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Biomedical subjects

M Hull

Publications and source records attributed to M Hull.

At least 19 recordsLinked to original sources
PubMed1999

The receptor recycling pathway contains two distinct populations of early endosomes with different sorting functions.

Receptor recycling involves two endosome populations, peripheral early endosomes and perinuclear recycling endosomes. In polarized epithelial cells, either or both populations must be able to sort apical from basolateral proteins, returning each to its appropriate plasma membrane domain. However, neither the roles of early versus recycling endosomes in polarity nor their relationship to each other has been quantitatively evaluated. Using a combined morphological, biochemical, and kinetic approach, we found these two endosome populations to represent physically and functionally distinct compartments. Early and recycling endosomes were resolved on Optiprep gradients and shown to be differentially associated with rab4, rab11, and transferrin receptor; rab4 was enriched on early endosomes and at least partially depleted from recycling endosomes, with the opposite being true for rab11 and transferrin receptor. The two populations were also pharmacologically distinct, with AlF4 selectively blocking export of transferrin receptor from recycling endosomes to the basolateral plasma membrane. We applied these observations to a detailed kinetic analysis of transferrin and dimeric IgA recycling and transcytosis. The data from these experiments permitted the construction of a testable, mathematical model which enabled a dissection of the roles of early and recycling endosomes in polarized receptor transport. Contrary to expectations, the majority (>65%) of recycling to the basolateral surface is likely to occur from early endosomes, but with relatively little sorting of apical from basolateral proteins. Instead, more complete segregation of basolateral receptors from receptors intended for transcytosis occurred upon delivery to recycling endosomes.

Aluminum Compounds↗
PubMed1999

Comparison of therapy detection times between implantable cardioverter defibrillators with standard dual- and single-chamber pacing.

Previous implantable cardioverter defibrillators (ICDs) required patients in need of dual-chamber (DDD) pacing for improved hemodynamic status to undergo implantation of separate devices to treat bradycardia and/or ventricular arrhythmias. An investigation was conducted to verify the performance of a new ICD that combines both therapies.Sixty-nine patients at 17 European and Canadian centers were implanted with VENTAK AV models 1810/1815, ICD's that includes DDD pacing and algorithms designed to differentiate between atrial and ventricular arrhythmias. 36 of the cohort were compared to 32 patients tested at six centers with an external test device (VENTAK MINI). In both cohorts detection times were calculated for ventricular fibrillation (VF) induced at implant. The mean detection times (DT) from the VENTAK AV device were compared to the DT from the VENTAK MINI device. Patient characteristics of the VENTAK AV and the VENTAK MINI control groups were similar. Mean VF detection time (+/-SD) with the VENTAK AV device was 2.21 +/- 0.54 seconds, as compared with 1.87 +/- 0.62 seconds with the VENTAK MINI (p < 0.01), indicating that the difference in means did not exceed one second. The VENTAK AV system function did not demonstrate interaction with the pacemaker function, as indicated by the clinical significance with the detection times of the study device. The difference in detection times between cohorts did not statistically exceed one second. Appropriate detection of the new ICD was not compromised by the addition of the dual-chamber pacing therapy.

Adolescent↗
PubMed1999

Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist.

BACKGROUND: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration. AIM: To investigate whether acute gastroduodenal injury induced in humans by aspirin can be prevented by the endothelin-1 antagonist, bosentan. METHODS: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misoprostol 400 mg). Treatment order was randomized by Latin square design. Subjects were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured up to 5 h post-dose. RESULTS: There was a significant reduction in the mean number of erosions in the aspirin plus bosentan and aspirin plus misoprostol groups after the first dose of aspirin, compared with controls (aspirin plus placebo) (P<0.05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group. The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the 1st dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02). CONCLUSION: Endothelin receptor antagonism by bosentan can protect the gastric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be effective.

Adult↗
PubMed1999

Older road users. Issues for general practitioners.

BACKGROUND: As our population ages it is anticipated that a greater number of older drivers will be on the roads. This raises the possibility of an increased number of road crashes. Predictors of increased risk of road accidents need to be identified in order for appropriate advice to be given on how to reduce the road risk. OBJECTIVE: This article aims to provide insights about the problems posed by older drivers together with practical guidance for general practitioners. DISCUSSION: Advice from medical practitioners is often heeded by older patients in relation to their ability to drive. Using resources such as Assessing Fitness to Drive will aid the GP in making an informed decision in relation to this.

Accidents, Traffic↗
PubMed1998

Ground and surface water developmental toxicity at a municipal landfill: description and weather-related variation.

Contaminated groundwater poses a significant health hazard and may also impact wildlife such as amphibians when it surfaces. Using FETAX (Frog Embryo Teratogenesis Assay-Xenopus), the developmental toxicity of ground and surface water samples near a closed municipal landfill at Norman, OK, were evaluated. The groundwater samples were taken from a network of wells in a shallow, unconfined aquifer downgradient from the landfill. Surface water samples were obtained from a pond and small stream adjacent to the landfill. Surface water samples from a reference site in similar habitat were also analyzed. Groundwater samples were highly toxic in the area near the landfill, indicating a plume of toxicants. Surface water samples from the landfill site demonstrated elevated developmental toxicity. This toxicity was temporally variable and was significantly correlated with weather conditions during the 3 days prior to sampling. Mortality was negatively correlated with cumulative rain and relative humidity. Mortality was positively correlated with solar radiation and net radiation. No significant correlations were observed between mortality and weather parameters for days 4-7 preceding sampling.

Animals↗
PubMed1998

Infections with nonthoracotomy implantable cardioverter defibrillators: can these be prevented? Endotak Lead Clinical Investigators.

Nonthoracotomy ICDs are believed to be the best therapeutic modality for treatment of life-threatening ventricular arrhythmias. Little is known about the risk of infection with initial implantation of these devices. We studied the incidence, clinical characteristics, and risk factors associated with infections in 1,831 patients with nonthoracotomy ICD from the Endotak-C nonthoracotomy lead registry of Cardiac Pacemakers, Inc. A transvenous lead was implanted in 950 patients (51.9%) and a combination transvenous plus subcutaneous patch was used in 881 patients (48.1%). Nine preselected data variables were studied, and all investigators identified as having patients with infections were personally contacted. Infections occurred in 22 (1.2%) of 1,831 patients receiving this nonthoracotomy ICD system. The mean time to infection was 5.7 +/- 6.5 months (range 1-25 months). Staphylococci were isolated in 58% of patients with reported infection. The presence of a subcutaneous defibrillator patch system was associated with the development of infection. Six of 950 patients (0.63%) with a totally transvenous lead system developed infection versus 16 of 838 (1.9%) patients with a transvenous lead plus subcutaneous patch system configuration (P = 0.015, Chi-square test), with an unadjusted estimated odds ratio of 3.06 (CI 1.19-7.86). The risk of infection encountered with the nonthoracotomy ICD is low, estimated from our data to be 1.2%. Placement of a subcutaneous defibrillator patch appears to be an independent risk factor for development of infection.

Adolescent↗
PubMed1997

Developmental regulation of MHC class II transport in mouse dendritic cells.

Dendritic cells (DCs) have the unique capacity to initiate primary and secondary immune responses. They acquire antigens in peripheral tissues and migrate to lymphoid organs where they present processed peptides to T cells. DCs must therefore exist in distinct functional states, an idea that is supported by observations that they downregulate endocytosis and upregulate surface molecules of the class II major histocompatibility complex (MHC) upon maturation. Here we investigate the features of DC maturation by reconstituting the terminal differentiation of mouse DCs in vitro and in situ. We find that early DCs, corresponding to those found in peripheral tissues, exhibit a phenotype in which most class II molecules are intracellular and localized to lysosomes. Upon maturation, these cells give rise to a new intermediate phenotype in which intracellular class II molecules are found in peripheral non-lysosomal vesicles, similar to the specialized CIIV population seen in B cells. The intermediate cells then differentiate into late DCs which express almost all of their class II molecules on the plasma membrane. These variations in class II compartmentalization are accompanied by dramatic alterations in the intracellular transport of the new class II molecules and in antigen presentation. We found that although early DCs could not present antigen immediately after uptake, efficient presentation of the previously internalized antigen occurred after maturation, 24-48 hours later. By regulating class II transport and compartmentalization, DCs are able to delay antigen display, a property crucial to their role in immune surveillance.

Amino Acid Sequence↗
PubMed1997

Mitotic phosphorylation of rab4 prevents binding to a specific receptor on endosome membranes.

Phosphorylation of the monomeric GTPase rab4 in mitotic cells leads to its relocalization from endosome membranes to the cytosol. To determine the mechanism underlying this change in distribution, we established an in vitro assay that reconstituted specific binding of rab4 when endosome-containing membranes were incubated with rab4 complexed with its cytosolic chaperone, GDP dissociation inhibitor (GDI). rab4 was found to bind to a saturable receptor associated with highly purified endosomes. Membrane binding and nucleotide exchange were physically distinct, since an active soluble fragment of the rab4 receptor, but not rab4 nucleotide exchange activity, could be released from membranes by elastase cleavage. Interestingly, the soluble fragment could be used to fully reconstitute rab4 membrane binding. In vitro phosphorylation of rab4 by cdc2/cyclin B kinase did not affect formation of rab4-GDI complexes, but did completely inhibit rab4 binding to its receptor. In contrast, in vitro phosphorylation of membranes did not result in the dissociation of bound rab4, nor were mitotic membranes deficient with respect to binding non-phosphorylated rab4. Thus, mitotic cells appear to accumulate rab4 in the cytosol by phosphorylating rab4 during the soluble phase of its normal activity cycle, thereby preventing membrane attachment.

Animals↗
PubMed1997

Can we identify who will adhere to long-term physical activity? Signal detection methodology as a potential aid to clinical decision making.

Signal detection methodology was used to identify the best combination of predictors of long-term exercise adherence in 269 healthy, initially sedentary adults ages 50-65 years. Less educated individuals who were assigned to supervised home-based exercise of either higher or lower intensity and who were less stressed and less fit at baseline than other individuals had the greatest probability of successful adherence by the 2nd year. Overweight individuals assigned to a group-based exercise program were the least likely to be successful 2 years later. Predictors of short-term (1-year) adherence were generally similar to predictors of 2-year adherence. Signal detection analysis may be useful for identifying subgroups of people at risk for underadherence who subsequently might be targeted for intervention.

Aged↗
PubMed1996

Circadian variation in defibrillation energy requirements.

BACKGROUND: Reports have demonstrated a circadian variation in the incidence of acute myocardial infarction, ventricular arrhythmias, and sudden cardiac death. We tested the hypothesis that a similar circadian variation exists for defibrillation energy requirements in humans. METHODS AND RESULTS: We reviewed the time of defibrillation threshold (DFT) measurements in 134 patients with implantable cardioverter-defibrillators (ICDs) who underwent 345 DFT measurements. The DFT was determined in 130 patients at implantation, in 121 at a 2 months, and in 94 at 6 months. All patients had nonthoracotomy systems. The morning DFT (8 AM to 12 noon) was 15.1 +/- 1.2 J compared with 13.1 +/- 0.9 J in the midafternoon (12 noon to 4 PM) and 13.0 +/- 0.7 J in the late afternoon (4 to 8 PM), P < .02. In a separate group of 930 patients implanted with an ICD system with date and time stamps for each therapy, we reviewed 1238 episodes of ventricular tachyarrhythmias treated with shock therapy. To corroborate the hypothesis that energy requirements for arrhythmia termination vary during the course of the day, we plotted the failed first shock frequency for all episodes per hour. There was a significant peak in failed first shocks in the morning compared with other time intervals (P = .02). CONCLUSIONS: There is a morning peak in DFT and a corresponding morning peak in failed first shock frequency. This morning peak resembles the peaks seen in other cardiac events, specifically sudden cardiac death. These findings have important implications for appropriate ICD function, particularly in patients with marginal DFTs.

Aged↗
PubMed1994

Stage II and III-A non-small cell cancer of the lung: results of surgical resection at Fairfax Hospital.

Carcinoma of the lung is the single leading cause of death in patients with cancer and is responsible for over a quarter of all such deaths. Encouraging survival rates have been demonstrated following surgical resection of local (Stage I) disease. This paper details the results achieved with surgical resection of 100 patients with more advanced local--regional non-small cell carcinoma of the lung (Stages II and III-A). Operative (30-day) mortalities were 2.4% for Stage II patients and 8.5% for Stage III-A patients. Respective, 5-year Kaplan-Meier survival estimates were 41% (+/- 10%) and 36% (+/- 7%) and included all deaths, cancer-related as well as unrelated. When patients were stratified by stage, neither gender, age, cell type, tumor size, nor extent of resection proved statistically significant relative to long-term survival. However, Stage III-A patients, classified T-3 with contiguous tumor involvement of mediastinum, suffered a higher operative mortality and a significantly lower probability of long-term survival (p = 0.04). Finally, the results and appropriateness of prospective, clinical trials utilizing adjuvant therapies in Stage II and III-A patients and neo-adjuvant therapies in Stage III-A patients are discussed.

Adenocarcinoma↗
PubMed1993

Ultrasound diagnosis of polycystic ovaries.

Ultrasound characterization of ovarian morphology has become an important aspect of gynecological endocrinology. The classic ultrasound features of polycystic ovaries are an increased number of small follicles together with abundant stroma. The exact criteria vary according to the ultrasound technique used. The method, however, has been validated both laparoscopically and histologically. Using laparoscopic inspection as a reference test, ultrasonography was calculated to have a sensitivity of 91% and a specificity of 100%. As a group, anovulatory women with PCO have the classic endocrine features of polycystic ovarian syndrome, but in a proportion of cases the finding of PCO at scan appears to be irrelevant to the presenting disorder. Ultrasound diagnosis of PCO is also limited by its inability to display either ovary in about 16% of women.

Female↗