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Biomedical subjects

B Hamilton

Publications and source records attributed to B Hamilton.

At least 19 recordsLinked to original sources
PubMed1997

The Saccharomyces cerevisiae peroxisomal 2,4-dienoyl-CoA reductase is encoded by the oleate-inducible gene SPS19.

beta-Oxidation is compartmentalized in mammals into both mitochondria and peroxisomes. Fatty acids with double bonds at even-numbered positions require for their degradation the auxiliary enzyme 2,4-dienoyl-CoA reductase, and at least three isoforms, two mitochondrial and one peroxisomal, exist in the rat. The Saccharomyces cerevisiae Sps19p is 34% similar to the human and rat mitochondrial reductases, and an SPS19 deleted strain was unable to utilize petroselineate (cis-C18:1(6)) as the sole carbon source, but remained viable on oleate (cis-C18:1(9)). Sps19p was purified to homogeneity from oleate-induced cells and the homodimeric enzyme (native molecular weight 69,000) converted 2,4-hexadienoyl-CoA into 3-hexenoyl-CoA in an NADPH-dependent manner and therefore contained 2,4-dienoyl-CoA reductase activity. Antibodies raised against Sps19p decorated the peroxisomal matrix of oleate-induced cells. SPS19 shares with the sporulation-specific SPS18 a common promoter region that contains an oleate response element. This element unidirectionally regulates transcription of the reductase and is sufficient for oleate induction of a promoterless CYC1-lacZ reporter gene. SPS19 is dispensable for growth and sporulation on solid acetate and oleate media, but is essential for these processes to occur on petroselineate.

Amino Acid Sequence↗
PubMed1997

A heterodimer of the Zn2Cys6 transcription factors Pip2p and Oaf1p controls induction of genes encoding peroxisomal proteins in Saccharomyces cerevisiae.

In the yeast Saccharomyces cerevisiae, two transcriptional activators belonging to the Zn2Cys6 protein family, Pip2p and Oaf1p, are involved in fatty-acid-dependent induction of genes encoding peroxisomal proteins. This induction is mediated via an upstream activation sequence called the oleate-response element (ORE). DNA-bandshift experiments with ORE probes and epitope-tagged proteins showed that two binary complexes occurred: in wild-type cells the major complex consisted of a Pip2p x Oaf1p heterodimer, but in cells in which Oaf1p was overexpressed an Oaf1p homodimer was also observed. The genes encoding Oaf1p and Pip2p were controlled in different ways. The OAF1 gene was constitutively expressed, while the PIP2 gene was induced upon growth on oleate, giving rise to positive autoregulatory control. We have shown that the Pip2p x Oaf1p heterodimer is responsible for the strong expression of the genes encoding peroxisomal proteins upon growth on oleate. Pip2p and Oaf1p form an example of a heterodimere of yeast Zn2Cys6 zinc-finger proteins binding to DNA.

Cloning, Molecular↗
PubMed1997

Regulation of the yeast SPS19 gene encoding peroxisomal 2,4-dienoyl-CoA reductase by the transcription factors Pip2p and Oaf1p: beta-oxidation is dispensable for Saccharomyces cerevisiae sporulation in acetate medium.

The yeast SPS19 gene encoding the peroxisomally targeted 2,4-dienoyl-CoA reductase shares its promoter region (291 bp) with the sporulation-specific gene SPS18. SPS19 is induced during sporulation in diploids but to a lesser extent than SPS18; under oleate induction conditions, SPS19, but not SPS18, is transcribed via an oleate response element (ORE) independently of ploidy or sporulation. The SPS19 ORE is the binding target of the Pip2p and Oaf1p transcription factors, and an SPS19-lacZ reporter gene, which is highly expressed in oleate-induced cells, is not activated in haploids devoid of either protein. We examined the expression of CYC1-lacZ reporter constructs carrying the SPS19 and CTA1 OREs in diploids propagated under sporulation conditions and have shown that OREs are not sufficient for heterologous expression during yeast development. In addition, diploids deleted at either PIP2 or OAF1 demonstrated abundant ascosporogenesis, indicating that these genes are not essential for sporulation. A deltapex6 strain lacking peroxisomal structures and one devoid of fatty acyl-CoA oxidase (deltapox1), the first step in fungal beta-oxidation, were both proficient for sporulation and, hence, beta-oxidation and the peroxisomal compartment containing it are dispensable for meiotic development.

Acetates↗
PubMed1997

Central venous catheters in patients with AIDS.

Central venous catheters (CVCs) for patients with AIDS are at risk of a number of complications including bacterial infections. A 6-year retrospective review was undertaken of the records of the 33 patients (42% infected by injection drug use (IDU)) who received intravenous therapy both in hospital and at home via CVCs. Twenty-eight per cent of 53 insertions suffered a complication, the commonest of which was a pneumothorax (8%). The post insertion complication rate was 0.98/100 catheter days (cd). Thrombotic occlusion (0.15/100 cd) was the commonest non septic event while sepsis was overall the commonest event (0.69/ 100 cd) of which half were considered serious (0.33/100 cd). The most frequently isolated organisms were Staphylococci spp. (71%). The median time to an exit site infection was 59 days and to serious catheter sepsis 86 days. Infection did not differ significantly with age, gender, transmission risk activity or catheter type although Portacaths had the lowest rate of infection (0.33/100 cd). The median survival of the 53 CVCs was 88 days although if the temporary catheters were excluded it was 118 days. Kaplan-Meier estimates of survival analysis revealed 55%, 32% and 19% of all the CVCs surviving 3, 6 and 12 months respectively. Our experience suggests that home intravenous therapy and previous IDU does not preclude the use of CVCs although further research is needed on reducing the infection-related complications of such therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Pip2p: a transcriptional regulator of peroxisome proliferation in the yeast Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, peroxisomes are the exclusive site for the degradation of fatty acids. Upon growth with the fatty acid oleic acid as sole carbon source, not only are the enzymes of beta-oxidation and catalase A induced, but also the peroxisomal compartment as a whole increases in volume and the number of organelles per cell rises. We previously identified a cis-acting DNA sequence [oleate response element (ORE)] involved in induction of genes encoding peroxisomal proteins. The aim of our investigation was to test whether a single mechanism acting via the ORE coordinates the events necessary for the proliferation of an entire organelle. Here we report the cloning and characterization of the oleate-specific transcriptional activator protein Pip2p (pip: peroxisome induction pathway). Pip2p contains a typical Zn(2)-Cys(6) cluster domain and binds to OREs. A pip2 deletion strain is impaired in growth on oleate as sole carbon source and the induction of beta-oxidation enzymes is abolished. Moreover, only a few, small peroxisomes per cell can be detected. These results indicate that fatty acids activate Pip2p, which in turn activates the transcription of genes encoding beta-oxidation components and acts as the crucial activator of peroxisomes.

Amino Acid Sequence↗
PubMed1996

Inpatient hospital utilization among veterans with traumatic spinal cord injury.

OBJECTIVE: To describe the pattern of inpatient hospital utilization, up to 15 years after injury, among a cohort of veterans with service-connected traumatic spinal cord injury (SCI). PATIENTS: A cohort of 1,250 male veterans, with traumatic SCI occurring between 1970 and 1986, who visited the VA within 1 year of injury, was assembled from VA administrative files; diagnosis was verified by examining hospital discharge summaries. DESIGN: Computerized record linkage among Department of Veterans Affairs (VA) administrative files was used to determine patterns of inpatient hospital utilization. MAIN OUTCOME MEASURE: Pattern of inpatient admissions and length of stay (LOS). RESULTS: Patients were typically white males injured in their mid-twenties. The initial VA hospitalization began approximately 6 weeks after injury and lasted 4 to 7 months, depending on injury level and completeness. Subsequent hospitalizations usually lasted approximately 10 days, but 22% of stays exceeded 1 months. Most hospitalizations took place in specialized SCI Centers. Comparing the 1980s with the 1970s, patients in the 1980s entered VA facilities sooner after injury, were more likely to visit SCI Centers, and had shorter initial stays. Rates for the incidence of rehospitalization decreased rapidly in years 2-5 after injury and declined less rapidly thereafter. Occupancy rates and proportion rehospitalized followed similar patterns. The incidence rate for persons with complete quadriplegia was approximately twice that of patients with incomplete paraplegia. Between 1970 and 1991, both the rehospitalization incidence rate and LOS decreased by approximately 20%. Only 10% of patients accounted for 46% of the total LOS. LOS during the first five years was predictive of later LOS. CONCLUSIONS: The pattern of rehospitalization in VA facilities was generally consistent with that of the Model Systems. Efforts toward preventing rehospitalization should target persons with previous high utilization.

Adolescent↗
PubMed1996

Evidence against a role for interleukin-10 in the regulation of growth of Mycobacterium avium in human monocytes.

Interleukin-10 (IL-10) inhibits intracellular Mycobacterium avium killing by cytokine-activated murine macrophages and may have a role in pathogenesis. Cytokine activities in supernatants of M. avium-infected human monocytes were maximal at 6-24 h for tumor necrosis factor (TNF)-alpha and 24-48 h for IL-10. TNF-alpha and IL-10 production increased with increasing M. avium-to-monocyte infection ratios (20:1 to 200:1). TNF-alpha production by monocytes infected with smooth, domed, and opaque organisms at 200:1 exceeded that of monocytes infected with smooth, flat, and transparent M. avium (P < .01). IL-10 induction demonstrated considerable strain-to-strain variability and did not correlate with intracellular M. avium growth. IL-10 significantly inhibited TNF-alpha, IL-1 beta, and IL-6 production by M. avium-infected monocytes. Coculturing monocytes with IL-10 after M. avium infection did not affect intracellular M. avium growth. Differential induction of TNF-alpha may be a factor in the intracellular growth of M. avium in human monocytes. IL-10, however, played no apparent role in pathogenicity in this model.

Base Sequence↗
PubMed1996

Halothane acts as a partial agonist of the alpha6 beta2 gamma2S GABA(A)receptor.

Whole-cell patch clamp recording was performed on human embryonic kidney 293 cells stably transfected with rat cDNAs for the alpha6, beta2, and gamma2S subunits of the GABA(A) receptor. The volatile anesthetic halothane directly activated a current in the absence of the ligand gamma-aminobutyric acid (GABA). Both the current amplitude and the rate of desensitization increased in a dose-dependent manner with an EC50 of 1.0+/-0.2 mM and a Hill coefficient (nh) of 1.5+/-0.1. The EC50 and nh for GABA to activate the receptor were 1.0+/-0.3 microM and 1.4+/-0.2, respectively. The peak amplitude of the halothane-activated current was about 4% of the maximal GABA response, which was not changed when the concentration of Ca2+ in the external solution was decreased from 2 mM to 0.2 mM. The reversal potential of both halothane- and GABA-activated currents changed with the external Cl- concentration as predicted by the Nernst equation for chloride ions. The halothane- and GABA-activated currents were blocked by both the noncompetitive GABA(A) receptor antagonist picrotoxin and the competitive GABA(A) receptor antagonist bicuculline. Schild plots revealed that the K(i)s for bicuculline to competitively antagonize the currents activated by halothane and GABA are similar (0.69 and 0.72 microM, respectively). These results indicate that halothane activates the alpha6 beta2 gamma2S GABA(A) receptor to induce a current similar to the GABA-induced current.

Animals↗
PubMed1996

The impact of health maintenance organization care authorization policy on an emergency department before California's new managed care law.

OBJECTIVE: To examine the effect on patient care of HMO-mandated calls for authorization prior to ED evaluation. The study examined this phenomenon prior to implementation of a California law that discourages such calls. METHODS: Concurrent data were collected for patients who presented to the ED and who had authorization calls made to their HMOs prior to their ED evaluations during the period September through December 1994. Data collected included: 1) the number of authorization calls made, 2) the frequency that ED care was deemed unnecessary by the HMO, 3) the outcomes of patients denied authorization, and 4) the time and personnel involved in completing calls. Follow-up phone calls were made to patients who left the ED after the HMO denied authorization for payment. RESULTS: The total ED census was 19,935 patient visits for the four-month period. Authorization calls were made for 4,642 (23%) of the ED visits. There were 545 patients (12%) in this group who had authorization denied and only 29 (5%) chose to remain in the ED for continued evaluation. The total time required to complete a call ranged from 20 minutes to 2.6 hours. Authorization calls and denials caused the following problems: 1) patients for whom calls were made were subject to delays in ED care; 2) at least seven patients referred to HMO clinics were referred back to the ED because the patient was too sick to receive clinic care; 3) patients were inconsistently asked to sign an against-medical-advice form when they chose to leave with unstable conditions; and 4) high-risk patients denied authorization included patients with final diagnoses of ectopic pregnancy, acute myocardial infarction, pulmonary embolus, respiratory failure, and sepsis. CONCLUSIONS: Calls for payment authorization prior to ED patient evaluation delay patient care and place some patients' health and safety in jeopardy.

California↗
PubMed1996

Maternal HIV and drug use: effect on health and social morbidity.

A retrospective analysis of routine child health surveillance information was performed on health visitor records of 459 children, to examine the independent effects of maternal HIV infection and drug use during pregnancy on morbidity in the first 3 years of life. No significant differences were observed in the developmental progress of children born to HIV infected or drug using women when compared to community controls. The pattern of medical consultations in the first 18 months of life was significantly different, maternal drug use exerting a negative influence on outpatient visits (odds ratio 0.6, 95% confidence interval 0.4 to 1.0). At 6 weeks, the majority of children lived with their birth parent(s), and no differences were observed between the groups. By 10 months of age, only 81% of children born to HIV infected drug using women lived with their parent(s). While maternal drug use and HIV did not have adverse effects on child health and development, these findings highlight the social implications for children affected by the heterosexual spread of HIV.

Adult↗
PubMed1995

Prospective identification and triage of nonemergency patients out of an emergency department: a 5-year study.

STUDY OBJECTIVE: To determine whether nonemergency patients can be prospectively identified by triage nurses and safely triaged out of the emergency department without treatment. METHODS: All adult patients (16 years or older) who presented to a university ED were provided an evaluation by a triage nurse. For a patient's case to be defined as nonemergency, four criteria were required: vital signs within a specific range, presence of 1 of 50 potentially nonemergent chief complaints, absence of key indicators found on screening examination, and absence of chest pain, abdominal pain, any severe pain, and inability to walk. Between July 1988 and July 1993, patients who satisfied these criteria were defined as nonemergency, refused care in the ED, and triaged out of the ED. Patients were referred to off-site clinics. The clinics had agreed to see patients in advance of the study, and the referral lists were frequently updated. Outcome data were obtained by telephone surveys to both triaged individuals and other health care providers. RESULTS: In this 5-year study, 176,074 adults presented to the ambulatory triage area in the ED, and 31,165 (18%) were defined as nonemergency, were not treated, and were referred elsewhere. Letters and telephone calls to all referral clinics, eight local EDs, and the coroner's office identified no instances of gross mistriage and only a small number of insignificant adverse outcomes. Telephone follow-up to individuals triaged away was successful in 34% of calls and showed that 39% of persons received care elsewhere on the same day, 35% received care within 3 days, and 26% decided not to seek medical care. A group of 1.0% sought care at other hospital EDs for minor complaints. CONCLUSION: A subset of patients with nonemergency problems can be prospectively identified and triaged out of the ED without significant adverse outcomes provided there is community support for follow-up care.

Adult↗
PubMed1995

Maternal HIV infection, drug use, and growth of uninfected children in their first 3 years.

OBJECTIVE: To determine the separate effects of maternal HIV infection and drug use during pregnancy on growth of uninfected children in their first 3 years. DESIGN: Retrospective analysis of measurements from health visitor records made during routine child health surveillance at 6 weeks, 10 months, and 3 years of age. Multilevel analysis allowed for between-infant variation in fitted growth lines, and adjustment for other factors. Growth was described in terms of an intercept (z score at term) and growth slopes (change in z score per year) up to, and from, 4 months. SUBJECTS: 290 case babies delivered in Edinburgh hospitals to women who reported injection drug use by either themselves or their HIV infected partner, and 186 community controls. A total of 131 (45%) of the case babies were born to women who used drugs, predominantly opiates, during pregnancy and 93 (32%) to HIV infected women. The eight infected children were excluded from analysis. MAIN OUTCOME MEASURES: Age and sex standardised z scores for height, weight, and body mass index. RESULTS: 459 (96%) of the 476 records for cases and controls were traced, yielding 1432 weight and 939 height measurements. Maternal HIV infection was not found to affect growth; at 3 years the estimated effect on weight z score was 0.16 with 95% confidence interval (-0.25 to 0.57) and for height 0.18 (-0.19 to 0.55). Drug use during pregnancy was associated with lighter babies at 40 weeks followed by depressed growth in the first four months, these infants remaining just slightly smaller at 3 years with an estimated effect on z scores of -0.5 for weight with 95% confidence interval (-0.89 to -0.11) and -0.37 (-0.72 to -0.02) for height. CONCLUSIONS: Maternal HIV infection does not adversely affect growth in uninfected infants, and the effect of drug use during pregnancy is limited to small decrease in size at 3 years.

Body Height↗
PubMed1994

Progressive multifocal leukoencephalopathy complicating Wiskott-Aldrich syndrome. Report of a case and review of the literature of progressive multifocal leukoencephalopathy with other inherited immunodeficiency states.

OBJECTIVE: To describe the occurrence of progressive multifocal leukoencephalopathy (PML) in association with Wiskott-Aldrich syndrome, an X-linked recessive disorder with impairment of both cellular and humoral immunity. DESIGN: A detailed analysis of this patient's clinical illness, immunologic factors, neuroradiographic findings, and brain histopathologic conditions was undertaken. The medical literature on PML complicating congenital immunodeficient states was also reviewed. SETTING: A 1500-bed, university-affiliated, public health hospital. PATIENT: A 15-year-old boy with Wiskott-Aldrich syndrome. His neurologic illness was heralded by dysarthria and right-sided weakness and the diagnosis was established by brain biopsy specimen. Survival from the time of onset of PML was 10 months. CONCLUSION: Although PML typically occurs in the setting of severe acquired cellular immunodeficiency, often as a consequence of acquired immunodeficiency syndrome, organ transplantation, and leukemia and lymphoma, it may rarely accompany inherited immunodeficiency syndromes. The reported childhood cases of PML include three patients, aged 5, 11, and 18 years, with other inherited immunodeficiency syndromes. This patient represents the first time (to our knowledge) that PML has been reported to occur in association with Wiskott-Aldrich syndrome.

Adolescent↗
PubMed1993

A Saccharomyces cerevisiae upstream activating sequence mediates induction of peroxisome proliferation by fatty acids.

Peroxisome proliferation in Saccharomyces cerevisiae is induced by fatty acids via as yet unknown mechanisms. We have initiated a study of these mechanisms by identifying control sequences sufficient for fatty acid control of the CTA1 gene (encoding the peroxisomal catalase A). Promoter regions previously shown to be necessary for control were tested for their potential to mediate induction by oleic acid to a CYC1::lacZ fusion gene. A region previously demonstrated to control CTA1 via the ADR1 transcription activator (bp -156 to -184) does not mediate induction by oleic acid. In contrast, an adjacent sequence (-184 to -198) is sufficient for oleic acid induction, and a neighbouring element (-197 to -215) has marginal inducing activity. These two elements are characterized by a consensus sequence, 5'-CGGNNNTNA ('peroxisome box'), which is found in a number of S. cerevisiae peroxisomal protein-encoding genes. Mutation of either the CGG or the TNA block in the box has a dramatic down-regulating effect on the gene expression in oleic acid medium.

Base Sequence↗
PubMed1993

Sequence analysis of pre-ferredoxin-NADP(+)-reductase cDNA from Cyanophora paradoxa specifying a precursor for a nucleus-encoded cyanelle polypeptide.

A cDNA clone for pre-ferredoxin-NADP+ reductase (FNR) was obtained by screening a Cyanophora paradoxa expression library with antibodies specific for cyanelle FNR. The 1.4 kb transcript was derived from a single-copy gene. The precursor (41 kDa) and mature forms (34 kDa) of FNR were identified by western blotting of in vitro translation products and cyanelle extracts, respectively. The derived amino acid sequence of the mature form was corroborated by data from N-terminal protein sequencing and yielded identity scores from 58% to 62% upon comparison with cyanobacterial FNRs. Sequence conservation seemed to be even more pronounced in comparison with enzymes from higher plants, but using the neighbor joining method the C. paradoxa sequence was clearly positioned between the prokaryotic and eukaryotic sequences. The transit peptide of 65 or 66 amino acids appeared to be totally unrelated to those from spinach, pea and ice plant but showed overall characteristics of stroma-targeting peptides.

Amino Acid Sequence↗
PubMed1993

Pathology of congenital syphilis in rabbits.

We have developed a model for congenital syphilis in the rabbit. This report provides additional information on newborn tissue pathology in animals that were infected in utero. A total of 35 pregnancies were evaluated, each containing 6 to 12 newborns. In the infected group, the mortality was approximately 50%; of the live newborns, half appeared normal and half were hyperreflexic, weak, and runty. Gross pathology in the sickly newborns was quite prevalent and involved enlarged spleens with isolated spots of necrosis; enlarged livers that were overtly congested and hemorrhagic and had numerous granular, white spots; and brains with hemorrhage in the occipital area. Histopathology was apparent in different tissues. Lymphocytes, plasma cells, and vacuolated macrophages were prominent in livers, spleens, brains, and bones. A few actively motile treponemes were visualized by dark-field microscopy within extracts of spleen and within cerebrospinal fluid. Low numbers of treponemes were also demonstrated in sections of brain and liver by using the Warthin-Starry silver stain technique. Blood hematocrits were decreased, and extramedullary hematopoiesis was prominent within spleens and livers; this is consistent with anemia. This rabbit model exhibits many of the same pathologic features commonly found in human congenital syphilis.

Animals↗