Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago

Prothrombin 20210G>A and factor V Leiden are common prothrombotic mutations in whites for which founder effects have been established. In this study, we analyzed the frequencies of 5 single nucleotide polymorphisms (SNPs) and 9 microsatellites flanking the prothrombin gene (F2) in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G>A mutation, we used the DMLE+2.0 program, which analyzed linkage disequilibria between the mutation and the multiple markers that had been assessed. This analysis yielded an age estimate of 23,720 years (95% credible set, 19,080-31,340 years). A similar analysis by the DMLE+2.0 program was performed on 5 SNPs from previously studied homozygotes for factor V Leiden and controls that yielded an age estimate of 21,340 years (95% credible set, 16,880-29,480 years). The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggest selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections).     

Obsessive-compulsive disorder in bipolar disorder patients with first manic episode

BACKGROUND: Evidence indicates that obsessive--compulsive disorder (OCD) co-occurs with schizophrenia and bipolar disorder (BD) at a higher rate than in the general population. The inflated rate of comorbidity may result from chronic illness, antipsychotic therapy or treatment-seeking behavior. To control for these factors we evaluated the prevalence of OCD in patients with first-episode acute mania who met DSM-IV criteria for BD-I, and compared them with our previously reported group of first-episode schizophrenia patients. METHOD: Fifty-six BD-I patients with a first-episode of acute mania were screened for OCD and additional comorbid disorders using the Structured Clinical Interview for DSM-IV Axis-I disorders and appropriate rating scales. RESULTS: Only one patient (1.8%) met DSM-IV criteria for OCD, and two (3.6%) met criteria for sub-threshold OCD. In contrast, there was a substantial aggregation of substance use disorders 32.1% (N=8), anxiety disorders, other than OCD 26.8% (N=15) and eating disorders 14.3% (N=8). LIMITATIONS: Small sample size, cross-sectional nature of the assessments and the inclusion of only BD-I patients. CONCLUSION: The rate of OCD in first-episode BD-I patients did not differ significantly from that found in the general population and was substantially lower than in previously reported first-episode schizophrenia patients (1.8% vs. 14%). We suggest that a preferential association of OCD with schizophrenia early in the course of illness represents a pathophysiological linkage between the two disorders, and putatively a specific schizo-obsessive subtype. In contrast, OCD in BD-I may stand for "true" comorbidity. Large-scale parallel comparative evaluations of comorbidity in BD-I and schizophrenia may contribute to the search for specific pathophysiological mechanisms of distinct comorbid-related subsets in either disorder.     

Strigolactone analogues induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogramed primary prostate cancer cells.

Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Treatment of cancer cells with strigolactone analogues was hallmarked by activation of the stress-related MAPKs: p38 and JNK and induction of stress-related genes; cell cycle arrest and apoptosis evident by increased percentages of cells in the sub-G1 fraction and Annexin V staining. In addition, we tested the response of patient-matched conditionally reprogrammed primary prostate normal and cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis confirmed by PARP1 cleavage compared to their normal counterpart cells. Thus, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.     

Interfering with the interaction between ErbB1, nucleolin and Ras as a potential treatment for glioblastoma

The three oncogenes, ErbB receptors, Ras proteins and nucleolin may contribute to malignant transformation. Previously, we demonstrated that nucleolin could bind both Ras protein and ErbB receptors. We also showed that the crosstalk between the three proteins facilitates anchorage independent growth and tumor growth in nude mice, and that inhibition of this interaction in prostate and colon cancer cells reduces tumorigenicity. In the present study, we show that treatment with Ras and nucleolin inhibitors reduces the oncogenic effect induced by ErbB1 receptor in U87-MG cells. This combined treatment enhances cell death, reduces cell proliferation and cell migration. Moreover, we demonstrate a pivotal role of nucleolin in ErbB1 activation by its ligand. Nucleolin inhibitor prevents EGF-induced receptor activation and its downstream signaling followed by reduced proliferation. Furthermore, inhibition of Ras by Salirasib (FTS), mainly reduces cell viability and motility. The combined treatment, which targets both Ras and nucleolin, additively reduces tumorigenicity both in vitro and in vivo. These results suggest that targeting both nucleolin and Ras may represent an additional opportunity for inhibiting cancers, including glioblastoma, that are driven by these oncogenes.     

Ideological Meaning Making After the Loss of a Child: The Case of Israeli Bereaved Parents

The study provides a view of ideological meaning-making processes of 10 Israelis who lost a child examining the parents’ perspectives and written public documents. The texts and interviews were analyzed using Gadamer's hermeneutic philosophy. Findings indicate that bereaved parents construct conflicting ideologically oriented viewpoints: doubting and affirming the Zionist ideology; ascribing sense and senselessness to the loss; and joining the ethos but keeping personal meanings. Our conclusion is consistent with theorists who reject the notion that the human narrative should be coherently unified. We point to potential links between relational dialectics and meaning-making theory and outline implications for practice.     

An autosomal genome-wide screen for celiac disease in Bedouin families

Celiac disease is a common, familial autoimmune disease caused by exposure to gliadin in wheat, and related prolamins in barley and rye. The prevalence of the disease is approximately 1:133. Celiac disease can cause significant morbidity. The only treatment is a gluten-free diet. A genome-wide search of 405 microsatellite markers was performed on samples from 18 Bedouin families with a minimum of two cases of celiac disease. Non-parametric and parametric (including both dominant and recessive models of inheritance) linkage analyses were performed. The most significant genome-wide linkage evidence was at chromosome 3p26 with an HLod of 3.21, under the dominant model. The only other HLod or NPL greater than 2 was at 4q35, with an HLod of 2.15 under a dominant model. The region at 3p26, previously reported in two linkage analyses, harbors interleukin receptor genes, plausible candidates for celiac disease.