Azoospermia factor deletions in varicocele cases with severe oligozoospermia

BACKGROUND: Varicocele is the most common cause of male infertility. The etiology and pathophysiology of varicocele are multifactorial. When low sperm counts are associated with varicocele, varicocelectomy can partially restore spermatogenesis and fertility. Few recent studies have reported that in some varicocele cases, there may be an associated genetic etiology. Presence of a genetic factor like azoospermia factor microdeletions may lead to irreversible spermatogenic arrest in these cases, but very few reports support these findings. However, it is still not understood why some cases improve after varicocelectomy and why some cases show no improvement in semen parameters postoperatively. AIM: It is important to distinguish varicocele cases from Yq microdeletions as these cases have irreversible testicular damage and thus carry a poor prognosis after varicocelectomy. SETTINGS: Research and Referral tertiary care hospital. Design: Prospective study. MATERIALS AND METHODS: Seventy-two infertile men with varicocele were referred for Yq microdeletion analysis from the infertility clinic of AIIMS and Army Research and Referral Hospital. Genomic DNA was isolated from blood and polymerase chain reaction microdeletion screening was done in these cases to determine the presence or deletion of AZF loci. RESULTS: In this study 7 (9.7%) varicocele cases harbored Yq microdeletion. The sperm count in cases which harbored Yq microdeletion was significantly lower than in cases without Yq microdeletion. CONCLUSION: Varicocele cases with Yq microdeletion do not show improvement in semen parameters post-varicocelectomy. Detection of Yq microdeletion determines prognosis and future management in such cases.     

Assessment of Intragranular and Extragranular Fracture in the Development of Tablet Tensile Strength

When a tablet is compacted from deformable granules and then broken, the fracture plane may cleave granules in 2 (intragranular fracture) or separate neighboring granules (extragranular fracture). In this study, a novel method was developed to quantify the extent of intragranular versus extragranular fracture by compacting tablets from multicolored ideal granules and evaluating fracture surfaces. The proportions of intragranular and extragranular fracture were quantified and modeled in light of a new metric; the deformation potential, Δ, reflecting the solid fraction increase as an initial granule bed is compressed into a final tablet. Results show that a measurable tablet strength is achieved at Δ > 0.18, but intragranular fracture is not observed until Δ > 0.21. At very large Δ, tablets experience almost exclusively intragranular fracture, yet the tablet tensile strength is considerably lower than that of a tablet compacted from raw powders versus precompacted granules. Thus, secondary compaction of granules appears to weaken the granule matrix, leading to reduced tablet tensile strength even in the presence of strong extragranular bonding.     

Interactions of the dipeptide ester prodrugs of acyclovir with the intestinal oligopeptide transporter: competitive inhibition of glycylsarcosine transport in human intestinal cell line-Caco-2

The oligopeptide transporter may be exploited to enhance the absorption of drugs by synthesizing their dipeptide ester prodrugs, which may be recognized as its substrates. Various dipeptide esters of acyclovir (ACV), an antiviral nucleoside analog, were synthesized. Enzymatic hydrolysis and affinity of the prodrugs toward the human intestinal peptide transporter hPEPT1 were studied using the human intestinal Caco-2 cell line. Affinity studies were performed by inhibiting the uptake of [(3)H]glycylsarcosine by the prodrugs. The uptake of glycylsarcosine was found to be saturable at higher concentrations and was competitively inhibited by the prodrugs of ACV. All prodrugs except Tyr-Gly-ACV demonstrated a higher affinity (1.41-4.96 mM) toward hPEPT1 than cephalexin (8.19 +/- 2.12 mM), which was used as a positive control. Two prodrugs, Gly-Val-ACV and Val-Val-ACV, showed comparable affinity to Val-ACV, an amino acid prodrug of ACV recognized by PEPT1/PEPT2. The permeability of Gly-Val-ACV (2.99 +/- 0.59 x 10(-6) cm/s) across Caco-2 was comparable with that of Val-ACV (3.01 +/- 0.21 x 10(-6) cm/s) and was significantly inhibited (63%) in presence of glycylsarcosine. The transport of GVACV across Caco-2 was saturable at higher concentrations, and the parameters were calculated as K(m) 3.16 +/- 0.31 mM and V(max) 0.014 +/- 0.00058 nmol cm(-2) min(-1). Overall, the results suggest that the dipeptide prodrugs of ACV have a high affinity toward the intestinal oligopeptide transporter hPEPT1 and therefore seem to be promising candidates in the treatment of ocular and oral herpesvirus infections, because cornea and intestinal epithelia seem to express the oligopeptide transporters.     

In vitro effects of clomiphene citrate on sperm parameters and fertilisation rate in male NMRI mice

Clomiphene citrate (CC), as a medication in male infertility, improves the sperm parameters in oral consumption but various detrimental side effects have been reported including testicular tumours, gynaecomastia, skin allergic reactions and ocular symptoms. Therefore, this study was designed to evaluate the in vitro effects of CC on sperm parameters and fertilisation rate in IVF protocol. Sperm samples of NMRI adult mice were divided into six groups: group 1 received no treatment (control group), while groups of 2, 3, 4, 5 and 6 (experimental groups) were incubated with the doses of 0.001, 0.01, 0.1, 1 and 10 µg/ml of CC in culture medium respectively. Sperm parameters (viability, morphology and motility), DNA fragmentation levels and fertilisation rate in IVF were evaluated. The results demonstrated that the doses of 0.1 µg/ml (p = .000007 for viability and p = .00006 for fertilisation rate) and 1 µg/ml (p = .032 for viability and p = .005 for fertilisation rate) CC cause a significant improvements; also, the dose of 0.1 µg/ml CC found effective on sperm motility (p = .0003). In the field of IVF, the application of 0.1 and 1 µg/ml of CC in the culture medium may improve the sperm parameters in IVF protocol with no side effects.     

Comparison of novel risk factors for cardiovascular disease between hemodialysis patients with and without protein-energy wasting

Purpose

The present study was designed to compare novel risk factors for cardiovascular diseases (CVD) between hemodialysis (HD) patients with or without protein-energy wasting (PEW) for determining novel risk factors for CVD in HD patients with PEW.

Methods

In this cross-sectional study, 291 HD patients were randomly selected from among 2,302 adult HD patients in Tehran hemodialysis centers. The presence of PEW in HD patients was determined by subjective global assessment. In addition, 4 mL blood was obtained before dialysis and analyzed for serum concentrations of novel risk factors for CVD, including C-reactive protein (CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), sE-selectin, malondialdehyde (MDA), nitric oxide (NO), endothelin-1 and lipoprotein (a) [Lp (a)].

Results

Serum CRP and sICAM-1 were significantly higher in HD patients with PEW as compared to those without PEW (P < 0.01), whereas there were no significant differences in serum sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) between the two groups. Serum CRP and sICAM-1 were significantly higher in HD patients with PEW type IIa and IIb than in those with PEW type I (P < 0.01).

Conclusion

The present study indicates that serum CRP and sICAM-1, as two CVD risk factors, increase in HD patients with PEW as compared to those without PEW and these increases occur in HD patients with PEW type IIa and IIb who have inflammation.     

Agreement between DSM-IV and ICD-10 criteria for opioid use disorders in two Iranian samples

The aim of this study was to determine the agreement between the two systems in opioid users in the general population and a clinical sample. Two series of data were used in this study. The first was the data of 236 home-residing opioid abusers aged 15–64, who had previously participated in the Iran Mental Health Survey (IranMHS) in 2011, and the second was the data of 104 general psychiatry patients from inpatient or outpatient wards of two psychiatry hospitals in Tehran. Opioid use disorders were evaluated with CIDI-version 2.1. The disorders were assessed in all participants who used opioid substances for at least 5 times during the past 12 months. In the sample from the general population, the agreement between the two systems on the diagnosis of dependence was excellent (0.81). The agreement between the two systems on the diagnosis of abuse and harmful use was 0.41. In the clinical sample, the agreement between the two systems on the diagnosis of dependence or any opioid use disorder was 0.96 and 0.93, respectively. The agreement between abuse and harmful use was 0.9 and − 0.02 with and without regarding hierarchy, respectively. The inter-rater reliability of both DSM-IV and ICD-10 systems for all diagnosis was more than 0.95. The results of the diagnosis of dependence in the two systems had a weak concordance with treatment. The diagnostic criteria of DSM-IV and ICD-10 regarding dependence are very similar and the diagnosis produced by each system is concordant with the other system. However, the two systems have noticeable discrepancies in the diagnosis of abuse and harmful use. The discrepancies result from their conceptual differences and necessitate further revision in the definition of these disorders in the two systems.     

A Nontraditional Faculty Development Initiative Using a Social Media Platform

Objective. To assess the outcomes from an 11-year nontraditional professional development activity implemented by female faculty members at several colleges and schools of pharmacy.Design. Within the context of an online fantasy football league, faculty members practiced community-based faculty development strategies, including peer mentoring, skills development, constructive feedback and other supportive behaviors.Assessment. Data were extracted from curriculum vitae to characterize the academic progress of participants and to quantify scholarly work collaborations among league members. Analyses were limited to members who had participated in the league for 10 or more consecutive years. Seventy-one collaborative scholarly works occurred among team managers, including presentation of 20 posters and 2 oral presentations at national or international meetings, publication of 29 peer-reviewed articles and 15 book chapters, and funding of 5 research projects.Conclusion. Social media platforms can foster nontraditional faculty development and mentoring by enhancing connectivity between pharmacy educators who share similar interests.     

Structure‐Based Design and Synthesis of a Small Molecule that Exhibits Anti‐inflammatory Activity by Inhibition of MyD88‐mediated Signaling to Bacterial Toxin Exposure

Both Gram‐positive and Gram‐negative pathogens or pathogen‐derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88‐mediated pro‐inflammatory cellular immunity for host defense. However, dysregulated MyD88‐mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB‐loop structure of MyD88 was capable of inhibiting pro‐inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non‐polar cyclohexane linker which strongly inhibited the production of pro‐inflammatory cytokines in human primary cells to SEB (IC₅₀ 1–50 μm ) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC₅₀ 10–200 μm ). Consistent with cytokine inhibition, in a ligand‐induced cell‐based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS‐induced MyD88‐mediated NF‐kB‐dependent expression of reporter activity (IC₅₀ 10–30 μm ). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro‐inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin‐induced inflated pro‐inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic.     

Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography

Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency theta rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent theta activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic gamma-band activation, which we refer to as the "edge effect." This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level.