Scrutinizing the therapeutic response of Phyllanthus exmblica's different doses to restore the immunomodulation potential in immunosuppressed female albino rats.

OBJECTIVE: Immunosuppression and microbial resistance are the major drawbacks in conventional pharmaceutics. The present research work was planned to screen and characterize phytochemical constituents present in Phyllanthus emblica and to explore the immunomodulation potential of P. emblica by evaluating stress markers and different biochemical parameters in animals. MATERIALS AND METHODS: The phytochemical analysis explored the presence of antioxidant profiles and revealed the radical scavenging activities. In the second phase, an animal trial was performed using female albino rats. Female rats (n=18) were administered three different doses of P. emblica (low dose 100 mg/kg, intermediate 200 mg/kg, and high dose 300 mg/kg) for three weeks. After a significant change (p<0.05) in antioxidant status i.e., TOS and TAS, hematological, biochemical parameters, and immunoregulation i.e., IgM and IgG were elevated. Statistical analysis (ANOVA) illustrates that these selected plants have a great impact on microbial resistance and immunosuppression and have shown highly significant results. RESULTS: The results of all in vitro and in vivo assays conducted as part of the recent research work offer considerable evidence that the chosen medicinal plant has the ability to induce specific hormone release and boost the immune system. CONCLUSIONS: Based on our findings, it is proposed that medicinal herbs may be isolated using cutting-edge approaches to tackle the issues of immunosuppression and microbial resistance.

Synchronous primary malignancies of papillary thyroid carcinoma and Hodgkin lymphoma: Interventions and outcome.

Thyroid carcinoma is uncommon. Papillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid carcinoma and is a recognised complication of prior exposure to ionizing radiation. Even more uncommon is the synchronous occurrence of PTC with Hodgkin lymphoma (HL) as multiple primary malignancies. We report a 33-year-old mother of three who developed asymptomatic thyroid nodule for four years, and neck swelling for the recent ten months. She denied constitutional symptoms or B symptoms, and thyroid profiles were normal. Initially, metastatic thyroid cancer was suspected based on ultrasound scan findings of enlarged left thyroid gland and enlarged supraclavicular lymph nodes (LN). However, fine needle aspiration examinations of the thyroid nodule were inconclusive, and the supraclavicular LN was suspicious of HL. Computerised tomography scan detected a large mass at the thyroid glands and lymphadenopathies in the mediastinal, hilar, subcarinal and axilla with dimensions up to 6 cm. Left hemi-thyroidectomy with left supraclavicular LN biopsy revealed PTC in the left thyroid lobe measuring 38 x 25 x 18 mm, and the left supraclavicular LN was not definitive of HL. Completion thyroidectomy on the right side, bilateral central neck dissection and excision biopsy of the right supraclavicular LN revealed the presence of HL in the right supraclavicular LN, and both HL and metastatic PTC in right central LN. After multidisciplinary discussions, the patient received chemotherapy at four weeks postoperatively and achieved complete remission. This report highlights the importance of patient-centered approach and multidisciplinary consensus within lack of established guidelines, given rarity of the case.

Association of GH polymorphisms with growth traits in buffaloes.

Members of the somatotrophic axis, especially GH and IGF1, are essential for growth. The association between GH polymorphisms and growth traits was numerously studied in cattle; however, no data are available for such association studies in buffalo. Therefore, this study was conducted to screen for polymorphisms in the GH gene and to study their putative association with growth traits in 200 Egyptian buffaloes. Polymerase chain reaction single-strand conformation polymorphism and sequencing were applied to look for polymorphisms in 3 loci spanning all exons and introns of buffalo GH. The C (MspI+) >T (MspI-) SNP in intron3, which is well known in cattle, was not detected in the examined buffaloes. However, 2 missense mutations were detected in exon5: one previously detected p.Leu153Val SNP, with very low frequencies for the mutant (Val) allele and one novel p.Asn174His SNP. At weaning age, the p.Leu153Val SNP was significantly associated with weaning body weight and gain with the positive effect of the wild allele (Leu) and higher GH serum, mRNA, and protein levels in animals with Leu/Asn and Leu/His haplotypes. At yearling age, the 2 SNPs associated with yearling weight and gain with positive effect for the mutant (Val and His) alleles with increased GH, and IGF1 serum, mRNA, and protein and GHR mRNA and protein levels in animals with Val/Asn haplotype. Therefore, the selection of Egyptian buffaloes with the Val/Asn haplotype could improve the growth traits of Egyptian buffaloes at yearling age which is the target age for perfect growing.

Primary extragonadal vaginal yolk sac tumour: A case report.

INTRODUCTION: Yolk sac tumour (YST) or endodermal sinus tumour is rare and typically seen in gonads. CASE REPORT: We described a case of extragonadal vaginal YST in a one year and seven months old girl who presented with vaginal discharge and bleeding, and discuss its differential diagnosis and potential pitfalls in immunohistochemistry. She was found to have a suprapubic mass on examination. The serum alpha fetoprotein was 11919.4 ng/mL. Computed tomography of the pelvis revealed a large 6.4 cm heterogenous pelvic mass. Colposcopic examination of the pelvis showed a fungating vaginal mass that was subsequently confirmed as a yolk sac tumour. Immunohistochemically, the malignant cells were positive toward CKAE1/AE3, AFP and glypican-3, as well as CD117. DISCUSSION: Solid pattern extragonadal vaginal YST may morphologically resemble dysgerminoma that is also CD117 positive, while the glandular pattern YST may have clear cytoplasm and is positive for cytokeratin; hence, may resemble clear cell carcinoma. Being mindful of these potential diagnostic caveats is necessary to prevent misdiagnosis.

Water transport mediated by murine urea transporters: implications for urine concentration mechanisms.

Urea transporters (UTs) facilitate urea diffusion across cell membranes and play an important role in the urinary concentration mechanisms in the kidney. Herein, we injected cRNAs encoding for c-Myc-tagged murine UT-B, UT-A2 or UT-A3 (versus water-injected control) in Lithobates oocytes and evaluated oocyte surface protein expression with biotinylation and immunoblotting, urea uptake using [14C] counts and water permeability (P f ) by video microscopy. Immunoblots of UT-injected oocyte membranes revealed bands with a molecular weight consistent with that of a UT monomer (34 kDa), and UT-injected oocytes displayed significantly increased and phloretin-sensitive urea uptake and P f when compared to day-matched control oocytes. Subtracting the water-injected urea uptake or P f values from those of UT-injected oocytes yielded UT-dependent values*. We demonstrate for the first time that UT-A2 and UT-A3 can transport water, and we confirm that UT-B is permeable to water. Moreover, the [14C] urea*/P f * ratios fell in the sequence mUT-B>mUT-A2>mUT-A3, indicating that UTs can exhibit selectivity to urea and/or water. It is likely that specific kidney regions with high levels of UTs will exhibit increased urea and/or water permeabilities, directly influencing urine concentration. Furthermore, UT-mediated water transport activity must be considered when developing UT-inhibitors as novel diuretics.This article has an associated First Person interview with the first author of the paper.

Measurement of stretched penile length in prepubertal boys in Egypt.

BACKGROUND: Early diagnosis of penile size abnormalities is both medically and psychologically important. It is important in the diagnosis of penile problems. Therefore, a current established reference for penile size in newborns and children is vital for diagnosis and early management of micropenis. OBJECTIVES: The aim of the present study was to establish reference values for penile length in newborn and prepubertal boys at different ages in Minia Governorate, Egypt. METHODS: The study was conducted on 1000 boys with ages ranging from 1 day to 13 years. Stretched penile length (SPL) was measured in mm by using a ruler with markings along the dorsum of the penis. The suprapubic fat tissue was pressed with one end of the ruler through the pubic ramus, and the penis was fully stretched and measured. RESULTS: The mean SPL increased with age from newborn to 5 years, with a rapid growth observed in the first 8 months of life. After 5 years, SPL showed a slower growth rate until the age of 10 years, where it started to increase significantly again. DISCUSSION: Comparison of the SPL in different age groups revealed significant statistical differences between most groups. It showed a noticeable and significant increase, especially from birth to the age of 5 years. Although there was a mild increase in SPL from 5 to 10 years, it showed a significant level in few age groups, indicating that the change is trivial. After that, high growth rate occurred again and statistical differences remained from age 10-13 years. CONCLUSION: An updated reference for normal SPL in Egyptian boys from birth to 13 years old was provided in this study.

Predictors of beef calf temperament at weaning and its impact on temperament at breeding and reproductive performance.

Two experiments were conducted to determine (i) factors influencing calf temperament at weaning, (ii) association between heifer-calf temperament at weaning and temperament at breeding and (iii) effect of heifer-calf temperament on pregnancy rate per artificial insemination (P/AI). In experiment 1, beef cows and their calves (n = 285) from three farms were used. Sire docility estimated progeny difference (EPD) score, birth type (normal or assisted), calf gender, calf behaviour (during 1st 4 weeks) and calf health status (until weaning) were recorded. Cows and calves were assigned a temperament score (0-calm; 1-excitable), and all cows were given a body condition score (BCS, 1-9; 1-emaciated; 9-obese) at weaning. Calf's illness (p < .05), low sire docility EPD score (p < .05), altered gait (p < .05), altered resting behaviour (p < .01), reduced/no play behaviour (p < .05) and cow excitable temperament (p < .001) increased calf excitable temperament at weaning. In experiment 2, replacement heifer-calves (n = 758) from 12 farms were assigned a temperament score at weaning and later at breeding. Blood from 40 calves at weaning and 31 heifers at initiation of synchronization (same animals) was collected by coccygeal venipuncture for determination of circulating cortisol and substance P concentrations. Heifers were assigned a BCS and reproductive tract score (RTS, 1-5; 1-immature, acyclic; 5-mature, cyclic), synchronized for fixed time AI, observed for oestrus and were artificially inseminated. Cortisol concentrations were increased in excitable heifer-calves compared to calm heifer-calves at weaning (p < .05), and substance P was increased in excitable compared to calm females both at weaning and breeding (p < .05). Low sire EPD docility score (p < .01), heifer-calf excitable temperament at weaning increased excitable temperament at breeding (p < .01). Controlling for BCS categories (p < .01), oestrous expression (p < .0001) and temperament at breeding by oestrous expression (p < .05), the calf's excitable temperament at weaning (p < .001) reduced P/AI (Calm, 62.7 (244/389) vs. Excitable, 53.4% (197/369); p < .01). In conclusion, selection of docile cows and sires with greater docility EPD score should be given consideration to reduce calf excitement. Temperament in beef female can be detected earlier in their life and could be used as a tool in the selection process and to improve their performances.

Effects of hyperaemia on left ventricular longitudinal strain in patients with suspected coronary artery disease : A first-pass stress perfusion cardiovascular magnetic resonance imaging study.

AIMS: Myocardial perfusion imaging during hyperaemic stress is commonly used to detect coronary artery disease. The aim of this study was to investigate the relationship between left ventricular global longitudinal strain (GLS), strain rate (GLSR), myocardial early (E') and late diastolic velocities (A') with adenosine stress first-pass perfusion cardiovascular magnetic resonance (CMR) imaging. METHODS AND RESULTS: 44 patients met the inclusion criteria and underwent CMR imaging. The CMR imaging protocol included: rest/stress horizontal long-axis (HLA) cine, rest/stress first-pass adenosine perfusion and late gadolinium enhancement imaging. Rest and stress HLA cine CMR images were analysed using feature-tracking software for the assessment of myocardial deformation. The presence of perfusion defects was scored on a binomial scale. In patients with hyperaemia-induced perfusion defects, rest global longitudinal strain GLS (-16.9 ± 3.7 vs. -19.6 ± 3.4; p-value = 0.02), E' (-86 ± 22 vs. -109 ± 38; p-value = 0.02), GLSR (69 ± 31 vs. 93 ± 38; p-value = 0.01) and stress GLS (-16.5 ± 4 vs. -21 ± 3.1; p < 0.001) were significantly reduced when compared with patients with no perfusion defects. Stress GLS was the strongest independent predictor of perfusion defects (odds ratio 1.43 95% confidence interval 1.14-1.78, p-value <0.001). A threshold of -19.8% for stress GLS demonstrated 78% sensitivity and 73% specificity for the presence of hyperaemia-induced perfusion defects. CONCLUSIONS: At peak myocardial hyperaemic stress, GLS is reduced in the presence of a perfusion defect in patients with suspected coronary artery disease. This reduction is most likely caused by reduced endocardial blood flow at maximal hyperaemia because of transmural redistribution of blood flow in the presence of significant coronary stenosis.

Flunixin meglumine improves pregnancy rate in embryo recipient beef cows with an excitable temperament.

Objectives were to determine effects of: 1) handling temperament and administration of flunixin meglumine, an inhibitor of prostaglandin F2a (PGF2a) synthesis, given at the time of embryo transfer, on pregnancy rates in beef cattle embryo transfer recipients; 2) handling temperament and flunixin meglumine on peripheral concentrations of progesterone, cortisol, substance-P, prostaglandin F metabolites (PGFM, (13,14-dihydro-15-keto-PGF2a) and isoprostane 8-epi PGF2a; and 3) flunixin meglumine treatment on proportion of non-pregnant recipient cows returning to estrus within an expected interval. Angus cross beef cows (n = 710) at 7 locations were assigned a body condition score (BCS: 1, emaciated; 9, obese) and a temperament score [0, calm, slow chute exit; walk (n = 352), 1, excited, fast chute exit; jump, trot or run (n = 358)] and were synchronized with Select-Synch with a controlled internal drug release (CIDR) protocol. Estrus detection aids were applied at CIDR removal and cows were observed thrice daily for estrus until 72 h. Recipient cows that expressed estrus and had a corpus luteum received a frozen-thawed embryo on Day 7 after estrus. At the time of transfer, recipient cows were randomly allocated to receive 10 mL of flunixin meglumine im, immediately after transfer (n = 365) or served as an untreated control (n = 345). In a subset of cows (n = 80), ovarian ultrasonography was performed on the day of embryo transfer to determine corpus luteum volume and blood samples were collected twice, at the time of embryo transfer and 7 d later. All cows received estrus detection aids again on Day 14 (7 d after embryo transfer) and were observed for estrus twice daily until Day 24. Accounting for treatment (P > 0.1), embryo transfer difficulty score (P < 0.1), temperament by treatment interaction (P < 0.05), recipient cows with calm temperament had a higher pregnancy rate compared to those with an excited temperament [59.4 (209/352) vs 51.7% (185/358)]. The pregnancy rate for excitable cows without flunixin meglumine was lower (46.3% 81/175) compared to excitable cows that did received flunixin meglumine [56.8% (104/183)], and calm cows that did [59.3% (108/182)] or did not [59.4% (104/170)] receive flunixin meglumine. Proportions of non-pregnant recipient cows returning to estrus on Days 18-24 were not different between flunixin meglumine and control groups, 87.6% (134/153) and 84.0% (137/163), respectively (P > 0.1). At the time of embryo transfer and 7 d later, there were moderate to strong correlations among circulating concentrations of progesterone, cortisol, substance-P, PGFM and isoprostane 8-epi PGF2a. Among excitable cows, progesterone concentrations were lower and cortisol, substance-P, PGFM and isoprostane 8-epi PGF2a concentrations were greater for cows in the control group compared to cows that received flunixin meglumine. In conclusion, administration of flunixin meglumine improved pregnancy rates in excitable recipient cows following embryo transfer without affecting the proportion of non-pregnant cows returning to estrus.

Relationship among circulating anti-Müllerian hormone, insulin like growth factor 1, cadmium and superovulatory response in dairy cows.

The objectives of this study were 1. to determine the associations among circulating anti-Mullerian hormone (AMH), insulin like growth factor 1 (IGF1) and cadmium (Cd) concentrations of lactating Holstein cows at the time of superovulation and 2. to determine the effect of circulating AMH, IGF1 and Cd concentrations on the superovulatory response in Holstein dairy cows. Holstein cows (n = 30) were milked thrice daily and housed and fed in free stall barn as a separate group. All animals were synchronized for superovulation and flushed. Three blood samples for AMH, IGF1 and Cd analysis were collected prior to superovulation, at estrus and at the time of embryo collection. The concentrations of blood makers prior to superovulation were highly correlated to superovulatory response. Circulating concentrations of AMH, IGF1 prior to superovulation were negatively correlated to Cd concentrations (P < 0.05). There was no correlation between circulating concentrations of AMH and IGF1. The number of corpus luteum (r = 0.71), total embryo (r = 0.67), total transferable embryo (r = 0.51) and total grade 1 embryo (r = 0.5) were positively correlated to AMH concentrations (P < 0.05). There was a trend for negative correlation found between circulating cadmium concentrations and total grade 1 embryo yield (P < 0.1). When cows were classified into quartiles (Q) of circulating AMH concentration, number of corpus luteum, and total embryos, total transferable embryos and total grade 1 embryos yield was significantly different for AMH quartiles. The superovulatory response parameters evaluated were increased with increased AMH concentrations; particularly we observed a >2-fold difference between first and fourth AMH quartiles in total transferable embryo yield and total grade 1 embryo yield. In conclusion, circulating AMH concentration was strongly associated with superovulatory response. Measuring AMH before enrolling cows in superovulation programs will likely allow practitioners to improve numbers of embryos produced and, thereby, reduce costs per embryo produced.

Role of microbial inoculation and industrial by-product phosphogypsum in growth and nutrient uptake of maize (Zea mays L.) grown in calcareous soil.

BACKGROUND: Alkaline soils with high calcium carbonate and low organic matter are deficient in plant nutrient availability. Use of organic and bio-fertilizers has been suggested to improve their properties. Therefore, a greenhouse experiment was conducted to evaluate the integrative role of phosphogypsum (PG; added at 0.0, 10, 30, and 50 g PG kg-1 ), cow manure (CM; added at 50 g kg-1 ) and mixed microbial inoculation (Incl.; Azotobacter chroococcum, and phosphate-solubilizing bacteria Bacillus megaterium var. phosphaticum and Pseudomonas fluorescens) on growth and nutrients (N, P, K, Fe, Mn, Zn and Cu) uptake of maize (Zea mays L.) in calcareous soil. Treatment effects on soil chemical and biological properties and the Cd and Pb availability to maize plants were also investigated. RESULTS: Applying PG decreased soil pH. The soil available P increased when soil was inoculated and/or treated with CM, especially with PG. The total microbial count and dehydrogenase activity were enhanced with PG+CM+Incl. TREATMENTS: Inoculated soils treated with PG showed significant increases in NPK uptake and maize plant growth. However, the most investigated treatments showed significant decreases in shoot micronutrients. Cd and Pb were not detected in maize shoots. CONCLUSIONS: Applying PG with microbial inoculation improved macronutrient uptake and plant growth. © 2017 Society of Chemical Industry.

Adverse effects of long-term administration of fluvoxamine on haematology, blood biochemistry and fertility in male albino rats: a possible effect of cessation.

Fluvoxamine is recommended as first-line treatment for a number of obsessive-compulsive disorders, anxiety disorders, social phobia, and post-traumatic stress disorder and panic disorder. The adverse effects of prolonged oral administration of fluvoxamine on haematology, biochemical parameters and fertility in male rats were evaluated in this study. Sixty adult male rats were allocated into 5 equal groups and orally treated with fluvoxamine 9 mg kg-1 b.wt. (low therapeutic dose, LTD) and 27 mg kg-1 b.wt. (high therapeutic dose, HTD), while the control rats received 0.5 ml distilled water for a period of 8 weeks. The 4th and 5th groups were gavaged with LTD and HTD of fluvoxamine for 8 weeks and then left untreated for another 8 weeks (recovery groups). HTD of fluvoxamine induced leukocytosis, lymphocytosis and monocytosis. LTD and HTD of fluvoxamine evoked hepatic, renal and cardiac dysfunction. Moreover, fluvoxamine treatment might lead to the risk of male infertility, which is indicated by its deleterious impacts on spermiogram and steroidogenesis hormones. They also induced oxidative stress, apoptosis in testicular tissue. Fortunately, the previous alterations were mostly reversed during the recovery period.

Evaluating the ameliorative efficacy of Spirulina platensis on spermatogenesis and steroidogenesis in cadmium-intoxicated rats.

The present study was conducted to evaluate the ameliorative efficacy of Spirulina platensis (SP) on reproductive dysfunctions induced by cadmium chloride (CdCl2) in male rats. Rats (n = 40) were divided into five groups (eight rats/each). Group 1: served as control without any treatment. Group 2: Rats were administered SP (150 mg/kg body weight (BW)) in drinking water for 10 days. Group 3: Rats were subcutaneously injected with CdCl2 (2 mg/kg BW) daily for 10 days. Group 4: Rats were co-treated with both CdCl2 (2 mg/kg BW) and SP (150 mg/kg BW) daily for 10 days (SP prophylactic group). Group 5: Rats received CdCl2 for 10 days followed by administration of SP alone in drinking water daily for another 30 days with the same mentioned routes and doses (SP treatment group). From our findings, the administration of SP alone or co-administration with Cd significantly attenuated the harmful effects of Cd, suggesting its beneficial role in improving spermatogenesis and steroidogenesis after Cd exposure.

Quercetin mitigates fenitrothion-induced testicular toxicity in rats.

Fenitrothion (FNT) is a widely used organophosphorus pesticide in agriculture. Quercetin (QR), a plant-derived flavonoid, has a free radical scavenging property. This study investigated the protective effect of QR on FNT-induced testicular toxicity in rats. Twenty-four male rats were divided into four groups. Group I (control) received normal saline. Group II was administered QR at the dose of 50 mg kg(-1) b.wt. Group III was orally administered FNT (20 mg kg(-1) b.wt). Group IV was gavaged FNT and QR together at the same doses. All administrations were performed daily by gavage and maintained for 70 days. Sperm parameters and histopathological changes in testes were investigated. Serum testosterone and luteinising hormone were estimated using radioimmunoassay kits. In testes, expressions of steroidogenic genes (3ß-hydroxysteroid dehydrogenase type 6, 17 ß-hydroxysteroid dehydrogenase type 3 and steroidogenic factor-1) and oxidative stress genes (catalase and superoxide dismutase) were determined using real-time PCR. FNT administration caused significant decreases in sperm count, motility and hormonal levels, a significant increase in abnormal sperm morphology and a significant down-regulation of steroidogenic and antioxidant genes in the testis. However, QR administration ameliorated FNT-induced toxic effects. Our results concluded that QR effectively mitigated testicular damage induced by FNT in rats.

The thoracic spine sign in bedside ultrasound. Three cases report.

The "thoracic spine sign" is visualized when anechoic or hypoechoic fluid is present in the pleural space. Fluid serves as a medium through which the thoracic vertebral bodies are visualized above the diaphragm. We present three cases of emergency department patients with a thoracic spine sign identified on bedside ultrasound. These patients were subsequently diagnosed with pleural fluid accumulations on chest radiograph. Our findings suggest that the identification of the sonographic spine sign may aid the physician in the evaluation and diagnosis of emergency department patients with thoracic complaints.

Galanin-like peptide (GALP) neurone-specific phosphoinositide 3-kinase signalling regulates GALP mRNA levels in the hypothalamus of males and luteinising hormone levels in both sexes.

Galanin-like peptide (GALP) neurones participate in the metabolic control of reproduction and are targets of insulin and leptin regulation. Phosphoinositide 3-kinase (PI3K) is common to the signalling pathways utilised by both insulin and leptin. Therefore, we investigated whether PI3K signalling in neurones expressing GALP plays a role in the transcriptional regulation of the GALP gene and in the metabolic control of luteinising hormone (LH) release. Accordingly, we deleted PI3K catalytic subunits p110α and p110ß via conditional gene targeting (cKO) in mice (GALP-p110α/ß cKO). To monitor PI3K signalling in GALP neurones, these animals were also crossed with Cre-dependent FoxO1GFP reporter mice. Compared to insulin-infused control animals, the PI3K-Akt-dependent FoxO1GFP nuclear exclusion in GALP neurones was abolished in GALP-p110α/ß cKO mice. We next used food deprivation to investigate whether the GALP-neurone specific ablation of PI3K activity affected the susceptibility of the gonadotrophic axis to negative energy balance. Treatment did not affect LH levels in either sex. However, a significant genotype effect on LH levels was observed in females. By contrast, no genotype effect on LH levels was observed in males. A sex-specific genotype effect on hypothalamic GALP mRNA was observed, with fed and fasted GALP-p110α/ß cKO males having lower GALP mRNA expression compared to wild-type fed males. Finally, the effects of gonadectomy and steroid hormone replacement on GALP mRNA levels were investigated. Compared to vehicle-treated mice, steroid hormone replacement reduced mediobasal hypothalamus GALP expression in wild-type and GALP-p110α/ß cKO animals. In addition, within the castrated and vehicle-treated group and compared to wild-type mice, LH levels were lower in GALP-p110α/ß cKO males. Double immunofluorescence using GALP-Cre/R26-YFP mice showed androgen and oestrogen receptor co-localisation within GALP neurones. Our data demonstrate that GALP neurones are direct targets of steroid hormones and that PI3K signalling regulates hypothalamic GALP mRNA expression and LH levels in a sex-specific fashion.

Beyond race and place: distal sociological determinants of HIV disparities.

Informed behavior change as an HIV prevention tool has yielded unequal successes across populations. Despite decades of HIV education, some individuals remain at high risk. The mainstream media often portrays these risk factors as products of race and national borders; however, a rich body of recent literature proposes a host of complex social factors that influence behavior, including, but not limited to: poverty, income inequality, stigmatizing social institutions and health care access. We examined the relationship between numerous social indicators and HIV incidence across eighty large U.S. cities in 1990 and 2000. During this time, major correlating factors included income inequality, poverty, educational attainment, residential segregation and marriage rates. However, these ecological factors were weighted differentially across risk groups (e.g. heterosexual, intravenous drug use, men who have sex with men (MSM)). Heterosexual risk rose significantly with poor economic indicators, while MSM risk depended more heavily on anti-homosexual stigma (as measured by same-sex marriage laws). HIV incidence among black individuals correlated significantly with numerous economic factors but also with segregation and imbalances in the male:female ratio (often an effect of mass incarceration). Our results support an overall model of HIV ecology where poverty, income inequality and social inequality (in the form of institutionalized racism and anti-homosexual stigma) have over time developed into synergistic drivers of disease transmission in the U.S., inhibiting information-based prevention efforts. The relative weights of these distal factors vary over time and by HIV risk group. Our testable model may be more generally applicable within the U.S. and beyond.

Functional cross-talk between ras and rho pathways: a Ras-specific GTPase-activating protein (p120RasGAP) competitively inhibits the RhoGAP activity of deleted in liver cancer (DLC) tumor suppressor by masking the catalytic arginine finger.

The three deleted in liver cancer genes (DLC1-3) encode Rho-specific GTPase-activating proteins (RhoGAPs). Their expression is frequently silenced in a variety of cancers. The RhoGAP activity, which is required for full DLC-dependent tumor suppressor activity, can be inhibited by the Src homology 3 (SH3) domain of a Ras-specific GAP (p120RasGAP). Here, we comprehensively investigated the molecular mechanism underlying cross-talk between two distinct regulators of small GTP-binding proteins using structural and biochemical methods. We demonstrate that only the SH3 domain of p120 selectively inhibits the RhoGAP activity of all three DLC isoforms as compared with a large set of other representative SH3 or RhoGAP proteins. Structural and mutational analyses provide new insights into a putative interaction mode of the p120 SH3 domain with the DLC1 RhoGAP domain that is atypical and does not follow the classical PXXP-directed interaction. Hence, p120 associates with the DLC1 RhoGAP domain by targeting the catalytic arginine finger and thus by competitively and very potently inhibiting RhoGAP activity. The novel findings of this study shed light on the molecular mechanisms underlying the DLC inhibitory effects of p120 and suggest a functional cross-talk between Ras and Rho proteins at the level of regulatory proteins.