Effects of Oestrogens and FSH on LH Stimulation of Steroid Production by Testis Leydig Cells from Immature Rats

Hypophysectomy of immature male rats results after 5 days in a decreased production of testosterone by isolated testis Leydig cells in response to LH. The LH responsiveness of the Leydig cells can be partly restored by treatment of the hypophysectomized rats with FSH. In continuation of previous reports on this subject (Steroids 28 (1976) 847; and 30 (1978) the following conclusions were derived from the results in the present paper: 1. After hypophysectomy of immature male rats the production of testosterone (T) as well as of 5‐pregnenolone (Δ5P) by isolated Leydig cells in response to LH is reduced. 2. Daily administration of FSH after hypophysectomy restores the Δ5P production in response to LH almost completely, but has a much smaller effect on the restoration of T production. 3. Administration of oestradiol benzoate (E2B) together with FSH has no effect on the restoration of LH‐stimulated Δ5P production, but causes a reduction of T production, when compared with Leydig cells from animals treated with FSH only. 4. Treatment of intact immature rats with E2B results in a decreased production of T and an increased production of Δ5P in isolated Leydig cells. 5. From experiments with labelled pregnenolone it appears that E2B and diethylstilboestrol (DES) inhibit the 17α‐hydroxylase activity of Leydig cells from intact as well as from hypophysectomized rats. This results in a reduced conversion of pregnenolone to C1:)‐steroids and in increased production of 3α‐hydroxy‐5α‐pregnan‐20‐one from δ5P. 6. The observed effects of FSH and E, were similar within a dose range of 100–10000 ng LH per 106 Leydig cells. Copyrigh

Occupational physicians' perceived barriers and suggested solutions to improve adherence to a guideline on mental health problems:Analysis of a peer group training

Background Despite the impact of mental health problems on sickness absence, only few occupational health guidelines addressing these problems are available. Moreover, adherence has found to be suboptimal. To improve adherence to the Dutch guideline on mental health problems a training was developed for Dutch occupational physicians (OPs) focusing on identifying barriers and addressing them. The aim of this study was to provide an overview of the barriers that OPs perceived in adhering to the Dutch guideline on mental health problems as well as their solutions to overcome them. Methods A qualitative study was conducted using data from the peer group training. Thirty-two (6 groups of 4 to 6) OPs received a multiple-session interactive training over the course of a year, focusing on identifying and addressing barriers, using a Plan-Do-Check-Act approach. Sessions were audio-taped and transcribed verbatim. Thematic content analysis was performed by two researchers with a selection of 50 % (21 out of 42) of the transcripts to identify the perceived barriers and the suggested solutions, using AtlasTi 7.0. Results Knowledge-related barriers were perceived regarding the content of all parts of the guideline. Commonly perceived attitude-related barriers were a lack of self-efficacy to perform certain guideline recommendations and difficulties with changing habits and routines. External barriers that were commonly perceived were work-contextual barriers, such as a lack of time/work pressure, tight contracts between occupational health services (OHSs) and employers, and conflicting policy of and a lack of collaboration with other parties (e.g. employer, other healthcare providers). The most often tested solutions by OPs during the training were sharing information, experiences, tips and tricks and referring to existing tools, or developing new tools to facilitate guideline usage. Conclusions Dutch OPs perceive a range of knowledge-related, attitude-related and external barriers in adhering to the guideline on mental health problems. The tested solutions during the training particularly seemed to focus on knowledge and attitude-related barriers. To optimally implement this or similar mental health guidelines, it may be important to complement guideline training and education of individual or groups of OPs, with interventions that address external barriers such as changing tight contracts, or improving communication and collaboration with other parties. Keywords Mental health, Practice guideline, Occupational medicine, Barriers, Solutions, Implementatio

Effectiveness of an intervention to enhance occupational physicians’ guideline adherence on sickness absence duration in workers with common mental disorders:A cluster-randomized controlled trial

Purpose Evidence-based guidelines in occupational health care improve the quality of care and may reduce sickness absence duration. Notwithstanding that, guideline adherence of occupational physicians (OPs) is limited. Based on the literature on guideline implementation, an intervention was developed that was shown to effectively improve self-reported adherence in OPs. The aim of present study was to evaluate whether this intervention leads to earlier return to work (RTW) in workers with common mental disorders (CMD). Methods In a two-armed cluster randomized controlled trial, 66 OPs were randomized. The trial included 3379 workers, with 1493 in the intervention group and 1886 in the control group. The outcome measures were: time to full RTW, time to first RTW, and total hours of sickness absence. Cox regression analyses and generalized linear mixed model analyses were used for the evaluations. Results The median time to RTW was 154 days among the 3228 workers with CMD. No significant differences occurred in (time to) full RTW between intervention and control group HR 0.96 (95% CI 0.81–1.15) nor for first RTW HR 0.96 (95% CI 0.80–1.15). The mean total hours of sickness absence was 478 h in the intervention group and 483 h in the control group. Conclusions The intervention to enhance OPs’ guideline adherence did not lead to earlier RTW in workers with CMD guided by the OPs. Possible explanations are the remaining external barriers for guideline use, and that perceived guideline adherence might not represent actual guideline adherence and improved care

Robust DC and efficient time-domain fast fault simulation

Purpose – Imperfections in manufacturing processes may cause unwanted connections (faults) that are added to the nominal, "golden", design of an electronic circuit. By fault simulation one simulates all situations. Normally this leads to a large list of simulations in which for each defect a steady-state (DC) solution is determined followed by a transient simulation. We improve the robustness and the e¿iciency of these simulations. Design/methodology/approach – Determining the DC solution can be very hard. For this we present an adaptive time domain source stepping procedure that can deal with controlled sources. The method can easily be combined with existing pseudo-transient procedures. The method is robust and e¿cient. In the subsequent transient simulation the solution of a fault is compared to a golden, fault-free, solution. A strategy is developed to e¿ciently simulate the faulty solutions until their moment of detection. Finding – We fully exploit the hierarchical structure the circuit in the simulation process to bypass parts of the circuit that appear to be una¿ected by the fault. Accurate prediction and e¿cient solution procedures lead to fast fault simulation. Originality/value – Our fast fault simulation helps to store a database with detectable deviations for each fault. If such a detectable output "matches" a result of a product that has been returned because of malfunctioning it helps to identify the subcircuit that may contain the real fault. One aims to detect as much as possible candidate faults. Because of the many options the simulations must be very e¿cient

High-grade vulvar intraepithelial neoplasia:comprehensive characterization and long-term vulvar carcinoma risk

Aims: Adequate diagnosis of human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent vulvar intraepithelial neoplasia (VIN) is essential but can be challenging. We comprehensively characterized a large population-based series of vulvar lesions, originally reported as high-grade VIN, and assessed the cancer risk.Methods and results: Baseline high-grade VIN of 751 patients were categorized by histopathological reassessment, integrating the results of immunohistochemistry (p16INK4a, p53, Ki-67) and HPV DNA testing. Integrated analyses resulted in 88.4% HPV-associated lesions (77.0% HSIL, 10.9% low-grade SIL [LSIL], and 0.4% vulvar squamous cell carcinoma [VSCC]), 10.9% HPV-independent lesions (6.1% HPV-independent VIN, 4.7% nondysplastic lesions, and 0.1% VSCC) and 1.1% inconclusive lesions. HSIL demonstrated p16INK4a block-positivity in 99.0%, increased Ki-67 in ≥2/3rd of the epithelium in 93.6%, and HPV positivity in 99.6%. In HSIL, a p53 wildtype mid-epithelial staining pattern was common (51.6%) while this was not observed in HPV-independent lesions. HPV-independent VIN harboured mutant p53 patterns in 65.2% and showed a wide morphological spectrum, ranging from differentiated to nondifferentiated (‘HPV-associated-like’, in 41.3%). Kaplan–Meier analyses showed a 10-year cancer risk of 8.0% in HPV-associated HSIL, 67.4% in HPV-independent VIN/p53mutant, and 27.8% in HPV-independent VIN/p53wildtype. Strikingly, the 10-year cancer risk was 73.3% in HPV-independent VIN with nondifferentiated (‘HPV-associated-like’) morphology.Conclusion: Immunohistochemistry by p16INK4a and p53 is highly recommended for optimal categorization into HPV-associated and HPV-independent VIN, which is of utmost importance given the different cancer risk. The high cancer risk of HPV-independent VIN underscores the need for surgical treatment and close follow-up, especially in case of a p53 mutant pattern and/or nondifferentiated morphology.</p

Informing the development of online weight management interventions:a qualitative investigation of primary care patient perceptions

Background: The internet is a potentially promising medium for delivering weight loss interventions. The current study sought to explore factors that might influence primary care patients’ initial uptake and continued use (up to four-weeks) of such programmes to help inform the development of novel, or refinement of existing, weight management interventions.Methods: Semi-structured interviews were conducted with 20 patients purposively sampled based on age, gender and BMI from a single rural general practice. The interviews were conducted 4 weeks after recruitment at the general practice and focused on experiences with using one of three freely available weight loss websites. Thematic Analysis was used to analyse the data.Results: Findings suggested that patients were initially motivated to engage with internet-based weight loss programmes by their accessibility and novelty. However, continued use was influenced by substantial facilitators and barriers, such as time and effort involved, reaction to prompts/reminders, and usefulness of information. Facilitation by face-to-face consultations with the GP was reported to be helpful in supporting change.Conclusions: Although primary care patients may not be ready yet to solely depend on online interventions for weight loss, their willingness to use them shows potential for use alongside face–to-face weight management advice or intervention. Recommendations to minimise barriers to engagement are provided

The Paget Trial:topical 5% imiquimod cream for noninvasive vulvar Paget disease

BACKGROUND: Vulvar Paget disease is an extremely rare skin disorder, which is most common in postmenopausal women. Most vulvar Paget disease cases are noninvasive; however, it may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The current treatment of choice for noninvasive vulvar Paget disease is wide local excision, which is challenging because of extensive intraepithelial spread and may cause severe morbidity. Recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. Imiquimod, a topical immune response modifier, has been shown to be effective in a few studies and case reports, and is a promising new treatment modality. OBJECTIVE: To prospectively investigate the efficacy, safety, and effect on quality of life of a standardized treatment schedule with 5% imiquimod cream in patients with noninvasive vulvar Paget disease. STUDY DESIGN: The Paget Trial is a multicenter prospective observational clinical study including 7 tertiary referral hospitals in the Netherlands. A total of 24 patients with noninvasive vulvar Paget disease were treated with topical 5% imiquimod cream 3 times a week for 16 weeks. The primary efficacy outcome was the reduction in lesion size at 12 weeks after the end of treatment. Secondary outcomes were safety, clinical response after 1 year, and quality of life. Safety was assessed by evaluation of adverse events and tolerability of treatment. Quality of life was investigated with 3 questionnaires taken before, during, and after treatment. RESULTS: Data were available for 23 patients, 82.6% of whom responded to therapy. A complete response was reported in 12 patients (52.2%), and 7 patients (30.4%) had a partial response. A histologic complete response was observed in 10 of the 12 patients with a complete response. Patients experienced side effects such as fatigue (66.7%-70.9%) and headaches (16.7%-45.8%), and almost 80% needed painkillers during treatment. Eight patients (34.8%) adjusted the treatment protocol to 2 applications a week, and 3 patients (13.0%) stopped treatment because of side effects after 4 to 11 weeks. Treatment improved quality of life, whereas a slight, temporary negative impact was observed during treatment. Two patients with a complete response developed a recurrence within 1 year after treatment. Follow-up showed 6 patients with a noninvasive recurrence after a median of 31 months (14-46 months) after the end of treatment. CONCLUSION: Topical 5% imiquimod cream can be an effective and safe treatment alternative for noninvasive vulvar Paget disease, particularly when compared with treatment with surgical excision

Occupational physicians' perceived barriers and suggested solutions to improve adherence to a guideline on mental health problems: Analysis of a peer group training

Background: Despite the impact of mental health problems on sickness absence, only few occupational health guidelines addressing these problems are available. Moreover, adherence has found to be suboptimal. To improve adherence to the Dutch guideline on mental health problems a training was developed for Dutch occupational physicians (OPs) focusing on identifying barriers and addressing them. The aim of this study was to provide an overview of the barriers that OPs perceived in adhering to the Dutch guideline on mental health problems as well as their solutions to overcome them. Methods: A qualitative study was conducted using data from the peer group training. Thirty-two (6 groups of 4 to 6) OPs received a multiple-session interactive training over the course of a year, focusing on identifying and addressing barriers, using a Plan-Do-Check-Act approach. Sessions were audio-taped and transcribed verbatim. Thematic content analysis was performed by two researchers with a selection of 50 % (21 out of 42) of the transcripts to identify the perceived barriers and the suggested solutions, using AtlasTi 7.0. Results: Knowledge-related barriers were perceived regarding the content of all parts of the guideline. Commonly perceived attitude-related barriers were a lack of self-efficacy to perform certain guideline recommendations and difficulties with changing habits and routines. External barriers that were commonly perceived were work-contextual barriers, such as a lack of time/work pressure, tight contracts between occupational health services (OHSs) and employers, and conflicting policy of and a lack of collaboration with other parties (e.g. employer, other healthcare providers). The most often tested solutions by OPs during the training were sharing information, experiences, tips and tricks and referring to existing tools, or developing new tools to facilitate guideline usage. Conclusions: Dutch OPs perceive a range of knowledge-related, attitude-related and external barriers in adhering to the guideline on mental health problems. The tested solutions during the training particularly seemed to focus on knowledge and attitude-related barriers. To optimally implement this or similar mental health guidelines, it may be important to complement guideline training and education of individual or groups of OPs, with interventions that address external barriers such as changing

Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity

A low fat oxidative capacity has been linked to muscle diacylglycerol (DAG) accumulation and insulin resistance. Alternatively, a low fat oxidation rate may stimulate glucose oxidation, thereby enhancing glucose disposal. Here, we investigated whether an ethyl-2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylate (etomoxir)-induced inhibition of fat oxidation leads to muscle fat storage and insulin resistance. An intervention in healthy male subjects was combined with studies in human primary myotubes. Furthermore, muscle DAG and triacylglycerol (TAG), mitochondrial function, and insulin signaling were examined in etomoxir-treated C57bl6 mice. In humans, etomoxir administration increased glucose oxidation at the expense of fat oxidation. This effect was accompanied by an increased abundance of GLUT4 at the sarcolemma and a lowering of plasma glucose levels, indicative of improved glucose homeostasis. In mice, etomoxir injections resulted in accumulation of muscle TAG and DAG, yet improved insulin-stimulated GLUT4 translocation. Also in human myotubes, insulin signaling was improved by etomoxir, in the presence of increased intramyocellular lipid accumulation. These insulin-sensitizing effects in mice and human myotubes were accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Our results show that a reduction in fat oxidation leading to accumulation of muscle DAG does not necessarily lead to insulin resistance, as the reduction in fat oxidation may activate AMPK