Biomedical subjects
Publications and source records attributed to S Green.
Platelet counts have been noted to be low in patients treated with high-oil diet therapy for adrenoleukodystrophy. We suggest that some of these observations are spurious but that others reflect a true thrombocytopenia. Visual platelet counts are recommended.
Peroxisome proliferators are a diverse group of rodent hepatocarcinogens that include hypolipidemic drugs, plasticizers and herbicides. These compounds when administered to rats and mice produce a dramatic increase in the size and number of hepatic peroxisomes and increase the capacity of the hepatocyte to metabolise fatty acids by inducing peroxisomal beta-oxidation enzymes such as acyl CoA oxidase. Members of the steroid hormone receptor superfamily of ligand-activated transcription factors have been identified that can be activated by peroxisome proliferators and are therefore called 'peroxisome proliferator activated receptors' (PPAR). There appear to be four PPAR isoforms within vertebrates termed alpha, beta, gamma and delta and the alpha isoform appears to be the one that is most strongly activated by synthetic peroxisome proliferators such as Wy-14,643. It has been demonstrated that PPAR alpha forms a heterodimer with the retinoid X receptor (RXR) and binds to specific DNA sequences located upstream of peroxisome proliferator responsive genes. It is therefore suggested that PPARs mediate the pleiotropic effects of peroxisome proliferators including the regulation of gene expression and rodent hepatocarcinogenesis. Rodents fed a high-fat diet develop peroxisome proliferation and many of the enzymes induced by peroxisome proliferators are involved in fatty acid metabolism. Furthermore, PPARs are activated by a wide range of fatty acids and hypolipidemic drugs, such as clofibrate, that lower triglyceride levels in man. Although it remains to be determined whether fatty acids and peroxisome proliferators bind directly to any PPAR these data suggest that the natural role of PPARs in man is to regulate lipid homeostasis. Interestingly, hypolipidaemic drugs fail to elicit peroxisome proliferation in human hepatocytes although hypolipidaemic effects are observed in patients. A further understanding of the role of PPAR in man will require: (1) the identification of additional human PPARs combined with functional analyses using these and other nuclear receptors that can antagonise PPAR action; (2) a comparison of the expression of these different receptors in human tissues; (3) a clearer understanding of how peroxisome proliferators and fatty acids activate PPAR; and (4) sequence analysis of the regulatory regions in the human counterparts of rodent peroxisome proliferator responsive genes. Together, these data will provide an important mechanism-based framework to assess the hazard of peroxisome proliferators to humans.
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High concentrations of nitrite present in saliva (derived from dietary nitrate) may, upon acidification, generate nitrogen oxides in the stomach in sufficient amounts to provide protection from swallowed pathogens. We now show that, in the rat, reduction of nitrate to nitrite is confined to a specialized area on the posterior surface of the tongue, which is heavily colonized by bacteria, and that nitrate reduction is absent in germ-free rats. We also show that in humans increased salivary nitrite production resulting from nitrate intake enhances oral nitric oxide production. We propose that the salivary generation of nitrite is accomplished by a symbiotic relationship involving nitrate-reducing bacteria on the tongue surface, which is designed to provide host defence against microbial pathogens in the mouth and lower gut. These results provide further evidence for beneficial effects of dietary nitrate.
This paper reports on the use of vignettes to study drug injectors' preparedness to share injecting equipment. Separate vignettes referring to borrowing and passing on injecting equipment have been submitted to 505 injecting drug users in Glasgow. Injectors were asked to identify their own likely response in each of the situations described within the vignettes. It was shown that even among those injectors not reporting any actual sharing in the last 6 months a significant proportion would still be prepared to share injecting equipment within certain situations. The preparedness to share injecting equipment was seen to be influenced by such factors as social distance, sex and length of time injecting. It is suggested that even in situations where drug injectors may have modified their behaviour in the direction of lower levels of reported sharing, a propensity to share may remain. This suggests the continuing need to provide injectors with easy access to sterile injecting equipment; in addition, services working with injecting drug users may need to focus not only upon actual sharing behaviour but also upon what we have described here as the preparedness to share. Indeed, the latter dimension should stand as a warning to services of the potential for sharing injecting equipment to increase in the future.
The use of high insemination concentration (HIC) for in vitro fertilization (IVF) was compared with intracytoplasmic sperm injection (ICSI) in cases of male factor infertility. Sibling oocytes (n = 252) from 24 patients were used, 123 for HIC and 129 for ICSI. Although the incidence of fertilization was decreased with HIC (48% v. 61%), this treatment was nevertheless a viable option for many patients, especially when ICSI was not available. However, there was a higher incidence of cytoplasmic fragmentation of embryos after HIC compared with ICSI (36% v. 10%, P = 0.003) and the outcome was significantly affected by the severity of teratozoospermia. Using a cut-off of 5% normal forms, the incidence of fertilization with HIC for the group with < 5% normal forms was 37% compared with 72% for the group with > 5% normal forms; there was also a significant decrease in cleavage rate (P = 0.05) and the number of regular embryos (P = 0.005), and an increase in cytoplasmic fragmentation (P = 0.006) in patients with < 5% normal forms. No distinction was made between cases of teratozoospermia when ICSI was used. The present study confirms the value of HIC as a first line treatment for male infertility, as long as ICSI remains significantly more expensive and concerns on safety are mooted. However, the use of sibling oocytes for ICSI is recommended, especially in cases with < 5% normal sperm morphology.
Utilizing real-time computer image analysis, individual spermatozoa were selected using microaspiration. Selection criteria were based on potential hyperactivation motility characteristics; the amplitude of lateral head displacement > 7.5 microns, curvilinear velocity > 70 microns/s and linearity of < 30%. For this pilot study, 16 patients (eight in each group) were recruited. Using subzonal insemination (SUZI), up to five (mean = 4.4 +/- 0.3) spermatozoa selected using computer-image sperm selection (CISS) were micro-injected, or up to 15 (mean = 12.8 +/- 1.3 SD) unselected spermatozoa. In the group which utilized CISS, 28 out of 49 (57%) oocytes were fertilized compared with 13 out of 52 (25%) utilizing conventional SUZI (P < 0.04); polyspermy was 20% (n = 10) and 2% (n = 1) respectively. CISS with SUZI showed increased efficiency in achieving fertilization and is a novel approach to studying individual sperm function in a sperm egg bioassay where gamete ratios are close to unity.
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The purpose of this study was to investigate firstly whether beta 1-integrin cell adhesion molecules are expressed by human spermatozoa, and secondly whether there is any relationship between the expression of beta 1-integrin cell adhesion molecules and the fertilizing ability of human spermatozoa in vitro. A total of 50 semen samples were examined. The samples were obtained from the male partners of couples undergoing in-vitro fertilization (IVF) for either unexplained, tubal or male factor infertility. A panel of six monoclonal antibodies against beta 1-integrin cell adhesion molecules and immunohistochemical techniques were used to identify the presence of these molecules on the spermatozoa. The percentage of spermatozoa showing strong immunolabelling with each monoclonal antibody was assessed in each sample. The relationship between these results and the aetiology of infertility and incidence of fertilization was examined. beta 1-Integrins, and primarily the ones with alpha 4-, alpha 5- and alpha 6-chains, were expressed by human spermatozoa. Compared with semen samples from unexplained or male factor infertility patients, samples from tubal infertility patients had a significantly higher (P < 0.05) percentage of spermatozoa expressing adhesion molecules. There was a positive correlation between the expression of alpha 4, alpha 5 and alpha 6 adhesion molecules and the fertilizing ability of spermatozoa. The positive correlation between the presence of certain beta 1-integrin cell adhesion molecules and the fertilizing ability of human spermatozoa suggests that integrins may be putative determinants in egg-sperm recognition and interaction.
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1. Validation of in vitro systems for studying neurotoxicants generally has not been accomplished, although in vitro tests have been used as screens to identify potential neurotoxic hazards and to study mechanisms. 2. A number of factors need to be taken into account when a test is validated: (i) a rationale for developing the test; (ii) clear biological or pathophysiological relevance of the endpoint to the effect detected in vivo; (iii) a standardized protocol and evidence of intra- and interlaboratory reproducibility; (iv) testing of chemicals representative of the categories of interest, including very toxic, moderately toxic and relatively non-toxic substances; and (v) a method to statistically evaluate the data. 3. Proper validation should lead to methods which can be used by regulatory agencies to make decisions regarding hazard/risk.
A number of neurotransmitters modulate cardiac dihydropyridine-sensitive L-type Ca2+ channels through several homologous G protein-coupled receptors. Previous studies that have examined receptor-Ca2+ channel interactions have suffered because of the coexpression of various receptor subtypes in native cells. To study the functional coupling of a particular receptor subtype to these channels, rabbit cardiac Ca2+ channel alpha 1 and skeletal beta and alpha 2/delta subunits were stably expressed in baby hamster kidney cells. In this stable cell line, Ca2+ channels remained at high levels (> 1000 fmol/mg protein, or 2700 channels per cell) over extended times. The expressed recombinant Ca2+ channels displayed the voltage dependence of activation and inactivation, unitary conductance, and pharmacology characteristic of native cardiac L-type Ca2+ channels. Subsequent coexpression of the beta 1-adrenoceptors (150 to 300 fmol/mg protein) with the Ca2+ channels resulted in cell responsiveness to the extracellular application of isoproterenol. These results indicate that heterogeneous expression in mammalian cells provides a useful system for studying both biophysical analysis of Ca2+ channel properties and receptor-coupled regulatory processes.
PURPOSE: To compare 1 year of therapy with continuous cyclophosphamide, methotrexate, fluorouracil (5-FU), vincristine, and prednisone (CMFVP) with a short course of treatment with a doxorubicin-based regimen in the postsurgical adjuvant treatment of patients with hormone receptor-negative, node-positive breast cancer. PATIENTS AND METHODS: Five-hundred thirty-one eligible women with hormone receptor-negative, node-positive breast cancer were randomized to receive either 1 year of therapy with CMFVP or 20 weeks of therapy with four 5-week courses of treatment with 5-FU, doxorubicin, cyclophosphamide, and methotrexate (FAC-M). RESULTS: At a median follow-up time of 4.9 years, the two treatment arms cannot be demonstrated to be different with respect to overall survival (stratified log-rank, P = .27). The 5-year survival rate is 64% on the CMFVP arm and 61% on the FAC-M arm. CMFVP produces marginally superior disease-free survival (P = .06). The estimated 5-year disease-free survival rate is 55% for patients treated with CMFVP as opposed to 50% for patients treated with FAC-M. CONCLUSION: Neither regimen was shown to be superior in terms of overall survival. Because the disease-free survival produced by CMFVP is marginally superior to that produced by FAC-M, we do not recommend FAC-M for further investigation or for routine use. Possible implications of this study are discussed in the context of other adjuvant chemotherapy trials.
The development of simple, noninvasive tests of work capacities, underpinned primarily by anaerobic metabolism, proliferated in the early 1970s. A 30-second maximal cycle test developed at the Wingate Institute initiated efforts to develop work tests of anaerobic capacities. Such tests can be developed using any ergometer which simulates competitive conditions and enables an accurate determination of mechanical work output. A 10-second all-out test is commonly used to measure maximal work output generated primarily via the hydrolysis of high-energy phosphagens (i.e. the alactic work capacity). In contrast, a variety of constant-load and all-out tests of anaerobic (alactic plus lactic) work capacity have been proposed. It has been suggested that all-out tests provide more information about physiological capabilities and are easier to apply than constant-load tests. The optimal duration for an all-out test of anaerobic work capacity is proposed at 30 seconds, a duration which may also provide the basis for the development of accurate field tests of anaerobic capacity. There is evidence that the y-intercept of the maximal work-derivation regression is a valid work estimate of anaerobic capacity in athletes, although its utility is undermined by the number of tests required for its derivation.
A patient with known prostatic cancer presented with bilateral orbital masses. On CT there was a bulky soft-tissue mass in the cranial aspect of each orbit. An open biopsy revealed undifferentiated tissue that stained strongly positive for prostatic-specific acid phosphatase, confirming the diagnosis of metastatic prostate carcinoma.
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Dengue virus infections are a major cause of morbidity and mortality in tropical and subtropical areas of the world. The immunopathological mechanisms that result in severe complications of dengue virus infection, i.e. dengue hemorrhagic fever (DHF), are important to determine. Primary dengue virus infections induce serotype-specific and serotype-cross-reactive, CD4+ and CD8+ memory cytotoxic T lymphocytes (CTL). In secondary infections with a virus of a different serotype from that which caused primary infections, the presence of cross-reactive non-neutralizing antibodies results in an increased number of infected monocytes by dengue virus--antibody complexes. This in turn results in marked activation of serotype cross-reactive CD4+ and CD8+ memory CTL. We hypothesize that the rapid release of cytokines and chemical mediators caused by T cell activation and by CTL-mediated lysis of dengue virus-infected monocytes triggers the plasma leakage and hemorrhage that occurs in DHF.