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Biomedical subjects

P Williams

Publications and source records attributed to P Williams.

At least 199 records · Page 11Linked to original sources
PubMed1997

Analysis of the carbapenem gene cluster of Erwinia carotovora: definition of the antibiotic biosynthetic genes and evidence for a novel beta-lactam resistance mechanism.

Members of two genera of Gram-negative bacteria, Serratia and Erwinia, produce a beta-lactam antibiotic, 1-carbapen-2-em-3-carboxylic acid. We have reported previously the cloning and sequencing of the genes responsible for production of this carbapenem in Erwinia carotovora. These genes are organized as an operon, carA--H, and are controlled by a LuxR-type transcriptional activator, encoded by the linked carR gene. We report in this paper the genetic dissection of this putative operon to determine the function of each of the genes. We demonstrate by mutational analysis that the products of the first five genes of the operon are involved in the synthesis of the carbapenem molecule. Three of these, carABC, are absolutely required. In addition, we provide evidence for the existence of a novel carbapenem resistance mechanism, encoded by the CarF and carG genes. Both products of these overlapping and potentially translationally coupled genes have functional, N-terminal signal peptides. Removal of these genes from the Erwinia chromosome results in a carbapenem-sensitive phenotype. We assume that these novel beta-lactam resistance genes have evolved in concert with the biosynthetic genes to ensure 'self-resistance' in the Erwinia carbapenem producer.

Amino Acid Sequence↗
PubMed1997

High expression of naked plasmid DNA in muscles of young rodents.

There is a time window at 2 weeks of age for achieving very high levels of foreign gene expression from the intramuscular injection of naked plasmid DNA in mice and rats. The highest expression, over 1 microg of luciferase protein/muscle, was obtained in Balb/C mice using constructs containing the CMV promoter, a chimeric intron and the luc+ luciferase gene. Approximately 50% of the myofibers were intensely blue following the intramuscular injection of a beta-galactosidase expression vector in 2 week old Balb/C mice. The effects of age, mouse strain and construct were multiplicative, resulting in >1000-fold greater luciferase and approximately 20-fold more beta-galactosidase-positive cells. These high levels of expression were unstable and were not observed in larger animals (dog, rhesus monkey). These results indicate that enormous levels of foreign gene expression can be obtained in muscle with naked DNA in vivo and will enable the temporary effects of gene function and expression in rodent muscle to be expeditiously studied.

Age Factors↗
PubMed1997

Hospitalization of aboriginal and non-aboriginal patients for respiratory tract diseases in Western Australia, 1988-1993.

BACKGROUND: Aboriginal people have lower health standards than other Australians. Respiratory tract diseases are prominent causes of high morbidity and mortality rates in the Aboriginal population. However, very little is known about the patterns of respiratory illnesses which affect these people. METHOD: This paper compares Aboriginal and non-Aboriginal age-specific hospitalization patterns for respiratory tract diseases from 1988 to 1993 in Western Australia (WA). RESULTS: Aboriginal people were admitted for respiratory diseases 2-16 times more frequently than non-Aboriginals of the same age with considerable discrepancies in hospitalization rates particularly in infants, young children and older adults. High admission rates for acute respiratory tract infections, pneumonia and asthma occurred in Aboriginal infants. Pneumonia was a disproportionately frequent cause of admissions in Aboriginal infants, children and adults. Pneumonia is a more frequent cause of admission among non-metropolitan compared to metropolitan Aboriginals. Asthma was a frequent cause of admissions of Aboriginal children and hospitalization rates for this disease were higher in non-metropolitan than metropolitan areas. Chronic obstructive airway disease and respiratory tract carcinoma were important uses of hospitalization in older Aboriginals. CONCLUSIONS: Admission rates for respiratory conditions were consistently higher among the Aboriginal population and in non-metropolitan areas. The overwhelming importance of infections among Aboriginal admissions has significant implications for the prevention and management of respiratory diseases among Aboriginal people.

Adolescent↗
PubMed1997

The role of automated peritoneal dialysis (APD) in an integrated dialysis programme.

While there is no doubt that renal transplantation would be the preferred option for all patients suffering from end stage renal disease, this is sadly an unrealistic aim for many patients in the UK. There is a shortage of donor organs and, with the increasing percentage of elderly patients on dialysis, under 50% of all dialysis patients are on the national transplant waiting list. Of the 12,000 or so patients on dialysis in the UK, approximately half receive haemodialysis and half peritoneal dialysis. In the last few years, there has been a resurgence of interest in automated peritoneal dialysis and just under 20% of the peritoneal dialysis population currently receive this mode of therapy. The advantages of automated peritoneal dialysis include the capacity for an increased dialysis prescription, increased freedom and quality of life and a decreased risk of peritonitis and intra peritoneal pressure related problems. These advantages may offset the increased cost of automated peritoneal dialysis and long-term patient morbidity and mortality may be diminished by its provision in an integrated dialysis programme.

Adolescent↗
PubMed1997

Dose-related effects of dietary iron supplementation in producing hepatic iron overload in rats.

The influence of varying the level of supplemental dietary iron on the development of hepatic iron overload was examined in rats. Two days after giving birth, Porton rats were fed a diet supplemented with 0, 0.5, 1 or 2% carbonyl iron, to institute dietary iron supplementation to the young via breast milk. After weaning, the offspring continued to receive the assigned diet until 32 weeks of age. Liver biopsies were taken from some rats at 8, 16 and 24 weeks of age and from all rats at 32 weeks of age, for assessment of iron overload. For both male and female rats, hepatic iron content was increased in a dose-related manner by feeding supplemented diet. Hepatic iron content of male rats tended to reach a plateau after 8, 16 weeks of supplementation, while that of female rats continued to rise throughout the experimental period, such that the hepatic iron content of female rats was 2.8-fold that of similarly treated males at 32 weeks of age. Iron supplementation was associated with only moderate retardation of growth. By choosing an appropriate level of iron supplementation, good (grade III-IV) hepatic iron loading can be achieved with minimal adverse effects on the animals' overall health.

Animals↗
PubMed1997

Effects of group exercise on cognitive functioning and mood in older women.

A randomised controlled trial was conducted to determine whether a 12-month program of group exercise had beneficial effects on physiological and cognitive functioning and mood in 187 older community-dwelling women. The exercisers (n = 94) and controls (n = 93) were well matched in terms of the test measures and a number of health and life-style assessments. The mean number of classes attended by the 71 exercise subjects who completed the program was 59.0 (range 26 to 82). At the end of the trial, the exercisers showed significant improvements in reaction time, strength, memory span and measures of wellbeing when compared with the controls. There was also an indication that anxiety had been reduced in the exercisers. Within the exercise group, improvements in memory span were associated with concomitant improvements in both reaction time and muscle strength. Also, within this group, initial mood measures were significantly inversely associated with improvements at retest, which suggests that the program may have normalised mood states in subjects who had high initial depression, anxiety and stress levels, rather than inducing improvements in all subjects. These findings suggest that group exercise has beneficial effects on physiological and cognitive functioning and wellbeing in older people.

Affect↗
PubMed1997

Environmental health conditions in remote and rural aboriginal communities in western Australia.

During 1994-1995 environmental health conditions of about 13,760 persons in 155 remote and rural Aboriginal communities in 20 local shires in Western Australia (WA) were surveyed. A semiquantitative questionnaire sought data about the communities and their services, including water supplies, power, sanitation and disposal of solid and liquid waste; a separate section dealt with conditions of individual dwellings. Data were recorded by experienced local workers. Thirty-five communities considered to have the worst conditions were evaluated on-site by a team of senior personnel in mid-1995. Environmental health problems were prevalent and often serious: over one-third of the communities had water supply or sanitation problems and 70 per cent had housing problems, with overcrowding and substandard housing being commonplace. Thirty-six per cent had difficulties with waste water disposal, 37 per cent had no rubbish disposal, and in others, the methods of disposal were often inadequate; pests were problems in 44 per cent of communities and the hygiene and maintenance of communal toilets was unacceptable in 25 per cent. Seventy-two per cent had no on-site environmental health worker and 44 per cent had no on-site or visiting medical, nursing or health worker personnel. An action plan was developed and the highest-priority communities were targeted in a program of major works (for example, housing, drainage and sewerage) and minor works, which have been commenced. The remote-area environmental health workers' program is being expanded. Increased intersectoral collaboration and enhanced community involvement in decision making have occurred as a result of this work.

Child Welfare↗
PubMed1997

A randomized trial of group outpatient visits for chronically ill older HMO members: the Cooperative Health Care Clinic.

OBJECTIVE: To compare the impact of group outpatient visits to traditional "physician-patient dyad" care among older chronically ill HMO members on health services utilization and cost, self-reported health status, and patient and physician satisfaction. DESIGN: A 1-year randomized trial. SETTING: A group model HMO in the Denver Metropolitan area. PARTICIPANTS: Three hundred twenty-one members aged 65 and older, randomized to a group visit intervention (n = 160) or to usual care (n = 161). INTERVENTION: Patients with high health services utilization and one or more chronic conditions had monthly group visits with their primary care physician and nurse. Visits included health education, prevention measures, opportunities for socialization, mutual support, and for one-to-one consultations with their physician, where necessary. MEASUREMENTS: Health services utilization and associated cost, health status, and patient and physician satisfaction. RESULTS: Outcome measures obtained after a 1-year follow-up period showed that group participants had fewer emergency room visits (P = .009), visits to subspecialists (P = .028), and repeat hospital admissions per patient (P = .051). Group participants made more visits (P = .021) and calls (P = .038) to nurses than control group patients and fewer calls to physicians (P = .019). In addition, a greater percentage of group participants received influenza and pneumonia vaccinations (P < .001). Group participants had greater overall satisfaction with care (P = .019), and participating physicians reported higher levels of satisfaction with the groups than with individual care. No differences were observed between groups on self-reported health and functional status. Cost of care per member per month was $14.79 less for the group participants. CONCLUSIONS: Group visits for chronically ill patients reduce repeat hospital admissions and emergency care use, reduce cost of care, deliver certain preventive services more effectively, and increase patient and physician satisfaction.

Aged↗
PubMed1997

Cell density-regulated recovery of starved biofilm populations of ammonia-oxidizing bacteria.

The speed of recovery of cell suspensions and biofilm populations of the ammonia oxidizer Nitrosomonas europaea, following starvation was determined. Stationary-phase cells, washed and resuspended in ammoniumfree inorganic medium, were starved for periods of up to 42 days, after which the medium was supplemented with ammonium and subsequent growth was monitored by measuring nitrite concentration changes. Cultures exhibited a lag phase prior to exponential nitrite production, which increased from 8.72 h (no starvation) to 153 h after starvation for 42 days. Biofilm populations of N. europaea colonizing sand or soil particles in continuous-flow, fixed column reactors were starved by continuous supply of ammonium-free medium. Following resupply of ammonium, starved biofilms exhibited no lag phase prior to nitrite production, even after starvation for 43.2 days, although there was evidence of cell loss during starvation. Biofilm formation will therefore provide a significant ecological advantage for ammonia oxidizers in natural environments in which the substrate supply is intermittent. Cell density-dependent phenomena in a number of gram-negative bacteria are mediated by N-acyl homoserine lactones (AHL), including N-(3-oxohexanoyl)-L-homoserine lactone (OHHL). Addition of both ammonium and OHHL to cell suspensions starved for 28 days decreased the lag phase in a concentration-dependent manner from 53.4 h to a minimum of 10.8 h. AHL production by N. europaea was detected by using a luxR-luxAB AHL reporter system. The results suggest that rapid recovery of high-density biofilm populations may be due to production and accumulation of OHHL to levels not possible in relatively low-density cell suspensions.

Ammonia↗
PubMed1997

Quorum sensing in Aeromonas hydrophila and Aeromonas salmonicida: identification of the LuxRI homologs AhyRI and AsaRI and their cognate N-acylhomoserine lactone signal molecules.

Spent culture supernatants from both Aeromonas hydrophila and Aeromonas salmonicida activate a range of biosensors responsive to N-acylhomoserine lactones (AHLs). The genes for a quorum sensing signal generator and a response regulator were cloned from each Aeromonas species and termed ahyRI and asaRI, respectively. Protein sequence homology analysis places the gene products within the growing family of LuxRI homologs. ahyR and asaR are transcribed divergently from ahyI and asaI, respectively, and in both Aeromonas species, the genes downstream have been identified by DNA sequence and PCR analysis. Downstream of both ahyI and asaI is a gene with close homology to iciA, an inhibitor of chromosome replication in Escherichia coli, a finding which implies that in Aeromonas, cell division may be linked to quorum sensing. The major signal molecule synthesized via both AhyI and AsaI was purified from spent culture supernatants and identified as N-(butanoyl)-L-homoserine lactone (BHL) by thin-layer chromatography, high-pressure liquid chromatography analysis, and mass spectrometry. In addition, a second, minor AHL, N-hexanoyl-L-homoserine lactone, was identified. Transcriptional reporter studies with ahyI::luxCDABE fusions indicate that AhyR and BHL are both required for ahyI transcription. For A. salmonicida, although the addition of exogenous BHL gives only a small stimulation of the production of serine protease with comparison to the control culture, the incorporation of a longer-chain AHL, N-(3-oxodecanoyl)-L-homoserine lactone, reduced the final level (by approximately 50%) and delayed the appearance (from an A650 of 0.9 in the control to an A650 of 1.2 in the test) of protease in the culture supernatant. These data add A. hydrophila and A. salmonicida to the growing family of gram-negative bacteria now known to control gene expression through quorum sensing.

4-Butyrolactone↗
PubMed1997

N-acyl-homoserine lactone-mediated regulation of phenazine gene expression by Pseudomonas aureofaciens 30-84 in the wheat rhizosphere.

Pseudomonas aureofaciens 30-84 is a soilborne bacterium that colonizes the wheat rhizosphere. This strain produces three phenazine antibiotics which suppress take-all disease of wheat by inhibition of the causative agent Gaeumannomyces graminis var. tritici. Phenazines also enhance survival of 30-84 within the wheat rhizosphere in competition with other organisms. Expression of the phenazine biosynthetic operon is controlled by the phzR/phzI N-acyl-homoserine lactone (AHL) response system (L. S. Pierson III et al., J. Bacterial 176:3966-3974, 1994; D. W. Wood and L. S. Pierson III, Gene 168:49-53, 1996). By using high-pressure liquid chromatography coupled with high-resolution mass spectrometry, the AHL produced by PhzI has now been identified as N-hexanoyl-homoserine lactone (HHL). In addition, the ability of HHL to serve as an interpopulation signal molecule in the wheat rhizosphere has been examined by using isogenic reporter strains. Disruption of phzI reduced expression of the phenazine biosynthetic operon 1,000-fold in the wheat rhizosphere. Coinoculation of an isogenic strain which produced the endogenous HHL signal restored phenazine gene expression in the phzI mutant to wild-type levels in situ. These results demonstrate that HHL is required for phenazine expression in situ and is an effective interpopulation signal molecule in the wheat rhizosphere.

4-Butyrolactone↗
PubMed1997

Quorum sensing in Vibrio anguillarum: characterization of the vanI/vanR locus and identification of the autoinducer N-(3-oxodecanoyl)-L-homoserine lactone.

Certain gram-negative pathogens are known to control virulence gene expression through cell-cell communication via small diffusible signal molecules termed autoinducers. This intercellular signal transduction mechanism termed quorum sensing depends on the interaction of an N-acylhomoserine lactone (AHL) auto-inducer molecule with a receptor protein belonging to the LuxR family of positive transcriptional activators. Vibrio anguillarum is a gram-negative pathogen capable of causing a terminal hemorrhagic septicemia known as vibriosis in fish such as rainbow trout. In this study, we sought to determine whether V. anguillarum employs AHLs to regulate virulence gene expression. Spent V. anguillarum culture supernatants stimulated bioluminescence in a recombinant lux-based Escherichia coli AHL biosensor strain, whereas they both stimulated and inhibited AHL-mediated violacein pigment production in Chromobacterium violaceum. This finding suggested that V. anguillarum may produce multiple AHL signal molecules. Using high-performance liquid chromatography and high-resolution tandem mass spectrometry, we identified the major V. anguillarum AHL as N-(3-oxodecanoyl)-L-homoserine lactone (ODHL), a structure which was unequivocally confirmed by chemical synthesis. The gene (vanI) responsible for ODHL synthesis was cloned and sequenced and shown to belong to the LuxI family of putative AHL synthases. Further sequencing downstream of vanI revealed a second gene (vanR) related to the LuxR family of transcriptional activators. Although deletion of vanI abolished ODHL synthesis, no reduction of either metalloprotease production or virulence in a fish infection model was observed. However, the vanI mutant remained capable of weakly activating both bioluminescence and violacein in the E. coli and C. violaceum biosensors, respectively, indicating the existence of additional layers of AHL-mediated regulatory complexity.

Amino Acid Sequence↗
PubMed1997

Brain of the conscious dog is sensitive to physiological changes in circulating insulin.

The aim of this study was to determine whether a selective, physiologically relevant increase in blood-borne insulin perfusing the brain has an impact on the counterregulatory response to hypoglycemia. Experiments were carried out on 12 conscious 18-h-fasted dogs. Insulin was infused (1 mU x kg(-1) x min(-1)) in separate, randomized studies into a peripheral vein (n = 6) or both carotid and vertebral arteries (n = 6). This resulted in equivalent systemic insulinemia (38 +/- 2 vs. 35 +/- 5 microU/ml) but differing head insulin levels (38 +/- 2 microU/ml during peripheral infusion and an estimated 90 microU/ml during head insulin infusion). Glucose was infused during peripheral insulin infusion to equate the level of hypoglycemia (58 +/- 2 mg/dl) to that obtained during head insulin infusion (57 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and hypoglycemia, incremental area under the curve responses for epinephrine, glucagon and cortisol were increased during head insulin infusion (P < 0.05). Net hepatic glucose output, gluconeogenesis, and lipolysis were increased 50-100% (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog 1) physiologically relevant increases of blood-borne insulin to the head can amplify neuroendocrine and metabolic counterregulatory responses and 2) glucagon secretion can be regulated, in part, by neural efferent activity.

Alanine↗
PubMed1997

Leptin increases energy expenditure and selectively promotes fat metabolism in ob/ob mice.

Obesity occurs whenever energy intake exceeds energy expenditure. The ob gene product leptin is a potent anorectic agent when administered to ob/ob mice, but its effects on energy expenditure have not been investigated in detail. The present study was designed to analyze the acute metabolic effects of leptin in vivo. Analysis of oxygen consumption in ob/ob mice demonstrated a reduction in energy expenditure compared with lean controls; this reduction showed a diurnal fluctuation and was most evident during the light cycle. A single intraperitoneal dose of leptin increased oxygen consumption during the light cycle in ob/ob mice, ablating the circadian fluctuation in this parameter. In addition, leptin had a profound effect on fuel selection: the respiratory quotient was markedly reduced, indicating a reduction in carbohydrate oxidation and an increase in fat oxidation. These acute effects of leptin on metabolic parameters are consistent with the selective loss of body fat observed on chronic leptin treatment and suggest that increased energy utilization plays an important role in the anti-obese actions of leptin.

Analysis of Variance↗
PubMed1997

Histaminergic contribution to the metabolic effects of neuroglucopenia.

We examined the contribution of central histamine receptor (H1 and H2) blockade to the glucoregulatory responses to intracerebroventricular 2-deoxy-D-glucose (2-DG) in conscious dogs. Intracerebroventricular 2-DG (2.5 mg.kg-1.min-1 for 15 min) increased plasma glucose (2-fold), blood lactate (4-fold), and glycerol (2-fold) levels. The rate of hepatic glucose production (Ra), determined isotopically, was increased two-fold. Significant increases over basal were also noted in plasma epinephrine, norepinephrine, insulin, glucagon, and cortisol. Pretreatment with cyproheptadine and cimetidine (100 micrograms each icv 15 min before 2-DG) attenuated the 2-DG-induced hyperglycemia by approximately 50% and delayed and attenuated the increase in glucose Ra (approximately 85% vs. 2-fold in group 1). Pretreatment with H1 and H2 antagonists inhibited the increases in epinephrine, norepinephrine, and glucagon in response to neuroglucopenia but did not affect the cortisol response. These findings suggest that some of the metabolic effects of neuroglucopenia, particularly the hyperglycemic response, the increased hepatic uptake of gluconeogenic precursors, and the enhanced glucose Ra, are partly mediated through central histaminergic receptor activation. This appears to be through effects of histaminergic activation on the autonomic and hormonal responses to central neuroglucopenia.

Alanine↗
PubMed1997

Spirometry values in stable lung transplant recipients.

To clarify the usefulness of spirometry to assess the function of the lung allograft post-transplant, we retrospectively reviewed 351 sequential spirometry measurements performed by 65 healthy recipients after the 80th postoperative day when the clinical evaluation and fiberoptic bronchoscopy with transbronchial biopsies and bronchoalveolar lavage excluded significant rejection or infection in the allograft. The mean coefficients of variation (CV) and significant values for change (SC) for the FVC, FEV1, and FEF25-75% were calculated according to the type of transplant procedure (heart-lung and double-lung [HL-DL] versus single-lung [SL]), and to the time after transplant when the spirometry measurements were obtained < or = 1 yr versus > 1 yr). The SC for the FVC decreased with time after transplantation for both HL-DL (< or = 1 yr: 17% versus > 1 yr: 7%) and SL recipients (< or = 1 yr: 13% versus > 1 yr: 8%). The higher degree of variability within the first year was primarily due to increasing values especially in the HL-DL recipients. The SC for the FEV1 also decreased over time for HL-DL recipients (< or = 1 yr: 18% versus > 1 yr: 9%) but was similar for SL recipients at both intervals (13%). Our results suggest that decreases of > or = 11% in FVC or 12% in FEV1 in HL-DL recipients and > or = 12% in FVC or 13% in FEV1 for SL recipients indicate a significant decrease in allograft function that may be due to infection or rejection.

Forced Expiratory Volume↗
PubMed1997

Hepatic gene expression of apolipoprotein B100 during early lactation in underfed, high producing dairy cows.

The hepatic gene expression of apolipoprotein B, the major protein of very low density lipoproteins in plasma, was studied using 8 Holstein x Friesian cows during the first 12 wk of lactation. Cows were fattened during gestation and were underfed just after parturition to increase fat mobilization and subsequent hepatic steatosis. Intracellular concentrations of apolipoprotein B and apolipoprotein B mRNA and control parameters (albumin, total lipids, RNA, and proteins) were determined in liver samples obtained by biopsy from each cow on four occasions at 1, 2, 4, and 12 wk after calving. Results were compared with those obtained from 5 dry cows in late pregnancy and 4 dry nonpregnant cows. The hepatic concentration of apolipoprotein B was lower (approximately 25%) during wk 1, 2, and 4 after calving, a period of intense liver steatosis (44.2 to 95.7 mg of triglycerides/g of fresh tissue), than for nonsteatotic dry cows (pregnant or nonpregnant); hepatic concentrations were also lower than those during wk 12. In contrast, hepatic concentrations of mRNA coding for apolipoprotein B, total proteins, RNA, and albumin did not vary significantly during early lactation. These results suggested that synthesis of apolipoprotein B during early lactation is specifically regulated at a posttranscriptional level by a decrease in the rate of translation, or by a higher rate of intracellular degradation of apolipoprotein B, or both.

Albumins↗