A polymorphism in <Emphasis Type="Italic">PTPN2</Emphasis> gene is associated with an earlier onset of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) genome-wide study found association of PTPN2 with three autoimmune diseases, among them is type 1 diabetes (T1D). This result was confirmed by a follow-up study that pointed to new independent signals within the region. However, both studies were performed in patients with an early-onset T1D. We aimed at replicating the previous results and studying the influence of these polymorphisms in the age at T1D debut. We genotyped 439 T1D Spanish subjects (age at onset, 1 to 65 years) and 861 controls for two PTPN2 single nucleotide polymorphisms (SNPs), rs2542151 and rs478582, and studied the effect of both polymorphisms in age at onset through stratified and continuous analyses. The frequency of rs2542151*G carriers was significantly higher in the early-onset group compared with late-onset patients (p = 0.023) and with controls (OR = 1.61 [1.14–2.26]; p = 0.005). No significant differences were found between controls and late-onset patients. The log-rank chi-square test for the Kaplan–Meier plots (carriers of susceptibility allele vs non carriers) was statistically significant (χ _1df² = 4.485; p = 0.034), yielding an earlier disease debut for G carriers. The analysis of the SNP rs478582 did not reach statistical significance. In summary, we replicate the association detected by the WTCCC and propose that the rs2542151*G allele confers risk to an earlier onset of T1D.     

DPY19L2 deletion as a major cause of globozoospermia

Globozoospermia, characterized by round-headed spermatozoa, is a rare (< 0.1% in male infertile patients) and severe teratozoospermia consisting primarily of spermatozoa lacking an acrosome. Studying a Jordanian consanguineous family in which five brothers were diagnosed with complete globozoospermia, we showed that the four out of five analyzed infertile brothers carried a homozygous deletion of 200 kb on chromosome 12 encompassing only DPY19L2. Very similar deletions were found in three additional unrelated patients, suggesting that DPY19L2 deletion is a major cause of globozoospermia, given that 19% (4 of 21) of the analyzed patients had such deletion. The deletion is most probably due to a nonallelic homologous recombination (NAHR), because the gene is surrounded by two low copy repeats (LCRs). We found DPY19L2 deletion in patients from three different origins and two different breakpoints, strongly suggesting that the deletion results from recurrent events linked to the specific architectural feature of this locus rather than from a founder effect, without fully excluding a recent founder effect. DPY19L2 is associated with a complete form of globozoospermia, as is the case for the first two genes found to be associated with globozoospermia, SPATA16 or PICK1. However, in contrast to SPATA16, for which no pregnancy was reported, pregnancies were achieved, via intracytoplasmic sperm injection, for two patients with DPY19L2 deletion, who then fathered three children.     

Bovine peripheral blood MSCs chemotax towards inflammation and embryo implantation stimuli

Mesenchymal stem cells (MSCs) have a great potential in regenerative medicine because of their multipotential and immunoregulatory capacities, while in early pregnancy they could participate in the immunotolerance of the mother towards the embryo. Peripheral blood constitutes an accessible source of MSCs. We successfully isolated peripheral blood MSC (pbMSCs) lines, with or without previous bone marrow mobilization. All pbMSCs lines obtained in both conditions presented classical MSC markers and properties, alkaline phosphatase activity and multipotent capacity to differentiate among adipogenic, osteogenic or chondrogenic lineages, and suppressed the proliferation of T cells. pbMSCs showed migratory capacity without cytokine stimulation while increasing their migration rate in the presence of inflammatory or embryo implantation stimuli. Interestingly, in contrast to MSCs derived from endometrial tissue, three pbMSCs lines also showed increased migration towards the IFN‐τ implantation cytokine. Moreover, the secretome produced by an early implantation stage embryonic trophectoderm cell line showed a chemoattractant effect in pbMSCs. Our results suggest that circulating MSCs are present in the peripheral blood under healthy conditions. The fact that both the inflammation and implantation signals induced pbMSCs chemotaxis highlights MSC heterogeneity and suggests that their migratory capacity may differ according to their tissue of origin and would suggest the possible active recruitment of MSCs from bone marrow during pregnancy to repress the immune response to prevent the embryo rejection by the maternal organism.     

Toward spatio‐temporal delineation of positive interactions in ecology

Given unprecedented rates of biodiversity loss, there is an urgency to better understand the ecological consequences of interactions among organisms that may lost or altered. Positive interactions among organisms of the same or different species that directly or indirectly improve performance of at least one participant can structure populations and communities and control ecosystem process. However, we are still in need of synthetic approaches to better understand how positive interactions scale spatio‐temporally across a range of taxa and ecosystems. Here, we synthesize two complementary approaches to more rigorously describe positive interactions and their consequences among organisms, across taxa, and over spatio‐temporal scales. In the first approach, which we call the mechanistic approach, we make a distinction between two principal mechanisms of facilitation—habitat modification and resource modification. Considering the differences in these two mechanisms is critical because it delineates the potential spatio‐temporal bounds over which a positive interaction can occur. We offer guidance on improved sampling regimes for quantification of these mechanistic interactions and their consequences. Second, we present a trait‐based approach in which traits of facilitators or traits of beneficiaries can modulate their magnitude of effect or how they respond to either of the positive interaction mechanisms, respectively. Therefore, both approaches can be integrated together by quantifying the degree to which a focal facilitator's or beneficiary's traits explain the magnitude of a positive effect in space and time. Furthermore, we demonstrate how field measurements and analytical techniques can be used to collect and analyze data to test the predictions presented herein. We conclude by discussing how these approaches can be applied to contemporary challenges in ecology, such as conservation and restoration and suggest avenues for future research.     

Modulation of arsenic trioxide-induced apoptosis by genistein and functionally related agents in U937 human leukaemia cells. Regulation by ROS and mitogen-activated protein kinases

The proved radio- and chemo-sensitizing capacity of genistein supports the potential use of this isoflavone in antitumour therapies. In this regard, we recently reported that genistein potentiates apoptosis induction by the anti-leukaemic agent arsenic trioxide (ATO) via reactive oxygen species (ROS) generation and p38-MAPK activation. In the present study we analyze the action of agents sharing functional similarities with the isoflavone, namely 17-β-estradiol, the DNA topoisomerase II poison etoposide, and the tyrosine kinase (PTK) inhibitors herbimycin A, epigallocatechin-3-gallate (EGCG) and adaphostin, in U937 and other human acute myeloid leukaemia cell lines. Co-treatment with 17-β-estradiol or etoposide failed to stimulate ROS production and potentiate ATO-provoked apoptosis, although etoposide caused G₂/M cycle arrest, in the same manner as genistein. By contrast, all PTK inhibitors increased ATO-provoked apoptosis, with similar efficacy as genistein. Daidzein, a genistein analogue without PTK-inhibiting activity, failed to potentiate apoptosis, and co-treatment with orthovanadate attenuated the sensitizing capacity of genistein. Apoptosis potentiation by PTK inhibitors was associated to ROS over-accumulation and stimulation of p38-MAPK phosphorylation, was mimicked by conventional pro-oxidant agents (exogenous H₂O₂ and the glutathione-depleting agent dl-buthionine-(S,R)-sulfoximine), and was attenuated by the antioxidant agent N-acetyl-l-cysteine, and by the p38-MAPK inhibitor SB203580 or p38-MAPK-directed siRNAs. On the other hand, the PTK inhibitors caused disparate effects on ERK phosphorylation, and co-treatment with the MEK/ERK inhibitor PD98059 enhanced the pro-apoptotic capacity of the PTK inhibitors. These results suggest that PTK inhibition, together with ROS generation and p38-MAPK activation, are responsible for the chemo-sensitizing action of genistein and functionally related agents in leukaemia cells.     

Larger Hip Circumference Independently Predicts Health and Longevity in a Swedish Female Cohort

Objective: The waist circumference is widely viewed as a simple but effective measure for assessing obesity‐related health risks, whereas measurement of the hip circumference is not currently prioritized. This study examines health risks associated specifically with hip circumference in a cohort of Swedish women, to determine whether information may be lost by excluding the hip circumference from health surveys. Research Methods and Procedures: The subjects described in this report constitute a population‐based sample of 38‐ to 60‐year‐old women who underwent anthropometric examinations in 1968. The 24‐year incidence rates have been ascertained for myocardial infarction, combined cardiovascular diseases, and diabetes. All‐cause, cardiovascular, and myocardial infarction mortality also were evaluated. Results: Hip circumference was a significant independent inverse risk estimator for all endpoints studied. Using Cox regression with adjustment for age, smoking, body mass index, and waist circumference, the remaining variability associated with larger hips was associated with significantly fewer adverse health outcomes. The hip circumference became statistically informative after body mass index adjustment. The strongest protective associations were observed for cardiovascular disease and diabetes endpoints, although significant trends were also seen for total mortality. Considering hip and waist simultaneously, the strength of the inverse association for large hips generally exceeded the positive association for waist. Discussion: Recent interest in the waist circumference as an effective screening tool has taken the focus off of the hip circumference. The present results suggest that collection of hip measurements should not be discontinued in assessment of obesity‐related risk status and health promotion.     

Use of melengestrol acetate in feed for contraception in herds of captive ungulates

Herds of blackbuck antelope (Antilopa cervicapra) and barasingha (Cervus duvauceli), axis (Cervus axis), sambar (Cervus unicolor), and Formosan sika (Cervus nippon taiwanaus) deer at the Wildlife Conservation Society/Bronx Zoo (WCS/BZ) were fed melengestrol acetate (MGA) at a concentration of 0.000154% in pelleted feed for various periods of times during 1991–2001. The target dose per animal of MGA was 1–2 mg per day. Contraceptive rates during treatment were 100% for blackbuck antelope and barasingha, sambar, and sika deer, and approximately 93% for axis deer. There were no observed adverse effects from MGA treatment on gestation. Post‐treatment reproductive rates were lower than pretreatment rates. Zoo Biol 22:455–463, 2003. © 2003 Wiley‐Liss, Inc.