Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

AIMS: Conflicting results exist regarding bone mineral density (BMD), metabolism and reproductive function of adult patients with congenital adrenal hyperplasia (CAH). We evaluated the long-term outcome and the impact of chronic glucocorticoid replacement in these patients. METHODS: Physical characteristics, serum hormone concentrations, BMD and metabolism were studied in 45 consecutive CAH adult patients. RESULTS: Among the 36 women, only 14 (39%) had regular menses. Among the 27 women with classical CAH, the mean number of surgical reconstructions of virilized genitalia was 2.1 +/- 0.2. Twenty of them (74%) were sexually active. Three men presented with testicular adrenal rest tumors. Twenty-five patients (55%) had decreased BMD at the femoral neck and/or at the lumbar spine. BMI was correlated with the BMD T-score at the femoral neck (p < 0.001) and at the lumbar spine (p < 0.01). Hydrocortisone dose was negatively correlated with the BMD T-score at the femoral neck (p = 0.04). Subjects with osteopenia had a significantly lower BMI and received higher hydrocortisone dose than those with normal BMD. Overweight was found in 21 patients (47%). There was a significantly positive correlation between HOMA and BMI (p < 0.001), and between HOMA and 17-OHP levels (p = 0.016). CONCLUSIONS: Adult patients with CAH treated with long-term glucocorticoids are at risk for decreased BMD, increased BMI, and disturbed reproductive function.     

Genetic interaction of Gsc and Dkk1 in head morphogenesis of the mouse

Mouse embryos lacking Gsc and Dkk1 function display severe deficiencies in craniofacial structures which are not found in either Dkk1 homozygous null or Gsc homozygous null mutant embryos. Loss of Gsc has a dosage-related effect on the severity of head truncation phenotype in Dkk1 heterozygous embryos. The synergistic effect of these mutations in enhancing head truncation provides direct evidence of a genetic interaction between Gsc and Dkk1, which display overlapping expression in the prechordal mesoderm. In the absence of Gsc activity, the expression of Dkk1, WNT genes and a transgenic reporter for WNT signalling are altered. Our results show that Gsc and Dkk1 functions are non-redundant in the anterior mesendoderm for normal anterior development and Gsc may influence Wnt signalling as a negative regulator.     

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

The majority of amyotrophic lateral sclerosis (ALS) cases as well as many patients suffering from frontotemporal lobar dementia (FTLD) with ubiquitinated inclusion bodies show TDP-43 pathology, the protein encoded by the TAR DNA-binding protein (Tardbp) gene. We used recombinase-mediated cassette exchange to introduce an ALS patient cDNA into the mouse Tdp-43 locus. Expression levels of human A315T TDP-43 protein were 300% elevated in heterozygotes, whereas the endogenous mouse Tdp-43 was decreased to 20% of wild type levels as a result of disturbed feedback regulation. Heterozygous TDP-43^A315TKi mutants lost 10% of their body weight and developed insoluble TDP-43 protein starting as early as 3 months after birth, a pathology that was exacerbated with age. We analyzed the splicing patterns of known Tdp-43 target genes as well as genome-wide gene expression levels in different tissues that indicated mitochondrial dysfunction. In heterozygous mutant animals, we observed a relative decrease in expression of Parkin (Park2) and the fatty acid transporter CD36 along with an increase in fatty acids, HDL cholesterol, and glucose in the blood. As seen in transmission electron microscopy, neuronal cells in motor cortices of TDP-43^A315TKi animals had abnormal neuronal mitochondrial cristae formation. Motor neurons were reduced to 90%, but only slight motoric impairment was detected. The observed phenotype was interpreted as a predisease model, which might be valuable for the identification of further environmental or genetic triggers of neurodegeneration.     

The Role of Social Context in Shaping Student-Athlete Opinions

How do student-athletes form opinions? This is a particularly important question given ongoing debates about whether student-athletes should be paid and/or allowed to unionize. These debates concern the rights and benefits accrued directly to student-athletes, and thus, understanding their attitudes is of obvious import. Yet, virtually no recent work has delved into how student-athletes form opinions on these issues. We fill this gap with a theoretical framework that predicts changes in social context alter opinions. This leads to the hypothesis that opinions will change once a student-athlete completes his/her career and finds him/herself in a distinct social network. We test the prediction with a survey, implemented in 2012, of one of the most notable athletic conferences in the National Collegiate Athletic Association (NCAA): the Big Ten. We find that post-career student-athletes demonstrate higher levels of support for pay for play and unionization. Our results suggest that student-athletes'' opinions seem to depend on their extant social contexts. While our data, from 2012, neither speak to current opinions – given the quickly evolving landscape of college athletics – nor demonstrate what reforms may be “best,” they do accentuate the power of social context in shaping student-athletes'' attitudes.     

Prothymosin alpha: a ubiquitous polypeptide with potential use in cancer diagnosis and therapy

The thymus is a central lymphoid organ with crucial role in generating T cells and maintaining homeostasis of the immune system. More than 30 peptides, initially referred to as “thymic hormones,” are produced by this gland. Although the majority of them have not been proven to be thymus-specific, thymic peptides comprise an effective group of regulators, mediating important immune functions. Thymosin fraction five (TFV) was the first thymic extract shown to stimulate lymphocyte proliferation and differentiation. Subsequent fractionation of TFV led to the isolation and characterization of a series of immunoactive peptides/polypeptides, members of the thymosin family. Extensive research on prothymosin α (proTα) and thymosin α1 (Tα1) showed that they are of clinical significance and potential medical use. They may serve as molecular markers for cancer prognosis and/or as therapeutic agents for treating immunodeficiencies, autoimmune diseases and malignancies. Although the molecular mechanisms underlying their effect are yet not fully elucidated, proTα and Tα1 could be considered as candidates for cancer immunotherapy. In this review, we will focus in principle on the eventual clinical utility of proTα, both as a tumor biomarker and in triggering anticancer immune responses. Considering the experience acquired via the use of Tα1 to treat cancer patients, we will also discuss potential approaches for the future introduction of proTα into the clinical setting.     

Lis1 Acts as a "Clutch" between the ATPase and Microtubule-Binding Domains of the Dynein Motor

The lissencephaly protein Lis1 has been reported to regulate the mechanical behavior of cytoplasmic dynein, the primary minus-end-directed microtubule motor. However, the regulatory mechanism remains poorly understood. Here, we address this issue using purified proteins from Saccharomyces cerevisiae and a combination of techniques, including single-molecule imaging and single-particle electron microscopy. We show that rather than binding to the main ATPase site within dynein's AAA+ ring or its microtubule-binding stalk directly, Lis1 engages the interface between these elements. Lis1 causes individual dynein motors to remain attached to microtubules for extended periods, even during cycles of ATP hydrolysis that would canonically induce detachment. Thus, Lis1 operates like a "clutch" that prevents dynein's ATPase domain from transmitting a detachment signal to its track-binding domain. We discuss how these findings provide a conserved mechanism for dynein functions in living cells that require prolonged microtubule attachments.     

Myo2p, a class V myosin in budding yeast, associates with a large ribonucleic acid-protein complex that contains mRNAs and subunits of the RNA-processing body

Myo2p is an essential class V myosin in budding yeast with several identified functions in organelle trafficking and spindle orientation. The present study demonstrates that Myo2p is a component of a large RNA-containing complex (Myo2p-RNP) that is distinct from polysomes based on sedimentation analysis and lack of ribosomal subunits in the Myo2p-RNP. Microarray analysis of RNAs that coimmunoprecipitate with Myo2p revealed the presence of a large number of mRNAs in this complex. The Myo2p-RNA complex is in part composed of the RNA processing body (P-body) based on coprecipitation with P-body protein subunits and partial colocalization of Myo2p with P-bodies. P-body disassembly is delayed in the motor mutant, myo2-66, indicating that Myo2p may facilitate the release of mRNAs from the P-body.     

Regulation of R7 and R8 differentiation by the spalt genes

Photoreceptor development begins in the larval eye imaginal disc, where eight distinct photoreceptor cells (R1-R8) are sequentially recruited into each of the developing ommatidial clusters. Final photoreceptor differentiation, including rhabdomere formation and rhodopsin expression, is completed during pupal life. During pupation, spalt was previously proposed to promote R7 and R8 terminal differentiation. Here we show that spalt is required for proper R7 differentiation during the third instar larval stage since the expression of several R7 larval markers (prospero, enhancer of split mdelta0.5, and runt) is lost in spalt mutant clones. In R8, spalt is not required for cell specification or differentiation in the larval disc but promotes terminal differentiation during pupation. We show that spalt is necessary for senseless expression in R8 and sufficient to induce ectopic senseless in R1-R6 during pupation. Moreover, misexpression of spalt or senseless is sufficient to induce ectopic rhodopsin 6 expression and partial suppression of rhodopsin 1. We demonstrate that spalt and senseless are part of a genetic network, which regulates rhodopsin 6 and rhodopsin 1. Taken together, our results suggest that while spalt is required for R7 differentiation during larval stages, spalt and senseless promote terminal R8 differentiation during pupal stages, including the regulation of rhodopsin expression.     

Hematopoietic stem cell transplantation for Crohn's disease: Gaps,doubts and perspectives

Crohn's disease(CD) is an inflammatory bowel disease that can affect any site of the digestive system. It occurs due to an immunological imbalance and is responsible for intestinal mucosal lesions and complications such as fistulas and stenoses. Treatment aims to stabilize the disease, reducing the symptoms and healing intestinal lesions. Surgical procedures are common in patients. Cell therapy was initially used to treat this disease in patients who also suffered from lymphoma and leukemia and were considered to be good candidates for autologous and allogeneic transplantation. After transplantation, an improvement was also observed in their CD. In 2003, the procedure began to be used to treat the disease itself, and several case series and randomized studies have been published since then; this approach currently comprises a new option in the treatment of CD. However, considerable doubt along with significant gaps in our knowledge continue to exist in relation to cell therapy for CD. Cell therapy is currently restricted to the autologous modality of hematopoietic stem cell transplantation and, experimentally, to mesenchymal stromal cells to directly treat lesions of the anal mucosa. This article presents the supporting claims for transplantation as well as aspects related to the mobilization regime, conditioning and perspectives of cell therapy.     

Jaguar mobbing by giant otter groups

Group-living in carnivores is mostly associated with cooperative hunting and anti-predator defense. Giant otters (Pteronura brasiliensis) live in monogamous and cooperative breeding groups, where mechanisms other than cooperative foraging may be driving group maintenance in the species. We herein describe three interactions between giant otters and jaguars (Panthera onca) observed in the wild, two of which involved groups of otters and one, a lone individual. In the two group instances, the otters mobbed the jaguar until it left the area. The mobbing behavior displayed in these instances likely reinforces the advantages of living in groups, reducing predation risk and promoting group cohesion, with resulting territorial and fitness benefits.