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Biomedical subjects

B Hamilton

Publications and source records attributed to B Hamilton.

At least 37 records · Page 2Linked to original sources
PubMed2000

Elderly injury: a profile of trauma experience in the Sunshine (Retirement) State.

OBJECTIVE: By using mandatory discharge data from a state agency, the records of 116,687 patients hospitalized for treatment of injury were evaluated to develop an epidemiologic and demographic profile of this population and to compare outcomes of patients treated in state-designated trauma centers (TC) with those treated in nontrauma centers (NTC). METHODS: Injury severity was calculated by using the International Classification Injury Severity Score methodology to compute individual diagnosis survival risk ratios from 698,187 reported diagnoses, and then by using these survival risk ratios to determine probability of survival for every patient. The population was then categorized by age, injury type, treatment facility designation, injury severity as indicated by probability of survival, and discharge disposition. Incidence of potentially preventable death was compared between TC and NTC, as was the effect on outcome of noninjury comorbidity. RESULTS: The average age of this population was 58 +/- 26 years with significant skew toward the elderly in NTC (mean age, 62 +/- 26 years). The most commonly encountered injuries likewise reflected the elderly nature of this population. Although 71.3% received care in NTC, the majority of severely injured were treated in TC. Potentially preventable mortality (>0.5) was significantly lower in TC. The effect of noninjury comorbidity on outcome was better managed by TC, both in terms of decreased mortality and in proportion of patients discharged home. CONCLUSION: These data demonstrate the unique characteristics of injury victims treated in the state of Florida and indicate that the developing trauma system is demonstrating productivity in terms of avoidance of preventable death, efficient management of noninjury comorbid problems, and more complete recovery as indicated by proportion of patients discharged to home.

Aged↗
PubMed1999

Function of human mitochondrial 2,4-dienoyl-CoA reductase and rat monofunctional Delta3-Delta2-enoyl-CoA isomerase in beta-oxidation of unsaturated fatty acids.

Human 2,4-dienoyl-CoA reductase (2,4-reductase; DECR) and rat monofunctional Delta(3)-Delta(2)-enoyl-CoA isomerase (rat 3, 2-isomerase; ECI) are thought to be mitochondrial auxiliary enzymes involved in the beta-oxidation of unsaturated fatty acids. However, their function during this process has not been demonstrated. Although they lack obvious peroxisomal targeting signals (PTSs), both proteins have been suggested previously to also occur in the mammalian peroxisomal compartment. The putative function and peroxisomal location of the two mammalian proteins can be examined in yeast, since beta-oxidation of unsaturated fatty acids is a compartmentalized process in Saccharomyces cerevisiae requiring peroxisomal 2,4-dienoyl-CoA reductase (Sps19p) and peroxisomal 3, 2-isomerase (Eci1p). A yeast sps19Delta mutant expressing human 2, 4-reductase ending with the native C-terminus could not grow on petroselinic acid [cis-C(18:1(6))] medium but could grow when the protein was extended with a PTS tripeptide, SKL (Ser-Lys-Leu). We therefore reason that the human protein is a physiological 2, 4-reductase but that it is probably not peroxisomal. Rat 3, 2-isomerase expressed in a yeast eci1Delta strain was able to re-establish growth on oleic acid [cis-C(18:1(9))] medium irrespective of an SKL extension. Since we had shown that Delta(2,4) double bonds could not be metabolized extra-peroxisomally to restore growth of the sps19Delta strain, we postulate that rat 3,2-isomerase acted on the Delta(3) unsaturated metabolite of oleic acid by replacing the mutant's missing activity from within the peroxisomes. Immunoblotting of fractionated yeast cells expressing rat 3, 2-isomerase in combination with electron microscopy supported our proposal that the protein functioned in peroxisomes. The results presented here shed new light on the function and location of human mitochondrial 2,4-reductase and rat monofunctional 3,2-isomerase.

Animals↗
PubMed1999

Small terminal deletion of 1p and duplication of 1q: cytogenetics, FISH studies, and clinical observations at newborn and at age 16 years.

A small, extra chromosome segment added to 1p was found by Q-banding 16 years ago in a newborn baby with low birth weight, short stature, wide open fontanelle, small palpebral fissures, depressed nose bridge, and inguinal hernia. This chromosome abnormality has been characterized recently with G-banding and fluorescence in situ hybridization using multiple DNA probes. The karyotype is now described as 46,XY, der(1)(qter-->p36.13::q42.3-->qter), representing a small deletion of 1p36.13-pter and a small duplication of 1q42.3-qter. Re-examination of this patient at age 16 years showed marked psychomotor delay, severely accentuated dorsal kyphosis and scoliosis, pectus excavatum, and other anomalies but no clinical signs of neuroblastoma. Comparison of the clinical findings in this case with those described in the patients having either a deletion of 1p36-pter or a duplication of 1q42-qter further illustrated the complexity of the genotype-phenotype relationship.

Adolescent↗
PubMed1999

Functional analysis of the Zn(2)Cys(6) transcription factors Oaf1p and Pip2p. Different roles in fatty acid induction of beta-oxidation in Saccharomyces cerevisiae.

Fatty acid induction of the peroxisomal beta-oxidation machinery in Saccharomyces cerevisiae involves transcriptional control of genes regulated by the oleate response element (ORE). Glucose as the preferred carbon source antagonizes this effect. Induction is dependent on the Zn(2)Cys(6) family members Oaf1p and Pip2p, which bind to this element as a heterodimer. We show here by ectopically expressing both components and LexA fusion derivatives that this transcription factor complex is only active in the presence of oleate. In contrast to Pip2p, Oaf1p is responsive to oleate activation in the absence of the other component of the heterodimer. Therefore, it is the exclusive receptor of the oleate signal. Pip2p is active also under noninducing conditions but is effectively inhibited when complexed with Oaf1p in the absence of inducer. It contributes to the trans-activation properties of the Oaf1p-Pip2p heterodimer and is required for efficient binding of Oaf1p to OREs in vivo. Repression of ORE-dependent transcription by glucose occurs via both Oaf1p and Pip2p. By dissecting functional domains of both proteins, we identified a region required for regulated activity of the C-terminal activation domain. These findings allow us to postulate a model for carbon source-regulated transcription of peroxisomal protein genes.

Cysteine↗
PubMed1999

A novel element in the promoter of the Saccharomyces cerevisiae gene SPS19 enhances ORE-dependent up-regulation in oleic acid and is essential for de-repression.

In Saccharomyces cerevisiae cells grown on oleic acid, genes encoding enzymes of beta-oxidation are induced by the interaction of a transcription factor composed of Pip2p and Oaflp with an oleate response element (ORE) in their promoters. The SPS19 gene, which encodes peroxisomal 2,4-dienoyl-CoA reductase, an auxiliary beta-oxidation enzyme, has been shown previously to be up-regulated by a canonical ORE. To determine whether additional elements contribute to this transcriptional upregulation, deletion analysis of the SPS19 promoter was conducted using SPS19-lacZ reporter genes. In a reporter construct containing a deletion adjacent to the ORE, transcriptional activation of SPS19 in oleic acid medium was impaired. Together with an additional segment that overlaps a portion of the canonical ORE, this region forms a continuous element (termed UAS(SPS19)) that is essential for de-repression of SPS19 when glucose levels are low. The potentially bi-partite UAS(SPS19) element was able to initiate bi-directional transcription from a promoterless CYC1-lacZ reporter construct under de-repression conditions, whereas the canonical ORE was not. In oleic acid-containing medium, UAS(SPS19) stimulated transcription of the reporter gene 2.4-fold compared to the intact SPS19 ORE, but did so only in the presence of Pip2p and Oaf1p. UAS(SPS19), which is similar to a transcriptional enhancer in the promoter of the sporulation-specific gene SPS4, was shown specifically to bind several proteins, including Pip2p and Oaflp. We propose that UAS(SPS19) and other sequences like it are required to enhance the transcriptional effects mediated by more specific response elements.

Base Sequence↗
PubMed1999

Effects of overlapping parametric resonances on the particle diffusion process.

The evolution of the beam distribution in a double-rf system with a phase modulation on either the primary or secondary rf cavity was measured. We find that the particle diffusion process obeys the Einstein relation if the phase space becomes globally chaotic. When dominant parametric resonances still exist in the phase space, particles stream along the separatrices of the dominant resonance, and the beam width exhibits characteristic oscillatory structure. The particle-tracking simulations for the double-rf system are employed to reveal the essential diffusion mechanism. Coherent octupolar motion has been observed in the bunch beam excitation. The evolution of the longitudinal phase space in the octupole mode is displayed.

Journal Article↗
PubMed1999

New horizons in stroke rehabilitation research.

To promote health services research in stroke rehabilitation, we gathered information about stroke rehabilitation structures, processes, and outcomes (SPO), using extant databases and the Donabedian theoretical model of health services evaluation. We found that, in the United States, over S3.6 billion was spent by third-party payers in 1992 on rehabilitation, including stroke. Total disability-related costs now amount to over $170 billion per year. However, there are few studies identifying cost-effective stroke rehabilitation practices. Existing studies indicate that the organizational structure of rehabilitation influences stroke outcomes, but it is less clear exactly what organizational practices constitute optimal stroke rehabilitation. Data about specific, beneficial rehabilitation processes are scanty for stroke. There are a number of valid and reliable outcome measures pertinent to stroke rehabilitation health services research. We conclude that health services research in stroke rehabilitation is sparse. To be more informative, rehabilitation health services research should be guided by the SPO model.

Cost-Benefit Analysis↗
PubMed1998

Peroxisomal Delta3-cis-Delta2-trans-enoyl-CoA isomerase encoded by ECI1 is required for growth of the yeast Saccharomyces cerevisiae on unsaturated fatty acids.

We have identified the Saccharomyces cerevisiae gene ECI1 encoding Delta3-cis-Delta2-trans-enoyl-CoA isomerase that acts as an auxiliary enzyme in the beta-oxidation of (poly)unsaturated fatty acids. A mutant devoid of Eci1p was unable to grow on media containing unsaturated fatty acids such as oleic acid but was proficient for growth when a saturated fatty acid such as palmitic acid was the sole carbon source. Levels of ECI1 transcript were elevated in cells grown on oleic acid medium due to the presence in the ECI1 promoter of an oleate response element that bound the transcription factors Pip2p and Oaf1p. Eci1p was heterologously expressed in Escherichia coli and purified to homogeneity. It was found to be a hexameric protein with a subunit of molecular mass 32, 000 Da that converted 3-hexenoyl-CoA to trans-2-hexenoyl-CoA. Eci1p is the only known member of the hydratase/isomerase protein family with isomerase and/or 2-enoyl-CoA hydratase 1 activities that does not contain a conserved glutamate at its active site. Using a green fluorescent protein fusion, Eci1p was shown to be located in peroxisomes of wild-type yeast cells. Rat peroxisomal multifunctional enzyme type I containing Delta3-cis-Delta2-trans-enoyl-CoA isomerase activity was expressed in ECI1-deleted yeast cells, and this restored growth on oleic acid.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1998

The incidence and prevalence of HIV infection among childbearing women living in Edinburgh city, 1982-1995.

OBJECTIVE: To track the complete course of the HIV epidemic among women from the city of Edinburgh who delivered babies during 1982-1995. METHODS: The performance of the modified Serodia HIV test on dried blood spots from archived neonatal metabolic screening cards stored for up to 11 years was evaluated by testing 221 cards from neonates whose mothers' HIV infection status was already known (100 HIV-positive, 121 HIV-negative). Unlinked anonymous HIV testing of cards from neonates born during 1982-1989 was then performed and the resulting prevalence data were combined with existing data from 1990-1995. Maximum and minimum limits of HIV incidence among women during the 36-month period prior to delivery were calculated using data held on a clinical database of HIV-infected pregnant women that had been generated under strict conditions of confidentiality; these data included the date of the woman's first HIV-positive and, if available, last HIV-negative specimen. RESULTS: The evaluation revealed a sensitivity of 91%, not clearly related to storage time, and a specificity of 100%. HIV infection first entered Edinburgh's childbearing population during the early 1980s with prevalence peaking at 0.4% in 1986 and then decreasing to 0.1% in 1995; a similar incidence profile was seen during this period. Since 1986, the first full year that HIV testing was available, 78% of all infections were known during the pregnancy, 13% were identified retrospectively, and only 10% (10 cases) remain unaccounted for. For infected cases during 1984-1987, 78% were injecting drug users (IDU) and only 22% acquired their infection sexually; this distribution had reversed by 1992-1995. CONCLUSION: HIV testing of neonatal metabolic screening cards stored for up to 11 years can yield results of sufficient accuracy for epidemiological purposes. There has been a substantial decline in the prevalence and incidence of HIV since the mid-1980s. Although new infections are still occurring, the numbers are small. The decline may largely be explained by the impact of preventive measures on the spread of HIV amongst IDU, and thus from IDU to their sexual partners.

Cohort Studies↗
PubMed1998

Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity.

Msn2p and the partially redundant factor Msn4p are key regulators of stress-responsive gene expression in Saccharomyces cerevisiae. They are required for the transcription of a number of genes coding for proteins with stress-protective functions. Both Msn2p and Msn4p are Cys2His2 zinc finger proteins and bind to the stress response element (STRE). In vivo footprinting studies show that the occupation of STREs is enhanced in stressed cells and dependent on the presence of Msn2p and Msn4p. Both factors accumulate in the nucleus under stress conditions, such as heat shock, osmotic stress, carbon-source starvation, and in the presence of ethanol or sorbate. Stress-induced nuclear localization was found to be rapid, reversible, and independent of protein synthesis. Nuclear localization of Msn2p and Msn4p was shown to be correlated inversely to cAMP levels and protein kinase A (PKA) activity. A region with significant homologies shared between Msn2p and Msn4p is sufficient to confer stress-regulated localization to a SV40-NLS-GFP fusion protein. Serine to alanine or aspartate substitutions in a conserved PKA consensus site abolished cAMP-driven nuclear export and cytoplasmic localization in unstressed cells. We propose stress and cAMP-regulated intracellular localization of Msn2p to be a key step in STRE-dependent transcription and in the general stress response.

Amino Acid Sequence↗
PubMed1998

Fate and role of peroxisomes during the life cycle of the yeast Saccharomyces cerevisiae: inheritance of peroxisomes during meiosis.

Sporulation in the yeast Saccharormyces cerevisiae is a meiotic developmental process that occurs in MATa/MATalpha heterozygotes in response to nutrient deprivation. Here, the fate and role of peroxisomes during sporulation and germination has been examined by a combination of immunoelectron microscopy and the use of pex mutants defective in peroxisomal functions. Using a green fluorescent protein probe targeted to peroxisomes we show that peroxisomes are inherited through meiosis and that they do not increase in number either during sporulation or spore germination. In addition, there is no requirement for peroxisome degradation prior to spore packaging. Unlike the situation in filamentous fungi, peroxisomes do not proliferate during the yeast life cycle. Functional peroxisomes are dispensable for efficient meiotic development on acetate medium since homozygous delta pex6 diploids sporulated well and produced mature spores that were resistant to diethyl ether. Like haploids, diploid cells can proliferate their peroxisomes in response to oleate as sole carbon source in liquid medium, but under these conditions they do not sporulate. On solid oleate medium, homozygous pex5, delta pex6, and pex7 cells were unable to sporulate efficiently, whereas the wild type was. The results presented here are discussed in terms of the transmission of organelles to progeny cells.

Culture Media↗
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↗