Search PubMed⌕ Search

Biomedical subjects

K Butler

Publications and source records attributed to K Butler.

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

The design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors.

The further optimisation of the novel lead compound CGH752 (Fig. 1) is described. By introducing various substituents into the 6-position of the 3,3-dimethyltetrahydroquinoline (DMTHQS) ring we have been able to favourably affect the in vitro and in vivo activity, and the pharmacokinetics of such compounds. One of the inhibitors synthesised (CGH1484) is bioavailable and shows efficacy in animal models of thrombosis.

Administration, Oral↗
PubMed2000

Glycopeptide prescribing in a tertiary referral paediatric hospital and applicability of hospital infection control practices advisory committee (HICPAC) guidelines to children.

UNLABELLED: This study was undertaken to investigate the frequency of, indications for and appropriateness of glycopeptide prescription in a paediatric tertiary referral hospital and to assess the usefulness of the Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines. A prospective audit of all systemic glycopeptide prescriptions over a 2-month period was undertaken. Clinical and microbiological data were recorded. Of 2810 hospital admissions, systemic IV glycopeptides were prescribed on 57 occasions to 50 patients, 30 (52.6%) for vancomycin and 27 (47.4%) for teicoplanin. Prescriptions were for 34 males and 23 females aged from 2 weeks to 11 years (mean 15 months; median 9 months). Median hospital stay was 50 days. Glycopeptides were given to the following patient groups: cardiology 7 (12%), prophylaxis for cardiac surgery 11 (19%), post-cardiac surgery 1 (1.8%), oncology 14 (24.6%), post-gastrointestinal tract surgical 8 (14%), general surgical 9 (15. 8%) and medical 7 (12.3%). Twenty three children (41.8%) had central lines in situ. Reason for use of glycopeptide was therapeutic in 7 (12.3%), empiric in 38 (66.7%), and as prophylaxis in 12 (21.1%). Eight (14%) prescriptions met strict HICPAC criteria, but a further 22 (39%) prescriptions were considered appropriate in this high-risk population. Glycopeptides were chosen appropriately for cardiac surgery prophylaxis in a further 10 (18%) but timing and duration of use in this group was inappropriate. Of all prescriptions, use was empiric in 38 (76%) and appropriate cultures were obtained at the time of commencement in only 13 (34%) of these. Glycopeptides were not used for routine surgical prophylaxis or for first-line empiric treatment of febrile neutropenia. CONCLUSIONS: The strict implementation of HICPAC guidelines may not always be appropriate for children at risk of beta-lactam resistant gram-positive infections. Hospital guidelines need to be tailored to the patient population and microbial susceptibility patterns of each institution. Appropriate cultures should be obtained at the time glycopeptide treatment is begun so that duration of exposure can be limited.

Child↗
PubMed2000

Eradication of vancomycin resistant Enterococcus faecium from a paediatric oncology unit and prevalence of colonization in hospitalized and community-based children.

We previously reported an outbreak of vancomycin resistant enterococci (VRE) in a paediatric oncology unit in December 1995 which was associated with widespread environmental contamination of the unit with VRE. We undertook this study to evaluate the effectiveness of the infection control policy instituted subsequent to the outbreak and to investigate the underlying prevalence of VRE colonization in hospitalized, outpatient and community-based children. We sought to establish the molecular similarity of VRE isolates from the study. Stool specimens were obtained from outpatients at risk of VRE, hospital inpatients and from healthy community-based children. VRE colonization was eradicated from the inpatient unit within 11 months, but in outpatients, 16 months after the outbreak, 4 of 137 (2.9 %) attending oncology outpatients, 5 of 65 (7.7%) with cystic fibrosis and 1 of 12 (8.3 %) with liver disease were found to be colonized with VRE. The isolates were all Enterococcus faecium, Van A phenotype except one E. casseliflavus of the Van C phenotype. All were unique in SmaI DNA macrorestriction patterns with the exception of two isolates, which were similar to the original outbreak strain and three further isolates of a single strain but which differed from the outbreak strain. Of 315 hospital inpatients, 2.5 % were colonized with VRE of the Van C resistance phenotype but VRE was not detected in 116 healthy, community-based children. We conclude that effective strategies can successfully control spread of VRE but despite a low prevalence of VRE colonization in hospital patients and in community-based children, outbreaks can occur when infection control practices are not optimal. Continued vigilance to detect VRE and limit spread within hospitals is therefore necessary.

Adolescent↗
PubMed2000

VRE in the Republic of Ireland: clinical significance, characteristics and molecular similarity of isolates.

There have been increasing reports worldwide of vancomycin resistant enterococci (VRE) since they were first noted over ten years ago. This study sought to investigate the clinical significance of VRE in Ireland and to compare the phenotypic, genotypic and molecular characteristics of isolates recovered from patients in different institutions. The relative contribution of inter-hospital transmission of strains to the dissemination of VRE in Ireland was assessed. Hospital surveillance for VRE is not well established in Ireland. The organism has been detected in seven hospitals. Detection has been predominantly in oncology inpatients in large tertiary referral hospitals in the Dublin metropolitan area in whom strains generally represent asymptomatic gastrointestinal tract colonization. The predominant species is E. faecium with the Van A resistance phenotype. Twenty-seven (87) of 31 isolates from one unit were shown to be of the same or closely related strain as were 10 (63%) of 16 from another unit, indicating significant nosocomial transmission within institutions. There was no evidence for inter-hospital transmission of VRE. VRE is established in Ireland and nosocomial transmission readily occurs. Regular surveillance for VRE is indicated in high-risk populations in large institutions, specific risk factors for the acquisition of VRE need to be defined and optimal control and preventative strategies need to he instituted to detect and preempt the spread of this organism.

Adolescent↗
PubMed2000

Persistent occult hypoperfusion is associated with a significant increase in infection rate and mortality in major trauma patients.

OBJECTIVE: To investigate the hypothesis that occult hypoperfusion (OH) is associated with infectious episodes in major trauma patients. METHODS: Data were collected prospectively on all adult trauma patients admitted to the Surgical/Trauma Intensive Care Unit from November of 1996 to December of 1998. Treatment was managed by a single physician according to a defined resuscitation protocol directed at correcting OH (lactic acid [LA] > 2.4 mmol/L). RESULTS: Of a total of 381 consecutive patients, 118 never developed OH and 263 patients exhibited OH. Seventeen patients were excluded because their LA never corrected, and they all subsequently died. One hundred seventy-six infectious episodes occurred in 97 of the 364 patients remaining. The infection rate in patients with no elevation of LA was 13.6% (n = 118) compared with 12.7% (n = 110) in patients whose LA corrected by 12 hours, 40.5% (n = 79; p < 0.01 compared with all other groups) in patients whose LA corrected between 12 and 24 hours, and 65.9% (n = 57; p < 0.01 compared with all other groups) in patients who corrected after 24 hours. Among the patients with infections, there were 276 infection sites with 42% of infections involving the lung and 21% involving bacteremia. There was no difference in proportion of infections occurring at each site between groups. The mortality rate of patients who developed infections was 7.9% versus 1.9% in patients without infections (p < 0.05). Of the patients who developed infections, 69.8% versus 25.8% (p < 0.001) did not have their lactate levels normalized within 12 hours of emergency room admission. Logistic regression demonstrated that both the Injury Severity Score and OH > 12 hours were independently predictive of infection. CONCLUSION: A clear increase in infections occurred in patients with OH whose lactate levels did not correct by 12 hours, with an associated increase in length of stay, days in surgical/trauma intensive care unit, hospital charges, and mortality.

Acidosis, Lactic↗
PubMed2000

Interrelationships between dietary lysine, sex, and porcine somatotropin administration on growth performance and protein deposition in pigs between 80 and 120 kg live weight.

Sixty male and 60 female crossbred pigs were allocated to an experiment to investigate the effects of porcine somatotropin (pST) administration (0 or 6 mg/d) and dietary lysine content on growth performance, tissue deposition, and carcass characteristics over the live weight range of 80 to 120 kg. Pigs receiving pST were given diets containing 6.9, 7.8, 8.8, 9.7, 10.6, or 11.5 g lysine/kg, whereas control pigs received diets containing 4.8, 5.8, 6.9, 7.8, 8.8 or 9.7 g lysine/kg. These dietary levels ranged from 0.40 to 0.70 g available lysine/MJ of DE for pST-treated pigs and from 0.28 to 0.58 g available lysine/MJ of DE for control pigs. Pigs were individually housed in pens, and there were five replicates of each treatment. All diets contained 14.5 MJ of DE/kg and were offered for ad libitum consumption to pigs between 80 and 120 kg live weight. Growth rate increased exponentially and food conversion ratio (FCR) decreased exponentially with increasing levels of lysine. In addition, there was a significant sex x pST interaction such that pST reduced the sex difference in FCR. Growth rate was faster in boars than in gilts and was increased by pST at the higher levels of dietary lysine. Similarly, FCR was lower for boars than for gilts and was decreased by pST at the higher dietary lysine levels. The optimum growth rate and FCR were defined as the lysine level at which growth rate and FCR were 95% and 105%, respectively, of the lysine plateau. The optimum growth rate and FCR were achieved at similar dietary lysine contents and were approximately 0.35 and 0.52 g available lysine/MJ of DE for control and pST-treated pigs, respectively. Protein deposition in the carcass increased exponentially with increasing dietary lysine level, was higher in boars than in gilts, and was increased by pST at the higher dietary lysine contents. Sex had no effect on dietary lysine required to maximize protein deposition. The dietary lysine contents required to ensure 95% of plateau protein deposition of 104 and 153 g/d were 0.39 and 0.55 g available lysine/MJ of DE for control and pST-treated pigs, respectively. The increase in lysine requirement with pST seems to be commensurate with the increase in protein deposition.

Animal Feed↗
PubMed1999

X-ngnr-1 and Xath3 promote ectopic expression of sensory neuron markers in the neurula ectoderm and have distinct inducing properties in the retina.

Xath3 encodes a Xenopus neuronal-specific basic helix-loop-helix transcription factor related to the Drosophila proneural factor atonal. We show here that Xath3 acts downstream of X-ngnr-1 during neuronal differentiation in the neural plate and retina and that its expression and activity are modulated by Notch signaling. X-ngnr-1 activates Xath3 and NeuroD by different mechanisms, and the latter two genes crossactivate each other. In the ectoderm, X-ngnr-1 and Xath3 have similar activities, inducing ectopic sensory neurons. Among the sensory-specific markers tested, only those that label cranial neurons were found to be ectopically activated. By contrast, in the retina, X-ngnr-1 and Xath3 overexpression promote the development of overlapping but distinct subtypes of retinal neurons. Together, these data suggest that X-ngnr-1 and Xath3 regulate successive stages of early neuronal differentiation and that, in addition to their general proneural properties, they may contribute, in a context-dependent manner, to some aspect of neuronal identity.

Animals↗
PubMed1999

Design and synthesis of thrombin inhibitors: analogues of MD-805 with reduced stereogenicity and improved potency.

Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3, 3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g) had a K(i) of 6 nM (MD-805 K(i) = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

Animals↗
PubMed1999

Anterior endomesoderm specification in Xenopus by Wnt/beta-catenin and TGF-beta signalling pathways.

In Xenopus, XHex and cerberus are early marker genes of the anterior endomesoderm (AE), a subset of endoderm cells fated to form the liver and foregut and implicated in head induction. Using XHex and cerberus as markers we have examined the signals underlying AE induction. We show that the AE is specified by the early blastula in the absence of mesodermal signals but that cell-cell contact between presumptive AE cells is required. In overexpression experiments maternal Wnt/beta-catenin and TGF-beta signals (Vg1, Xnr1-2) can induce ectopic XHex and cerberus. Inhibiting these pathways with dominant interfering signalling components blocks endogenous XHex and cerberus expression. We assess the role of signals from the organiser and show that the BMP antagonists noggin and chordin are important for maintaining XHex and cerberus expression. Finally, ventral injection of XHex mRNA can induce ectopic cerberus. Our results indicate that endodermal and mesodermal patterning are closely coordinated and that the AE is likely to be specified by the combined action of dorsal Wnt/beta-catenin signals and endoderm-specific factors mediated by TGF-beta signalling. These results provide a starting point for understanding the molecular events underlying the progressive determination of endodermally derived organs, such as the liver and foregut.

Animals↗
PubMed1999

Hypoglycemia in multiple trauma victims.

The typical presentation of hypoglycemia involves a diaphoretic patient with a history of diabetes mellitus who is found with an altered mental status. The hypoglycemic patient's presentation may lead the physician to believe that the altered mentation may have been caused by some other condition. Hypoglycemia occurs rarely in the traumatic setting, yet is easily and rapidly diagnosed with bedside testing. A retrospective review was conducted in a university hospital emergency department (ED) (level 1 trauma center) of adult trauma patients with a Glasgow Coma Scale (GCS) score of <15 who had presented from July 1995 through August 1996. Hypoglycemia was defined as a serum glucose level of <60 mg/dL. A total of 926 patients (49% of all trauma cases encountered in the period) met entry criteria. Four (0.4%) cases of hypoglycemia were encountered in 1 nondiabetic and 3 diabetic patients; no patient had medical alert warnings. Rapid bedside screening identified 2 cases within a mean of 7 minutes after arrival; 1 patient had an improvement in mental status after dextrose therapy. Two cases were identified by formal laboratory analysis a mean of 35 minutes after ED arrival; dextrose therapy improved the mental status in 1 patient. These results show that hypoglycemia, rare in trauma patients with abnormal GCS scores, may mimic significant traumatic injury with mental status alterations. Physicians should consider such a diagnosis in patients with an abnormal GCS score and known risk situations for hypoglycemia, including diabetes mellitus and chronic alcohol use; in such cases, appropriate bedside screening should be performed after initial stabilization.

Adult↗
PubMed1999

The golden hour and the silver day: detection and correction of occult hypoperfusion within 24 hours improves outcome from major trauma.

BACKGROUND: The significance of occult hypoperfusion (OH) in the development of respiratory complications (RC), multiple system organ failure (MSOF), and death, and the effect of rapid identification and correction of OH in the severely injured trauma patient was investigated. METHODS: A pilot retrospective study and the analysis of a prospective protocol to correct OH were performed. Pilot study: all trauma patients admitted to our Level I trauma center between February and December of 1995, who survived greater than 48 hours, had an Injury Severity Score greater than or equal to 20, and intensive care unit stays greater than 48 hours were evaluated. Prospective study: patients admitted between January 1, 1996, and April 30, 1997, who survived greater than 24 hours, with Injury Severity Score greater than or equal to 20, and who were hemodynamically stable (systolic blood pressure greater than 100, pulse rate less than 120, and urine output greater than 1 mL/kg per hour) were included. Serum lactic acid (LA) levels were measured at arrival and at proscribed intervals. In the pilot study, initial LA levels were examined in relation to outcome and complications. In the prospective study, patients with two consecutive LA levels greater than 2.5 mmol/L underwent invasive monitoring and vigorous resuscitation to correct their lactic acidosis. RESULTS: Among the 31 patients studied in the pilot study, there were 4 deaths, 6 cases of MSOF, and 13 patients with RC. Lactic acidosis and poor cardiac performance, as evidenced by low cardiac index (CI) with normal filling pressures, were seen in all cases of MSOF and RC, as well as in all deaths. From these results, the prospective study was performed. Eighty-five intensive care unit patients met criteria for inclusion in the study. Six additional patients were excluded because of severe, untreatable intracranial hypertension at admission to the intensive care unit. Fifty-eight of these patients had OH in the first 24 hours. Forty-four patients corrected their OH within 24 hours with vigorous resuscitation. There were no deaths, three cases of MSOF, and 10 cases of RC in those patients who corrected OH within 24 hours. Persistent OH (>24 hours) was seen in 14 patients, despite resuscitative efforts, 43% of whom died. MSOF and RC were present in 36% and 50% of cases, respectively (p<0.05). CONCLUSION: Initial lactic acidosis is associated with lower cardiac performance and higher morbidity and mortality. Persistent OH is associated with higher rates of RC, MSOF, and death after severe trauma. Early identification and aggressive resuscitation aimed at correcting continued elevation in serum lactate improves survival and reduces complications in severely injured trauma patients.

Acidosis, Lactic↗
PubMed1999

Single cells can sense their position in a morphogen gradient.

Xenopus blastula cells show a morphogen-like response to activin by expressing different genes according to the concentration of activin to which they are exposed. To understand how cells recognize their position in a concentration gradient, it is essential to know whether each cell responds individually to activin concentration. An alternative idea, proposed by previous work, is that cells need to interact with their neighbours to generate a concentration-related response. To distinguish between these ideas, we have cultured blastula cells under conditions which provide different degrees of contact with other cells, allowing nil to maximum communication with their neighbours. The cultures include cells attached to fibronectin and cells resting unattached on an agarose base. The cultures also include cells that have no contact with any cell except their clonal progeny, cells that have lateral contact to neighbouring cells, and cells that are completely enveloped by other cells in a reaggregate. We have used RNase protection and in situ hybridization to assay the expression of the activin-responsive Xenopus genes Xbra, Xgsc, Xeomes, Xapod, Xchordin, Mix1, Xlim1 and Cerberus. We find no difference in gene expression between cells attached to fibronectin and those unattached on agarose. Most importantly, we find that cells respond to activin in a concentration-related way irrespective of their degree of contact with other cells. Therefore interaction among cells is not required for the interpretation of morphogen concentration, at least in the case of the early genes studied here. We conclude that isolated blastula cells can sense and respond individually to activin by expressing genes in a concentration-dependent way.

Activins↗
PubMed1999

Quantitative analysis of the cellular components of the fibrous tissue matrix surrounding ALCAP, HA, and TCP bioceramics using adult male rats as a model.

This investigation was specifically an attempt to correlate the thickness of this fibrous capsule and the various histological components that are seen in the fibrous capsule surrounding ALCAP, HA, and TCP ceramics at the S/C and I/P implantation sites in order to further elucidate the mechanisms of tissue-implant interaction. Eighteen male albino rats were randomly divided into three experimental groups (n = 5/group) and one control (n = 3). Animals in Groups I, II, and III were implanted with the ALCAP, HA, and TCP ceramics, respectively. Animals in Group IV were not implanted and acted as the control group. At 90 days post-implantation, the animals in all groups were euthanized and the fibrous tissue surrounding the ceramic devices and internal organs were harvested. After routine histological processing, sections of tissue was stained with hematoxylin and eosin and evaluated using light microscopy. Analysis of the data revealed the following: 1) The presence of macrophages, neutrophils, fibroblasts, vascularity, and thickness of the fibrous tissue matrix was found to be statistically different among the subcutaneously implanted ceramic groups (ANOVA, p < 0.01). 2) The presence of collagen (S/C) is not statistically different among the three ceramic groups (ANOVA, p = 0.76). 3) The presence of macrophages, neutrophils, fibroblasts, and collagen comprising the fibrous tissue surrounding the ALCAP, HA, and TCP ceramics (I/P), was found to be statistically different (ANOVA, p < 0.01). 4) Vascularity and thickness of the fibrous tissue surrounding the three I/P ceramics were not found to be statistically different among the three ceramic groups (ANOVA, p > 0.05).

Aluminum Compounds↗
PubMed1998

Maternal viral load, CD4 cell count and vertical transmission of HIV-1.

HIV load and CD4 cell numbers were measured among 95 HIV infected women during pregnancy in order to determine their value as prognostic markers for transmission of virus from mother to infant. Among the 94 live births, 13 children were infected with HIV, 69 were uninfected and 12 were of unknown infection status. HIV RNA levels, as measured by nucleic acid sequence based amplification, were significantly higher (P < 0.001) in women who transmitted virus than among those who did not transmit and maternal viral load was a stronger predictor of transmission than CD4 cell number. The predicted rate of transmission relative to maternal HIV RNA was 2% at 1,000 copies, 11% at 10,000 copies and 40% at 100,000 copies/ml. Little variation in viral load occurred during pregnancy and there was an association between viral load and prematurity, the mean gestation at delivery decreasing by 1.3 weeks for every 10-fold increase in maternal HIV RNA (P = 0.007). This study demonstrates that a high level of maternal HIV RNA is a risk factor for transmission of virus to the infant and maternal viral load is of more value as a prognostic marker for transmission risk than CD4 cell number. High viral load is also associated with premature delivery. Maternal viral load is therefore a useful marker on which to base management decisions during pregnancy.

CD4 Lymphocyte Count↗
PubMed1998

Control of a nosocomial outbreak of vancomycin resistant Enterococcus faecium in a paediatric oncology unit: risk factors for colonisation.

UNLABELLED: In order to determine the extent of vancomycin resistant enterococcus (VRE) colonisation within a paediatric oncology unit, the risk factors for the acquisition of the organism, the molecular epidemiology of the isolates and the impact of infection control measures, extensive patient and environmental surveillance was undertaken with identification, antibiotic susceptibility testing and pulsed-field gel electrophoresis (PFGE) of all VRE isolates. A matched case control study was carried out. Fourteen patients (19% of screened patients) with VRE colonisation were identified (12 with Enterococcus faecium). All isolates manifested the Van A phenotype. Extensive environmental contamination with VRE was present. PFGE of E. faecium isolates from 10 patients and from five of six environmental cultures revealed patterns suggesting genetic relatedness. Following comparison of the 14 cases with 41 controls matched for age (+/- 4 years) and cohabitation on the oncology unit, risk factors for colonisation with VRE included duration of neutropenia, (OR, 3.72; 95% CI, 1.0-13.1), and antibiotic therapy, (OR, 4.07; 95% CI, 1.08-15.3), the number of antibiotic agents received, (OR, 8.4; 95% CI, 1.34-34.3) and the duration of therapy with amikacin, (OR, 10.7; 95% CI, 1.4-81.5), ceftazidime, (OR, 11.5; 95% CI, 2.2 59.9) or teicoplanin, (OR, 12.3; 95% CI, 2.25-67.4). Implementation of stringent infection control measures reduced environmental contamination from 25% of samples in week 1 to none in week 11. Two additional colonised patients were identified during the subsequent 6 months. CONCLUSION: Risk factors for VRE colonization in paediatric oncology patients included duration of neutropenia, duration of any antibiotic therapy, exposure to ceftazidime, amikacin or teicoplanin and the number of antibiotics used. The study suggests that environmental contamination played an important role in patient-to-patient transmission of VRE and interventions including implementation of infection control measures were associated with a decreased incidence of gastro-intestinal colonisation.

Adolescent↗
PubMed1998

Long-term mechanical circulatory support system reliability recommendation: American Society for Artificial Internal Organs and The Society of Thoracic Surgeons: long-term mechanical circulatory support system reliability recommendation.

Jointly developed by members of the American Society for Artificial Internal Organs and the Society of Thoracic Surgeons along with staff from the Food and Drug Administration, the National Heart, Lung and Blood Institute and other experts, this recommendation describes the reliability considerations and goals for Investigational Device Exemption and Premarket Approval submissions for long-term, mechanical circulatory support systems. The recommendation includes a definition of system failure, a discussion of an appropriate reliability model, a suggested in vitro reliability test plan, reliability considerations for animal implantation tests, in vitro and animal in vivo performance goals, the qualification of design changes during the Investigational Device Exemption clinical trial, the development of a Failure Modes Effects and Criticality Analysis, and the reliability information for surgeons and patient candidates. The document will be periodically reviewed to assess its timeliness and appropriateness within five years.

Animals↗