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Biomedical subjects

M Hudson

Publications and source records attributed to M Hudson.

At least 19 recordsLinked to original sources
PubMed2001

Treatment of reinfarction after thrombolytic therapy for acute myocardial infarction: an analysis of outcome and treatment choices in the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (gusto I) and assessment of the safety of a new thrombolytic (assent 2) studies.

BACKGROUND: Early reinfarction after thrombolytic therapy is associated with adverse outcomes and increased mortality. Among patients with reinfarction in the 1992 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and the 1998 Assessment of the Safety of a New Thrombolytic (ASSENT 2) trials, we investigated temporal and regional differences in the use of repeat thrombolysis, revascularization (angioplasty and/or bypass surgery), or conservative measures and the outcomes of each management strategy. METHODS AND RESULTS: Data from the 4% of patients (n=2301) who experienced reinfarction after thrombolytic therapy were studied. Baseline characteristics, 30-day mortality, and incidence of total and hemorrhagic strokes were compared among the 3 treatment groups. The 30-day mortality did not differ between the repeat thrombolysis and revascularization groups (P=0.72), and it was significantly lower among patients treated by these 2 strategies than in those treated conservatively (11% and 11% versus 28%, respectively; P<0.001). Stroke rates did not differ significantly between the 3 treatment strategies (P=0.49). From 1992 to 1998, the percentage of reinfarction patients treated with repeat thrombolysis decreased from 29.3% to 18.5% in US centers and from 51.4% to 41.9% in all other centers (P<0.001). In contrast, use of revascularization procedures increased from 33.5% to 47.9% in US centers and from 8.1% to 23.0% in all other centers (P<0.001). CONCLUSIONS: Repeat thrombolysis and revascularization are associated with significantly lower mortality among reinfarction patients. Randomized trials are necessary to assess the exact risks and benefits of rethrombolysis versus interventional revascularization in this subset of high-risk patients presenting with reinfarction after thrombolytic therapy.

Aged↗
PubMed2001

Association of single nucleotide polymorphisms in the interleukin-4 gene and interleukin-4 receptor gene with Crohn's disease in a British population.

Interleukin-4 (IL-4) is an important cytokine in mucosal immunity and plays a critical role in the development of colitis in T-alpha cell receptor mutant mice. Functionally significant polymorphisms have been described in the genes encoding IL-4 and IL-4 receptor. To examine the role of these polymorphisms in disease susceptibility 98 patients with ulcerative colitis, 86 patients with Crohn's disease and 321 healthy controls were genotyped for polymorphisms at position -34 in the IL-4 gene and codon 576 in the IL-4 receptor gene. Thirty-two percent of patients with Crohn's disease carried one or two copies of the variant allele for IL-4 compared with 16% of the controls (P = 0.002). Forty-one percent of patients with Crohn's disease carried one or two copies of the variant IL-4 receptor allele compared with 31% of the controls (P = 0.09). Fifteen percent of patients with Crohn's disease carried combination of both (IL-4 and IL-4 receptor) variant alleles compared with 4% of the controls (P = 0.005). Association with alleles resulting in high IL-4 transcription and enhanced signalling activity suggests that IL-4 may have a role in the pathogenesis of Crohn's disease.

Base Sequence↗
PubMed2001

Second malignancy after treatment of childhood acute myeloid leukemia.

To investigate the cumulative incidence of second malignancy and the competing risk of death due to any other cause in patients who were treated for childhood acute myeloid leukemia (AML), we analyzed the outcomes in a cohort of 501 patients who were treated at St Jude Children's Research Hospital between 1970 and 1996. Five patients developed a second cancer (two carcinomas of the parotid gland, one non-Hodgkin's lymphoma, one supratentorial primitive neuroectodermal tumor, one acute lymphoblastic leukemia) as compared with 0.47 expected in the general population (standardized incidence ratio, 10.64; 95% confidence interval, 3.28 to 22.34). A third neoplasm (meningioma) developed in one patient. At 15 years after the diagnosis of AML, the estimated cumulative incidence of second malignancy was 1.34% +/- 0.61%, whereas the cumulative incidence of death due to any other cause was 72.96% +/- 2.14%. We concluded that although a more than 10-fold increased risk of development of cancer was found in survivors of childhood AML as compared to the general population, the risk of this late complication is small when compared to the much larger risk of death because of the primary leukemia or the early complications of its treatment. Future studies should focus on improving treatments for primary AML while preventing second malignancies.

Acute Disease↗
PubMed2001

Recombinant Neisseria meningitidis transferrin binding protein A protects against experimental meningococcal infection.

To better characterize the vaccine potential of Neisseria meningitidis transferrin binding proteins (Tbps), we have overexpressed TbpA and TbpB from Neisseria meningitidis isolate K454 in Escherichia coli. The ability to bind human transferrin was retained by both recombinant proteins, enabling purification by affinity chromotography. The recombinant Tbps were evaluated individually and in combination in a mouse intraperitoneal-infection model to determine their ability to protect against meningococcal infection and to induce cross-reactive and bactericidal antibodies. For the first time, TbpA was found to afford protection against meningococcal challenge when administered as the sole immunogen. In contrast to the protection conferred by TbpB, this protection extended to a serogroup C isolate and strain B16B6, a serogroup B isolate with a lower-molecular-weight TbpB than that from strain K454. However, serum from a TbpB-immunized rabbit was found to be significantly more bactericidal than that from a TbpA-immunized animal. Our evidence demonstrates that TbpA used as a vaccine antigen may provide protection against a wider range of meningococcal strains than does TbpB alone. This protection appears not to be due to complement-mediated lysis and indicates that serum bactericidal activity may not always be the most appropriate predictor of efficacy for protein-based meningococcal vaccines.

Animals↗
PubMed2000

Familial thrombophilia associated with fibrinogen paris V: Dusart syndrome.

We report on a family with a history of venous thromboembolism associated with fibrinogen Paris V (fibrinogen Aalpha-Arg554-->Cys). Ten members experienced thrombotic events, including 4 with fatal pulmonary emboli. Pulmonary embolism was the presenting feature in 4. Those with the mutation and a history of thrombosis had somewhat higher fibrinogen concentrations than those with the mutation and no thrombosis (294 +/- 70 mg/dL vs 217 +/- 37 mg/dL, respectively). The Paris V mutation consistently caused a prolongation of the reptilase time, and fibrin clots containing the abnormal fibrinogen were more translucent than normal clots. Given the early onset of symptoms and the initial presentation with pulmonary embolism in some family members, it was justifiable to offer prophylactic anticoagulation with warfarin to carriers of the mutation. Fibrinogen Paris V has now been reported in 4 apparently unrelated families, indicating that it is a relatively common cause of dysfibrinogenemia-associated thrombosis.

Adolescent↗
PubMed2000

Reduction in incidence of severe paracetamol poisoning.

We report substantial reductions in the frequency of severe paracetamol hepatotoxicity locally and nationally after legislative limitations on its sale. These reductions were not explained by changes in referral patterns or use of N-acetylcysteine.

Acetaminophen↗
PubMed2000

Do gastric and oesophageal varices bleed at different portal pressures and is TIPS an effective treatment?

BACKGROUND: It has been suggested that gastric varices bleed at lower portosystemic pressure gradients (PSPG) than oesophageal varices and that transjugular intrahepatic portosystemic shunt (TIPS) is a particularly effective treatment in these patients. AIMS: This study was undertaken to assess the difference in PSPG measured at the time of TIPS insertion between patients bleeding from gastric and those bleeding from oesophageal varices. Rebleeding and mortality rates between the two groups were also compared. PATIENTS AND METHODS: In a five year period, 64 patients (36 males and 28 females) undergoing TIPS for acute variceal bleeding had PSPG measured at the time of TIPS insertion. 12 patients underwent TIPS for gastric variceal haemorrhage (GVH) and 52 for oesophageal variceal haemorrhage (OVH). The median age was 53 years and 40/64 patients (63%) had alcoholic liver disease. The median Child's Pugh score was 8 for GVH and 9 for OVH patients. Median follow up was 75 weeks. RESULTS: There was no significant difference in median PSPG between patients with GVH, 21 mmHg (range 15-30 mmHg) and OVH, 22 mmHg (range 12-45 mmHg). Following TIPS, PSPG was 8.5 mmHg (range 3-11 mmHg) and 9 mmHg (range 4-20 mmHg) in GVH and OVH patients respectively. Rebleeding occurred in 2/12 (16%) GVH patients and 12/52 (23%) OVH patients (p= 1.0). Mortality during follow up was 25% (4/12) in the GVH and 25% (13/52) in the OVH patients. CONCLUSION: In this study, there was no difference between the pressures at which gastric and oesophageal varices bled. Rebleeding and mortality rates were similar in the two groups. TIPS is equally effective in the treatment of both oesophageal and gastric variceal haemorrhage.

Adult↗
PubMed2000

Late effects in survivors of infant leukemia.

Little is known about the incidence of and risk factor for late effects of infant leukemia. We evaluated 19 children with acute lymphoblastic leukemia and 15 with acute myeloid leukemia who were diagnosed at age 12 months or younger and have survived for more than 5 years after the diagnosis (median length of follow-up, 13 years; range, 5.7-29 years). Ten patients received chemotherapy alone (group A), 17 received chemotherapy and CNS-directed radiation therapy (CRT) (group B), and seven received chemotherapy, CRT and bone marrow transplantation (group C). The most frequently observed late sequelae included problems in growth (66% of survivors), learning (50%), hypothyroidism (15%), and pubertal development (12%). Cataract, cardiac and hearing abnormalities occurred in 6% of patients. Only eight patients (24%) survive without late effects. In comparison to patients in group A, patients in groups B and C had a higher incidence of having at least one late complication (P = 0.009), a greater decrease in height Z score at 5 years after diagnosis (P = 0.023), and a higher incidence of academic difficulties (P = 0.004). The estimated odds of academic difficulties increased by 18% (P = 0.032) for each month younger in age at the time of CRT. These results indicate that late sequelae are common in longterm survivors of infant leukemia and are often related to CRT and the patient's age at the time of CRT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

GPs' employment of locum doctors and satisfaction with their service.

BACKGROUND: Locum doctors provide cover during normal working hours for GPs absent due to holidays, sickness, maternity leave or for educational purposes. However, there is little information on the extent of the use of locums or of GPs' perception of their services. OBJECTIVES: To examine the level of use of locum doctors by GPs, the ease of recruitment and satisfaction with their services. METHODS: A postal survey of all general practices in one of the six health regions in England was carried out. Logistic regression analysis was used to examine the independent effects on locum use of practice size and type of area, source of recruitment and GPs' satisfaction with their services. RESULTS: A total of 935 (80.6%) general practices responded. Locum GPs were employed by 81.7% of practices in the previous 12 months. Two-thirds of practices reported problems obtaining locum cover, especially at short notice and for holiday periods. One-fifth of practices employing a locum in the previous 12 months were dissatisfied with the locum. CONCLUSIONS: There are high demands for, but a considerable shortage of, locum doctors in general practice. Educational and other initiatives for GPs may contribute to increased demands for locum cover. Difficulties in recruitment may be reduced by measures to improve the conditions of employment for doctors working as locums on a longer term basis. New codes of practice for employing locums may increase satisfaction with locum services.

Attitude of Health Personnel↗
PubMed2000

Effect of L-ornithine-L-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial.

BACKGROUND AND AIM: An oral glutamine load in cirrhotic patients awaiting liver transplantation was shown to cause a rise in blood ammonia and psychometric abnormalities which were reversed by hepatic transplantation. L-Ornithine-L-aspartate (LOLA) has been shown to reduce ammonia and improve psychometric function in patients with hepatic encephalopathy. The aim of the present study was to assess the effect of LOLA in healthy patients with cirrhosis and no evidence of clinical encephalopathy after challenging the central nervous system by administration of oral glutamine. PATIENTS AND METHODS: Eight cirrhotics (Child's B or C) without transjugular intrahepatic portosystemic shunts (TIPS) and seven with TIPS underwent two oral glutamine (20 g) challenges, receiving LOLA (5 g intravenously) on one occasion and placebo on the other in random order. Psychometric tests, including choice reaction time (CRT) and number connection test, were performed before and after glutamine, together with electroencephalography and blood ammonia. RESULTS: Mean basal ammonia was 27 (SEM 5) micromol/l in non-TIPS and 76 (10) micromol/l in TIPS patients (p<0.05). Basal CRT 2 was 0.643 (0.033) s in non-TIPS and 0.825 (0.076) s in TIPS patients (p<0.02). In non-TIPS patients, ammonia increased to 36 (10) micromol/l when LOLA was administered and to 62 (13) micromol/l with placebo (p<0.02). There was no alteration in psychometric function in non-TIPS patients after glutamine when LOLA was given but when placebo was given, glutamine caused prolongation of CRT (p=0.02). Glutamine did not affect psychometric function in TIPS patients with or without LOLA. CONCLUSION: This study showed that LOLA ameliorated the deleterious psychometric effects of glutamine in Child's grade B and C patients with cirrhosis without TIPS and supports its use in clinical practice in hepatic encephalopathy.

Ammonia↗
PubMed1999

The FAR1 locus encodes a novel nuclear protein specific to phytochrome A signaling.

The phytochrome family of photoreceptors has a well-defined role in regulating gene expression in response to informational light signals. Little is known, however, of the early steps of phytochrome signal transduction. Here we describe a new Arabidopsis mutant, far1 (far-red-impaired response), which has reduced responsiveness to continuous far-red light, but responds normally to other light wavelengths. This phenotype implies a specific requirement for FAR1 in phyA signal transduction. The far1 locus maps to the south arm of chromosome 4, and is not allelic to photomorphogenic loci identified previously. All five far1 alleles isolated have single nucleotide substitutions that introduce stop codons in a single ORF. The FAR1 gene encodes a protein with no significant sequence similarity to any proteins of known function. The FAR1 protein contains a predicted nuclear localization signal and is targeted to the nucleus in transient transfection assays. This result supports an emerging view that early steps in phytochrome signaling may be centered in the nucleus. The FAR1 gene defines a new multigene family, which consists of at least four genes in Arabidopsis. This observation raises the possibility of redundancy in the phyA-signaling pathway, which could account for the incomplete block of phyA signaling observed in the far1 mutant.

Alleles↗
PubMed1999

poc1: an Arabidopsis mutant perturbed in phytochrome signaling because of a T DNA insertion in the promoter of PIF3, a gene encoding a phytochrome-interacting bHLH protein.

The phytochrome family of informational photoreceptors has a central role in regulating light-responsive gene expression, but the mechanism of intracellular signal transduction has remained elusive. In a genetic screen for T DNA-tagged Arabidopsis mutants affected in early signaling intermediates, we identified poc1 (photocurrent 1), which exhibits enhanced responsiveness to red light. This phenotype is absent in a phyB (phytochrome B) null mutant background, indicating that the poc1 mutation enhances phyB signal transduction. The T DNA insertion in poc1 was found to be located in the promoter region of PIF3, a gene encoding a basic helix-loop-helix protein. The mutant phenotype seems to result from insertion-induced overexpression of this gene in red-light-grown seedlings, consistent with PIF3 functioning as a positively acting signaling intermediate. These findings, combined with data from a separate yeast two-hybrid screen that identified PIF3 as a phytochrome-interacting factor necessary for normal signaling, provide evidence that phytochrome signal transduction may include a direct pathway to photoresponsive nuclear genes via physical interaction of the photoreceptor molecules with the potential transcriptional regulator PIF3.

Arabidopsis↗
PubMed1999

Development of autoimmune hepatitis following liver transplantation for primary biliary cirrhosis.

Two patients undergoing liver transplantation for classical end-stage primary biliary cirrhosis (PBC) are described, who went on to develop de novo autoimmune hepatitis (AIH) in the transplanted liver. The presentation, in both instances, was with malaise and lethargy. Markedly elevated serum transaminases were found, together with a raised serum IgG and/or globulin fraction and histological features on liver biopsy typical of AIH. Both cases had had changes in their immunosuppressive therapy before the onset of AIH episodes, and both rapidly responded to reinstitution of steroid therapy. The finding, in each case, of a coincidental multiple HLA class I allele match between the recipient and their liver donor suggests that HLA class I-restricted mechanisms may play an important role in the pathogenesis of AIH.

Female↗
PubMed1999

Development of a novel bi-specific monoclonal antibody approach for tumour targeting.

To overcome the disadvantages of bi-specific antibody methodologies in vivo, a novel antibody approach has been designed to improve tumour targeting and effector to target ratio. The technique involves biotinylated anti-CD3 Fab fragments and streptavidinylated anti-tumour monoclonal antibodies (mAbs) that can spontaneously form cross-links. We describe here a method for the direct cross-linking of sulphydryl-conjugated HMFG1 (anti-MUC1 mucin mAb) to streptavidin by sulphosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate. Fab fragments generated by papain digestion of the 1452C11 antibody (anti-CD3 mAb without Fc to avoid peripheral activation of T-cells) were biotinylated with NHS-Iminobiotin. MUC1-transfected BALB/c breast cancer cell lines 413BCR and 425CCR and the parental cell line (410.4) were labelled with streptavidinylated mouse anti-MUC1 mucin mAb. BALB/c effector T-cells were separately labelled with biotinylated anti-CD3 Fab fragments (1452C11) and mixed with tumour cells in different effector to target ratios. Percentage of killing was assessed using the 51Cr cytotoxicity assay. Seventy per cent lysis was measured in the case of 413BCR (high MUC1 mucin expressor) and 40% in the case of 425CCR (low expressor) cell line. No lysis was apparent in the MUC1 negative cell line. These results demonstrate that the novel T-cell redirecting approach we have developed can produce effective immune lysis of target cells in vitro.

Animals↗
PubMed1999

The 1microg short Synacthen test in chronic fatigue syndrome.

OBJECTIVE: Many studies suggest mild hypocortisolism in chronic fatigue syndrome (CFS), usually assumed to be due to reduced suprahypothalamic drive to the hypothalamo-pituitary-adrenal (HPA) axis. We wished to explore further the state of the HPA axis in CFS using the 1 microg low dose short Synacthen test. DESIGN: Subjects received an intravenous bolus of 1 microg Synacthen; samples for cortisol estimation were taken at baseline and 2, 10, 20, 30, 40 and 60 minutes after injection. PATIENTS: We tested 20 subjects suffering from CFS according to the criteria of the Center for Diseases Control without psychiatric comorbidity and 20 matched healthy controls. All subjects were drug free for at least 1 month. MEASUREMENTS: We calculated the cortisol responses to the test as the maximum cortisol attained, the incremental rise in cortisol over baseline (Deltavalue) and as the integrated area under the curve. RESULTS: There were no significant differences in baseline cortisol or cortisol responses between patients and controls. However, responses generally were low, and many subjects' peak responses were prior to the standard 30 minute sampling time., CONCLUSIONS These results do not lend support to the theory that patients with chronic fatigue syndrome have a low adrenal reserve. However, results from studies assessing the HPA axis are proving to be inconsistent. We suggest that many other factors may be contributing to HPA axis alterations in chronic fatigue syndrome, including sleep disturbance, inactivity, altered circadian rhythmicity, illness chronicity, concomitant medication and comorbid psychiatric disturbance. These sources of heterogeneity need to be considered in future studies, and may explain the inconsistent findings to date.

Adult↗