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Biomedical subjects

M Smith

Publications and source records attributed to M Smith.

At least 289 records · Page 16Linked to original sources
PubMed1999

Cyclosporin A and tacrolimus (FK506) suppress expression of inducible nitric oxide synthase in vitro by different mechanisms.

1 The effects of the immunosuppressant drugs cyclosporin A and tacrolimus (FK506) on nitric oxide synthesis were examined in a murine macrophage cell line (J774) and rat vascular smooth muscle cells (VSMC) in culture for 24 and 48 h, respectively. 2 Cyclosporin A (0.01-10 microM) inhibited by up to 90% accumulation of nitrite induced by lipopolysaccharide (LPS) in both cell lines, but FK506 (0.01-10 microM) had a weaker effect on nitrite accumulation in these cells. Cyclosporin A and FK506 (at 1 microM) also significantly inhibited nitrite production induced by recombinant murine interferon-gamma (rIFNgamma) and recombinant murine interleukin-1beta (rIL-1beta) in J774 and VSMC, respectively. 3 In J774 cells, cyclosporin A (but not FK506) at 1 microM was inhibitory when co-incubated with the inducing agents but not when the cells were treated with the immunosuppressant before or after the inducer. In VSMC, nitrite production was inhibited by co-incubation of cyclosporin A or FK506 with the inducer, or when the immunosuppressants were pre-incubated with cells. In contrast, N-monomethyl L-arginine (NMMA) abolished nitrite production when incubated with either cell type during or after addition of inducing agent, but not if cells were preincubated with NMMA. 4 RNA extracted from treated J774 and VSMC was subjected to reverse transcription-polymerase chain reaction (RT-PCR). Cyclosporin A, but not FK506, suppressed expression of mRNA for NOS2 in a concentration-dependent manner when co-incubated with LPS. 5 The fact that the potency difference between cyclosporin A and FK506 for NO suppression is the opposite to that for inhibition of interleukin-2 generation suggests that the immunosuppressants act in J774 macrophages and VSMC through intracellular mechanisms that differ from those elucidated in T-cells. Cyclosporin A suppresses NOS2 gene transcription, but FK506 acts post-transcriptionally to suppress NO generation in VSMC. 6 Taken together the present data suggest that therapeutic concentrations of cyclosporin A, but not FK506, might well suppress NO production, but FK506 would not have this effect. Suppression of NO might contribute to the side effects of hypertension and nephrotoxicity associated with long-term use of cyclosporin A to prevent transplant rejection.

Animals↗
PubMed1999

Identification of a novel mutation in a non-Jewish factor XI deficient kindred.

The role of factor XI (FXI) in blood coagulation has been clarified in recent years by descriptions of FXI-deficient patients who are prone to excessive bleeding after haemostatic challenge. We have studied a large kindred of an Italian FXI-deficient patient with a previously undescribed mutation. The propositus, a 68-year-old woman, presented with a cerebral thromboembolic event but had no history of bleeding (FXI activity 1.6 U/dl). A sensitive ELISA failed to detect FXI antigen in the propositus. Sequence analysis of the entire FXI gene revealed a TGG to TGC transversion in codon 228 of exon 7 (FXI-W228C). This missense mutation results in a Trp to Cys substitution within the third apple domain of FXI. We conclude that this novel mutation occurred in a structurally conserved region and may therefore have interfered with either chain folding and secretion or stability of FXI and was responsible for the inherited abnormality seen in this kindred. It is unclear why this kindred does not exhibit a bleeding tendency but it may correlate with a FXI-like antigen and factor IX binding activity expressed on platelets.

Aged↗
PubMed1999

Heterozygous factor XI deficiency associated with three novel mutations.

To determine the utility of single-stranded conformation polymorphism (SSCP) analysis for screening mutations in the factor XI (fXI) gene, we investigated three patients with heterozygous factor XI deficiency. DNA sequence analysis confirmed three novel mutations; a CGC --> TGC (Arg308Cys) mutation in exon 9, a GCT-->GTT (Ala412Val) mutation in exon 11 and an AGC --> AGA (Ser576Arg) mutation in exon 15. We postulated on the structural implications of these missense mutations. Our results demonstrated that genotypic analysis is a useful tool for conclusive differentiation between heterozygous factor XI deficiency and normal subjects.

Factor XI Deficiency↗
PubMed1999

An assessment of prochlorperazine buccal for the prevention of nausea and vomiting during intravenous patient-controlled analgesia with morphine following abdominal hysterectomy.

The effectiveness of prochlorperazine buccal as an anti-emetic for the prevention of post-operative nausea and vomiting in patients using intravenous patient-controlled analgesia with morphine following abdominal hysterectomy has been assessed in a randomized, double-blind, placebo-controlled study. Forty-nine female patients participated with 26 allocated to the prochlorperazine buccal group and the remainder to the placebo group. Each received either placebo or prochlorperazine buccal 6 mg, in each case by the buccal route, 1 h prior to anaesthesia with further doses at 6, 18, 30 and 42 h, respectively. Symptom scores in respect of nausea, pain and sedation, the number without nausea, the number without vomiting and the requirement for rescue anti-emetic therapy were noted for each 4-h period during the 48-h study. Morphine utilization and taste associated with the study material were recorded. Data for 21 patients in the placebo group and 25 patients in the prochlorperazine buccal group were available for analysis. Patients in the prochlorperazine buccal group showed significantly lower mean nausea scores at 4-8 h (placebo group: mean nausea score 0.95; prochlorperazine buccal group: mean nausea score 0.36; P < 0.05) and at 16-20 h (placebo group: mean nausea score 1.24; prochlorperazine buccal group: mean nausea score 0.48; P < 0.05). Furthermore, the prochlorperazine buccal group showed significantly more patients without nausea at 4-8 h (placebo group: 11 patients out of 21; prochlorperazine buccal group: 20 patients out of 25; P < 0.05) and at 16-20 h (placebo group: nine patients out of 21; prochlorperazine buccal group: 18 patients out of 25; P < 0.05). The prochlorperazine buccal group showed a significantly higher number of patients rating the taste as unsatisfactory (placebo group: two patients out of 21; prochlorperazine buccal group: nine patients out of 25; P < 0.05). Intravenous droperidol is the current gold standard prophylactic anti-emetic in post-operative nausea and vomiting associated with intravenous patient controlled analgesia with morphine usage. This study has demonstrated a peri-operative prochlorperazine buccal regimen to be effective in post-operative nausea and vomiting prophylaxis in the use of intravenous patient controlled analgesia with morphine. Prochlorperazine buccal should be considered as an effective, inexpensive option for the prevention of post-operative nausea and vomiting in post-operative intravenous patient controlled analgesia with morphine administration.

Administration, Buccal↗
PubMed1999

Expression of B7.1 in a MUC1-expressing mouse mammary epithelial tumour cell line inhibits tumorigenicity but does not induce autoimmunity in MUC1 transgenic mice.

The MUC1 epithelial mucin, which is overexpressed and aberrantly glycosylated in breast and other carcinomas, is also expressed on the apical surface of most normal glandular epithelial cells. Since clinical trials evaluating the efficacy of MUC1-based vaccines have been initiated in breast cancer patients, it is important to address the question of whether an effective immune response to the cancer associated mucin can be generated without inducing autoimmunity. Since non-classic cytotoxic T lymphocyte (CTL) responses to MUC1 have been reported, it is also relevant to examine the role of costimulatory molecules in the effective presentation of MUC1 based antigens. We have therefore looked at the effect of expressing B7.1 on the tumorigenicity of a MUC1 expressing mammary epithelial cell line (410.4) in a transgenic mouse expressing MUC1 on its normal glandular epithelial tissues. Coexpression of B7.1 with MUC1 in 410. 4 cells resulted in a dramatic inhibition of tumour growth which depended on the activity of CD4+ and CD8+ T cells. The epithelial tissues in the transgenic mice able to reject the B7.1, MUC1-expressing tumours showed no evidence of degeneration and the mice survived their normal life span. The results demonstrate that an immune response to the MUC1 antigen can be induced in MUC1 transgenic mice and that presentation of the antigen, whether directly or by cross-priming, is markedly enhanced by coexpression of B7.1.

Animals↗
PubMed1999

An investigation of the components of best nursing practice in the care of acutely ill hospitalized older patients with coincidental dementia: a multi-method design.

The main aim of this study was to examine, from the consumer's perspective, the components of best nursing practice in the care of acutely ill hospitalized elderly people who coincidentally suffered from dementia. Due to the complexity of the problem under investigation a triangulated design was formulated. This design comprised survey methodology, audit and critical incident technique. Data derived from each of these approaches were analysed first in isolation and subsequently combined at a conceptual level. The sample comprised 213 people aged 65 years and older, who were consecutive admissions from two acute medical and two acute care of elderly people wards. Sixty-six per cent of these individuals were found to suffer from cognitive impairment, 40% experiencing severe problems. The documentary survey revealed that patients with normal or severely abnormal cognitive functioning were more likely to have this noted than those with mild-moderate levels of impairment. No evidence of formal assessment was located and only 15% of these patients had items included in their nursing care plans associated with their chronic confusion. A sub-sample of 41 chronically confused people and their main hospital visitor were invited to participate in critical incident interviews. These conversations led to the identification of four major themes which reflected the most valued aspects of the nursing care which had been received or observed. The relationship between documentary care scores and the proportion of positive descriptions of care within each of the four themes was explored. The findings indicate that acute nursing care is deemed only to be at its best when it is delivered in tandem with dementia care. Discrete areas for practice development are identified and standards to guide nursing care are proposed. In addition to the practice development issues raised by the work, the methodological lessons further advance the practice of multi-method research.

Acute Disease↗
PubMed1999

The widely conserved Era G-protein contains an RNA-binding domain required for Era function in vivo.

Era is a small G-protein widely conserved in eubacteria and eukaryotes. Although essential for bacterial growth and implicated in diverse cellular processes, its actual function remains unclear. Several lines of evidence suggest that Era may be involved in some aspect of RNA biology. The GTPase domain contains features in common with all G-proteins and is required for Era function in vivo. The C-terminal domain (EraCTD) bears scant similarity to proteins outside the Era subfamily. On the basis of sequence comparisons, we argue that the EraCTD is similar to, but distinct from, the KH RNA-binding domain. Although both contain the consensus VIGxxGxxI RNA-binding motif, the protein folds are probably different. We show that bacterial Era binds RNA in vitro and can form higher-order RNA-protein complexes. Mutations in the VIGxxGxxI motif and other conserved residues of the Escherichia coli EraCTD decrease RNA binding in vitro and have corresponding effects on Era function in vivo, including previously described effects on cell division and chromosome partitioning. Importantly, mutations in L-66, located in the predicted switch II region of the E. coli Era GTPase domain, also perturb binding, leading us to propose that the GTPase domain regulates RNA binding in response to unknown cellular cues. The possible biological significance of Era RNA binding is discussed.

Amino Acid Motifs↗
PubMed1999

Establishing a new university department of rural health: the first 2 years of the South Australian Centre for Rural and Remote Health.

This study aimed to describe the establishment of a new University Department of Rural Health (UDRH) in South Australia and to report early achievements. In May 1997, the UDRH was established, key staff were recruited, infrastructure was developed and in April 1998 a Joint University Committee on Rural and Remote Health was formed. By mid-1999, 14 full-time equivalent staff were employed in Whyalla and Adelaide. Early achievements include: review of undergraduate rural placements; increased rural clinical placements by 1000 student-weeks; partnership with the Dental School resulting in training opportunities and falling public waiting lists; multidisciplinary teaching practices in four rural sites; priority public health projects established; competitive research grants won; and a capital grant to strengthen Aboriginal health services infrastructure secured. These early achievements demonstrate UDRH potential to have a real impact on health worker education, service delivery, and public health status in rural and remote areas. This strong foundation must now be built on.

Curriculum↗
PubMed1999

Necrotizing enterocolitis in infants born to women with severe early preeclampsia and absent end-diastolic umbilical artery doppler flow velocity waveforms.

The aim of this study was to determine the prevalence of necrotizing enterocolitis (NEC) in infants born to a homogeneous group of women with severe preeclampsia before 34 weeks' gestation and who had absent end-diastolic umbilical artery Doppler flow (AEDF) or normal umbilical Doppler flow velocities (NUFV). A total of 242 infants were entered into the study. The mean birth weight was 1260.5 g (SD = 339) and the mean gestational age 30.5 weeks (SD = 2.0). Sixty-eight (28%) infants had AEDF, 43 (18%) had umbilical artery Doppler flow velocities between the 95th and 99th percentile, and 131 (54%) had NUFV. Forty-one (18%) infants developed NEC, of whom 20 (8%) developed definite and advanced NEC (grade 2 and 3). Of these, 16(80%) had grade 2 and 4(20%) had grade 3. Twenty-one (8%) infants developed suspected NEC (grade 1). The mean onset of grade 1 NEC (7.2 days) occurred significantly earlier than in those with grades 2 and 3 NEC (18.7 and 23.3 days, respectively). Of the 21 infants with grade 1 NEC, 10 (48%) had AEDF and 9 (43%) had NUFV. None of the infants with grades 2 or 3 NEC had AEDF. We conclude that although chronically hypoxemic fetuses born to women with severe early onset preeclampsia and AEDF respond by redistributing blood flow to vital organs and away from the gut; the intestinal compromise is of insufficient magnitude to induce intestinal necrosis or NEC. Enteral feeding, however, should be introduced cautiously in infants with AEDF, as so-called suspected NEC developed significantly more often in these infants.

Blood Flow Velocity↗
PubMed1999

Continuous measurement of cerebral oxygenation by near infrared spectroscopy during induction of anesthesia.

UNLABELLED: Near infrared spectroscopy (NIRS) measures tissue oxygenation continuously at the bedside. Major disturbances of cerebral oxygenation can be detected by using NIRS, but the ability to observe smaller changes is poorly documented. Although anesthetics generally depress cerebral metabolism and enhance oxygen delivery, the administration of etomidate has been associated with cerebral desaturation. We used this difference to study the ability of NIRS to detect the small changes associated with the onset of anesthesia. Thirty-six healthy patients were randomly allocated to have anesthesia induced with either etomidate, propofol, or thiopental. We found that there was a temporal association between the onset of anesthesia and NIRS-derived indices of cerebral oxygenation. Etomidate was associated with a decrease in cerebral oxygenation, whereas propofol and thiopental were associated with an increase in cerebral oxygenation. We conclude that NIRS is capable of detecting the small changes in cerebral oxygenation associated with the induction of general anesthesia and shows promise as a bedside investigational tool for the noninvasive assessment of cerebral oxygenation. IMPLICATIONS: We conclude that near infrared spectroscopy is capable of detecting the small changes in cerebral oxygenation associated with the induction of general anesthesia and shows promise as a bedside investigational tool for the noninvasive assessment of cerebral oxygenation.

Adult↗
PubMed1999

Immediate breast reconstruction with the TRAM flap after neoadjuvant therapy.

Neoadjuvant therapy is a relatively new weapon in the chemotherapeutic arsenal against breast carcinoma. However, there has been concern that preoperative chemotherapy might lead to an increased incidence of complications and delays in postoperative treatment. A retrospective study was performed at M.D. Anderson Cancer Center of all patients with locally advanced breast cancer who had undergone neoadjuvant therapy followed by mastectomy and immediate reconstruction with the transverse rectus abdominis musculocutaneous (TRAM) flap. Patients were evaluated for the incidence of complications and any delays in resumption of postoperative chemotherapy. Thirty-one patients underwent immediate reconstruction with the TRAM flap. Twenty-two patients were reconstructed with free TRAM flaps whereas 9 patients were reconstructed with pedicled TRAM flaps. Seventeen patients (55%) had complications postoperatively, but only 2 patients (6%) had a delay in the resumption of chemotherapy. Seven patients were smokers, five (71%) of whom had complications, which was not a significant difference from the rate in nonsmokers (50%). Although delays in postoperative chemotherapy occurred in smokers (29%, vs. 0% in nonsmokers), the number of patients was too small to attain statistical significance. Based on this study it is felt that immediate reconstruction with the TRAM flap can be performed safely in patients on a neoadjuvant protocol. Although not contraindicated, immediate reconstruction with the TRAM flap in smokers in this setting may be associated with higher morbidity.

Breast Neoplasms↗
PubMed1999

Phase II study of raltitrexed ('Tomudex') for patients with advanced soft tissue sarcomas refractory to doxorubicin-containing regimens.

Advanced soft tissue sarcomas (ASTS) refractory to therapy with doxorubicin and/or ifosfamide are highly resistant to therapy with other cytotoxic agents. The efficacy and safety of raltitrexed ('Tomudex') was assessed in patients with ASTS refractory to one or two doxorubicin- and/or ifosfamide-containing regimens in eight centers of the EORTC STBSG group. Raltitrexed was given at 3 mg/m2 as a 15 min i.v. infusion once every 3 weeks. Among the 23 patients [mean age 54 (range 25-73) years] included, 22 patients (15 males and seven females) were eligible and evaluable for response to therapy and 21 were evaluable for toxicity. Patients had previously received chemotherapy in metastatic phase (n=16), as adjuvant treatment (n=5) or both (n=1). The primary tumor was located in the trunk (n=11), in the limbs (n=8) or in the head and neck (n=3). Most patients (n=13) received two courses of raltitrexed (range 1-8). The best response was stable disease in five (23%) patients, while disease progression was noted in 17 patients (77%); the median time to disease progression was 6 weeks. The treatment was well tolerated with only one patient experiencing grade 4 neutropenia and thrombocytopenia, one patient experiencing grade 3 nausea, one lethargy, one headache, and one asthenia. Only one patient experienced febrile neutropenia. Raltitrexed as monotherapy is not an effective treatment for patients with ASTS who failed conventional chemotherapy with doxorubicin and ifosfamide.

Adult↗
PubMed1999

Immunity to breast cancer in mice immunized with X-irradiated breast cancer cells modified to secrete IL-12.

A mouse mammary adenocarcinoma cell line (410.4) originating in a BALB/c mouse, was transduced with a retroviral vector (TGF-mIL-12-Neo) that encoded murine IL-12. After confirmation of IL-12-secretion, the cells were tested for their tumorigenic properties in BALB/c mice. The results indicated that unlike other tumors modified for cytokine secretion, modification of 410.4 cells to secrete IL-12 (410.4-IL-12 cells) failed to eliminate the cells' neoplastic growth properties. Progressively growing tumors of 410.4-IL-12 cells invariably formed in syngeneic BALB/c mice and led, eventually, to the animals' death. However, the cells' immunogenic properties were preserved as indicated by the finding that immunizations with 410.4-IL-12 cells, inactivated before injection by X-irradiation, resulted in potent, long-term immunity toward unmodified 410.4 cells and protected the mice against the malignant proliferation of the breast cancer cells. We conclude that modification of 410.4 cells for IL-12-secretion augmented the response of syngeneic BALB/c mice to weakly immunogenic tumor-associated antigens expressed by the cells. The increase in the cells' immunogenic properties, however, was insufficient to prevent tumor growth in the mice. The results point toward the immunotherapeutic potential of X-irradiated tumor cells modified for the secretion of immune augmenting cytokines.

Adenocarcinoma↗
PubMed1999

Intraindividual variability and reliability in a 7-day exercise record.

PURPOSE: High levels of day-to-day or intraindividual variability implies unreliability of a measure of physical activity. Unreliability in a measure leads to attenuation of correlations with other variables. As intraindividual variability increases, the number of days necessary to assess physical activity to achieve the desired level of reliability increases. The use of an intraclass correlation to assess day-to-day reliability in a measure assumes compound symmetry. METHODS: This study reports on these issues in a sample of 165 elementary school teachers who maintained a 7-d record of physical activity each year for 3 yr. Analyses were conduced with physical activity measured as minutes, MET minutes, and kcal. Analyses were conducted with PROC MIXED in SAS controlling for the clustering effect by school. RESULTS: Compound symmetry could not be supported across 7 d of the record. The weekdays tended to intercorrelate, Saturday correlated at very low levels, and Sunday correlated with Monday only. Compound symmetry was supported across the three weeks. CONCLUSIONS: To achieve a reliability of 0.8 using a 7-d activity record requires 2 wk of assessment. The reliability of measures of physical activity require more careful attention, and likely require more points of assessment to achieve desired levels.

Activities of Daily Living↗
PubMed1999

An open label, randomised, crossover study comparing sotalol and atenolol in the treatment of symptomatic paroxysmal atrial fibrillation.

OBJECTIVE: To compare sotalol and atenolol in the treatment of symptomatic paroxysmal atrial fibrillation. DESIGN: Prospective, randomised, open label, crossover study. SETTING: University hospital. PATIENTS: 47 subjects aged over 50 years were recruited from the hospital outpatient department following ECG documentation of paroxysmal atrial fibrillation that coincided with symptoms. Six patients withdrew and 41 completed the trial. INTERVENTIONS: Patients were randomised to one month's treatment with sotalol 80 mg twice daily or atenolol 50 mg once daily. Treatment arms were then crossed over. Patients underwent 72 hour Holter monitoring before randomisation and repeat studies were carried out at the end of both treatment periods. Symptom assessments were completed using linear analogue scales and the Nottingham health profile. MAIN OUTCOME MEASURE: Frequency of paroxysmal atrial fibrillation; secondary outcome measures included average and total duration of paroxysmal atrial fibrillation, total ectopic count, and symptom assessments. RESULTS: A reduction in the number and duration of episodes of paroxysmal atrial fibrillation was noted following treatment with sotalol and atenolol. There was no difference in frequency of paroxysmal atrial fibrillation during treatment with sotalol or atenolol (median difference 0; 95% confidence interval (CI) 0 to 1; p = 0.47). There was no difference in total duration of paroxysmal atrial fibrillation (median difference 0 min; 95% CI -1 to 2; p = 0. 51) or in average duration (median difference 0 min; 95% CI 0 to 1; p = 0.31). No difference was found in total ectopic count between sotalol and atenolol (median difference -123; 95% CI -362 to 135; p = 0.14). Treatments were equally tolerated with no difference in linear analogue scores for symptoms of paroxysmal atrial fibrillation (median difference -5; 95% CI -20 to 5; p = 0.26) or in all categories of the Nottingham health profile. CONCLUSIONS: No difference was found in terms of ECG or symptomatic control of paroxysmal atrial fibrillation between prescribing sotalol 80 mg twice daily and atenolol 50 mg once daily. There was an improvement in paroxysmal atrial fibrillation from baseline following treatment with either sotalol or atenolol.

Adrenergic beta-Antagonists↗