Biomedical subjects
Publications and source records attributed to D Mitchell.
With the anticipated roll out of the main implications of the Government's white paper and the hoped for improvements in health care, it is a good time to review new roles for clinical directors in secondary and tertiary care trusts. This will inevitably mean changes in training needs for clinical directors who will face new demands and challenges as the complexity of life for them increases.
The crystal structures of cytochrome c oxidase from both bovine and Paracoccus denitrificans reveal two putative proton input channels that connect the heme-copper center, where dioxygen is reduced, to the internal aqueous phase. In this work we have examined the role of these two channels, looking at the effects of site-directed mutations of residues observed in each of the channels of the cytochrome c oxidase from Rhodobacter sphaeroides. A photoelectric technique was used to monitor the time-resolved electrogenic proton transfer steps associated with the photo-induced reduction of the ferryl-oxo form of heme a3 (Fe4+ = O2-) to the oxidized form (Fe3+OH-). This redox step requires the delivery of a "chemical" H+ to protonate the reduced oxygen atom and is also coupled to proton pumping. It is found that mutations in the K channel (K362M and T359A) have virtually no effect on the ferryl-oxo-to-oxidized (F-to-Ox) transition, although steady-state turnover is severely limited. In contrast, electrogenic proton transfer at this step is strongly suppressed by mutations in the D channel. The results strongly suggest that the functional roles of the two channels are not the separate delivery of chemical or pumped protons, as proposed recently [Iwata, S., Ostermeier, C., Ludwig, B. & Michel, H. (1995) Nature (London) 376, 660-669]. The D channel is likely to be involved in the uptake of both "chemical" and "pumped" protons in the F-to-Ox transition, whereas the K channel is probably idle at this partial reaction and is likely to be used for loading the enzyme with protons at some earlier steps of the catalytic cycle. This conclusion agrees with different redox states of heme a3 in the K362M and E286Q mutants under aerobic steady-state turnover conditions.
The detrimental effects of elevated intensities of mid-UV radiation (UVB), a result of stratospheric ozone depletion during the austral spring, on the primary producers of the Antarctic marine ecosystem have been well documented. Here we report that natural populations of Antarctic zooplankton also sustain significant DNA damage [measured as cyclobutane pyrimidine dimers (CPDs)] during periods of increased UVB flux. This is the first direct evidence that increased solar UVB may result in damage to marine organisms other than primary producers in Antarctica. The extent of DNA damage in pelagic icefish eggs correlated with daily incident UVB irradiance, reflecting the difference between acquisition and repair of CPDs. Patterns of DNA damage in fish larvae did not correlate with daily UVB flux, possibly due to different depth distributions and/or different capacities for DNA repair. Clearance of CPDs by Antarctic fish and krill was mediated primarily by the photoenzymatic repair system. Although repair rates were large for all species evaluated, they were apparently inadequate to prevent the transient accumulation of substantial CPD burdens. The capacity for DNA repair in Antarctic organisms was highest in those species whose early life history stages occupy the water column during periods of ozone depletion (austral spring) and lowest in fish species whose eggs and larvae are abundant during winter. Although the potential reduction in fitness of Antarctic zooplankton resulting from DNA damage is unknown, we suggest that increased solar UV may reduce recruitment and adversely affect trophic transfer of productivity by affecting heterotrophic species as well as primary producers.
Although the capillary wall represents an active interface between blood and tissue, the potential role of the capillary in blood flow control has not been determined. The goals were (i) to establish the presence of the capillary sensing and communication phenomenon (Dietrich and Tyml, Microvasc. Res. 43, 87-99, 1992) in mammalian microvasculature and (ii) to determine the relative sensitivity of the capillary and the arteriole to locally applied vasoactive agents. Using intravital video microscopy, norepinephrine (NE; 10(-7)-3 x 10(-3) M), acetylcholine (ACh; 10(-4)-10(-2) M), or bradykinin (BK; 10(-9)-10(-3) M) was applied via micropipettes on capillaries (300 microm downstream from feeding arterioles) or on arterioles, at the surface of the extensor digitorum longus muscle of anesthetized rats. Red blood cell velocity (VRBC) in capillaries and arteriolar diameters was measured from video recordings. The overall control VRBC and control diameter were 190 microm/sec and 8.3 microm, respectively. NE applied on the capillary caused a dose-dependent reduction in VRBC (up to 100%, i.e., 0 microm/sec) via a constriction of the feeding arteriole. Both ACh and BK applied on the capillary caused a dose-dependent increase in VRBC (up to 115%) via arteriolar dilation. Based on two different approaches, these responses could not be explained in terms of diffusion of agents from capillary to the arteriole. When testing for the relative sensitivity of the arteriole and the capillary, application of NE and ACh on arterioles caused VRBC and diameter responses similar to those of capillary stimulations. When testing for the speed of response in these two microvessels, the time of noticeable VRBC change after NE (i.e., 10% from control) was also similar. We concluded that (i) the rat skeletal muscle capillary could respond to a variety of locally applied materials and (ii) the capillary could have as profound an effect on microvascular flow as the arteriole. Thus capillary could have the potential to participate in microvascular flow control.
We used miniature data loggers to record temperature and activity in free-ranging springbok (Antidorcas marsupialis) naturally exposed to severe nocturnal cold and moderate diurnal heat. The animals were active throughout the day and night, with short rests; the intensity of activity increased during daylight. Arterial blood temperature, averaged over many days, exhibited a circadian rhythm with amplitude < 1 degree C, but with a wide range which resulted from sporadic rapid deviations of body temperature. Peak blood temperature occurred after sunset. Environmental thermal loads had no detectable effect on blood temperature, even though globe temperature varied by > 10 degrees from day to day and > 20 degrees C within a day. Brain temperature increased approximately linearly with blood temperature but with a slope < 1, so that selective brain cooling tended to be activated at high body temperature, but without a precise threshold for the onset of brain cooling. Low activity attenuated selective brain cooling and high activity abolished it, even at high brain temperature. Our results support the concept that selective brain cooling serves to modulate thermoregulation rather than to protect the brain against heat injury.
BACKGROUND: Previous research has shown that parasuicides' view of the future is characterized by an absence of anticipation of positive experiences rather than the presence of anticipation of negative experiences. The present study aimed to replicate this finding and examine whether it would also be found in parasuicides who were not depressed. METHOD: Depressed parasuicides (N = 27), non-depressed parasuicides (N = 17) and matched controls (N = 34) were assessed on their anticipation of future positive and negative experiences using an adapted fluency paradigm, where they were given a set time to generate future positive and negative anticipated experiences. RESULTS: Consistent with previous findings, parasuicides showed an overall reduced anticipation of positive experiences and no overall increased anticipation of negative experiences. However, the parasuicides did show evidence of increased negative anticipation for the immediate future. The results for depressed and non-depressed parasuicides were essentially the same. CONCLUSION: Lack of positive anticipation in the absence of increased negative anticipation is a feature of parasuicide. Although this lack of positive anticipation can occur in depression, it appears to be an independent feature of parasuicide.
Phytase is a high molecular weight acid phosphatase. The structure has an alpha/beta-domain similar to that of rat acid phosphatase and an alpha-domain with a new fold.
Arabidopsis seedlings repair UV-induced DNA damage via light-dependent and independent pathways. The mechanism of the "dark repair" pathway is still unknown. To determine the number of genes required for dark repair and to investigate the substrate-specificity of this process we isolated mutants with enhanced sensitivity to UV radiation in the absence of photoreactivating light. Seven independently derived UV sensitive mutants were isolated from an EMS-mutagenized population. These fell into six complementation groups, two of which (UVR1 and UVH1) have previously been defined. Four of these mutants are defective in the dark repair of UV-induced pyrimidine [6-4]pyrimidinone dimers. These four mutant lines are sensitive to the growth-inhibitory effects of gamma radiation, suggesting that this repair pathway is also involved in the repair of some type of gamma-induced DNA damage product. The requirement for the coordinate action of several different gene products for effective repair of pyrimidine dimers, as well as the nonspecific nature of the repair activity, is consistent with nucleotide excision repair mechanisms previously described in Saccharomyces cerevisiae and nonplant higher eukaryotes and inconsistent with substrate-specific base excision repair mechanisms found in some bacteria, bacteriophage, and fungi.
Bacteraemia of oral origin may result in infective endocarditis in susceptible individuals. The aim of this pilot study was to investigate the occurrence of bacteraemia due to periodontal probing. Thirty patients (15 male, 15 female; mean age 42.7 years) with untreated periodontitis were investigated. All were free of significant medical disorders and none had taken antibiotics in the previous month. Prior to and immediately following periodontal probing, 20 mL of venous blood were obtained from each patient and inoculated into aerobic and anaerobic blood culture bottles and incubated. Negative bottles were monitored continuously for three weeks before being discarded. Periodontal probing consisted of measuring pockets at six points around each tooth and recording the presence or absence of bleeding. A positive bacteraemia was recorded for three of the patients prior to probing. One patient exhibited Prevotella species whilst two exhibited skin commensals. Following probing, 13 patients (43 per cent) exhibited bacteraemia of oral origin. Viridans streptococci were the most common isolates (45 per cent). No significant correlations were found between bacteraemia and the severity of periodontitis or extent of bleeding on probing. The results indicate that periodontal probing can cause bacteraemia in patients with periodontitis. It would be advisable for patients considered at risk of developing infective endocarditis to receive antibiotic prophylaxis for periodontal probing if they have radiographic evidence of periodontitis.
Psychogenic stridor is a rare cause of apparent acute upper airway obstruction, usually occurring in young female adults. The alarming presence of inspiratory stridor leads to suspicion of organic disease, with urgent management directed towards treatment of suspected pathology. Careful history taking may suggest the correct diagnosis and early examination of the larynx, preferably by fibreoptic nasendoscopic examination, may identify the underlying abnormality of paradoxical adduction of the vocal cords on inspiration, accounting for the stridor. This characteristic feature allows a positive diagnosis to be made and may avoid potentially harmful and inappropriate interventions. Three cases are presented, illustrating an evolution of management.
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Bronchial asthma is characterized by episodic airway obstruction and associated with wheezing, a bronchodilator response, an elevation in total serum IgE, and atopy. To determine whether asthma is more common in subjects with severe alpha 1-antitrypsin deficiency (alpha 1-ATD) and airway obstruction, we compared 38 patients who had this condition (Group 1) with 22 control patients with chronic obstructive pulmonary disease (COPD) (Group 2) and with five subjects with alpha 1-ATD and normal spirometry (Group 3). Subjects were evaluated with a symptom questionnaire, pulmonary function testing, intradermal allergen testing, and serum IgE measurement. Self-reported wheezing was a common symptom in all patient groups, but attacks of wheezing with dyspnea were significantly more common in Group 1. Of those patients with airway obstruction, more than 50% showed a bronchodilator response whether suffering from alpha 1-ATD or not. Atopy was more common in Group 1 than in Group 2 (48% versus 27%). Mean serum IgE for all groups was similar but significantly greater in patients with atopy. We estimated the prevalence of asthma in the study groups on the basis of the criteria of attacks of wheezing, reversible airway obstruction, atopy, and that increased IgE. The proportion of patients with asthma in Group 1 was significantly greater than that in Group 2 (22% versus 5%, p < 0.05). Our study shows that with control for the degree of airway obstruction, asthma, as defined, is more common in patients with alpha 1-ATD than in those without it. We suggest that a lack of alpha 1-AT in airways increases the propensity to develop asthma.
We administered extracts of the horn of the African Black rhinoceros intragastrically to 7 rabbits, at the same time as injecting bacterial lipopolysaccharide (LPS) intravenously into the rabbits to produce fever. At a dose of horn (50 mg/kg) similar to that allegedly used to reduce human fever, and at ten times that dose, the fever response to LPS was not significantly different (P > 0.05, t-test) to the response to LPS injection when boiled water was administered instead of horn extract. The known antipyretic indomethacin, however, at a dose of 10 mg/kg significantly reduced the response to LPS.
1. Knowing the sexual abuse history of a patient contributes to a greater understanding of the patient's clinical problems and facilitates appropriate discharge planning. 2. Obtaining a history of sexual abuse is not always part of the nursing admission assessment sheet, and many staff members have little or no training on the therapeutic interventions for a history of sexual abuse. 3. The lack of staff training and the ambiguous nature of sexual abuse assessment must be examined in relationship to quality patient care.
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1. We measured body core and scrotal temperatures (Tbody and Tscrotum, respectively) of rams during 5 h of hot (40 degrees C) and cold (6 degrees C) exposure, for 6 h following intravenous injections of saline (0.9% NaCl) or 0.4 micrograms kg-1 of the purified lipopolysaccharide endotoxin of Salmonella typhosa (LPS), during 40 min of treadmill exercise, and for several days in their pens. 2. At 20-23 degrees C ambient temperature there were significant, but out of phase, circadian variations in Tbody and Tscrotum. Tscrotum was 3.30 +/- 0.03 degrees C lower than Tbody on average. 3. During cold exposure the tunica dartos muscles contracted, nevertheless Tscrotum fell and Tbody-Tscrotum increased. During heat exposure the tunica dartos muscle relaxed and scrotal sweat glands were activated, nevertheless Tscrotum rose and Tbody-Tscrotum decreased. There was no change in Tscrotum after LPS injection or during exercise, but Tbody increased in both cases. 4. We suggested that Tscrotum is regulated independently of Tbody via a feedback circuit involving scrotal thermoreceptors and effectors in the form of tunica dartos muscle activity and scrotal sweat gland activity. This local circuit is not affected by adjustments to the general thermo-regulatory control system during fever. The effector mechanisms were insufficient to maintain Tscrotum during the extremes of heat and cold exposure.
Three methods for preparing hydrophilic coatings on polysiloxane bonded CElect H-type capillary electrophoresis columns have been shown. The polyalkylsiloxane-bonded phase is the first coating layer on the capillary surface, and nonionic surfactant, hydrophilic polymer, or polymer surfactant, adsorbed onto this first later through hydrophobic interactions, forms the second coating layer. The resultant capillary surfaces are inert, hydrophilic, and suitable for highly efficient protein separations. The effectiveness and applicability of these capillary surface modification methods were tested for the separations of a variety of proteins over a wide range of buffer pH values under different capillary electrophoretic operations modes.