Testicular sperm aspiration (TESA) for infertile couples with severe or complete asthenozoospermia.

The aim of the study was to evaluate reproductive outcomes in a cohort of infertile couples with severe and complete asthenozoospermia undergoing TESA (testicular sperm aspiration) with ICSI. We conducted a retrospective study of 28 couples with complete or severe asthenozoospermia who underwent TESA between January 2010 and December 2015. We compared TESA-ICSI outcomes of these couples to ejaculate ICSI outcomes of 40 couples with severe asthenozoospermia treated during the same time period at our institution. Couples with female factor infertility and/or female aged ≥39 were excluded. Sperm retrieval rates and ICSI outcomes [(MII oocytes, fertilization rate, good embryo rate (transferred and frozen), couples with embryo transfer (per cycle started), clinical pregnancy (per embryo transfer)] were recorded. Patients were grouped based on whether they had ejaculated (Ej-group) or testicular (TESA-group) spermatozoa used. Testicular sperm patients were further classified based on whether they had complete asthenozoospermia (0% total motility) (Tc-group) or severe asthenozoospermia (≤1% progressive motility) (Ts-group). Mean (±SD) male and female ages were 36 ± 6 and 32 ± 4, respectively. Sperm recovery by testicular sperm aspiration (TESA) was successful in 100% (28/28) of the men. The overall clinical pregnancy rate (CPR) per cycle started was 34% (23/68) with a mean of 1.1 ± 0.4 embryos transferred per transfer. Fertilization rates were significantly lower in TESA-group compared to Ej-group (52% vs. 67%, respectively; p = 0.001), while male age was significantly higher in TESA-group compared to Ej-group (34 ± 6 vs. 37 ± 6, respectively; p = 0.03). Moreover, female age was significantly higher in Tc-group compared to Ts-group (30 ± 4 vs. 33 ± 3, respectively; p = 0.0285). However, there were no significant difference in clinical pregnancy rate per embryo transfer in the Tc-group, Ts-group, and Ej-group (50% vs. 45% vs. 57%, respectively; p = 0.8219). The data suggest that testicular sperm-ICSI is no better than ejaculated sperm-ICSI in couples with severe or complete asthenozoospermia. Randomized, controlled trials comparing ejaculated vs. testicular spermatozoa are needed to assess the true benefit of TESA-ICSI in these couples.

Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis.

BACKGROUND: TZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Phase 2a. METHODS: Patients with type 1 or 2 diabetes, delayed gastric half-emptying (T(1/2)), and ≥3 months gastroparesis symptoms randomized 1 : 1 : 1 to double-blind placebo, 10-mg, or 20-mg TZP-102 once daily for 12 weeks (Study TZP-102-CL-G003). Study TZP-102-CL-G004 patients randomized 1 : 1 to 10-mg TZP-102:placebo three-times-daily. Primary endpoint was change-from-baseline through Weeks 11-12 in Daily Diary of Gastroparesis Symptoms Questionnaire (GSDD) via electronic Patient Recorded Outcome device: worst severity of nausea, early satiety, bloating, and upper abdominal pain in 24 h (0 = none-to-5 = very severe). GSDD Composite Score for eligibility was ≥2.5 (Day-14-to-baseline). Patient Overall Treatment Evaluation (OTE) provided an anchor-based minimal clinically important difference (MCID) for GSDD Composite Score. KEY RESULTS: Study TZP-102-CL-G003 enrolled 201 outpatients: females 72%; Caucasians 87%; type 2 diabetes 61%; insulin-dependent 65%; age mean ± SD 53 ± 11.3 years; HbA1c 7.8 ± 1.5%; GCSI 3.4 ± 0.7; GSDD Composite 3.6 ± 0.6; gastric T1/2 131 ± 32 min; n = 69 (10-mg), n = 66 (20-mg), n = 66 (placebo). Primary endpoint (GSDD): significant improvement in all arms, although not for TZP-102 vs placebo: mean change-from-baseline -1.7, -1.4, -1.5 (10-mg, 20-mg, placebo); Gastroparesis Cardinal Symptom Index -1.8, -1.6, -1.5, respectively. The OTE (all patients) at Week-12 was: Patient 3.7 ± 3.2 and Physician 3.6 ± 3.0 with median score for both of 5.0 = important on scale of improvement; individual MCID was 1.61 and 0.94 for group analyses, greater than expected. Study TZP-102-CL-G004 with similar demographic/disease characteristics was prematurely terminated for efficacy futility (n = 64 with Week-4 assessments). CONCLUSIONS & INFERENCES: Efficacy of TZP-102 was not demonstrated compared with placebo in diabetic gastroparesis; however, there was substantial symptom improvement in all arms (ClinicalTrials.gov NCT01452815/NCT01664637).

A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis.

BACKGROUND: Gastroparesis causes significant morbidity and treatment options are limited. TZP-102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double-blind, placebo-controlled trial in patients with diabetic gastroparesis. METHODS: A total of 92 outpatients were randomized to once-daily administrations of 10-mg (n = 22), 20-mg (n = 21), 40-mg (n = 23) TZP-102 or placebo (n = 26). The primary endpoint was the change from baseline in gastric half-emptying time (T(½)) utilizing (13)C-breath test methodology and secondary endpoints included symptom improvement using patient-reported gastroparesis symptom scores (PAGI-SYM questionnaire) and patient and physician overall treatment evaluations (OTE). KEY RESULTS: Gastric T½ changes were not statistically significant between TZP-102 and placebo after 28 days of treatment at any dose. Clinical improvements (-1.0 to -1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI-SYM, which was significant vs placebo for all TZP-102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP-102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP-102 doses were well-tolerated with no adverse cardiac, weight, or glucose control outcomes. CONCLUSIONS & INFERENCES: TZP-102 for 28 days, at doses of 10-40 mg once daily, was well-tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient-defined outcomes in determining therapeutic benefit.

Analysis of microRNAs and their precursors in bovine early embryonic development.

In animals, the maternal-to-embryonic transition (MET) occurs in the first days of early development and involves the degradation of maternal transcripts that have been stored during oogenesis. Moreover, precise and specific control mechanisms govern the adequate synchronization of the MET events to promote the activation of the embryonic genome. These mechanisms are not well understood, but it is believed that microRNAs (miRNAs) could be one of the mechanisms involved. After a microarray screening study, we analysed the expression of specific miRNA during oocyte maturation and early embryo development until preimplantation stages. Two differentially expressed candidates were selected for further analysis. Mature and precursor forms of miR-21 and miR-130a were quantified by qRT-PCR in pools of 20 oocytes at GV (germinal vesicle), GV breakdown and metaphase II stages as well as in pools of embryos at the 2-cell, 4-cell, 8-cell and blastocyst stages. The results showed a linear increase during the 1-8 cell stage for the mature forms of miR-130a and miR-21 (P < 0.05 and P < 0.003, respectively) and for the precursor form of miR-130a (P < 0.002). To see if this increase was due to minor transcriptional activity, 2-cell embryos were exposed to α-amanitin for 30-34 h. Results showed a significant decrease in miR-21, pre-miR-21, miR-130a and SRFS3 in α-amanitin-treated embryos (P < 0.05). Considering the potential regulatory role of these miRNA, the bovine genome was screened to identify putative targets with a 3'UTR exact seed match. This study suggests that miRNAs could be important players in the MET, as expression profiles suggest a potential regulation role during early development steps.

Posttreatment exacerbation of hepatitis B virus (HBV) infection in long-term HBV trials of emtricitabine.

Posttreatment exacerbation of hepatitis B virus (HBV) infection in long-term HBV trials of emtricitabine occurred in 23% of patients. Development of antibody to hepatitis e antigen did not prevent hepatic flare. One patient with marked bridging fibrosis required liver transplantation. Patients with advanced liver disease are at risk for hepatic flare with decompensation if active treatment is withdrawn (e.g., when highly active antiretroviral treatment is modified).

Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection.

A multicenter, open-label study was performed to evaluate the safety, anti-hepatitis B virus (anti-HBV) activity, and pharmacokinetics of emtricitabine therapy administered once daily for 8 weeks to patients infected with HBV. Clinical and virologic evaluations were completed at the baseline; at 7, 14, 28, 42, and 56 days during treatment; and at 24, 48, and 28 days posttreatment. Forty-nine patients were enrolled in five dose cohorts (doses of 25, 50, 100, 200, and 300 mg, all of which were administered once daily [q.d.]). Peak plasma emtricitabine concentrations occurred within 1.5 h following dosing. Plasma emtricitabine concentrations (maximum concentrations of drug in plasma and areas under the concentration-time curves) increased nearly dose proportionally over the 25- to 300-mg dose range, with relatively small intersubject variabilities. The plasma half-life of emtricitabine ranged from 6 to 9 h. HBV DNA levels were measured by the Digene HBV Hybrid Capture II assay. Viral suppression (reduction in log(10) serum HBV DNA levels) occurred in all dose cohorts. All doses demonstrated potent and rapid antiviral activities, with a trend toward a greater suppression with daily doses of 100 mg or greater. At 2 months, the median change in the serum HBV DNA level from the baseline level ranged from -1.7 log(10) for the 25-mg dose administered q.d. to -3.3 log(10) for the 300 mg dose administered q.d. Emtricitabine was well tolerated over the 2-month dosing period. These results support further clinical development of emtricitabine for the treatment of chronic hepatitis B infection.

Screening for carcinoma of the prostate with prostate specific antigen.

A free screening clinic for cancer of the prostate was held in Madison County, New York, in September 1990, in conjunction with Prostate Cancer Awareness Week, a program of the Prostate Cancer Educational Council. Serum prostate specific antigen and digital rectal examination were used to screen 565 men. The two tests were equally effective in identifying patients with carcinoma. Of 118 patients with one or both tests positive, 54 were biopsied. Carcinoma was found in 20 of these. Four carcinomas were found in patients with prostate specific antigen (PSA) greater than four ng per ml with negative rectal examination. The costs for adding PSA to the protocol appeared reasonable in terms of the number of carcinomas identified.

Hepatic granuloma resulting from Enterobius vermicularis.

A nodule of the liver was incidentally noted during left colectomy for a large villous adenoma in a 74-year-old man. Microscopic examination disclosed a granuloma of the liver containing numerous Enterobius vermicularis ova and a cross-section of the nematode. This is the fourth reported case of hepatic oxyuriasis and the second case reported in North America.