Female sexual receptivity is defective in juvenile hormone-deficient mutants of theapterous gene ofDrosophila melanogaster

During reproductive maturation of female insects, the acquisition of sexual receptivity is coordinated with ovarian development. Juvenile homone regulates vitellogenesis in the ovaries, but the action of this hormone in the development of sexual behavior is less well-understood. A strain ofDrosophila melanogaster carrying a mutation in theapterous gene(ap ⁴) was known to exhibit arrested vitellogenesis (rescuable by applying exogenous juvenile hormone), sterility of both sexes, and a deficiency of juvenile hormone. In this study, we examined the effects of mutations ofap on female receptivity and its relationship to juvenile hormone. We observed abnormally low female receptivity in homozygousap strains, and heteroallelic combinations ofap mutations exhibited low receptivity. For female receptivity,ap showed no dominance (i.e.,ap/ap ⁺ was intermediate betweenap/ap andap ⁺/ap ⁺). Low receptivity mapped genetically to theap locus. The reduction in female receptivity in these mutants is positively correlated with levels of juvenile hormone synthesized by their corpora allata.This work was supported in part by The Scheinfeld Center for Humans Genetics in the Social Sciences (J.R.), The National Science Foundation (BNS-882 1339 to J.R.), BARD (No. IS-1664-89R to D.S.), The Israel Cancer Research Fund (grant to D.S.), The Rekanati Foundation of Tel Aviv University (grant to D.S.), and The Israeli Fruit Council (award to M.A.)     

Genetic testing for hearing loss: different motivations for the same outcome

Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11-q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11-q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15-associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5' flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family-based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5' flanking region and intron 2 splicing region may be evaluated in further studies.     

A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4

Preterm birth is a leading cause of neonatal morbidity and mortality. Despite a growing body of evidence correlating inflammation with preterm birth, the signal transduction pathways responsible for the emptying of the uterus in the setting of intrauterine inflammation has not been elucidated. We now report a unique, reproducible mouse model of localized intrauterine inflammation. This model results in 100% preterm delivery with no maternal mortality. Using our model, we also show that platelet-activating factor is a crucial mediator of both inflammation-induced preterm birth and fetal demise. Using C3H/HeJ mice, we demonstrate that toll-like receptor-4 (TLR-4) plays a role in lipopolysaccharide-induced preterm birth but not in inflammation-induced fetal death. Immunohistochemistry studies demonstrate the presence of the platelet-activating factor receptor in both endometrial glands and smooth muscle in uterine tissues. Molecular studies demonstrate the differential expression of platelet-activating factor receptor and TLR-4 in uterine and cervical tissue throughout gestation. Quantitative polymerase chain reaction revealed an up-regulation of TLR-4 in the fundal region of the uterus in response to intrauterine inflammation. The use of this model will increase our understanding of the significant clinical problem of inflammation-induced preterm birth and will elucidate signal transduction pathways involved in an inflammatory state.     

Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease

It is unresolved whether elevated homocysteine in coronary artery disease (CAD) is the cause of arteriosclerosis or its consequence. In contrast, genetic variants of enzymes that metabolize homocysteine cannot be altered by arteriosclerosis. Consequently, their association with CAD would permit to imply causality. We modeled by regression analysis the effect of 11 variants in the methionine cycle upon CAD manifestation in 591 controls and 278 CAD patients. Among the examined variants only the carriership for the c.844ins68 in the cystathionine beta-synthase (CBS) gene was associated with a significantly lowered risk of CAD (OR=0.56; 95% CI=0.35-0.90 in the univariable, and OR=0.41, 95% CI=0.19-0.89 for obese people in the multivariable analysis, respectively). Healthy carriers of the c.844ins68 variant exhibited, compared to the wild type controls, significantly higher postload ratios of blood S-adenosylmethionine to S-adenosylhomocysteine (61.4 vs. 54.9, p=0.001) and of plasma total cysteine to homocysteine (8.6 vs. 7.3, p=0.004). The changes in these metabolites are compatible with an improved methylation status and with enhanced activity of homocysteine transsulfuration. In conclusion, the coincidence of clinical and biochemical effects of a common c.844ins68 CBS variant supports the hypothesis that compounds relating to homocysteine metabolism may play role in the development and/or progression of CAD.     

Depolarization-induced retrograde synaptic inhibition in the mouse cerebellar cortex is mediated by 2-arachidonoylglycerol

Endocannabinoids acting on CB₁ cannabinoid receptors are involved in short- and long-term depression of synaptic transmission. The aim of the present study was to determine which endocannabinoid, anandamide or 2-arachidonoylglycerol (2-AG), is involved in depolarization-induced suppression of inhibition (DSI) in the cerebellar cortex, which is the most widely studied form of short-term depression. Depolarization of Purkinje cells in the mouse cerebellum led to an increase in intracellular calcium concentration and to suppression of the inhibitory input to these neurons (i.e. DSI occurred). Orlistat and RHC80267, two blockers of sn -1-diacylglycerol lipase, the enzyme catalysing 2-AG formation, abolished DSI by acting downstream of calcium influx. In contrast, DSI occurred also in the presence of a phospholipase C inhibitor. Intact operation of the calcium-dependent messengers calmodulin and Ca²⁺–calmodulin-dependent protein kinase II were necessary for DSI. DSI was potentiated by an inhibitor of the main 2-AG-degrading enzyme, monoacylglycerol lipase. Interference with the anandamide metabolizing enzyme, fatty acid amide hydrolase, did not modify DSI. Thus, three kinds of observations identified 2-AG as the endocannabinoid involved in DSI in the mouse cerebellum: DSI was abolished by diacylglycerol lipase inhibitors; DSI was potentiated by a monoglyceride lipase inhibitor; and DSI was not changed by an inhibitor of fatty acid amide hydrolase. Further experiments indicated that 2-AG is the endocannabinoid mediating short-term retrograde signalling also at other synapses: orlistat abolished DSI in the rat cerebellum, DSI in the mouse substantia nigra pars reticulata and depolarization-induced suppression of excitation in the mouse cerebellum.     

Lack of association of angiotensin I-converting enzyme gene polymorphism and premature myocardial infarction in Mauritian Indians

Eighty-five young Mauritian Indians, male survivors of premature myocardial infarction (MI) and thus belonging to a high risk group, were compared with 108 stringently selected controls for a possible association between premature MI and an insertion/deletion (I/D) polymorphism in the gene encoding angiotensin I-converting enzyme (ACE). The frequency of the D allele was 0.42 in the MI group and 0.43 in the control group, and thus no association between I/D polymorphism of ACE with susceptibility to early-onset MI was found in this population group. Other gene components of the renin-angiotensin system and lipid metabolism need to be explored to understand the genetic factors involved in causing MI at an early age.     

Lymphoproliferative disease after transplantation

Herein we describe 7 cases of posttransplantation lymphoproliferative disease (PTLD), 5 in men and 2 in women (aged from 25 to 62 years), occurring from 4 months to 12 years (mean, 7 years) after transplantation. Our patients were recipients of kidney, kidney and pancreas, heart, and autologous peripheral haematopoetic stem cells. Four cases were diagnosed as monomorphic and three as polymorphic type of PTLD according to the WHO classification. Monoclonal immunoglobuline heavy chain gene rearrangement was detected in two monomorphic lesions and one polymorphic lesion by polymerase chain reaction (PCR). In the two cases of polymorphic and the one case of monomorphic PTLD, the presence of EBV was visualised by immunohistochemical staining of some transformed lymphoid cells for latent membrane protein (LMP) of EBV. The presence of type A EBV was demonstrated by PCR. The patients were treated by reduction or discontinuation of immunosuppression and by chemotherapy. In 2 cases, a part of the organ affected by lymphoma (sigmoid colon and pancreas) was surgically resected. Four patients died of causes related to PTLD (2 to 15 months after the diagnosis), mainly of infectious complications. Two other patients who achieved remission died of unrelated causes. Only the youngest man is alive and in the complete remission 10 months after the diagnosis of PTLD.     

Lipomatous myofibroblastoma: a potential diagnostic pitfall in the spectrum of the spindle cell lesions of the breast

We report on two cases of myofibroblastoma (MFB) of the breast comprised predominantly of a mature fatty component, representing approximately three quarters of the entire tumour area. Both tumours consisted of a well-circumscribed lipomatous tumour mass containing dispersed nodular or irregularly shaped spindled cellular areas. The fatty component was represented exclusively by mature adipocytes, uniform in size and shape, lacking nuclear pleomorphism. The cellular areas contained spindly to oval cells with morphological and immunophenotypical features typical of MFB. The two components were so intimately admixed that a finger-like infiltrating growth pattern was apparent. The cases reported here as "lipomatous MFB" aim to clarify further the morphological spectrum of MFB of the breast. Lipomatous MFB may potentially mimic other benign or aggressive tumour-like lesions or even bland-looking malignant spindle cell tumours such as fibromatosis, nodular fasciitis, spindle cell lipoma, spindle cell liposarcoma, spindle cell variant of metaplastic carcinoma, spindle cell malignant myoepithelioma, and low-grade fibrosarcoma/malignant fibrous histiocytoma. The histogenesis of the present bimorphic mesenchymal tumours could be explained as the result of a dual, myofibroblastic and lipomatous, differentiation from a common pluripotential mesenchymal precursor cell, probably represented by the vimentin+/CD34+ fibroblast of the mammary stroma.