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Background: Planned gene therapies for retinitis pigmentosa (RP) depend on viable photoreceptors for efficacy. Understanding disease severity at presentation, and drivers that influence time to presentation is important when planning interventions. We examined features that influence RP severity at initial presentation., Methods: Multi-centre retrospective cohort study of RP patients at initial presentation. Disease severity was scored using ellipsoid zone (EZ) width on SD-OCT and logistic regression used to determine risk factors for advanced disease at presentation., Results: A total of 146 unrelated RP patients were included. Median age at onset and presentation was 40.5 (range 1-74) and 50.1 (range 3.9-81.8), respectively. Severe disease (<5° of remaining EZ width) was present in 28.1% of cases at presentation. Patients with family history of RP had greater odds of severe disease (OR 3.29, 95% CI 1.56, 6.95; p = 0.002), while male gender, race, age, syndromic features, and socioeconomic status did not. Patients with affected siblings (median EZ width 6.2°; p = 0.01), but not affected parents (median EZ width 9.4°; p = 0.99), presented with severe EZ loss compared to patients without family history (median EZ width 13.1°). Patients with affected siblings had delayed presentation (≥5 years; OR 5.76, 95% CI 1.817, 18.262; p = 0.003) compared to patients without family history., Conclusions: Family history influences the stage of disease at which RP patients initially seek ophthalmology review. This has implications for patient counselling and the number of patients who may benefit from future therapies., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

(1) Purpose: ABCA4 -associated retinal degeneration ( ABCA4 -RD) is a phenotypically diverse disease that often evades diagnosis, even by experienced retinal specialists. This may lead to inappropriate management, delayed genetic testing, or inaccurate interpretation of genetic testing results. Here, we illustrate the phenotypic diversity of ABCA4 -RD using a series of representative cases and compare these to other conditions that closely mimic ABCA4 -RD. (2) Methods: Genetically confirmed ABCA4 -RD cases with representative phenotypes were selected from an inherited retinal disease cohort in Singapore and compared to phenocopies involving other retinal diseases. (3) Results: ABCA4 -RD phenotypes in this series included typical adolescent-onset Stargardt disease with flecks, bull's eye maculopathy without flecks, fundus flavimaculatus, late-onset Stargardt disease, and severe early-onset Stargardt disease. Phenocopies of ABCA4 -RD in this series included macular dystrophy, pattern dystrophy, cone dystrophy, advanced retinitis pigmentosa, Leber congenital amaurosis, drug toxicity, and age-related macular degeneration. Key distinguishing features that often suggested a diagnosis of ABCA4 -RD were the presence of peripapillary sparing, macular involvement and centrifugal distribution, and a recessive pedigree. (4) Conclusions: ABCA4 -RD demonstrates a remarkable phenotypic spectrum that makes diagnosis challenging. Awareness of the clinical spectrum of disease can facilitate prompt recognition and accurate diagnostic testing.

Purpose: The study aimed to describe the phenotypic features of retinitis pigmentosa (RP) associated with the previously described EYS C2139Y variant in Singaporeans and establish the importance of this variant as a prevalent cause of RP among East Asians., Methods: A clinical phenotyping and exome-sequencing study was conducted on consecutive patients with nonsyndromic RP. Epidemiological analysis was performed using Singaporean and global population-based genetic data., Results: A study of 150 consecutive unrelated individuals with nonsyndromic RP found that 87 (58%) of cases had plausible genotypes. A previously described missense variant in the EYS gene, 6416G>A (C2139Y), occurred heterozygously or homozygously in 17 of 150 families (11.3%), all with autosomal recessive RP. Symptom onset in EYS C2139Y-related RP ranged from 6 to 45 years, with visual acuity ranging from 20/20 at 21 years to no light perception by 48 years. C2139Y-related RP had typical findings, including sectoral RP in cases with EYS E2703X in trans . The median age at presentation was 45 years and visual fields declined to less than 20° (Goldmann V4e isopter) by age 65 years. Intereye correlation for visual acuity, fields, and ellipsoid band width was high (r 2 = 0.77-0.95). Carrier prevalence was 0.66% (allele frequency of 0.33%) in Singaporean Chinese and 0.34% in East Asians, suggesting a global disease burden exceeding 10,000 individuals., Conclusion: The EYS C2139Y variant is common in Singaporean RP patients and other ethnic Chinese populations. Targeted molecular therapy for this single variant could potentially treat a significant proportion of RP cases worldwide.

Photolytic degradation of brominated flame retardants is one of the potential decomposition pathways in the environment, and for some flame retardants such as ethane-bis(pentabromophenyl) (EBP), also called decabromodiphenyl ethane, there are concerns that degradation products may be harmful. In this paper, we present photolytic studies of EBP in high-impact polystyrene (HIPS) and polypropylene impact copolymer (PP) using accelerated weatherometry. The half-life of photolytic debromination of EBP in HIPS was estimated to be more than 200 years, which can be contrasted with half-lives of minutes for photolysis conducted on dilute EBP solutions. Perhaps more importantly, there was no subsequent debromination to the octabrominated congeners or lower. No evidence of debromination was seen in PP, which confirms the importance of matrix effects. We also saw no evidence of accelerated resin photooxidation caused by EBP. These studies demonstrate that EBP is much more photolytically stable in resins than structurally-similar decabromodiphenyl ether, and a read-across comparison between the two flame retardant molecules for this degradation pathway is misleading., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Rajeev S. Mathur reports a relationship with Albemarle Corporation that includes: employment and equity or stocks. Bijay Banstola reports a relationship with Albemarle Corporation that includes: employment and equity or stocks. Kelsey M. Lopez reports a relationship with Albemarle Corporation that includes: employment. Mark W. Beach reports a relationship with Albemarle Corporation that includes: employment and equity or stocks. Daniel De Schryver reports a relationship with Albemarle Corporation that includes: employment and equity or stocks., (Copyright © 2023 Albemarle Corporation. Published by Elsevier Ltd.. All rights reserved.)

Study Question: We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research., What Is Known Already: Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research., Study Design Size Duration: Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health's consensus development conference., Participants/materials Setting Methods: An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes., Study Funding/competing Interests: This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open . K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests., Trial Registration Number: Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586., Trial Registration Date: N/A., Date of First Patient’s Enrolment: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Diaphragmatic hernia is an important cause of emergency hospital admission associated with significant morbidity. It usually results from congenital defect or rupture in the diaphragm due to trauma. Prompt and appropriate diagnosis is necessary in patients with this condition, as surgical intervention by either abdominal or thoracic approach may be necessary. Here, we report a case of left-sided diaphragmatic hernia presenting with sudden onset of breathlessness, respiratory distress and left-sided chest pain radiating to the abdomen, mimicking pneumothorax, treated successfully with surgical intervention.

Background: The purpose of this study was to assess the accuracy of ovulation detection by the DuoFertility(®) monitor compared with transvaginal ultrasound in infertile women with regular menstrual cycles., Methods: Eight infertile patients, aged 27-40 years, with a body mass index of 19-29, regular menses, normal ovaries on pelvic ultrasound scan, and normal early follicular luteinizing hormone (LH), follicle-stimulating hormone, and prolactin were recruited from infertility clinics in primary and secondary care for this pilot, prospective, observational study. The patients were asked to use the DuoFertility monitor for the whole cycle, with investigators and patients blind to DuoFertility data. Daily urine LH monitoring commenced on cycle day 8, with daily transvaginal ultrasound following the first positive LH until ovulation was observed. Ovulation was further confirmed by serum progesterone. The main outcome measure was detection of ovulation by the DuoFertility monitor, and correlation between day of ovulation assessed by DuoFertility and ultrasound., Results: DuoFertility identified ovulation as having occurred within one day of that determined via ultrasound in all cycles. The sensitivity of ovulation detection was 100% (95% confidence interval 82-100). The specificity could not be concluded from the data., Conclusion: In infertile women with regular cycles, the DuoFertility monitor appears to accurately identify ovulatory cycles and the day of ovulation.

Objective: The Endometriosis Health Profile-30 (EHP-30), an endometriosis-specific health-related quality of life (HRQoL) questionnaire, forms part of our service evaluation of all women undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis in our reproductive medicine unit. We used the EHP-30 to investigate patient-reported outcomes in all patients undergoing this procedure., Study Design: Retrospective review of 16 women with endometriosis undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy for debilitating symptoms after other modalities of treatment had failed. Patients completed EHP-30 questionnaires before the operation and again three months after surgery., Results: Total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis results in a significant improvement in HRQoL. The impact was greatest in the core domains--control and powerlessness, emotional wellbeing and social support. There was a 100% response rate for the core domains whereas in the modular domains, missing response rates ranged from 12.5% to 62.5%, with the percentage of missing data being greatest in the concern on infertility and relationship with children domains. Pain was significantly positively correlated with control and powerlessness, emotional wellbeing, work life and relationship with children. After multiple regression analyses, only control and powerlessness and emotional wellbeing were found to be predictive of pain. Additionally, changes in pain before and after total abdominal hysterectomy and bilateral salpingo-oophorectomy were significantly positively correlated with the changes in the core domains--control and powerlessness, emotional wellbeing and self image. After multiple regression analyses, change in pain was found to be predictive of ΔControl and powerlessness in our study subjects., Conclusion: Total abdominal hysterectomy and bilateral salpingo-oophorectomy significantly improves HRQoL in patients debilitated by symptoms attributable to endometriosis and in whom other modalities of treatment have failed., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Questionnaires are widely used in epidemiological studies to measure eczema symptom prevalence, but there are concerns regarding their accuracy if used as a diagnostic tool., Objectives: To compare the performance of a validated eczema symptom questionnaire and a standardized skin examination protocol employed in the second phase of the International Study of Asthma and Allergies in Childhood (ISAAC)., Methods: A total of 30,358 schoolchildren aged 8-12 years from 18 countries were examined for flexural eczema. Parents also completed an eczema symptom questionnaire. We compared prevalence estimates at the population level based on the questionnaire vs. physical examination. We also compared the skin examination and the ISAAC questionnaire in making a diagnosis of flexural eczema., Results: The point prevalences for flexural eczema at centre level based on a single examination were lower than the questionnaire-based 12-month period prevalences (mean centre prevalence 3.9% vs. 9.4%). Correlation between prevalences of both outcome measures was high (r = 0.77, P < 0.001). At the individual level, questionnaire-derived symptoms of 'persistent flexural eczema in the past 12 months' missed < 10% of cases of flexural eczema detected on physical examination. However, between 33% and 100% of questionnaire-based symptoms of 'persistent flexural eczema in the past 12 months' were not confirmed on examination., Conclusions: ISAAC questionnaire-derived symptom prevalences are sufficiently precise for comparisons between populations. Where diagnostic precision at the individual level is important, questionnaires should be validated and potentially modified in those populations beforehand, or a standardized skin examination protocol should be used.

With the object to strengthen the clinical status of tuberculous sarcoidosis, we present in this article, the case records published in internationally recognized journals by specialists. From review of clinical material, we have also formulated a table that defines diagnostic criteria of tuberculous sarcoidosis.

Objectives: An early non-invasive diagnosis of cervical cancer and its metastasis can save lives. We have shown that serum IGF-II levels can be effectively used for a specific early diagnosis of cervical cancer. Here, we shall determine if serum levels of vascular endothelial growth factors B and C (VEGF-A [corrected] VEGF-C) associated with vasculogenic and lymphogenic metastasis may be used for an early diagnosis of advanced metastatic cervical cancer and compare these levels with those of the serum IGF-II and IGF-binding protein 3 (IGF-BP3)., Material and Methods: (a) Serum levels of IGF-II, IGF-BP3, VEGF-A [corrected] (VEGF(165)) and VEGF-C (ELISA kits) were determined in: 82 controls with normal Pap smears; 29 women with atypical squamous cells of undetermined significance (ASCUS) and normal cervical biopsy; 46 ASCUS and cervical intraepithelial neoplasia (CIN) on biopsy; 8 pre-therapy CIN-I; 23 successfully treated CIN-I; 75 persistent CIN-I; 14 CIN-II/III pre-therapy; 14 successfully treated CIN-II/III; 70 persistent CIN-II/III; 86 pre-therapy cervical cancer; 26 in early grades of cervical cancer; 21 in late grades of cervical cancer; 22 cervical cancer patients in remission; 50 persistent cervical cancer; 18 with ovarian cancer; and 57 with endometrial cancer. (b) Serial serum samples collected over 5 years in 5 women with progressing cervical cancer were also tested. (c) Serum and tissue VEGF-C were enumerated in 20 matched serum (ELISA) and tissue (semi-quantitative immunofluorescent antibody assay) samples from controls, early cervical cancer, late cervical cancer, ovarian cancer and endometrial cancer patients. Student's t test, chi-square analysis and linear regression analysis were used., Results: (a) As anticipated, serum IGF-II levels were elevated as early as ASCUS with CIN on biopsy and continued to be elevated in CIN (all grades; pre-therapy and persistent) and cervical cancer (pre-therapy, early, late and persistent). Serum IGF-II levels were normal in ASCUS with normal biopsy, successfully treated CIN-I, II/III, cervical cancer as well as pre-therapy ovarian and endometrial cancers (therapy efficacy: P < 0.0001 by chi-square analysis). Serum IGF-BP3 showed a significant decrease with advancing disease. Serum VEGF-A [corrected] levels were the highest in pre-therapy, early, advanced and persistent cervical cancer, as well as in ovarian and endometrial cancers. Serum VEGF-C levels, on the other hand, were the highest in late and persistent cervical cancers, but not in ovarian or endometrial cancers. (b) In the 5 women with serial samples, the serum levels of the growth factors showed similar trends. (c) VEGF-C levels in serum and tissue were elevated in cervical cancers especially in advanced grades, while they were normal in serum and tissue from the controls and women with ovarian and endometrial cancers. There was a highly significant positive correlation between VEGF-C and IGF-II and a negative correlation between IGF-BP3 and VEGF-C (P < 0.0001)., Conclusion: Serum IGF-II up-regulation is specific to cervical cancer and helps in the early diagnosis of malignant proliferation, while serum VEGF-C up-regulation appears to be a unique marker for an early diagnosis of cervical cancer metastasis. VEGF-C and IGF-II systems appear to be interrelated in cervical cancer, contributing to the early malignant cell proliferation and lympho-vascular metastasis. Serum IGF-BP3 and VEGF-A [corrected] appear to be common markers for all gynecological cancers.

Objectives: Epidermal Growth Factor Receptor (EGF-R) up-regulation in cervical cancer cells leads to an increase in cell proliferative Insulin-like Growth Factor II (IGF-II) and Vascular Endothelial Growth Factor (VEGF) and a decrease of the anti-proliferative IGF-binding protein-3 (IGF-BP3). The objectives for this study are: (a) to find if VEGF, in turn, up-regulates EGF-R and down-regulates IGF-BP3; (b) to determine if human papilloma virus (HPV-E6) mediates this action of VEGF in HPV-positive cells; and (c) to verify if these effects are reflected in changes in cell proliferation, Methods: We used HPV-positive HeLa (Black), ME-180 and CaSki (Caucasian) and HPV-negative HT-3 (Caucasian) cell lines. (a) Levels of HPV-E6 in the HPV-positive cells were enumerated after treating the cells for 24 h with 20 ng/ml of VEGF using our semi-quantitative immunofluorescent antibody assay. (b) Cellular levels of EGF-R, HPV-E6, IGF-II and IGF-BP3 were enumerated in ME-180 and CaSki cells incubated for 24 h with 5, 10 and 20 ng/ml of VEGF. (c) HPV-negative HT-3 and HPV-positive ME-180 and CaSki cells were incubated with 20 ng/ml VEGF alone or in combination with antibodies to HPV-E6 and EGF-R. HPV-E6 (measured only in HPV-positive cells), EGF-R, IGF-II and IGF-BP3 levels were measured. (d) Cell proliferation was determined using cell proliferation Bradykinine-U colorimetric assay, in HT-3, HeLa and ME-180 cell lines in the presence of VEGF alone and with HPV-E6 antibodies., Results: (a) In all the HPV-positive cell lines, 20 ng/ml VEGF significantly increased (30-50%; P < 0.0001) the HPV-E6. (b) In the ME-180 and CaSki cells, VEGF treatment up-regulated EGF-R, IGF-II and HPV-E6 and down-regulated IGF-BP3 in a dose-dependent manner (P < 0.001). (c) These effects of VEGF were eliminated when the HPV-positive cells were co-incubated with antibodies to HPV-E6 or EGF-R. In the HPV-negative HT-3 cells, VEGF decreased IGF-BP3 while increasing EGF-R and IGF-II levels. Antibodies to EGF-R eliminated these effects (P < 0.0001). (d) Treatment with VEGF resulted in increased cell proliferation in HT-3, HeLa and ME-180 cells; co-incubation with HPV-E6 antibodies abrogated this effect only in the HPV-positive cells., Conclusions: In cervical cancer, VEGF up-regulates EGF-R and down-regulates IGF-BP3, thus amplifying the cell proliferative activity of EGF-R. This action of VEGF seems to be mediated, directly through EGF-R or indirectly through HPV-E6 in the HPV-positive cancers, while EGF-R up-regulation appears to play a major role in the HPV-negative cervical cancers.

Problem: Smoking and infection with human papilloma virus (HPV) are major risk factors for cervical cancer. Our earlier work shows that nicotine enhances cellular proliferation of cervical cancer cell lines by up-regulating epidermal growth factor (EGF) and its receptor EGF-R, which leads to increased insulin-like growth factor II in vitro. We found that the vascular endothelial growth factor (VEGF)-C, one of the five isoforms of VEGF, may be specifically involved in lymphogenic metastasis of cervical cancer. This has prompted us to study if in vitro nicotine treatment will up-regulate VEGF-C alongside EGF-R levels, while down regulating the anti-proliferative transforming growth factor (TGF)-beta levels in HPV positive cervical cancer cell lines., Method of Study: Cervical cancer cell lines CaSki, HeLa and ME-180, were cultured in serum free DMEM medium for 24-hr, and treated with 10 ng/mL nicotine in the medium supplemented with 10% fetal bovine serum. A group of untreated cells served as controls. The cells were cultured in chamber slides (for immunofluorescent antibody assay) as well as microtiter plate wells (for BrdU cell proliferation assay). The cellular levels of VEGF-C, TGF-beta, EGF-R and HPV-E6 (early protein 6) were measured by a semi-quantitative immunofluorescent antibody assay. The cell proliferation and immunofluorescent assay data were analyzed by a Student's t-test., Results: Cell proliferation was significantly increased after nicotine treatment in all the cell lines. The VEGF-C levels were significantly increased, while TGF-beta levels were decreased by nicotine in all the cell lines (P < 0.00001). EGF-R levels were also significantly increased after nicotine treatment in HeLa and ME-180, while HPV-E6 levels remained unchanged in all three., Conclusions: Nicotine up regulates expression of cell proliferative VEGF-C and EGF-R, while down-regulating anti-proliferative TGF-beta. Our data suggest that nicotine in circulation and in cervical squamous epithelial cells may promote not only rapid tumor growth but its lympho-angiogenic spread (VEGF-C) as well. It appears that nicotine does not promote HPV spread in the cervical cancer cells.

Cervical cancer is a major gynecologic malignancy around the world. However, current diagnostic methods such as Pap smear and human papilloma virus (HPV) testing are insufficient for an early diagnosis of cervical cancer, follow-up on therapy efficacy or to identify the women who might progress to cervical cancer (only about 1-5% of the HPV-positive women will develop cervical cancer). Patients with atypical squamous cells of undetermined significance (ASC-US) clearly need a better screening test. Developing a non-invasive method for early diagnosis of cervical cancer is essential. Our in vitro and translational research data support the hypothesis that: 1. Squamous cell cervical cancer is related to specific upregulation of tissue and serum Insulin-like Growth Factor-II levels (IGF-II; 100% sensitivity and 100% specificity). Serum IGF-I, but not IGF-II levels are elevated in other gynecological, breast, lung and prostate cancers. Serum IGF-II test helps in diagnosing cervical cancer as early as ASC-US or cervical intraepithelial neoplasia (CIN)-I and in monitoring therapy efficacy (p < 0.001 by Student's 't' test and Chi-square analysis). 2. Concomittant to increased serum IGF-II levels, IGF-Binding Protein 3 (IGF-BP3) levels are significantly decreased in persistent CIN and cervical cancer (p < 0.0001). As IGF-BP3 modulates IGF-II biological activity, significantly decreased serum IGF-BP3 levels (levels normalize after therapy; p < 0.001) may indicate a poor prognosis. Similar to serum IGF-II, serum IGF-BP3 levels help monitoring therapy efficacy in cervical cancer and advanced CIN. Measurement of serum IGF-II levels will help in early diagnosis of cervical cancer and monitoring of therapy outcome. Serum IGF-BP3 in conjunction with IGF-II levels may help in predicting prognosis as well as monitoring therapy efficacy.

Purpose: Chronological age, or biological age as indicated by elevated FSH levels, are related to ovarian reserve. This study addresses the likelihood of cancellation of IVF treatment due to a poor ovarian response utilising both basal serum FSH and woman's age., Methods: A prospective cohort of 536 infertile but ovulating women were studied in their first cycle of IVF treatment. Standardised methods of pituitary desensitisation and ovarian stimulation prior to IVF treatment were employed. Treatment cycles cancelled due to a poor ovarian response to gonadotrophins were studied. A series of logistic regression models were used to explore the probabilities of cancellation in relation to age and FSH., Results: Both age and basal serum FSH levels were independently associated with the risk of treatment cancellation. A low risk of treatment cancellation was observed in women under the age of 35 irrespective of serum FSH, however in older women the risk of treatment cancellation was most likely in women with a high FSH., Conclusions: In combination both age and FSH may serve as a valuable indicator of poor ovarian response leading to treatment cancellation. However, among older women FSH has particular importance, while less so in younger women with regular menstrual cycles.

Objective: We aimed to further document that elevated levels of circulating insulin-like growth factor II (IGF-II) are associated with cervical cancer and to test the hypothesis that there may be an inverse association between IGF-II and IGF-binding protein 3 (IGF-BP3)., Methods: Serum IGF-II and IGF-BP3 levels were measured, using ELISA kits (Diagnostic Systems Laboratories), in 23 controls; 16 ASC-US with normal biopsies; 14 ASC-US with advanced CIN; 2 pretherapy CIN-I; 8 successfully treated CIN-I; 24 persistent CIN I; 14 pretherapy CIN II/III; 10 posttherapy CIN II/III with normal biopsies; 18 persistent CIN-II/III; 7 with pretherapy cervical cancer; 19 with posttherapy cervical cancer under remission; 15 with posttherapy persistent/recurrent cervical cancer; 10 with persistent ovarian or endometrial cancer; and 3 with endometrial or vulvar with cervical cancer. Student's t test and linear regression analysis were used., Results: Compared to controls (493 +/- 90 ng/ml) and women with other gynecological cancers, serum IGF-II levels were significantly increased in women with ASC-US, with advanced CIN on biopsy (P < 0.0001), persistent CIN-I (993 +/- 262 ng/ml; P < 0.0001), pretherapy advanced CIN (1086 +/- 240; P < 0.0001), pretherapy cervical cancer patients (1746 +/- 318 ng/ml; P < 0.0001) and posttherapy persistent/recurrent CIN (1094 +/- 300; P < 0.0001); and cervical cancer (1395 +/- 189; P < 0.0001). After therapy, the IGF-II levels returned to normal in both CIN and cervical cancer patients under remission. Elevated serum IGF-II levels had 100% sensitivity and 87% specificity for cervical cancer and 81% sensitivity and 82% specificity for CIN. The levels of IGF-BP3 were significantly reduced in women with CIN before and after therapy (P < 0.0001) and in cervical cancer patients before and after therapy (P < 0.001). There was an inverse relationship between serum IGF-II and BP-3 levels (P < 0.01). Decreased serum IGF-BP3 levels had a sensitivity of 72% and specificity of 75% for cervical cancer and 81% sensitivity and 83% specificity for CIN. When both markers were considered together the sensitivity was 72% and specificity 84% for cervical cancer, while for CIN, the sensitivity was 57% and specificity 81%., Conclusion: Serum IGF-II may be a reliable marker for early diagnosis and monitoring therapy efficacy (sensitivity and specificity of 100% versus normal controls), while IGF-BP3 levels can be reliably used to predict prognosis.

Objectives: Our hypothesis is that insulin-like growth factor binding protein 3 (IGF-BP3) would downregulate epidermal growth factor receptor (EGF-R) levels in cervical cancer cell lines, thereby reducing cellular IGF-II and angiogenesis-related vascular endothelial cell growth factor (VEGF). As folate deficiency is a risk factor in cervical cancer, we sought to determine if folic acid treatment might increase IGF-BP3 production, thereby inhibiting malignant cell proliferation., Methods: We determined the cellular levels of EGF-R, IGF-II, and VEGF in the cervical cancer cell lines HeLa, ME-180 (both positive for human papilloma virus; HPV), and HT-3 (HPV-negative), following their treatment with IGF-BP3. Levels of IGF-BP3 in these cells before and after treatment with folic acid and VEGF were also enumerated, using a computerized semiquantitative immunofluorescent antibody assay., Results: Treatment with IGF-BP3 significantly reduced the levels (mean intensity per pixel) of EGF-R, IGF-II, and VEGF in all three cell lines and IGF-I receptor (IGF-IR) in representative ME-180 cell line. Treatment with antiproliferative folic acid increased IGF-BP3 levels while the proliferative VEGF depleted cellular IGF-BP3 in all the cell lines., Conclusions: Levels of EGF-R, IGF-II, IGF-IR, and VEGF are significantly reduced following treatment with IGF-BP3 in cervical cancer. We observed increased levels of IGF-BP3 by folic acid, and decreased IGF-BP3 levels by VEGF. Downregulation of EGF-R by IGF-BP3 suggests an IGF-independent action. Folate deficiency is a risk factor in cervical cancer. Our results suggest that folic acid supplementation can lead to inhibition of cervical cancer cell growth by promoting increased IGF-BP3 levels.

Background: Insulin-like growth factor-1 (IGF-1) is known to play a role in ovarian follicular development augmenting the action of FSH. Low intrafollicular concentrations have been detected in women who respond poorly to gonadotrophins. This study addresses the relationship between serum IGF-1 levels following pituitary desensitization and ovarian response to gonadotrophin stimulation., Methods: This is a case-control study of 78 patients undergoing IVF-embryo transfer treatment. Thirty-nine strictly-defined poor responder patients requiring 50 or more ampoules (75 IU FSH) to reach oocyte retrieval were compared with 39 age-matched normal responders, requiring fewer than 50 ampoules. IGF-1 concentrations were determined by extraction radioimmunoassay on serum samples obtained after pituitary desensitization but prior to gonadotrophin stimulation., Results: Despite highly significant differences in measures of ovarian response between groups, the mean serum IGF-1 concentration was not statistically significantly different between poor and normal responders [(31.5 nmol/l [95% confidence interval (CI) 28.5-34.5] versus 34.5 nmol/l (95% CI 31.8-37.2)] respectively. No correlation between oocyte number or total gonadotrophin used and serum IGF-1 concentration was observed., Conclusion: Whilst IGF-1 influences ovarian follicular development this study suggests that serum IGF-1 does not predict ovarian response and does not differentiate between critically-defined poor and normal responders.

Problem: We have previously reported elevated serum levels of cervical human papilloma viral proteins E6 and E7 and serum insulin-like growth factor II (IGF-II) in women with cervical cancer and advanced cervical intraepithelial neoplasia. As most women with cervical cancer have elevated levels of serum IGF-II, we sought to determine whether the cervical cancer and lymph node biopsies from these women demonstrated increased production of IGF-II and whether this elevation was also present in ovarian and endometrial cancers., Method of Study: We used the semi-quantitative immunofluorescent antibody assay established in our laboratory to identify the levels of IGF-II in 21 cervical cancers (seven with matching lymph nodes), 18 benign cervical biopsies, 13 endometrial cancers, 15 benign endometrial biopsies, 5 ovarian cancers, and 15 benign ovarian biopsies., Results: The immunofluorescent IGF-II levels (relative intensity per pixel) were the highest in cervical cancers; they were significantly higher than in matched controls. IGF-II levels were not higher in ovarian cancers and only slightly elevated in endometrial cancers. The presence of IGF-II in pelvic lymph nodes of women with cervical cancer paralleled with those in the cervical cancers. Interestingly, we could identify small nests of metastases of malignant cells in the nodes (pauci-cellular metastasis) by using IGF-II as the marker., Conclusion: We propose that measurement and identification of IGF-II in the cervical biopsy may be a sensitive method of detecting cervical cancer and metastatic spread in the lymph nodes.

Aim: To investigate the effect of adrenalectomy (ADX) on the epididymidis of Sprague-Dawley rats., Methods: The histological, biochemical (cholesterol protein, zinc, copper, alkaline and acid phosphatase aryl sulphatase, lactic dehydrogenase and leucine amino peptidase) and hormonal (FSH, LH and testosterone) changes of caput and cauda epididymis in ADX rats were observed., Results: Organ wet weight, histological studies and morphometric measurements indicated a cellular degeneration in caput and cauda epididymis of ADX rats. Serum testosterone level was significantly lower in ADX than in sham-operated rats, while the serum FSH and LH were below the detection limit of 1 mIU/mL. The enzymatic activity was higher in ADX than in sham-operated rats. Epididymal zinc level increased whereas copper level decreased in ADX rats compared to the sham-operated., Conclusion: Adrenalectomy leads to degeneration of caput and cauda epididymidis epithelial cells as a result of decreased supply of testosterone.

Aim: To study the effects of adrenalectomy and hydrocortisone on the ventral prostate of SD rats., Methods: In adrenalectomised (ADX) and ADX + hydrocortisone (1, 2, or 4 mg) treated rats, the prostatic histology and the cholesterol, protein, zinc, and copper levels and the enzymic profile (acid phosphatase, alkaline phosphatase, aryl sulphatase, lactic dehydrogenase, and leucine aminopeptidase) in the prostatic tissue were determined; the serum hormonal profile (testosterone, FSH and LH) was also assayed., Results: Adrenalectomy caused a progressive degeneration in prostatic structure that was not reversed by hydrocortisone treatment. The serum testosterone were significantly lower in ADX than in sham operated rats and lower in ADX + hydrocortisone than in ADX-C rats (P < 0. 01). The serum FSH and LH were below the detection limit of 1 mIU/mL. The enzymatic activity was higher in ADX than in sham operated rats and higher in ADX + hydrocortisone than in ADX-C rats (P < 0.05-0.01). The prostatic zinc levels were significantly higher in sham operated than in ADX, and higher in ADX-C than in ADX + hydrocortisone rats (P < 0.05-0.01). The prostatic copper level was significantly lower in sham operated than in ADX, and lower in ADX-C than in the ADX + hydrocortisone rats (P < 0.01)., Conclusion: In rats, adrenalectomy leads to pathological and functional changes of the prostate. Hydrocortisone treatment at the doses employed did not reverse these changes.

Background: About 90% of cervical cancers and advanced cervical intraepithelial neoplasia (CIN II/III) are squamous epithelial cells with mRNA for human papillomavirus (HPV)16 and 18 and up-regulated epidermal growth factor receptor (EGF-R). Since presence of proteins rather than mRNA may be truly indicative of active infection or disease progression, establishing reliable methods for quantifying these proteins in cervical biopsies is important., Method: We have established an objective semi-quantitative immunofluorescent antibody assay to reliably assess the levels of HPV-E6/E7 and EGF-R proteins in the cervical biopsies from 12 normal women, five women with CIN I, 15 with CIN II/III and ten with cervical cancer., Results: HPV-E6/E7 and EGF-R, when present, were specific to para-basal, basal and squamous epithelial cells (negative in stromal cells). Nine of ten women with cervical cancer and 15 (14 CIN II/III; 1 CIN I) of 20 women with CIN were positive for HPV-E6/E7. All 12 controls were HPV-negative. The controls and six women with CIN (four with CIN I) negative for HPV had low levels of EGF-R. The only exception was one woman with cervical cancer negative for HPV, with high levels of EGF-R. Levels of HPV-E6/E7 and EGF-R were significantly higher (P < 0.001 vs. controls) in women with advanced CIN II and III (P< 0.05 vs. controls in CIN I) and cervical cancer. The HPV-E6/E7 and EGF-R levels correlated significantly (r = 18.98; P < 0.001, by linear regression analysis)., Conclusion: We have established a highly specific and sensitive semi-quantitative immunofluorescent antibody assay for measuring levels of HPV-E6/E7 proteins and EGF-R in archival cervical biopsies. Our data suggest an association between HPV-E6/E7 and EGF-R.

Problem: To ascertain if cervical epithelial epidermal growth factor receptor (EGF-R) and serum insulin-like growth factor II (IGF-II) levels are potential markers for cervical cancer., Method of Study: We tested cervical biopsies obtained from 18 controls, 3 women with cervical intraepithelial neoplasia (CIN) I, 17 women with CIN II and III, and 12 women with cervical cancer for EGF-R using a quantitative immunofluorescent antibody assay. We measured serum IGF-II levels using an enzyme-linked immunosorbent assay in 20 controls, 26 CIN patients, 12 with cervical cancer before therapy, 5 with cervical cancer for < 1 year, and 9 others > 1 year after therapy., Results: The levels of cervical EGF-R in women with CIN and cervical cancer were significantly higher (P<0.05 for CIN I; P<0.001 for patients with CIN II and III or cervical cancer) than in controls. Women with cervical cancer (P<0.001 vs. controls) or advanced CIN (P = 0.03) had elevated levels of serum IGF-II, while the women with CIN I had levels similar to controls. Women with cervical cancer in the post-therapy period had significantly lower serum IGF-II levels than the women with cervical cancer before therapy (P<0.001)., Conclusion: Cervical epithelial EGF-R and serum IGF-II levels may be used for the diagnosis and prognosis of cervical cancer.

Problem: Over-expression of epidermal growth factor-receptors (EGF-R) has been described in a variety of cancers, including cervical cancer. Nicotine may increase cellular proliferation rates through a mechanism involving EGF or EGF-R. In this study, we ascertain the effect of EGF antibodies on nicotine-enhanced proliferation rates in two cervical cancer cell lines., Method of Study: We studied (a) nicotine-induced increase in the cellular expression of EGF-R in human papillomavirus (HPV)-positive ME-180 and HPV-negative HT-3 cervical cancer cell line cultures, using a semi-quantitative immunofluorescent antibody assay; (b) alterations in cellular proliferation in association with changes in EGF-R levels; and (c) the EGF-R mediation by EGF., Results: Nicotine exposure at physiologically attainable plasma concentrations caused increased expression of EGF-R in both cervical cancer cell lines. Up-regulation of EGF-R was associated with increased cellular proliferation. Decreased expression of EGF-R was associated with decreased cellular proliferation. These data were consistent with EGF-R expression as a mechanism for the control of proliferation of the cervical cancer cells. The action of nicotine was abrogated when antibodies to EGF were added, implying that nicotine up-regulation of EGF-R may be mediated by EGF., Conclusions: Our data show that nicotine-induced proliferation of cervical cancer cells is mediated through EGF-R over-expression and that this action of nicotine utilizes EGF.

Objective: To compare patient and cycle characteristics among three study groups: early ovarian hyperstimulation syndrome (OHSS), late OHSS, and non-OHSS., Design: Prospective observational study., Setting: University assisted conception service., Patient(s): Women undergoing in vitro fertilization, intracytoplasmic sperm injection or gamete intrafallopian transfer treatment at Bristol University In Vitro Fertilization Service between January 1, 1995, and December 31, 1998., Intervention: None., Main Outcome Measure(s): Patient age, prevalence of polycystic ovaries, gonadotropin requirement, peak serum estradiol (E(2)) concentration, number of oocytes retrieved, clinical pregnancy rate, number of gestation sacs, and severity of OHSS., Result(s): Women with early OHSS had significantly higher serum E(2) levels and lower gonadotropin requirements than did the other groups. Cycles with either early or late OHSS had significantly more oocytes collected than those without OHSS. Serum E(2) and oocyte numbers did not accurately predict the risk of developing late OHSS. Clinical pregnancies occurred in all cycles with late OHSS, and multiple pregnancies were significantly more frequent in the late OHSS group than in the other groups. Late OHSS was more likely than early OHSS to be severe., Conclusion(s): Early OHSS relates to "excessive" preovulatory response to stimulation, whereas late OHSS depends on the occurrence of pregnancy, is likelier to be severe, and is only poorly related to preovulatory events.

Objective: To further elucidate cortisol metabolism in the follicular microenvironment at the time of oocyte retrieval, the presence of 11beta-hydroxysteroid dehydrogenase (HSD) messenger (m)RNA transcripts in oocytes; cumulus cells; granulosa cells; and CD45(+), CD15(+) leukocytes was assessed semiquantitatively., Design: Controlled study using semiquantitative assessment of 11beta-HSD mRNA., Setting: University IVF center., Patient(s): Twenty-six patients undergoing controlled ovarian hyperstimulation for assisted conception., Intervention(s): Metaphase II oocytes; cumulus cells; granulosa cells, and CD45(+), CD15(+) leukocytes from individual follicular fluid aspirates., Main Outcome Measures: Semiquantitative analysis of PCR products after total RNA extraction and complementary DNA synthesis., Result(s): Periovulatory human oocytes; cumulus cells; CD45(+), CD15(+) leukocytes; and granulosa cells consistently express type 1 but not type 2 11beta-HSD mRNA. Expression of mRNA is greatest in cumulus cells. Type 1 11beta-HSD mRNA expression varies considerably in all cell types and among individual follicles and patients., Conclusion(s): These studies of mRNA expression suggest that the enzymes present both in and around the periovulatory oocyte will favor a high-cortisol environment.

The objective of this study is to evaluate the effect of chronic hemodialysis on serum progesterone level in pregnancy. Serum progesterone levels were measured predialysis and postdialysis using the radioimmunoassay technique in seven gravid women with renal failure requiring hemodialysis. Uterine contractions were measured before and after hemodialysis using home uterine activity monitoring (HUAM) in two patients. Thirty-three paired serum samples were obtained between 14 and 39 weeks' gestation. The mean change in serum progesterone level postdialysis throughout pregnancy ranged from -52.0% to +8.7% for each individual patient. The change in serum progesterone level was unrelated to gestational age. The woman experiencing the most significant decrease in serum progesterone level with dialysis continued her pregnancy to greater than 39 weeks. No significant increase in uterine contraction frequency was noted on HUAM postdialysis (P = 0.22), although both monitored patients experienced a small increase in serum progesterone levels. In conclusion, serum progesterone values showed a variable patient-specific response when measured predialysis and postdialysis in pregnancies complicated by renal failure. There was no significant increase in uterine activity noted postdialysis. Progesterone withdrawal does not appear to explain the increased frequency of preterm delivery in women after dialysis.

We discuss a patient with sarcoidosis presenting with cranial neuropathy and a cerebral mass lesion evident on imaging. Also, we review from the literature six patients with sarcoidosis presenting with cerebral mass lesion. We emphasize the diagnostic role of Mantoux test site biopsy in patients with dominant or isolated neurologic presentation because the involved sites are not easily accessible and Kveim's test antigen is not commercially available.

Administration of glucocorticoid (1, 2 and 4 mg) in excess leads to degeneration of epididymides as supported by cellular degeneration, sperm density and morphometric measurements. Zinc level increased statistically after 1, 2 and 4 mg hydrocortisone treatment while copper increased after 1 and 2 mg treatment. Cholesterol, protein and leucine aminopeptidase levels increased and decreased significantly in caput and cauda respectively. Activity of alkaline phosphatase reduced significantly while the treatment of hydrocortisone at different doses elevated acid phosphatase, aryl sulphatase and lactate dehydrogenase activities. Evidently, these changes are as a result of onset of cellular degeneration leading to impairment of metabolic/secretory activity of epididymal cells. The possible involvement of pituitary-testis axis in hydrocortisone induced epididymal degeneration and functional inhibition has been discussed.

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphoryl-choline) (PAF) is a potent signaling phospholipid which has pleiotropic biological properties in addition to platelet activation. PAF has been detected in the spermatozoa in a number of species. The concentration of PAF is inversely related to human spermatozoa quality. There are no reports on the presence of PAF in nonhuman primate spermatozoa. Therefore, the primary objective of this study was to determine if PAF is present in the spermatozoa from the squirrel monkey (which is a seasonal breeder). A second objective was to determine if PAF levels change from the breeding to the nonbreeding season. Endogenous lipids were extracted from mature Bolivian squirrel monkeys (Saimiri boliviensis) spermatozoa and assayed for the presence of PAF by [125I] radioimmunoassay. PAF was detected in all samples assayed. PAF levels were significantly higher (P < 0.01) during the breeding season (mean: 3.58 ng/10(6) spermatozoa) than the nonbreeding season (mean: 0.76 ng/10(6) spermatozoa). The data demonstrate that PAF is present in squirrel monkey spermatozoa, with higher levels found during the breeding season. Additional studies are warranted to elucidate the role of PAF in spermatozoa function.

This review examines recent evidence suggesting a role for the immune system, in particular cytokines, in the pathogenesis of ovarian hyperstimulation syndrome (OHSS). Ovarian tissue is known to contain cells capable of producing a range of immunological mediators and the concentrations of these have been shown to be elevated in serum and ascitic fluid from women with established OHSS. Available evidence points to a role for vascular endothelial growth factor and interleukin-2, possibly acting through other intermediary cytokines, in the pathogenesis of OHSS. However, each individual has a unique cytokine profile and several cytokines may share biological actions, making it difficult to interpret data on isolated cytokine concentrations from relatively small numbers of patients. Improved understanding of the role of the immune system in the development of OHSS may have implications for the prediction, prevention and management of this iatrogenic condition.

Results were collected from 11 studies comparing intrauterine insemination (IUI) with intracervical insemination (ICI) of frozen donor semen, 10 studies comparing IUI with timed natural intercourse (NI) or ICI in couples with semen defects and seven studies comparing ICI with NI or ICI in couples with unexplained infertility. IUI significantly increased the pregnancy rate relative to favourably timed ICI in donor insemination (DI) with frozen semen both with and without gonadotrophin stimulation of the female partner (odds ratios (95% confidence interval) 1.92 (1.02-3.61) and 2.63 (1.52-4.54) respectively). The benefit of IUI tended to be less when the pregnancy rate for ICI was high and IUI had no benefit with fresh donor semen. Overall IUI was of significant benefit in the male factor couples compared with NI-ICI (odds ratio 2.20 (1.43-3.39) and the advantage appeared to be maintained when comparison was confined to properly timed ICI although the odds ratios were not significantly greater than 1. IUI had no benefit relative to favourably timed NI-ICI for couples with unexplained infertility; an apparent advantage overall was produced by studies where NI was late. None of the studies on male factor used a sperm function test to define male subfertility and three only included couples with good mucus penetration by sperm. The range of semen defects defined was such that many couples would have had a good chance of conceiving naturally given a normal female partner but nevertheless the overall pregnancy rate (4.8%) was considerably less than in the unexplained group (11.6%), suggesting that some sperm dysfunction was present. We conclude that the available evidence suggests that IUI is valuable for DI with cryopreserved semen and for couples with mild to moderately impaired semen quality and postulate that it overcomes failure to fertilize due to impaired mucus penetration and poor survival in the female reproductive tract.

Thromboxane A2 (TXA2) has been implicated as an important mediator of cardiovascular diseases. Aortas obtained from male rats are more sensitive to TXA2 mimetics compared with those obtained from females. A similar phenomenon has been reported in canine coronary arteries. To determine whether there is a gender-related difference in the regulation of TXA2 receptors by androgenic steroids, we determined the effect of testosterone and dihydrotestosterone (DHT) on TXA2 receptor density in cultured rat aortic smooth-muscle (RASM) cells and guinea pig coronary artery smooth-muscle (CASM) cells. TXA2 receptor density (B(max)) and dissociation constant (Kd) were determined by radioligand binding studies with (125)I-BOP, a TXA2 receptor agonist. Testosterone significantly (p < 0.05) increased TXA2 receptor density in cultured RASM cells and guinea pig CASM cells. DHT significantly (p < 0.005) increased the B(max) in male RASM cells (62 +/- 2 vs. 40 +/- 3 fmol/mg protein; n = 7; p < 0.005). DHT increased the B(max) values in both male and female RASM cells, but the increase was significantly (p < 0.05) less in female than in male RASM cells (57 +/- 10% increase for male and 31 +/- 5% for female). Androgen-receptor protein was detected in RASM cells by Western blot and was less in the female RASM cells than in the male. The results indicate that RASM cells possess an androgen receptor and that gender-related differences exist in the regulation of expression of TXA2 receptors by androgens.

Testosterone has been implicated as a risk factor for cardiovascular diseases and thromboxane A2 (TXA2) may be an important pathophysiologic mediator for them. Testosterone has been shown to increase TXA2 receptor density in several cell types. Testosterone is reduced at the 5 alpha position to its active metabolite, dihydrotestosterone, by 5 alpha-reductase. We determined the effects of epristeride, a 5 alpha-reductase inhibitor, on the density of TXA2 receptors in rat aortic smooth muscle cells and human erythroleukemia cells, a megakaryocyte-like cell, in vitro, and in rat platelets and aortic membranes in vivo. In rat aortic smooth muscle cells, epristeride significantly (P < .01, n = 5) blocked the effect of testosterone to increase TXA2 receptor density (Bmax: 44 +/- 3, 76 +/- 7, 48 +/- 4 and 46 +/- 4 fmol/mg protein, for control cells, cells treated with testosterone (200 nM), cells treated with testosterone and epristeride (10 nM) and cells treated with epristeride, respectively. Epristeride did not block the effect of testosterone in human erythroleukemia cells. Treatment of male rats with epristeride for 2 weeks significantly (P < .01) decreased TXA2 receptor density in aortic membranes (41 +/- 3 for vehicle, n = 10; 27 +/- 3 fmol/mg protein for epristeride, n = 11) but did not significantly change TXA2 receptor density in platelets. Maximum contractile responses of rat aortas to U46619, a TXA2 mimetic, were significantly (P < .001) lower in epristeride-treated rats than in vehicle-treated rats (4.2 +/- 0.1 for vehicle, n = 16, 3.0 +/- 0.2 g tension for epristeride, n = 15). In conclusion, regulation of expression of TXA2 receptors by testosterone in cells of vascular origin, but not in platelets, appears to be via DHT.

Previous studies have demonstrated an increased thromboxane A2 (TXA2) receptor expression in human erythroleukemia (HEL) cells and rat aortic smooth muscle (RASM) cells in response to testosterone treatment. HEL cells have served as a model for megakaryocytes, the progenitor cell for platelets. Platelets have previously been shown to convert androstenedione to testosterone. This study investigated the effects of androstenedione on the TXA2 receptor density in HEL and cultured RASM cells. Both cell lines were incubated with vehicle, 150 nM testosterone or 250, 500 or 750nM androstenedione for 48 hours. Co-incubation with testosterone or androstenedione significantly (p<0.05) increased the maximum number of TXA2 binding sites (Bmax) in HEL cells compared to controls. There was no significant change in Kd values. In a separate series of experiments, HEL cells were incubated with the androgen receptor antagonist hydroxyflutamide (2.5mM). Treatment with androstenedione (500nM) significantly (p<0.05) increased the Bmax value by 35% compared to control and hydroxyflutamide completely antagonized this effect of androstenedione. Incubation with hydroxyflutamide alone had no effect on the Bmax values compared to control. RASM cells also showed an increase in Bmax values by 25% and 23% over control (95+/-6.6, 118+/-7.2 and 117+/-5.1 fmoles/mg protein, control, testosterone and androstenedione, n=3). Both cell lines converted androstenedione to testosterone. The results raise the possibility that the adrenal androgen, androstenedione can regulate the expression of TXA2 receptors either on its own or via conversion to testosterone and through an androgen receptor.

Degenerative changes such as decreased seminiferous tubule diameter, Leydig cell nuclear diameter, spermatogenic arrest, oedematous fluid in the interstitium and lumen of seminiferous tubules and increased levels of zinc, copper and enzymes (lactate dehydrogenase, LDH; leucine aminopeptidase, LAP; and aryl sulphatase) in adrenalectomised rats suggest a possible role of adrenal cortex and its hormones in spermatogonial cell proliferation and subsequent differentiation, homeostasis of biological trace elements and behaviour of enzymes. Atrophy of Leydig cells and the degenerative changes in testes of adrenalectomised rats can be attributed to reduced supply of testosterone. Hydrocortisone, administered through a single dose acted as hyperstate of hydrocortisone for a short duration, thereby inhibiting steroidogenesis either directly by affecting Leydig cell testosterone production or indirectly by affecting the release of LH from pituitary gland and thus caused degeneration of germinal epithelium. Once hydrocortisone (half life < 12 hr) was metabolized, the animals returned to adrenalectomised state, the degeneration persisted. Thus, hydrocortisone administered through a single dose was insufficient to sustain spermatogenesis. Chronic administration at physiological dose may renew spermatogenesis. Increased levels of LDH, LAP and arylsulphatase are, probably, necessary for cellular degeneration. Zinc and copper exhibited an increase and the rise can be corroborated to (1) failure of regulatory mechanism(s) that control the flow of the elements across the blood-testes barrier; and (2) increased oedematous fluid formed by cellular deaths of the germinal epithelium.

Background: In normal subjects treadmill exercise usually produces the greatest maximal oxygen consumption (VO2max). This may not be true for patients with severe chronic obstructive pulmonary disease (COPD) in whom bicycle exercise, which offers support for the shoulder girdle, may produce a higher oxygen consumption than treadmill exercise. The aim of this study was to determine which mode of exercise produced the greatest oxygen consumption in patients with severe COPD., Methods: Eight patients with severe COPD (forced expiratory volume in one second (FEV1) more than three standardised residuals below predicted) exercised to a symptom limited maximum on a bicycle and on a treadmill on separate days. The workload on the bicycle wa increased by 10 watts each minute, and the treadmill gradient was increased by 2.5% alternate minutes whilst the speed remained constant. Measurements of oxygen consumption (VO2), ventilation (VE), heart rate, and oxygen saturation were made, and capillary blood gases were measured before and immediately after exercise. Lactate concentration was measured before and four minutes after exercise., Results: There were no differences at peak exercise between the two forms of exercise for VO2 (median 11.7 and 12.2 ml/min/kg for bicycle and treadmill, respectively), for VE (median 26.6 and 25.0 l/min, respectively), and for heart rate (median 119 and 115 beats/min, respectively). The median lactate levels after bicycle exercise were higher than those after the treadmill (2.42 v 0.94 mmol/l)., Conclusions: Although only a small number of patients was studied and individual variability was large, there was no clear difference between the two forms of exercise. Regular bicycle exercise was unfamiliar to this group of patients and generated the greatest lactate response. The results do not support the hypothesis that bicycle exercise will produce a better performance in patients with severe COPD, but the two modes of exercise cannot be used interchangeably.

Unlabelled: PURPOSE AND STUDY PLAN: Men who are habitual smokers tend to have poor semen quality. We studied the effect of nicotine on sperm motility in vitro. Spermatozoa from 13 normal fertile nonsmoking donors, washed free of seminal plasma, were treated with medium alone (control); and, 10 mM, 5 mM, 1 mM and 0.1 mM nicotine (concentrations estimated to approximate residual concentrations of nicotine in the testes of heavy smokers). Computerized sperm motion analysis (CASA) was done at 2, 4, 6 and 24 h after incubation., Results: Sperm motility, beat/cross frequency, linearity and maximum anterior lateral head displacement (ALH max.) were significantly decreased across nominal dosages (P < 0.001 by repeated measures analysis of variance). Of the concentrations tested, 0.1 mM had no effect; 1 mM significantly decreased sperm motility (P = 0.003) and linearity (P = 0.02); 5 mM decreased the beat frequency (P = 0.001) and linearity (0.02); and 10 mM markedly decreased motility (P = 0.0001), beat frequency (P = 0.0002), linearity (P = 0.02) and ALH max. (P = 0.02). The interactions between dose and time were insignificant., Conclusion: Nicotine at concentrations of > or = 1 mM significantly decreased sperm motion characteristics after different periods of incubation, whereas 0.1 mM concentration had the least effect.

Thromboxane A2 (TXA2) has been implicated as an important mediator of cardiovascular diseases, and male rat aortas are reported to be more sensitive to it than female aortas. The effects of sex steroids to regulate the expression of TXA2 receptors in cultured male rat aortic smooth muscle cells (RASMC) were determined. TXA2 receptor density (Bmax) and affinity (Kd) were determined via radioligand binding studies with [125I]BOP, a TXA2 receptor agonist. Testosterone increased Bmax in a concentration-dependent manner without any significant change in Kd. Cycloheximide, actinomycin D, and the 5 alpha-reductase inhibitor L645,390 significantly (P < 0.01) blocked the effect of testosterone. Dihydrotestosterone, the active metabolite of testosterone, increased Bmax and was more potent than testosterone. To determine if there is a sex-related difference in response to testosterone, its effect in cultured female RASMC was assessed. Testosterone increased Bmax in female RASMC but the increase was significantly (P < 0.001) less than that seen in male RASMC. These results indicate that androgenic steroids regulate the expression of vascular TXA2 receptors.