Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q.

Partial trisomy distal 4q (denoted 4q+) is a human chromosomal disorder caused by duplication of the distal end of the long arm of chromosome 4 (Chr4). This disorder manifests typical phenotypes, including craniofacial, renal, heart and thumb developmental defects. Although these clinical features are likely caused by a dosage imbalance in the gene network involving the trisomic region, the causative gene or genes and the molecular bases are largely unknown. Here, we report mouse Recombination-induced mutation 4 (Rim4) as a model animal of 4q+. The Rim4 genome contains an insertion of a 6.5 Mb fragment from mouse chromosome 8 into chromosome 6. This insertion fragment contains 17 genes, including Hand2, that encode the basic helix-loop-helix transcription factor and is syntenic to the distal end of human Chr4, 4q32.3 to 4q34.1, which is responsible for 4q+. A comparison of phenotypes between patients with Rim4 and 4q+ revealed that Rim4 shows direct parallels with many phenotypes of 4q+ such as craniofacial, heart, cervical vertebra and limb deformities. Rebalancing the gene dosage by a genetic cross with Hand2 knockout mice ameliorated symptoms of the heart and limb deformities of Rim4. Conversely, an increase in copy number of Hand2 in wild-type mice recaptures the heart and limb deformities of Rim4. Our results collectively demonstrate that overdosage of Hand2 is a major cause for at least the limb and heart phenotypes of 4q+ and that mouse Rim4 provides a unique animal model for understanding the molecular bases underlying the complex phenotypes of 4q+.

Effect of community-based intervention using depression screening on elderly suicide risk: a meta-analysis of the evidence from Japan.

A systematic review was undertaken to quantify the effect of community-based depression screening (CDS) with follow-up on the completed suicide risk for residents aged 65 and over. Five quasi-experimental studies in Japanese regions with high suicide rates were included in the meta-analysis. Combined incidence rate ratios (95% confidence intervals) by the Mantel-Haenszel method and by the DerSimonian-Laird method in two homogenous studies implementing the follow-up conducted by psychiatrists were 0.30 (0.13-0.68) and 0.33 (0.14-0.80) in men, and 0.33 (0.19-0.58) and 0.33 (0.19-0.60) in women, respectively; and those in three homogenous studies implementing the follow-up conducted by general practitioners were 0.73 (0.45-1.18) and 0.74 (0.45-1.23) in men, and 0.36 (0.21-0.60) and 0.39 (0.22-0.66) in women, respectively. There are very few studies included, however, to demonstrate an association between CDS and the reduced risk, suggesting gender difference in the effectiveness.

Outcomes of community-based screening for depression and suicide prevention among Japanese elders.

PURPOSE: In this study we evaluate outcomes of a community-based program to prevent suicide among elderly individuals aged 65 and older. DESIGN AND METHODS: We used a quasi-experimental design with intervention and referent municipalities. The program included a 7-year implementation of depression screening with follow-up by general practitioners and a 10-year implementation of public education conducted in Yasuzuka (population 4,940; elderly suicide rate for women, 275/100,000; for men, 323/100,000). We estimated changes in the risk of completing suicide before and after the 10-year implementation by the incidence-rate ratio (IRR). RESULTS: The risk for women in the intervention area was reduced by 64% (age-adjusted IRR=0.36; 95% confidence interval=0.14-0.93), whereas there was no significant change in the risk for men in the intervention area and either men or women in the referent municipalities. A ratio of the IRR for women aged 65 to 74 in the intervention area to that in its prefecture was estimated at 0.23 (90% confidence interval=0.05-0.99), showing that the risk reduction was greater than the secular trend. IMPLICATIONS: The management of depression by use of community resources involving public health and primary care physicians is effective in the prevention of suicide for elderly women but uncertain for men.

Preventing elderly suicide through primary care by community-based screening for depression in rural Japan.

Depression is a major cause of suicide among the elderly. Few previous community-based interventions against depression have reduced the suicide rate. This study aims to evaluate outcomes of a community-based program to prevent suicide among the elderly using a quasi-experimental design with a neighboring reference group. The program, including depression screening with follow-up and health education through primary care and public health nursing, was implemented for 10 years in Matsudai town, a rural area of Japan (population 6,015; suicide rate per 10(5) [65-year-olds] for males 290.6, and for females 361.3). Changes in the suicide risk were estimated by the incidence rate ratio (IRR). The female risk of completing suicide in the intervention area was reduced by 70% (age-adjusted IRR: 0.30; 95% CI: 0.14-0.67), while there was no change in the risk for males in the intervention area nor for males or females in the reference area (Kawanishi town: population 9,425; elderly suicide rate for males 212.2, females 151.9). A ratio of the female IRR in the intervention area to that in its prefecture was also estimated at 0.45 (95% CI: 0.19-0.97), showing that the reduction of suicide risk in the intervention area was greater than the historical trend. A community intervention against suicide using management of depression with nonpsychiatric, primary health care would be effective for elderly females, but not males.