demonstrate that some of these compounds, such as glochidone, betulinic acid, alpha- and beta-amyrin acetate, isoquercitrin, etc. showed pronounced antinociceptive properties in the writhing test and formalin test in mice. These data confirm our previous work concerning the antinociceptive action of the hydroalcoholic extract of I. pes-caprae and justify, at least in part, the popular use of this plant for the treatment of dolorous processes.

Impact of drug therapy on benign prostatic hyperplasia-specific quality of life.

Quality of life (QOL) is an important issue when assessing medical treatment of benign prostatic hyperplasia (BPH). There are many QOL questionnaires available, and disease-specific questionnaires are being developed. Currently, most patients undergoing treatment for BPH receive alpha-blockers or finasteride. To determine which QOL measures are being used, we did a Medline search covering the past 10 years and found 11 studies in which BPH-QOL was investigated. The wide variety of questionnaires used made comparison between drug studies difficult. When comparing studies that used at least one similar questionnaire to that of another drug study, we found alpha-blocker treatment excelled over finasteride in improving BPH-QOL in the areas of earlier response, larger decreases in mean changes, and reduced sexual side effects. QOL assessment should be a routine part of BPH treatment, and more standardized and validated measures should be used to allow for comparative, meaningful analyses.