Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report.

Prokineticin 2 (Prok2) or prokineticin-receptor2 (Prok-R2) gene mutations are associated with Kallmann syndrome (KS). We describe a new homozygous mutation of Prok-R2 gene in a man displaying KS with an apparent reversal of hypogonadism. The proband, offspring of consanguineous parents, presented at age 19 years with absent puberty, no sense of smell, low testosterone and gonadotrophin levels. Magnetic resonance imaging showed olfactory bulb absence. The patient achieved virilization and spermatogenesis with gonadotrophin administration. Two years after discontinuing hormonal therapy, he maintained moderate oligozoospermia and normal testosterone levels. Prok2 and Prok- R2 gene sequence analyses were performed. The proband had a homozygous mutation in Prok-R2 exon 2 that harbours the c.T820>A base substitution, causing the introduction of an aspartic acid in place of valine at position 274 (Val274Asp). His mother had the same mutation in heterozygous state. This report describes a novel homozygous mutation of Prok-R2 gene in a man with variant KS, underlying the role of Prok-R2 gene in the olfactory and reproductive system development in humans. Present findings indicate that markedly delayed activation of gonadotrophin secretion may occur in some KS cases with definite gene defects, and that oligozoospermia might result from a variant form of reversible hypogonadotrophic hypogonadism

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network

Two Males with SRY-Positive 46,XX Testicular Disorder of Sex Development

The 46,XX testicular disorder of sex development (46,XX testicular DSD) is a rare phenotype associated with disorder of the sex chromosomes. We describe the clinical, molecular, and cytogenetic findings of a 16-and a 30-year-old male patient with sex-determining region Y (SRY)-positive 46,XX testicular DSD. Chromosomal analysis revealed 46,XX karyotype. Fluorescence in situ hybridization (FISH) showed the SRY region translocated to the short arm of the X chromosome. The presence of the SRY gene was also confirmed by polymerase chain reaction (PCR). The X chromosome inactivation (XCI) assay showed that both patients have a random pattern of X chromosome inactivation. This report compares the symptoms and features of the SRY-positive 46,XX testicular DSD patients. © 2013 Informa Healthcare USA, Inc

Missense mutations in the ABVB6 transporter cause dominat familial pseudohyperkaliemia

Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K1] inwhole blood stored at or below room temperature, without additional hematological abnormalities. Functionalgene mapping and sequencing analysis of the candidate genes within the 2q35–q36 critical intervalidentified—in 20 affected individuals among three multigenerational FP families—two novel heterozygousmissense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutionsaltered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, inerythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation didnot alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursorcells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase duringin vitro erythroid differentiation of CD341 erythroid precursors and the erythroleukemia cell lines HELand K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptidefound in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K1leak characteristic of this condition

Econometric modeling of tobacco exports in the milieu of changing global and national policy regimes: repercussions on the Indian tobacco sector

IntroductionTobacco, an important commercial crop, plays a crucial role in farmers' incomes and livelihoods to a sizable population and contributes significant exchange earnings to the Indian economy. Currently, India is the second-largest tobacco producer after China, with a production of 758 million kg (13% of global production) and exports of ~190 million kg of tobacco (9% of global tobacco export volume). However, there are uncertainties surrounding the tobacco sector, such as growing public health and environmental issues associated with tobacco production and consumption and changing national and international tobacco-related policy regimes. In this context, the current study investigates the determinants of tobacco exports and geographical shifts in export destinations over the years.MethodsThe statistical models employed are co-integration, and vector error-correlation models to test the short-run and long-run dynamics relationship between tobacco exports and the explanatory variables, and the Markov chain approach to find out geographical shifts in export destinations.Results and discussionThe econometric model estimated the relationship between the tobacco export volume with domestic production, export price, and global demand for Indian tobacco, and investigated the geographical shift in export destinations of tobacco in the context of changing global and national policy regimes on the sector. The econometric modeling framework confirms that there exists a statistically significant relationship between Indian tobacco export demand, domestic production, export price, and world demand for Indian tobacco. The geographical shift was evident in major export destinations during the post-WHO-FCTC (Framework Convention on Tobacco Control) regime. The model findings direct that India should take advantage of the export price, and global demand for tobacco as India ratified WHO-FCTC; there is no scope for horizontal expansion of the area under tobacco. This modeling framework aids as a tool to direct and explore the possible options with a greater emphasis on export-centric farming system in tobacco production by augmenting crop compliance and quality to meet the standards of international markets

Community-based prevention leads to an increase in condom use and a reduction in sexually transmitted infections (STIs) among men who have sex with men (MSM) and female sex workers (FSW): the Frontiers Prevention Project (FPP) evaluation results

<p>Abstract</p> <p>Background</p> <p>India has an estimated 2.0 million to 3.1 million people living with HIV; it has the highest number of HIV-positive people in Asia and ranks third in the world. The Frontiers Prevention Project (FPP) was implemented in 2002 to conduct targeted prevention intervention geared towards female sex workers (FSW) and men who have sex with men (MSM) in the state of Andhra Pradesh (AP). This paper reports the overall changes in behaviour and STI outcomes between 2003/4 and 2007 and also describes the changes attributed to the FPP.</p> <p>Methods</p> <p>The evaluation used two cross-sectional surveys among MSM and FSW at 24 sites in AP. Surveys were implemented using a similar methodology. Univariate analyses were conducted by comparing means: baseline vs. four-year follow-up and FPP vs. non-FPP. For both MSM and FSW, random and fixed-effects logit regression models at the site level were estimated for <it>condom use with last partner</it>, <it>syphilis sero-positivity </it>and <it>HSV 2 sero-positivity</it>. In addition, for FSW we estimated models for <it>condom use with regular partner</it>, and for MSM we estimated models for <it>condom use with last female partner</it>.</p> <p>Results</p> <p>Among MSM, fixed-effects analysis revealed that FPP was positively correlated with the probability of <it>condom use with last female sexual partner </it>and negatively correlated with the individual probability of <it>sero-positivity to syphilis and HSV 2</it>. Among FSW, the FPP intervention was significantly correlated with increased <it>condom use with regular partners </it>and with lower probability of <it>STI sero-positivity</it>.</p> <p>Discussion</p> <p>Important changes in behaviours related to an increase in prevention activities translated to reductions in STI sero-prevalence in AP, India. In contrast with non-FPP sites, the FPP sites experienced an intense community approach as part of the FPP intervention, and the general increase in condom use and its effect on STI sero-prevalence reflected the efficacy of these intense prevention activities focused on key populations in AP.</p

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients

Background: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. Methods: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. Results: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87–0.94), with an additional relative risk for CVD of 0.92 (0.87–0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75–0.93), 0.76 (0.67–0.85), 0.69 (0.59–0.79), or 0.63 (0.52–0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. Conclusions: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials

A novel method for pain control: infiltration free local anesthesia technique (INFLATE) for transrectal prostatic biopsy using transcutaneous electrical nerve stimulation (TENS)

Purpose: To describe a novel method for the control of pain during prostate biopsies, infiltration free local anesthesia technique (INFLATE) for transrectal prostatic biopsies with no further needle insertions for local anesthetic infiltration. Methods: A total of 138 men with elevated prostate-specific antigen levels and/or abnormal digital rectal examination findings were included in the study. Of the patients, 73 were assigned to the INFLATE group and 65 to the TRUS-PNB group. Demographic data, PSA levels, findings of digital rectal examinations, and multiparametric prostatic magnetic resonance imaging were recorded. In the INFLATE group, a two-channel TENStem eco basic device with two electrodes was used for pain control during the biopsy. For the TRUS-PNB group, 60 mg lidocaine gel was given intrarectally in addition to infiltration of a prilocaine and bupivacaine mixture (5 mL of 2% prilocaine + 5 mL of 0.25% bupivacaine). Pain perception was assessed using a linear numeric rating scale. Results: The mean ages, BMIs, prostate volumes, and PSA levels were similar between the two groups (p > 0.05). Of the 56 participants with prostate adenocarcinoma, 28 were in the INFLATE group, and 28 were in the TRUS-PNB group with a 40.6% overall cancer detection rate. The mean preoperative and post-operative pain scores during probe insertion, biopsy and post-biopsy were similar between the groups (p > 0.05). Conclusion: The results of the study confirmed that INFLATE for transrectal prostate biopsy using a TENS device could safely and effectively be used for pain control with the advantage of two fewer needle attempts with no increase in significant complications. © 2019, Springer Nature B.V