Partial impairment of cytokine responses in Tyk2-deficient mice

To assess the role of the Janus kinase (Jak) family member Tyk2, we have generated Tyk2-/- mice. In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2-/- mice display reduced responses to IFNalpha/beta and IL-12 and a selective deficiency in Stat3 activation in these pathways. Unexpectedly, IFNgamma signaling is also impaired in Tyk2-/- mice. Tyk2-/- macrophages fail to produce nitric oxide upon lipopolysaccharide induction. Tyk2-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge. These data imply a selective contribution of Tyk2 to the signals triggered by various biological stimuli and cytokine receptors.     

Intracytoplasmic sperm injection allows fertilization and development of a chromosomally balanced embryo from a binovular zona pellucida

A binovular zona pellucida was found in two in-vitro fertilization (IVF) treatment cycles. In both cases, two oocytes of slightly unequal size were enclosed within a single zona pellucida, the larger oocyte appearing as a metaphase II oocyte while the smaller one as an immature oocyte with a germinal vesicle. Intracytoplasmic sperm injection performed in the mature oocyte of each pair led to normal fertilization and embryonic development in both cases. Results of genetic analysis performed by fluorescence in-situ hybridization in one of the two treatment cycles were consistent with a diploid chromosomal status of both the non-injected immature oocyte as well as the embryo which developed following the microinjection. These results indicate that, in this case, the binovular zona pellucida was most probably created when granulosa cells failed to separate two distinct oocytes during follicular formation. It may also imply that selective fertilization of a single mature oocyte in a binovular zona pellucida by intracytoplasmic sperm injection can lead to the development of a chromosomally balanced embryo and can prevent the undesired consequences that may result if the two oocytes are fertilized in the course of standard IVF.      

Histologic hypercellularity in a biopsied normal parathyroid gland does not correlate with hyperfunction in primary hyperparathyroidism

BackgroundAbout 15% of patients with primary hyperparathyroidism have multiglandular disease, thus during resection of an apparent single adenoma, a visibly normal parathyroid may be identified and biopsied. Using long-term biochemical follow-up, we examined whether normal parathyroid hypercellularity correlates with multiglandular disease or primary hyperparathyroidism recurrence.MethodsWe reviewed all patients who from 2001 to 2015 had an initial operation for sporadic primary hyperparathyroidism with removal of 1 gland, routine normal parathyroid biopsy, intraoperative parathyroid hormone monitoring, and follow-up of ≥3 years. Recurrence was defined by hypercalcemia after documented cure at 6 months, and hypercellularity by standard histologic criteria.ResultsOf 134 patients with mean follow-up of 9.4 years (range, 3.1?15.9), 132 (98.5%) exhibited cure at 6 months. Two had initial failure, and 8 of 132 (6.1%) developed recurrent hyperparathyroidism (mean 5.8 y, range 4?10.6). The normal parathyroid was hypercellular in 14 of 132 (10.6%) of the cured patients, and this rate did not differ for those with long-term cure (12/124, 9.7%) versus recurrence (2/8, 25%, P = .2). The positive predictive value of normal parathyroid hypercellularity for recurrence was low (14.3%), and the negative predictive value of normal parathyroid normocellularity was high (94.9%).ConclusionDuring the initial operation for primary hyperparathyroidism, 10% of normal parathyroids are hypercellular, but this does not signify missed multiglandular disease. In contrast, normal parathyroid normocellularity has high predictive value for durable cure (95%), slightly better than visual identification of a second normal parathyroid (94%).     

Endovascular Biopsy and Endothelial Cell Gene Expression Analysis of Dialysis Arteriovenous Fistulas: A Feasibility Study

Purpose

To demonstrate feasibility of endothelial cell (EC) biopsy from dialysis arteriovenous fistulas (AVFs) with the use of guidewires and to characterize gene expression differences between ECs from stenotic and nonstenotic outflow vein segments.

Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR

Background

Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.

Male infertility: possible association with valproate exposure

PURPOSE: To describe a potential association between male infertility and valproate (VPA) exposure. VPA has been implicated in the development of polycystic ovarian disease and subsequent menstrual and infertility problems in women with epilepsy. Infertility has been well described in population-based studies of persons with epilepsy. The low marital rates for men with epilepsy have previously been thought to play a major contributing role. METHODS: We report a case of a 32-year-old man whose wife and he were able to bear a child before the development of his epilepsy. With VPA monotherapy, the family were unable to conceive despite 4 years of unprotected intercourse. An infertility evaluation of the man revealed a very low sperm count of < 50,000/ml, no motile sperm, < 10% viability, and 100% with abnormal structure. Follicle-stimulating hormone, luteinizing hormone, and testosterone levels were normal. RESULTS: Felbamate (FBM) was initiated and VPA discontinued for improved seizure control. Within 4 months, the couple conceived their second child. A seminal analysis revealed a sperm count of > 16 million, 50% motility, 78% viability, and 72% with abnormal structure. CONCLUSIONS: One must be cautious in extrapolating from a case report, but these findings strongly suggest a direct effect of VPA on spermatic structure and function.     

Histological study of hair follicles treated with a 3-msec pulsed ruby laser

BACKGROUND AND OBJECTIVE: Ruby laser energy at 694 mn is moderately absorbed by melanin and minimally absorbed by other skin chromophores. This property and its depth of penetration into dermis permit absorption into pigmented hair follicles, thus making it suited to photothermolysis of these appendages. Clinical reports of the efficacy of such lasers for removal of unwanted hair are emerging in large numbers, but scientific data regarding the exact mechanism of action is still lacking. This study aims to evaluate and define further the histological responses of hair follicles to 3-msec pulsed ruby laser light. STUDY DESIGN/MATERIALS AND METHODS: Twenty-four patients with brown or black axillary or groin hair were treated with a 3-msec ruby laser at fluences from 10 to 40 J/cm2 on one, two, or three occasions. Biopsies were taken at various intervals from immediately to 8 weeks after treatments. Biopsies were fixed and stained with either nitroblue tetrazolium chloride or hematoxylin and eosin for histological examination. RESULTS: One treatment induced changes typical of catagen followed by telogen at all fluences. The papillae always remained viable. Two and three treatments resulted in atypical telogen, with infundibular dilatation and plugging, and marked proliferation of the stem outer sheath. New anagen follicles were evident even after three treatments at 12- and then 8-week intervals and were biopsied 6 weeks later, but there were no hairs extending to or through the epidermis. CONCLUSION: There was no evidence of permanent follicle death after one ruby laser treatment. However, despite evidence of persistence of follicular elements after two and three treatments, it is possible that laser-induced damage to the isthmus and upper stem may interfere with the interaction between dermal and epidermal germinative cells, thus inhibiting or altering the normal hair cycle.     

A birth in non-mosaic Klinefelter's syndrome after testicular fine needle aspiration, intracytoplasmic sperm injection and preimplantation genetic diagnosis

Non-mosaic Klinefelter patients are generally azoospermic due to primary testicular failure. Nevertheless, in some cases, testicular spermatozoa may be recovered and utilized to fertilize oocytes via intracytoplasmic sperm injection (ICSI). As the risk for an increased number of gonosomes in these spermatozoa is unclear, preimplantation genetic diagnosis (PGD) may be attempted in the resulting embryos. In the present study, we report our experience with the combined approach of sperm retrieval by testicular fine needle aspiration (FNA), ICSI and PGD in seven consecutive non-mosaic Klinefelter individuals. In four patients, between one and five spermatozoa were retrieved in five out of nine consecutive attempts. In a fifth patient, only 10 round spermatids could be isolated. Mature spermatozoa were injected into a total of 16 metaphase-II oocytes, of which 11 (69%) remained intact. Two distinct pronuclei (2PN) were observed in four oocytes (36%) while a single pronucleus (1PN) was documented in two oocytes. Five cleavage stage embryos developed from the oocytes of two couples. Upon the request of one couple, their three embryos (two derived from 1PN oocytes) were transferred without PGD but pregnancy was not achieved. PGD by fluorescence in-situ hybridization (FISH) was performed in the two embryos of the other couple which were derived from normal fertilization. PGD results of one embryo were 18,18,X,X,Y, the embryo was not transferred and FISH analysis of the remaining blastomeres identified variable chromosome numbers in the nuclei. The second embryo was diagnosed as normal and was transferred, resulting in a successful pregnancy and birth. In conclusion, the results of this report indicate that a pregnancy and birth may be attained in azoospermic non-mosaic Klinefelter individuals by testicular FNA combined with ICSI. Due to the unknown risk of gonosomes aneuploidy in embryos from Klinefelter patients, PGD or prenatal diagnosis should be recommended.      

Some parameters of conditioned immunosuppression: species difference and CS-US delay

Three experiments were conducted in which an illness-inducing immunosuppressant, cyclophosphamide (an unconditioned stimulus, US) was associated with a previously presented saccharin solution conditioned stimulus (CS). In each experiment, reexposure to the CS produced a conditioned suppression of the plaque-forming-cell response in the experimental groups. Experiment I demonstrated this result with Fisher 344 rats. Experiment II replicated the effect with Balb/c mice. In Experiment III conditioned immunosuppression was demonstrated when mice received CS-US delays as long as 6 hours. No evidence of a delay gradient was present in either the behavioral or the immunologic data. These parallel findings offer no support for the idea of a dissociation between the taste aversion and conditioned immunosuppression processes.     

Risk-sensitive neurons in macaque posterior cingulate cortex

People and animals often demonstrate strong attraction or aversion to options with uncertain or risky rewards, yet the neural substrate of subjective risk preferences has rarely been investigated. Here we show that monkeys systematically preferred the risky target in a visual gambling task in which they chose between two targets offering the same mean reward but differing in reward uncertainty. Neuronal activity in posterior cingulate cortex (CGp), a brain area linked to visual orienting and reward processing, increased when monkeys made risky choices and scaled with the degree of risk. CGp activation was better predicted by the subjective salience of a chosen target than by its actual value. These data suggest that CGp signals the subjective preferences that guide visual orienting.