Biomedical subjects
S Cook
Publications and source records attributed to S Cook.
Taking environmental action: what you can do.
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Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype.
OBJECTIVE: To define the clinical spectrum of glucocorticoid-remediable aldosteronism (GRA) in a large kindred. DESIGN: Screening all at-risk relatives of a proband for GRA using a specific biochemical phenotype and collecting of medical histories of kindred members from five generations. SETTING: Outpatient General Clinical Research Centers and patients' homes. MEASUREMENTS: Screening was done while patients were on a self-selected diet and included blood pressure determinations; serum potassium and plasma renin activity and aldosterone measurements; and 24-hour urinary tetrahydroaldosterone, 18-oxotetrahydrocortisol, and 18-hydroxycortisol measurements. RESULTS: Diagnosis of GRA was established on the basis of a previously described specific biochemical abnormality, overproduction of the cortisol C-18 oxidation products (18-oxotetrahydrocortisol and 18-hydroxycortisol) in urine and their ratio relative to tetrahydroaldosterone. Glucocorticoid-remediable aldosteronism was diagnosed in 11 additional patients spanning three generations; this group included the youngest patient (3 months old) ever diagnosed with GRA. Complete penetrance of the biochemical abnormality is likely, with 11 of 18 at-risk patients displaying the phenotype. All patients with GRA had elevated blood pressure. Affected adult patients had been diagnosed as hypertensive before reaching 21 years of age (n = 7 mean, 16.1 +/- 3.4 years). All affected patients were normokalemic (4.3 +/- 0.3 mmol/L). CONCLUSION: Hypertension is a characteristic feature of GRA. Elevated blood pressure in this kindred developed at an early age and often was severe. Because a normal potassium level does not exclude the diagnosis of GRA, the disorder may be underdiagnosed. The value of a specific cortisol C-18 oxidation phenotype in the diagnosis of GRA has been confirmed.
A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension.
Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyperaldosteronism and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids. These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata. Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA. Here we demonstrate complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete linkage, odds ratio of 170,000:1). This mutation can account for all the physiological abnormalities of GRA. Our result represents the demonstration of a mutation causing hypertension in otherwise phenotypically normal animals or humans.
Impact of the Los Angeles County Trauma System on the survival of seriously injured patients.
We compared the survival of 658 seriously injured patients treated in Los Angeles County in the Fall of 1982 (prior to the activation of the trauma system) with that of 766 such patients treated in the Fall of 1984 (when the system was young and composed of essentially a full complement of trauma centers). We demonstrated a statistically significant improvement in the adjusted odds of survival for 1984 over 1982 with regard to victims of motor vehicle collisions who sustained multiple serious injuries (1980 Injury Severity Score: 26-50) (p = 0.042). For the data set as a whole, although an improvement in survivorship over this period was suggested by the data, statistical significance could not be demonstrated.
Immunosuppression by whole-body irradiation and its effect on oedema in experimental cerebral ischaemia.
The effect of global immunosuppression by sublethal whole body X-irradiation on the development of cerebral oedema was assessed 24 h after right middle cerebral artery occlusion in the rat. Irradiation produced a significant leukopenia and thrombocytopaenia, and significantly reduced cortical oedema when compared to non-irradiated control animals.
The effect of immunosuppression on the development of cerebral oedema in an experimental model of intracerebral haemorrhage: whole body and regional irradiation.
The oedema which forms around an intracerebral haemorrhage has a complex aetiology. The immune response may have a role in its formation. There is clinical and experimental evidence that circulating leucocytes and platelets may mediate oedema formation. Global depletion of circulating leucocytes and platelets by whole body irradiation in a rodent model of intracerebral haemorrhage was found to confer protection against both ischaemia and oedema formation. This was not a direct effect of irradiation of the brain. The possible mechanisms for this protection are discussed.
Advanced certificate programs.
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Nursing and midwifery research: making it happen.
The organisation of a series of research awareness workshops for nurses and midwives in the North East Thames Regional Health Authority is described. The workshops, which aim to 'demystify' nursing research for practitioners, are particularly pertinent in view of government and nursing drives to raise the profile of research. Evaluations from workshop participants have shown a high degree of satisfaction with content and presentation.
Formation of the perinuclear theca in spermatozoa of diverse mammalian species: relationship of the manchette and multiple band polypeptides.
The perinuclear theca is a novel cytoskeletal consisting of a densely layered lamina that surrounds the nucleus of mammalian sperm. Using antibodies specific for the multiple band polypeptides present in the perinuclear theca of bull sperm, we show that a heterogeneous group of immunological related proteins are present in the sperm heads of other mammals with greatly different morphologies, including guinea pig, hamster, rat, and mouse. In none of the species were identical groups of immunoreactive polypeptides found, although immunoreactive proteins of molecular weights 65,000 to 80,000 were present in the sperm heads of all species examined. Immunoreactive proteins less than Mr 55,000 were prominent in rat sperm heads and mouse sperm: guinea pig, hamster, and rat sperm heads and mouse sperm had one band in common at approximately Mr 50,000. Different immunoreactive proteins were present in isolated sperm tails. The perinuclear theca first appeared in the subacrosomal space of round to elongating spermatids. Later, with the caudal movement of the manchette, the postacrosomal segment of the perinuclear theca was deposited in a cephalad to caudal direction along the sperm nucleus. Concomitantly, the cytoplasmic space between the nuclear envelope and the plasma membrane narrowed such that only the theca occupied this portion of the sperm head. Immunoreactivity accompanied the ultrastructural appearance of the subacrosomal layer and the postacrosomal segment. The periods of spermiogenesis, in which sub- and post-acrosomal components of the perinuclear theca are formed and the morphogenesis of sperm organelles with which these elements are associated, suggest that components of this cytoskeletal structure function to join the acrosome and the postacrosomal plasma membrane to the nucleus.
Nascent protein requirement for completion of meiotic maturation and pronuclear development: examination of fertilized and A-23187-activated surf clam (Spisula solidissima) eggs.
The involvement of newly synthesized proteins and calcium in meiotic processes, sperm nuclear transformations, and pronuclear development was examined in emetine-treated, fertilized, and A-23187-activated Spisula eggs by observing changes in the morphogenesis of the maternal and paternal chromatin. Emetine treatment (50 micrograms/ml) initiated 30 min before fertilization or A-23187 activation inhibited incorporation of [3H]leucine into TCA-precipitable material and blocked second polar body formation. Sperm incorporation and the initial enlargement of the sperm nucleus were unaffected; however, the dramatic enlargement and transformation of the sperm nucleus into a male pronucleus, which normally follow polar body formation, were delayed 10 to 20 min. Unlike the situation in untreated, control eggs, male pronuclear development took place while the maternally derived chromosomes remained condensed. It was not until approximately 20 min after the normal period of pronuclear development that the maternal chromosomes dispersed and formed a female pronucleus in emetine-treated, fertilized eggs. Formation of pronuclei, however, was unaffected in both emetine-treated, A-23187-activated eggs and fertilized eggs incubated with A-23187. These observations indicate that germinal vesicle breakdown, first polar body formation, and initial transformations of the sperm nucleus are independent of newly synthesized proteins. Inhibition of second polar body formation and the delay in pronuclear development brought about by emetine, as well as the appearance of silver grains over pronuclei in autoradiographs of control eggs incubated with [3H]leucine demonstrate that nascent proteins are involved with the completion of meiotic maturation and the development of male and female pronuclei. The ability of A-23187 to override the inhibitory effects of emetine on pronuclear development suggests that both nascent protein and calcium signals are involved in regulating the status of the maternal and paternal chromatin during pronuclear development.
Pronuclear formation in starfish eggs inseminated at different stages of meiotic maturation: correlation of sperm nuclear transformations and activity of the maternal chromatin.
Changes in sperm nuclei incorporated into starfish, Asterina miniata, eggs inseminated at different stages of meiosis have been correlated with the progression of meiotic maturation. A single, uniform rate of sperm expansion characterized eggs inseminated at the completion of meiosis. In oocytes inseminated at metaphase I and II the sperm nucleus underwent an initial expansion at a rate comparable to that seen in eggs inseminated at the pronuclear stage. However, in oocytes inseminated at metaphase I, the sperm nucleus ceased expanding by meiosis II and condensed into chromosomes which persisted until the completion of meiotic maturation. Concomitant with the formation and expansion of the female pronucleus, sperm chromatin of oocytes inseminated at metaphase I enlarged and developed into male pronuclei. Condensation of the initially expanded sperm nucleus in oocytes inseminated at metaphase II was not observed. Instead, the enlarged sperm nucleus underwent a dramatic increase in expansion commensurate with that taking place with the maternal chromatin to form a female pronucleus. Fusion of the relatively large female pronucleus and a much smaller male pronucleus was observed in eggs fertilized at the completion of meiotic maturation. In oocytes inseminated at metaphase I and II, the male and female pronuclei, which were similar in size, migrated into juxtaposition, and as separate structures underwent prophase. The chromosomes in each pronucleus condensed, intermixed, and became aligned on the metaphase palate of the mitotic spindle in preparation for the first cleavage division. These observations demonstrate that the time of insemination with respect to the stage of meiotic maturation has a significant effect on sperm nuclear transformations and pronuclear morphogenesis.
Behavior-change strategies used by a sample of physicians for patients at risk of coronary problems.
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Successful percutaneous extraction of a chronic left ventricular pacing lead.
This report describes a patient with a chronic endocardial left ventricular pacing lead. To avoid the risk of future embolization, it was felt that the lead should be removed and right ventricular pacing established. The lead was carefully evaluated by transesophageal echocardiography to exclude adherent thrombus. Successful percutaneous lead extraction was accomplished without sequelae, thus avoiding the morbidity of a thoracotomy.
The effect of immunosuppression with whole body and regional irradiation on the development of cerebral oedema in a rat model of intracerebral haemorrhage.
A lesion simulating intracerebral haemorrhage was produced in the right caudate nucleus of rats immunosuppressed with whole body or regional irradiation. Whole body irradiation produced significant leucopaenia and thrombocytopaenia and conferred protection against cerebral ischaemia and oedema when compared to nonirradiated control animals. Local radiation to the head or torso did not confer protection.
Changes in blood lipids and lipoproteins in chronic alcoholics during alcohol withdrawal.
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Characterization of an acrosomal matrix protein in hamster and bovine spermatids and spermatozoa.
Experiments have been carried out characterizing an Mr 22,000 protein present in the acrosomes of hamster and bull spermatozoa. The Mr 22,000 protein is resistant to solubilization in detergent solutions containing high or low salt and has a pI of -5.2. With various lectins, the protein from hamster sperm was shown to be sparingly glycosylated with N-acetylglucosamine, mannose, and galactose while that from the bull demonstrated a slight reactivity for galactose. Using a specific monoclonal antibody (MAB 4/18), the Mr 22,000 polypeptide has been localized exclusively to the acrosomes of mature testicular and epididymal hamster and bovine sperm. Acrosomal components of differentiating bovine and hamster spermatids in tissue sections did not react with the monoclonal antibody, although the protein was present in immunoblots of round spermatids. In bovine sperm, MAB 4/18-staining at the ultrastructural level with immunogold-labeled second antibody was present as a reticulum throughout the acrosomal cap and as punctate aggregates in the equatorial segment. In hamster sperm, MAB 4/18-reactivity was present along the periphery of the acrosome in conjunction with matrix components (M1 and M2), as well as along the inner acrosomal membrane. These observations indicate that the acrosomes of bovine and hamster sperm possess an immunologically related Mr 22,000 protein and suggest that differences in MAB 4/18-staining of spermatids and spermatozoa is a result of epitope modification and/or a change in accessibility of the epitope to the antibody probe during the course of spermiogenesis. Based on its localization and solubility properties, we suggest that the Mr 22,000 protein, in conjunction with other polypeptides, forms a structural framework to maintain acrosomal shape and/or compartmentalize acrosomal contents.
Molecular mechanisms of sea-urchin sperm activation before fertilization.
Several mechanisms are used to control the behaviour of sea urchin spermatozoa while fertilizing eggs. These include discrete regulatory steps that modulate the sperm activation sequence from spawning to gamete membrane fusion. After release from the testis, sperm motility is instantaneously activated, by using intracellular pH as a throttle mechanism to control the rate of the dynein motor that catalyses axonemal bending. To support motility, energy is transported from the mitochondrion to the tail, by using a shuttle mechanism involving phosphocreatine diffusion. This shuttle employs a novel, endotriplicated, creatine kinase of Mr 140,000 in the flagellar axoneme as its terminus. The steering mechanism that determines where the spermatozoon swims is unknown, but may involve an egg peptide-induced guanylate cyclase activation, mediated by a cGMP-dependent Ca2+ channel, and attenuated by a plasma membrane cGMP phosphodiesterase. Upon arriving at the egg, which is identified by virtue of its proteoglycan coat (egg jelly), the spermatozoon undergoes a univesicular secretion that prepares it to fuse with the egg. This acrosome reaction involves several altered ionic fluxes in its mechanism, terminating in a massive Ca2+ uptake. If the spermatozoon is fortunate enough to fuse with an egg, a new member of the species is generated; if the acrosome reaction occurs without gamete fusion, the spermatozoon rapidly dies. All of these activation processes involve changes in the intracellular ionic milieu that are co-ordinated with altered enzyme activities, often in a causal fashion. Even with our current imperfect understanding of the process, a few of the steps in sperm activation may be defined by biochemical pathways that include specific modulatory control points.