Biomedical subjects
John Dark
Publications and source records attributed to John Dark.
A profile of John Dark, FRCS, FRCP. Interview by Jim McGuigan.
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Carbamazepine-induced interstitial pneumonitis in a lung transplant patient.
A 19-year-old female lung transplant recipient developed peripheral eosinophilia and interstitial infiltrates on chest radiograph shortly after commencing carbamazepine. A lung biopsy was consistent with interstitial pneumonitis and following withdrawal of the drug and treatment with steroids her symptoms resolved. This is the first described case of carbamezipine-induced pneumonitis in the lung transplant population.
Neuropeptide Y induces torpor-like hypothermia in Siberian hamsters.
Intracerebroventricular (ICV) injections of neuropeptide Y (NPY) are known to decrease body temperature (Tb) of laboratory rats by 1-3 degrees C. Several NPY pathways in the brain terminate in hypothalamic structures involved in energy balance and thermoregulation. Laboratory rats are homeothermic, maintaining Tb within a narrow range. We examined the effect of ICV injected NPY on Tb in the heterothermic Siberian hamster (Phodopus sungorus), a species that naturally undergoes daily torpor in which Tb decreases by as much as 15-20 degrees C. Minimum effective dose was determined in preliminary testing then various doses of NPY were tested in cold-acclimated Siberian hamsters while food was withheld. NPY markedly reduced Tb in the heterothermic Siberian hamster. In addition, the reduction in Tb in 63% of the observations was sufficient to reach the criterion for daily torpor (Tb < 32 degrees C for at least 30 min). Neither the incidence of torpor nor its depth or duration was related to NPY dose. Both likelihood and magnitude of response varied within animals on different test days. NPY decreased 24-h food intake and this was exaggerated in the animals reaching criterion for torpor; the decrease in food intake was positively correlated with the magnitude of the decrease in Tb. The mild hypothermia seen in homeothermic laboratory rats after NPY injected ICV is exaggerated, often greatly, in the heterothermic Siberian hamster. NPY treatment may be activating hypothalamic systems that normally integrate endogenous torpor-producing signals and initiate torpor.
Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part III: donor-related risk factors and markers.
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Annual lipid cycles in hibernators: integration of physiology and behavior.
Mammalian hibernation is a temporary suspension of euthermia allowing endotherms to undergo reversible hypothermia and generate a marked savings in energy expenditure. In most fat-storing hibernator species, seasonal changes in food intake, triacylglycerol deposition, metabolism, and reproductive development are controlled by a circannual clock. In ground-dwelling sciurid rodents (ground squirrels and marmots), for example, energy intake increases during a summer body mass gain phase, and toward the end of this phase metabolic rate also begins to decrease, resulting in a profound increase in lipid deposition as fat. Increased activity of lipogenic hormones and enzymes correspond with this increase. The hibernation mass loss phase begins after the body mass peak in the fall and ends in spring. During this phase, stored lipids are slowly utilized in a programmed manner by undergoing deep torpor or hibernation during which the hypothalamic setpoint for body temperature is typically reduced to just above 0 degrees C. Throughout the hibernation season, bouts of deep torpor are punctuated by periodic arousals in which brown adipose tissue thermogenesis plays a critical role. Lipid oxidation nearly exclusively fuels deep torpor and most of the rewarming process. The fatty acid composition of stored lipids can affect the depth and duration of deep torpor, and saturated fatty acids may be preferentially used during hibernation, whereas polyunsaturated fatty acids may be preferentially retained. Female and underweight male hibernators terminate hibernation in spring when aboveground food becomes available; in contrast, heavier males with sufficient lipid reserves spontaneously terminate hibernation several weeks before females and independent of food availability. Mating occurs shortly after emergence from hibernation, and the lipid cycle begins again with the completion of reproduction. Lipid deposition and mobilization, temperature regulation, reproduction, and circannual timing are intimately interdependent. The unique manner in which they are controlled during the annual cycle, especially lipid reserves, makes hibernators valuable and promising models for research into the mechanisms underlying these processes in all mammals.
Mechanical versus medical bridge to transplantation in children. What is the best timing for mechanical bridge?
OBJECTIVE: Precise timing of mechanical circulatory support as a bridge to transplantation is crucial for successful outcome. In our practice, increasing metabolic injury resulting from third organ (renal/gut) dysfunction is an indication for mechanical circulatory support. It is not known how metabolic injury would influence the outcomes in these patients. In this study we compared biochemical and clinical parameters between children who received mechanical circulatory support and those who were treated with medical management alone as a bridge to transplantation. METHODS: Data from 24 patients were retrospectively analysed from their records. There were 11 patients in the mechanical group. In this group, five patients received biventricular assist device, five received veno arterial extra corporeal membrane oxygenation and one received left ventricular assist device. In the medical group, there were 13 patients who received various levels of inotropic support before transplantation. Five clinical and three biochemical parameters were identified and compared between the mechanical and medical groups. Mortality prior to transplantation was also compared between the two groups. Transplantation was the end point of the study. RESULTS: Serum creatinine and serum lactate levels were significantly higher in the mechanical group (P=0.006 and 0.001, respectively), reflecting advanced metabolic injury in these patients. Mean fractional shortening in the mechanical group was 8.4%, compared to 14.5% in the medical group which was statistically significant (P=0.02). All of the 11 patients in the mechanical group were ventilated compared to 7 of the 13 (53.8%) in the medical group. Need for renal support was higher in the mechanical group (83.3%) in comparison to none in the medical group (P=0.023). Mortality in both groups was comparable with two patients in each group. 11 patients in the medical group (84.6%) and 9 in the mechanical group (81.8%) reached transplantation. CONCLUSION: This study confirmed that patients in the mechanical group were considerably worse in metabolic terms when compared to the medical group. Final outcome of bridging them to transplantation was comparable. This study seem to support the justification of reserving the mechanical circulatory support to those who are metabolically more injured without adversely affecting their outcomes.
Reduced leptin concentrations are permissive for display of torpor in Siberian hamsters.
A photoperiod with a short photophase induces a winterlike phenotype in Siberian hamsters that includes a progressive decrease in food intake and body mass and reproductive organ regression, as well as reversible hypothermia in the form of short-duration torpor. Torpor substantially reduces energy utilization and is not initiated until body mass, fat stores, and serum leptin concentrations are at their nadir. Because photoperiod-dependent torpor is delayed until fat reserves are lowest, leptin concentrations may be a permissive factor for torpor onset. This conjecture was tested by implanting osmotic minipumps into Siberian hamsters manifesting spontaneous torpor; the animals received a constant release of leptin or vehicle for 14 days. Exogenous leptin treatment eliminated torpor in a significant proportion of treated hamsters, whereas treatment with the vehicle did not. Similarly, endogenous serum leptin concentrations were markedly reduced in all animals undergoing daily torpor. Although simply reducing leptin concentrations below a threshold value is not sufficient for torpor initiation, reduced leptin concentrations nevertheless appear necessary for its occurrence. It is proposed that drastically reduced leptin concentrations provide a "starvation signal" to an as yet unidentified central mechanism mediating torpor initiation.
First report of no-react bovine internal mammary artery performance and patency.
BACKGROUND: No-React treatment is known to render tissues resistant to calcific degeneration and to reduce early inflammatory response. No-React bovine internal mammary artery (NR-IMA) is available for restricted use in Europe. In this first study, our aim was to use magnetic resonance imaging (MRI) to investigate the clinical performance and patency rates of this conduit. METHODS: Seven patients received 8 grafts with NR-IMA. Approval from the Medical Devices Agency of the United Kingdom was obtained for use of this material. One patient needed salvage coronary artery bypass grafting (CABG). Graft patency was investigated with cardiac MRI. One patient was excluded from the MRI study because of the presence of intracerebral metal clips. The mean follow-up period was 2.5 years with a range of 1 to 4.5 years. RESULTS: There was no mortality in this group. After treatment 6 patients were asymptomatic, and 1 patient had class II anginal symptoms. Four (57%) of the 7 NR-IMA grafts remained patent. The longest patency was 4.5 years in a patient who underwent salvage CABG. Other associated grafts in this cohort of patients were 5 left internal mammary arteries (all patent), 1 radial artery graft (patent), and 7 saphenous vein grafts (4 [57%] of 7 patent). There were no occluded NR-IMA grafts in a patient with patent vein grafts. CONCLUSION: We concluded that at 2.5 year follow-up, NR-IMA had a patency rate of 57% (4 of 7 cases). This rate matched the vein graft patency rate in this cohort of patients. With the longest patency of 4.5 years, use of NR-IMA seems to hold promise for the future.
Effect of mitral valve repair/replacement surgery on atrial arrhythmia behavior.
BACKGROUND AND AIMS OF THE STUDY: Few data have been published on the effects of mitral valve surgery on atrial rhythm. The study aims were to determine the effects of surgery on: (i) persistence of atrial fibrillation (AF); (ii) measures of left atrial and ventricular dimensions; and (iii) ECG P-wave duration. METHODS: A retrospective case-note review of 92 patients with chronic mitral regurgitation was undertaken. Variables determined included prevalence and duration of AF; incidence of new-onset or persistence of AF after surgery; rhythm changes in relation to age, gender, left atrial and ventricular dimensions and function, anti-arrhythmic drug usage and ECG P-wave duration in sinus rhythm prior to surgery. RESULTS: Only 4/47 (8.5%) patients with any history of AF before surgery were in sinus rhythm at six months after surgery. All 28 patients with persistent AF for >12 months and 41/45 (91%) in sinus rhythm before surgery retained these rhythms after surgery. The left atrial dimension was decreased after surgery, in the whole group (51.3 +/- 9.0 versus 48.4 +/- 9.5 mm; p = 0.011) and in the subgroup in sinus rhythm, but not in the subgroup in AF. The left ventricular end-diastolic dimension decreased in the group as a whole (60.6 +/- 6.2 versus 53.0 +/- 8.7 mm; p = 0.0001) and in both subgroups after surgery. In 24 patients with 12- lead ECGs in sinus rhythm before and three months after surgery, P-wave duration remained unchanged. However, this measure decreased in the 18 patients in sinus rhythm consistently, but increased in the six patients continuing to have paroxysmal AF after surgery. CONCLUSION: Mitral valve surgery alone restored sinus rhythm in only 8.5% of patients with any previous history of AF. Concomitant anti-arrhythmic procedures should be considered for all patients with AF who undergo mitral valve surgery.
The suprachiasmatic nucleus is essential for circadian body temperature rhythms in hibernating ground squirrels.
Body temperature (T(b)) was recorded at 10 min intervals over 2.5 years in female golden-mantled ground squirrels that sustained complete ablation of the suprachiasmatic nucleus (SCNx). Animals housed at an ambient temperature (T(a)) of 6.5 degrees C were housed in a 12 hr light/dark cycle for 19 months followed by 11 months in constant light. The circadian rhythm of T(b) was permanently eliminated in euthermic and torpid SCNx squirrels, but not in those with partial destruction of the SCN or in neurologically intact control animals. Among control animals, some low-amplitude T(b) rhythms during torpor were driven by small (<0.1 degrees C) diurnal changes in T(a). During torpor bouts in which T(b) rhythms were unaffected by T(a), T(b) rhythm period ranged from 23.7 to 28.5 hr. Both SCNx and control squirrels were more likely to enter torpor at night and to arouse during the day in the presence of the light/dark cycle, whereas entry into and arousal from torpor occurred at random clock times in both SCNx and control animals housed in constant light. Absence of circadian rhythms 2.5 years after SCN ablation indicates that extra-SCN pacemakers are unable to mediate circadian organization in euthermic or torpid ground squirrels. The presence of diurnal rhythms of entry into and arousal from torpor in SCNx animals held under a light/dark cycle, and their absence in constant light, suggest that light can reach the retina of hibernating ground squirrels maintained in the laboratory and affect hibernation via an SCN-independent mechanism.