Single blastocyst transfer after ICSI from ejaculate spermatozoa, percutaneous epididymal sperm aspiration (PESA) or testicular sperm extraction (TESE)

Purpose: To investigate the outcome of IVF following intracytoplasmic sperm injection (ICSI) from ejaculate, percutaneous epididymal sperm aspiration (PESA) and testicular sperm extraction (TESE), with subsequent blastocyst culture and single blastocyst transfer. Methods: Single blastocyst transfer was performed after ejaculate ICSI (oligozoospermia) in 587 patients, TESE/PESA (azoospermia) in 31 patients, and standard IVF in 680 women. Results: There were only minor differences in IVF characteristics between the standard IVF and the PESA-TESE couples. Couples where ejaculate ICSI were performed seemed to represent a slightly poorer prognostic group. A viable fetus after the 12th gestational week, i.e. ongoing pregnancy, was present in 41.4% after ICSI/ET, 51.6% after PESA-TESE/ET and in 40.4% after standard IVF/ET (no significant differences). Conclusion: Single blastocyst transfer after ejaculate ICSI or after PESA/TESE appears to give similar results as conventional IVF blastocyst culture.     

Contribution of the paracellular route to the pH-dependent epithelial permeability to cationic drugs

The aim of this work was to investigate the contribution of the paracellular route to the pH-dependent permeability to cationic drugs in three models expressing different drug permeabilities: hexadecane membranes (HDMs), Caco-2, and 2/4/A1 cell monolayers. The high- and low-permeability drugs alfentanil and cimetidine were used as model drugs. The paracellular permeability was calculated: 1. from the assumption that the ionized form (P(mi)) permeates a cell monolayer only by the paracellular route, and 2. on basis of the pore-restricted diffusion. For both drugs, sigmoidal relationships between membrane permeability and pH were observed in all models. The P(mi) was in excellent agreement with the paracellular permeability of cimetidine in the two cell models, whereas no significant P(mi) of the drugs could be observed in HDM. The results showed that the paracellular route has a significant role in the permeability of small basic hydrophilic drugs, such as cimetidine in leaky, small intestinal-like epithelia such as 2/4/A1. By contrast, in tighter epithelia such as Caco-2 and in artificial membranes such as HDM, the permeability of the ionized forms of the drugs and the paracellular permeability are lower or insignificant, respectively. These findings will have implications in the experimental design and data interpretation of pH-dependent drug transport experiments in cell culture models as well as in artificial membrane models such as HDM and parallel artificial membrane permeability assay (PAMPA).     

Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients’ refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m², with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m² under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.     

Single Nucleotide Polymorphisms in the FADS Gene Cluster but not the ELOVL2 Gene are Associated with Serum Polyunsaturated Fatty Acid Composition and Development of Allergy (in a Swedish Birth Cohort)

Exposure to polyunsaturated fatty acids (PUFA) influences immune function and may affect the risk of allergy development. Long chain PUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by FADS and ELOVL genes. In 211 subjects, we investigated whether polymorphisms in the FADS gene cluster and the ELOVL2 gene were associated with allergy or PUFA composition in serum phospholipids in a Swedish birth-cohort sampled at birth and at 13 years of age; allergy was diagnosed at 13 years of age. Minor allele carriers of rs102275 and rs174448 (FADS gene cluster) had decreased proportions of 20:4 n-6 in cord and adolescent serum and increased proportions of 20:3 n-6 in cord serum as well as a nominally reduced risk of developing atopic eczema, but not respiratory allergy, at 13 years of age. Minor allele carriers of rs17606561 in the ELOVL2 gene had nominally decreased proportions of 20:4 n-6 in cord serum but ELOVL polymorphisms (rs2236212 and rs17606561) were not associated with allergy development. Thus, reduced capacity to desaturase n-6 PUFAs due to FADS polymorphisms was nominally associated with reduced risk for eczema development, which could indicate a pathogenic role for long-chain PUFAs in allergy development.     

Sexual risk behavior in women with cervical human papillomavirus infection

In a study of 972 women, sexual characteristics of 66 women with a cervical human papillomavirus infection (CHPI) were compared to the remaining study population. Among a number of sexual variables that were significantly correlated with CHPI were number of lifetime sexual partners, short partnerships, many recent partners, infidelity, casual travel sex, sexual début abroad, oral and anal sex, and sexual abuse. In multifactorial analyses four variables remained significantly correlated with CHPI, i.e., number of lifetime sexual partners, casual travel sex, sexual début abroad, and infidelity. It is concluded that CHPI shows most of the epidemiological characteristics of a sexually transmitted disease.     

Safety,Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers

AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first‐in‐man, single and repeat dose‐escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once‐daily treatment. Plasma exposure suggested dose‐proportional pharmacokinetics and dose‐related effects on 24‐hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA‐S and 4β‐OH‐cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus–pituitary–adrenal (HPA) effects appeared to be marginally greater in the Japanese‐ versus the Caucasian‐dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 μg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit–risk ratio may be improved relative to conventional inhaled steroids.     

Sexual behavior of women with repeated episodes of vulvovaginal candidiasis

One hundred and two women with a history of a median of six episodes of vulvovaginal candidiasis (VVC) and 204 age-matched controls participated in a structured in-depth interview on sexual behavior. Mean and median ages of the two groups were 26.7 and 26 years, respectively. Sexual characteristics, associated with VVC in crude analyses, were adjusted in multifactorial analyses for coital frequency, experience of casual sex, vaginal irritation, smoking, alcohol habits, and having a steady partner. In addition, education, as a measure of socioeconomic status, was added in the multifactorial analyses. VVC was not associated with multiple sexual partners or ever-experience of causal sex. Sexual variables that remained significant or were of borderline significance after adjustment were: age at first intercourse (p=0.001), casual sex partners the previous month (odds ratio (OR)=3.1), sex during menstruation (OR=1.7), regular oral sex (OR=2.4), experience of anal intercourse ever (OR=2.4), oral intercourse the last month (OR=3.1), and frequency of oral intercourse (p=0.02). Thus, the study indicates that certain sexual activities are associated with repeated episodes of VVC.     

Cadmium in kidneys in Swedes measured in vivo using X-ray fluorescence analysis

An X-ray fluorescence (XRF) technique using plane polarized X-rays for excitation was used for in vivo measurements of cadmium in the kidney cortex among non-occupationally exposed members of the general population in southern Sweden. The measured concentrations of cadmium in the kidney cortex of smokers (median 28 g/g, n = 10) were significantly higher (P = 0.0036) as compared to those in non-smokers (median 8 g/g, n = 10), and so were the cadmium concentrations in blood and urine. The results show that smoking considerably increases the cadmium concentration in the kidney cortex and that smoking is a major source of cadmium exposure in the general population of Sweden. Except in the presence of very deeply situated kidneys, where the minimum detectable concentration is high, non-invasive in vivo XRF analysis of kidney cadmium should be a useful tool for evaluating the effects of long-term low-level exposure to cadmium and the risk of kidney damage.