Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs)

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil

Pelvic actinomycosis presenting with a large abscess and bowel stenosis with marked response to conservative treatment: a case report

Pelvic actinomycosis is a rare disease that can result in abscess formation, bowel obstruction, and other serious complications. Moreover, the correct diagnosis can seldom be established before radical surgery because the disease often mimics pelvic neoplasms. It has been recently recognized that pelvic actinomycosis is associated with long-term use of an intrauterine contraceptive device

Information transmission in oscillatory neural activity

Periodic neural activity not locked to the stimulus or to motor responses is usually ignored. Here, we present new tools for modeling and quantifying the information transmission based on periodic neural activity that occurs with quasi-random phase relative to the stimulus. We propose a model to reproduce characteristic features of oscillatory spike trains, such as histograms of inter-spike intervals and phase locking of spikes to an oscillatory influence. The proposed model is based on an inhomogeneous Gamma process governed by a density function that is a product of the usual stimulus-dependent rate and a quasi-periodic function. Further, we present an analysis method generalizing the direct method (Rieke et al, 1999; Brenner et al, 2000) to assess the information content in such data. We demonstrate these tools on recordings from relay cells in the lateral geniculate nucleus of the cat.Comment: 18 pages, 8 figures, to appear in Biological Cybernetic

Lung cancer risk among German male uranium miners: a cohort study, 1946–1998

From 1946 to 1990 extensive uranium mining was conducted in the southern parts of the former German Democratic Republic. The overall workforce included several 100 000 individuals. A cohort of 59 001 former male employees of the Wismut Company was established, forming a large retrospective uranium miners' cohort for the time period 1946–1998. Mean duration of follow-up was 30.5 years with a total of 1 801 630 person-years. Loss to follow-up was low at 5.3%. Of the workers, 16 598 (28.1%) died during the study period. Based on 2388 lung cancer deaths, the radon-related lung cancer risk is evaluated. The excess relative risk (ERR) per working level month (WLM) was estimated as 0.21% (95% CI: 0.18–0.24). It was dependent on time since exposure and on attained age. The highest ERR/WLM was observed 15–24 years after exposure and in the youngest age group (<55 years of age). While a strong inverse exposure-rate effect was detected for high exposures, no significant association was detected at exposures below 100 WLM. Excess relative risk /WLM was not modified by duration of exposure. The results would indicate the need to re-estimate the effects of risk modifying factors in current risk models as duration of exposure did not modify the ERR/WLM and there was only a modest decline of ERR/WLM with increasing time since exposure

The European Legal Framework on Cybercrime

This article analyzes the European legal framework on cybercrime. Initially, it argues the challenges of cybercrime to traditional criminal justice systems. Subsequently, it focuses on the criminal law framework on cybercrime with a mainly European perspective. The European legal framework provides a three-path solution: the reduction of frictions among national legislations, the introduction of new investigative powers and the facilitation of international cooperation. The article presents and discusses each solution. Further, it argues that the effective implementation of the main legal instruments does not seem to depend on the legal enforceability of these international measures. Contrarily, other, non legal, factors such as national security, politics, the economy and the public opinion appear to stimulate the spontaneous implementation of the European legal framework. In this context, the added value of the EU action is rather low, although the Treaty of Lisbon and the Stockholm Programme may improve this situation in the long ter

Regulation of human endometrial function: mechanisms relevant to uterine bleeding

This review focuses on the complex events that occur in the endometrium after progesterone is withdrawn (or blocked) and menstrual bleeding ensues. A detailed understanding of these local mechanisms will enhance our knowledge of disturbed endometrial/uterine function – including problems with excessively heavy menstrual bleeding, endometriosis and breakthrough bleeding with progestin only contraception. The development of novel strategies to manage these clinically significant problems depends on such new understanding as does the development of new contraceptives which avoid the endometrial side effect of breakthrough bleeding

Effects of urodilatin on natriuresis in cirrhosis patients with sodium retention

BACKGROUND: Sodium retention and ascites are serious clinical problems in cirrhosis. Urodilatin (URO) is a peptide with paracrine effects in decreasing sodium reabsorption in the distal nephron. Our aim was to investigate the renal potency of synthetic URO on urine sodium excretion in cirrhosis patients with sodium retention and ascites. METHODS: Seven cirrhosis patients with diuretics-resistant sodium retention received a short-term (90 min) infusion of URO in a single-blind, placebo-controlled cross-over study. In the basal state after rehydration the patients had urine sodium excretion < 50 mmol/24 h. RESULTS: URO transiently increased urine sodium excretion from 22 ± 16 μmol/min (mean ± SD) to 78 ± 41 μmol/min (P < 0.05) and there was no effect of placebo (29 ± 14 to 44 ± 32). The increase of URO's second messenger after the receptor, cGMP, was normal. URO had no effect on urine flow or on blood pressure. Most of the patients had highly elevated plasma levels of renin, angiotensin II and aldosterone and URO did not change these. CONCLUSION: The short-term low-dose URO infusion increased the sodium excretion of the patients. The increase was small but systematic and potentially clinically important for such patients. The small response contrasts the preserved responsiveness of the URO receptors. The markedly activated systemic pressor hormones in cirrhosis evidently antagonized the local tubular effects of URO

K65R in Subtype C HIV-1 Isolates from Patients Failing on a First-Line Regimen Including d4T or AZT: Comparison of Sanger and UDP Sequencing Data

BACKGROUND: We and others have shown that subtype C HIV-1 isolates from patients failing on a regimen containing stavudine (d4T) or zidovudine (AZT) exhibit thymidine-associated mutations (TAMs) and K65R which can impair the efficacy of Tenofovir (TDF) at second line. Depending on the various studies, the prevalence of K65R substitution as determined by the Sanger method ranges from 4 to 30%. Our aim was to determine whether ultra-deep pyrosequencing (UDPS) could provide more information than the Sanger method about selection of K65R in this population of patients. METHODS: 27 subtype C HIV-1 isolates from treated patients failing on a regimen with d4T or AZT plus lamivudine (3TC) plus nevirapine (NVP) or efavirenz (EFV) and who had been sequenced by Sanger were investigated by UDPS at codon 65 of the reverse transcriptase (RT). 18 isolates from naïve patients and dilutions of a control K65R plasmid were analysed by Sanger plus UDPS. RESULTS: Analysis of Sanger sequences of subtype C HIV-1 isolates from naïve patients exhibited expected polymorphic substitutions compared to subtype B but no drug resistance mutations (DRMs). Quantitation of K65R variants by UDPS ranged from <0.4% to 3.08%. Sanger sequences of viral isolates from patients at failure of d4T or AZT plus 3TC plus NVP or EFV showed numerous DRMs to nucleoside reverse transcriptase inhibitors (NRTIs) including M184V, thymidine-associated mutations (TAMs) plus DRMs to non- nucleoside reverse transcriptase inhibitors (NNRTIs). Two K65R were observed by Sanger in this series of 27 samples with UDPS percentages of 27 and 87%. Other samples without K65R by Sanger exhibited quantities of K65R variants ranging from <0.4% to 0.80%, which were below the values observed in isolates from naïve patients. CONCLUSIONS: While Sanger sequencing of subtype C isolates from treated patients at failure of d4T or AZT plus 3TC plus NVP or EFV exhibited numerous mutations including TAMs and 8% K65R, UDPS quantitation of K65R variants in the same series did not provide any more information than Sanger

Gender-differences of in vitro colonic motility after chemo- and radiotherapy in humans.

Background: The aim of the present in vitro study was to investigate, in different genders, motor responses in surgical colonic specimens from patients with rectal cancer undergoing and not undergoing chemotherapy with capecitabine and radiotherapy. Methods: This in vitro study was conducted from October 2015 to August 2017 at the Experimental Pharmacology Laboratory at the National Institute “S. de Bellis” after collecting samples at the Department of Surgery. Segments of sigmoid colon were obtained from 15 patients (Male (M)/Female (F) = 8/7; control group, CG) operated on for elective colorectal resection for rectal cancer without obstruction and 14 patients (M/F = 7/7; study group, SG) operated on for elective colorectal resection for rectal cancer who also received chemotherapy, based on capecitabine twice daily, and radiotherapy. Isometric tension was measured on colonic circular muscle strips exposed to increasing carbachol or histamine concentrations to obtain concentration-response curves. The motor responses to electrically evoked stimulation were also investigated. Results: In males, carbachol and histamine caused concentration-dependent contractions in the CG and SG. An increased sensitivity and a higher response to carbachol and histamine were observed in SG than CG (P &lt; 0.01). On the contrary, in females, the response to carbachol was not significantly different in CG from the SG and the maximal responses to carbachol were greater in CG than in SG (P &lt; 0.001). The same applied to histamine for half-maximal effective concentrations and maximal response in that they were not significantly different in CG from the SG. Electrically evoked contractions were significantly more pronounced in males, especially in the SG (P &lt; 0.05). Conclusions: This preliminary in vitro study has shown gender differences in motor responses of colonic circular muscle strips in patients who had received chemotherapy with capecitabine and radiotherapy