Biomedical subjects
Publications and source records attributed to S Collins.
In a randomized controlled trial, an intensive promotional campaign failed to increase the uptake of vaccination against influenza among health care workers. The uptake of vaccination was low.
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Interest in the biology of adipose tissue has undergone a revival in recent years with the discovery of a host of genes that contribute to the regulation of satiety and metabolic rate. The catecholamines have long been known to be key modulators of adipose tissue lipolysis and the hydrolysis of triglyceride energy stores. However, more recent efforts to understand the role of individual adrenergic receptor subtypes expressed in adipocytes and their signal transduction pathways have revealed a complexity not previously appreciated. Combined with this interest in the modulation of adipocyte metabolism is a renewed focus upon brown adipose tissue and the mechanisms of whole body thermogenesis in general. The discovery of novel homologs of the brown fat uncoupling protein (UCP) such as UCP2 and UCP3 has provoked intensive study of these mitochondrial proteins and the role that they play in fuel metabolism. The story of the novel UCPs has proven to be intriguing and still incompletely understood. Here, we review the status of adipose tissue from inert storage depot to endocrine organ, interesting signal transduction pathways triggered by beta-adrenergic receptors in adipocytes, the potential of these receptors for discriminating and coordinated metabolic regulation, and current views on the role of UCP2 and UCP3 based on physiological studies and gene knockout models.
A prospective survey was undertaken to determine the prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Of the 78 admissions surveyed, 10 patients were confused or too unwell to take part and 25 were pain-free. The remaining 43 reported 86 pains (range 1-6 per patient); of these patients, 27 (63%) had breakthrough pain and identified 52 pains (range 1-5 per patient). Breakthrough pain was classified as somatic (46%) visceral (14%), neuropathic (25%) or mixed aetiology (15%); 60% of pains were severe or excruciating. The mean number of daily breakthrough pain episodes was five (range 1-13), 54% of which occurred suddenly. Most pains (56%) were unpredictable; 75% lasted less than 30 min. These findings suggest that breakthrough pain is common in patients with non-malignant terminal disease; it is frequent, short lasting and often unpredictable, thus making treatment difficult.
Norepinephrine has long been known to stimulate the pulsatile and preovulatory release of LH-releasing hormone (LHRH). In vivo and in vitro studies indicate that these effects are mediated primarily through alpha(1)-adrenergic receptors (alpha(1)-ARs). With the immortalized hypothalamic LHRH neurons, we have found that alpha(1)-adrenergic agents directly stimulate the secretion of LHRH in a dose-dependent manner. Ligand binding and RNA studies demonstrate that the GT1 cells contain both alpha(1A)- and alpha(1B)-ARs. Competition binding experiments show that approximately 75% of the binding is due to alpha(1B)-ARs; the remainder is made up of alpha(1A)-ARs. Receptor activation leads to stimulation of PLC. PLC beta 1 and PLC beta 3 are expressed in GT1 neurons, and these PLCs are probably responsible for the release of diacylglycerol and IP as well as the increase in intracellular calcium. The mobilization of cytoplasmic calcium is sufficient to stimulate cytosolic PLA(2) (cPLA(2)) and release arachidonic acid. A dissection of the contributions of the phospholipases to LHRH secretion suggests that cPLA(2) acts downstream of PLC and that it significantly augments the PLC-stimulated LHRH secretory response. Inasmuch as the alpha(1)-ARs are known to play a critical role in LHRH physiology, we propose that both PLC and cPLA(2) are critical in regulating and amplifying LHRH release.
The beta-adrenergic receptors (betaARs) are members of the large family of G protein-coupled receptors. There are three betaAR subtypes (beta1AR, beta2AR beta3AR), each of which is coupled to Galphas and the stimulation of intracellular cAMP levels. While beta1AR and beta2AR are broadly expressed throughout tissues of the body, beta3AR is found predominantly in adipocytes. Stimulation of the betaARs leads to lipolysis in white adipocytes and nonshivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the betaAR system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, we and others have shown that selective beta3AR agonists are able to prevent or reverse obesity and the loss of betaAR expression and to stimulate thermogenesis. This chapter will review the current understanding of the role of the sympathetic nervous system and the adipocyte betaARs in models of obesity; the physiologic impact of changes in betaAR expression on body composition and thermogenesis; and the regulation and unique properties of betaAR subtypes in brown and white adipocytes. The latter includes our recent discovery of novel signal transduction mechanisms utilized by beta3AR to activate simultaneously the protein kinase A and MAP kinase pathways. The impact of understanding these pathways and their potential role in modulating adaptive thermogenesis is discussed.
This paper explores the prevalence and health care utilization of dually eligible Medicare and Medicaid participants among New Jersey Medicaid recipients with AIDS using linked administrative data. Merged Medicaid claims and AIDS surveillance data were used to analyze participation in the Medicare program by Medicaid recipients in New Jersey diagnosed with AIDS who received services between January 1988 and March 1996. We found that nearly 30% of Medicaid participants had Medicare claims during the observation period, suggesting that Medicare is becoming an important payer of HIV care among individuals eligible for Medicaid. Traditionally disadvantaged groups such as women and racial minorities were less likely to be dually eligible for Medicare, reflecting differences in survival and in eligibility requirements for Social Security Disability Insurance (SSDI). Controlling for other characteristics, dually eligible individuals had shorter lengths of stay and had lower charges per inpatient stay than Medicaid only enrollees. Dual eligibles were also more likely to use antiretroviral (ARV) drugs and were more consistent users of ARV treatment measured by the proportion of time on ARV therapy. Our study suggests that persons with AIDS who may qualify for Medicare because of their disability are different than individuals who only received Medicaid reimbursed services in terms of their health care utilization. Further research is needed to determine the cause of such differences which may include socioeconomic differences between dual eligibles and Medicaid only eligibles, dissimilarities in health status between the two groups, and variation in aspects of insurance coverage particularly in the choice and reimbursement of office-based physicians.
Following recent published evidence regarding the experimental transmission of prion diseases via blood transfusion, dental practitioners have expressed their concern about the potential impact of these transmissible spongiform encephalopathies on dental care provision. This review provides updated information on Creutzfeldt-Jakob disease and related disorders and highlights their potential significance for the practice of clinical dentistry. The current guidelines in Australia relating to infection control and clinical dental procedures are discussed together with recommended guidelines and considerations from the United Kingdom and the World Health Organization (WHO).
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PTP-1B is a ubiquitously expressed intracellular protein tyrosine phosphatase (PTP) that has been implicated in the negative regulation of insulin signaling. Mice deficient in PTP-1B were found to have an enhanced insulin sensitivity and a resistance to diet-induced obesity. Interestingly, the human PTP-1B gene maps to chromosome 20q13.1 in a region that has been associated with diabetes and obesity. Although there has been a partial characterization of the 3' end of the human PTP-1B gene, the complete gene organization has not been described. In order to further characterize the PTP-1B gene, we have cloned and determined the genomic organization for both the human and mouse PTP-1B genes including the promoter. The human gene spans >74 kb and features a large first intron of >54 kb; the mouse gene likewise contains a large first intron, although the exact size has not been determined. The organization of the human and mouse PTP-1B genes is identical except for an additional exon at the 3' end of the human that is absent in the mouse. The mouse PTP-1B gene maps to the distal arm of mouse chromosome 2 in the region H2-H3. This region is associated with a mouse obesity quantitative trait locus (QTL) and is syntenic with human chromosome 20. The promoter region of both the human and mouse genes contain no TATA box but multiple GC-rich sequences that contain a number of consensus SP-1 binding sites. The basal activity of the human PTP-1B promoter was characterized in Hep G2 cells using up to 8 kb of 5' flanking sequence. A 432 bp promoter construct immediately upstream of the ATG was able to confer maximal promoter activity. Within this sequence, there are at least three GC-rich sequences and one CCAAT box, and deletion of any of these elements results in decreased promoter activity. In addition, the promoter in a number of mouse strains contains, 3.5 kb upstream of the start codon, an insertion of an intracisternal a particle (IAP) element that possibly could alter the expression of PTP-1B mRNA in these strains.
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Both beta(2)- and beta(3)-adrenergic receptors (ARs) are able to activate the extracellular signal-regulated kinase (ERK) pathway. We previously showed that c-Src is required for ERK activation by beta(2)AR and that it is recruited to activated beta(2)AR through binding of the Src homology 3 (SH3) domain to proline-rich regions of the adapter protein beta-arrestin1. Despite the absence of sites for phosphorylation and beta-arrestin binding, ERK activation by beta(3)AR still requires c-Src. Agonist activation of beta(2)AR, but not beta(3)AR, led to redistribution of green fluorescent protein-tagged beta-arrestin to the plasma membrane. In beta-arrestin-deficient COS-7 cells, beta-agonist-dependent co-precipitation of c-Src with the beta(2)AR required exogenous beta-arrestin, but activated beta(3)AR co-precipitated c-Src in the absence or presence of beta-arrestin. ERK activation and Src co-precipitation with beta(3)AR also occurred in adipocytes in an agonist-dependent and pertussis toxin-sensitive manner. Protein interaction studies show that the beta(3)AR interacts directly with the SH3 domain of Src through proline-rich motifs (PXXP) in the third intracellular loop and the carboxyl terminus. ERK activation and Src co-precipitation were abolished in cells expressing point mutations in these PXXP motifs. Together, these data describe a novel mechanism of ERK activation by a G protein-coupled receptor in which the intracellular domains directly recruit c-Src.
Uncoupling protein 2 (UCP2) belongs to the mitochondrial anion carrier family and partially uncouples respiration from ATP synthesis when expressed in recombinant yeast mitochondria. We generated a highly sensitive polyclonal antibody against human UCP2. Its reactivity toward mitochondrial proteins was compared between wild type and ucp2(-/-) mice, leading to non-ambiguous identification of UCP2. We detected UCP2 in spleen, lung, stomach, and white adipose tissue. No UCP2 was detected in heart, skeletal muscle, liver, and brown adipose tissue. The level of UCP2 in spleen mitochondria is less than 1% of the level of UCP1 in brown adipose tissue mitochondria. Starvation and LPS treatments increase UCP2 level up to 12 times in lung and stomach, which supports the hypothesis that UCP2 responds to oxidative stress situations. Stimulation of the UCP2 expression occurs without any change in UCP2 mRNA levels. This is explained by translational regulation of the UCP2 mRNA. We have shown that an upstream open reading frame located in exon two of the ucp2 gene strongly inhibits the expression of the protein. This further level of regulation of the ucp2 gene provides a mechanism by which expression can be strongly and rapidly induced under stress conditions.
OBJECTIVE: To improve diagnostic criteria for sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Pooled data on initial and final diagnostic classification of suspected CJD patients were accumulated, including results of investigations derived from a coordinated multinational study of CJD. Prospective analysis for a comparison of clinical and neuropathologic diagnoses and evaluation of the sensitivity and specificity of EEG and 14-3-3 CSF immunoassay were conducted. RESULTS: Data on 1,003 patients with suspected CJD were collected using a standard questionnaire. After follow-up was carried out, complete clinical data and neuropathologic diagnoses were available in 805 cases. In these patients, the sensitivity of the detection of periodic sharp wave complexes in the EEG was 66%, with a specificity of 74%. The detection of 14-3-3 proteins in the CSF correlated with the clinical diagnosis in 94% (sensitivity). The specificity (84%) was higher than that of EEG. A combination of both investigations further increased the sensitivity but decreased the specificity. CONCLUSIONS: Incorporation of CSF 14-3-3 analysis in the diagnostic criteria for CJD significantly increases the sensitivity of case definition. Amended diagnostic criteria for CJD are proposed.
CONTEXT: In the setting of famine, infection is likely to cause mortality among severely malnourished persons. Although clinical signs are likely to be useful prognostic indicators in this setting, use of a clinical assessment model has not been studied. OBJECTIVE: To examine the use of clinical signs in the prediction of short-term mortality in severely malnourished adults and adolescents during famine. DESIGN: Retrospective cohort study. SETTING: Concern Worldwide Adult Therapeutic Feeding Center in Baidoa, Somalia. PATIENTS: Data from the clinical records of 383 adult and adolescent inpatients admitted to the center between November 1992 through March 1993 who were aged 15 years or older and had a body mass index (BMI) of 13.5 kg/m(2) or less or any signs of edematous malnutrition. MAIN OUTCOME MEASURES: Association of mortality with presence or absence of 8 clinical signs (edema, hydration, ascites, dysentery, diarrhea, anemia, chest infection, and ability to stand) and BMI at admission, and sensitivity and specificity of models including a count of clinical signs and BMI in the prediction of mortality at the center. RESULTS: Ninety-one patients (23.8%) died, with a median time to death of 8 days from admission. Of the 8 clinical signs, severe edema (unadjusted odds ratio [OR], 2.45; 95% confidence interval [CI], 1.41-4.27), apparent dehydration (unadjusted OR, 2. 73; 95% CI, 1.60-4.66), and inability to stand (unadjusted OR, 2.96; 95% CI, 1.40-6.26) were independently associated with mortality. The most useful clinical model was that based on the presence of any 1 of these 3 signs, with a sensitivity of 77% and a specificity of 59%. Ability of admission BMI to predict mortality was less than random. CONCLUSIONS: Models based on clinical signs predicted death better than BMI. Simple counts of clinical signs performed as well as more complex models based on the addition of ORs. Counting relevant clinical signs is an easy and effective prognostic tool in severe adult and adolescent malnutrition during famine; however, it is not sensitive enough for use as a screening tool. JAMA. 2000;284:621-626
BACKGROUND: The transmissible spongiform encephalopathies constitute a fascinating and biologically unique group of invariably fatal neurodegenerative disorders that affect both animals and humans. Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia represent the more common human phenotypes. Excluding the small number of iatrogenically transmitted cases, approximately 85% to 90% of patients develop CJD without identifiable explanation, with an increasing number of different mutations in the prion protein gene (PRNP) recognized as probably causative in the remainder. OBJECTIVE: To report on an 82-year-old woman with pathologically confirmed CJD found unexpectedly to harbor a novel mutation in PRNP. METHODS: Routine clinical investigations were undertaken to elucidate the cause of the rapidly progressive dementia and neurological decline manifested by the patient, including magnetic resonance imaging of the brain, electroencephalography, and cerebrospinal fluid analysis for the 14-3-3 beta protein. Standard postmortem neuropathological examination of the brain was performed, including immunocytochemistry of representative sections to detect the prion protein. Posthumous genetic analysis of the open reading frame of PRNP was performed on frozen brain tissue using polymerase chain reaction and direct sequencing. RESULTS: Concomitant with the exclusion of alternative diagnoses, the presence of characteristic periodic sharp-wave complexes on the electroencephalogram in combination with a positive result for 14-3-3 beta protein in the cerebrospinal fluid led to a confident clinical diagnosis of CJD, confirmed at autopsy. There was no family history of dementia or similar neurological illness, but patrilineal medical information was incomplete. Unexpectedly, full sequencing of the PRNP open reading frame revealed a single novel mutation consisting of an adenine-to-guanine substitution at nucleotide 611, causing alanine to replace threonine at codon 188. CONCLUSIONS: In addition to expanding the range of PRNP mutations associated with human prion diseases, we believe this case is important for the following reasons. First, from an epidemiological perspective, the avoidance of occasional incorrect classification of patients manifesting neurodegenerative disorders that may have a genetic basis requires systematic genotyping, particularly when there are uncertainties regarding the family history. Second, the incidence of spongiform encephalopathy in elderly patients beyond the typical age range may be underestimated and does not preclude a genetic basis. Finally, as a corollary, this case highlights problematic issues in human transmissible spongiform encephalopathies, as illustrated by disease penetrance and age of onset in genotype-phenotype correlations.