mtDNA haplogroups and frequency patterns in Europe.
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DNA, Mitochondrial↗
Biomedical subjects
M Richards
Publications and source records attributed to M Richards.
Elevated plasma cholecystokinin at high altitude: metabolic implications for the anorexia of acute mountain sickness.
The aims of the present study were to measure the satiety neuropeptide cholecystokinin (CCK) in humans at terrestrial high altitude to investigate its possible role in the pathophysiology of anorexia, cachexia, and acute mountain sickness (AMS). Nineteen male mountaineers aged 38 +/- 12 years participated in a 20 +/- 5 day trek to Mt. Kanchenjunga basecamp (BC) located at 5,100 m, where they remained for 7 +/- 5 days. Subjects were examined at rest and during a maximal exercise test at sea-level before/after the expedition (SL1/SL2) and during the BC sojourn. There was a mild increase in Lake Louise AMS score from 1.1 +/- 1.2 points at SL1 to 2.3 +/- 2.3 points by the end of the first day at BC (P < 0.05). A marked increase in resting plasma CCK was observed on the morning of the second day at BC relative to sea-level control values (62.9 +/- 42.2 pmol/L(-1) vs. SL1: 4.3 +/- 8.3 pmol/L(-1), P < 0.05 vs. SL2: 26.5 +/- 25.2 pmol/L(-1), P < 0.05). Maximal exercise increased CCK by 78.5 +/- 24.8 pmol/L(-1), (P < 0.05 vs. resting value) during the SL1 test and increased the plasma concentration of non-esterified fatty acids and glycerol at BC (P < 0.05 vs. SL1/SL2). The CCK response was not different in five subjects who presented with anorexia on Day 2 compared with those with a normal appetite. While there was no relationship between the increase in CCK and AMS score at BC, a more pronounced increase in resting CCK was observed in subjects with AMS (> or =3 points at the end of Day 1 at BC) compared with those without (+98.9 +/- 1.4 pmol/L(-1) vs. +67.6 +/- 37.2 pmol/L(-1), P < 0.05). Caloric intake remained remarkably low during the stay at BC (8.9 +/- 1.4 MJ.d(-1)) despite a progressive decrease in total body mass (-4.5 +/- 2.1 kg after 31 +/- 13 h at BC, P < 0.05 vs. SL1/SL2), which appeared to be due to a selective loss of torso adipose tissue. These findings suggest that the satiogenic effects of CCK may have contributed to the observed caloric deficit and subsequent cachexia at high altitude despite adequate availability of palatable foods. The metabolic implications of elevated CCK in AMS remain to be elucidated.
Adult↗
Cognitive links across the lifecourse and implications for health in later life.
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Aged↗
No association between breast-feeding and adult psychosis in two national birth cohorts.
BACKGROUND: It has been proposed that breast-feeding might have a protective effect against the development of adult schizophrenia. AIMS: To test this hypothesis. METHOD: Using prospective data from two UK national birth cohorts, the feeding histories of those who later developed schizophrenia were compared with the remaining population at risk. Analyses in each cohort were considered to be independent tests of the hypothesis. RESULTS: There were no differences in feeding histories. In the 1946 birth cohort (n = 4447) 30 cases of DSM-III-R schizophrenia arose by age 43; 24.1% of cases v. 23.6% of controls were entirely bottle-fed; 17.3% v. 12.3% were breast-fed for under 1 month; 58.6% v. 64.1% were breast-fed beyond 1 month. In the 1958 cohort (n = 18,856), 40 cases of CATEGO nuclear schizophrenia arose by age 28; 24.1% of cases v. 31.7% of controls were entirely bottle-fed; 27.6% v. 24.9% were breast-fed for under 1 month; 48.3% v. 43.4% were breast-fed beyond 1 month. CONCLUSIONS: These findings provide no evidence of any effect of breast-feeding in protecting against the risk of later schizophrenia.
Adolescent↗
Increased distraction rates influence precursor tissue composition without affecting bone regeneration.
The effect of increased distraction rate on bony tissue differentiation was studied using a paired bilateral model of rat femur lengthening. After a 6-day latency period, one randomly selected femur for each rat was distracted at 0.5 mm/day (normal rate) for 12 days, and the contralateral femur was distracted at 1.5 mm/day (increased rate) for 4 days. Femoral lengthening for each side was 6.0 mm, leaving the increased rate leg with an extra 8 days of consolidation compared with the normal rate limb. Group I rats (n = 9) were killed at day 18 postsurgery and analyzed for cartilage tissue composition and distribution. Group II rats (n = 7) were killed on day 36 postsurgery and analyzed by three-dimensional microcomputed tomography (MCT) for changes in new bone volume. Digital color analysis of slides stained with type II collagen antibody showed increases in cartilaginous tissue formation on the increased rate side (1.51 mm2 vs. 0.83 mm2; p = 0.10). No differences in new bone volume were detected between increased rate limbs and their contralateral controls (46.13 mm3 vs. 42.69 mm3; p = 0.63). These findings suggest that intermediate distraction rates may influence precursor tissue composition without affecting the final amount of new bone formed. Because damage to the tissue was not detected at either time point, these changes in chondrogenesis may reflect sensitivity of the pluripotential gap tissue to tension accumulation during lengthening. Future work with this in vivo model is focused on improving our understanding of the mechanisms behind this strain sensitivity.
Animals↗
Myocardial infarction with and without reperfusion in sheep: early cardiac and neurohumoral changes.
There are few stable and reproducible large-animal models of chronic heart failure produced by ischaemic damage to the myocardium. Here we characterize a novel method of inducing myocardial damage in closed-chest sheep by catheter delivery of thrombogenic coils, and compare this with a newly described open-artery model of cardiac injury in sheep. Sham controls were compared with animals subjected to (a) 90 min of coronary artery occlusion/reperfusion by PTCA (percutaneous transluminal coronary angioplasty) balloon, and (b) permanent coronary artery occlusion induced by catheter delivery of thrombogenic coils (seven sheep/group). Both balloon occlusion/reperfusion and permanent coil occlusion resulted in well-defined anteroapical infarcts, as documented by ECG changes, significant rises in creatine kinase (both groups P<0.001) and troponin-T (both groups P<0.05), and post-mortem examination. Washout of enzymes was much more rapid in the reperfused group (P<0. 01). Infarction resulted in significant reductions in left ventricular (LV) ejection fraction (both groups P<0.01) and regional wall abnormalities. Ejection fraction 7 days post-coil (21.3+/-4.2%) was significantly lower (P<0.01) than that 7 days post-balloon (38. 8+/-4.5%). Coil-induced infarction was associated with acutely reduced arterial pressure (P<0.05), and increases in heart rate (P<0. 05), atrial pressures (P<0.05), plasma brain natriuretic peptide levels (P<0.05) and adrenaline levels (P<0.05). Rises seen in plasma endothelin levels in sham controls were blunted in the coil group (P<0.001). Haemodynamic changes were less marked in the balloon group. In conclusion, restriction of coronary artery occlusion to 90 min results in infarction, but less LV dysfunction with reduced early remodelling, compared with permanent occlusion. Acute changes in biochemical markers, haemodynamics, neurohormones and LV function confirm that these are excellent models of open- and closed-artery myocardial infarction leading to asymptomatic LV dysfunction.
Analysis of Variance↗
Mitochondrial DNA recombination-no need to panic.
Recombination has recently been invoked as an explanation for the large amount of homoplasy observed in a collection of complete or nearly complete human mitochondrial sequences. Here we show that some of the data on which this conclusion was based are likely to be unreliable and that if these data are excluded, the results are no longer significant.
Animals↗
Investigation of hypersensitivity to fractionated low-dose radiation exposure.
PURPOSE: Hypersensitivity to cell killing of exponentially growing cells exposed to X-rays and gamma rays has been reported for doses below about 0.5 Gy. The reported results have been interpreted to suggest that a dose of 0.5 Gy or less is not sufficient to trigger an inducible repair mechanism. The purpose of this study was to examine this suggested hypersensitivity after multiple low doses (0.3 Gy) of gamma rays where a) the effect would be expected to be significantly magnified, and b) the effect might be of clinical relevance. METHODS AND MATERIALS: C3H 10T1/2 mouse embryo cells were grown to confluence in culture vessels. While in plateau phase of growth, cells were exposed to 6 Gy of gamma rays, delivered in either 6 Gy, 3 Gy, 2 Gy, 1 Gy, or 0.3 Gy well-separated fractions. Corresponding experiments were performed with V-79 and C3H 10T1/2 cells in exponential growth. Cells were replated at low density and assayed for clonogenicity. RESULTS: The results of this study were not inconsistent with some hypersensitivity at low doses, in that 20 fractions each of 0.3 Gy produced a slightly lower (though nonsignificant) surviving fraction compared with the same dose given in 2-Gy fractions. However, the results of the 20 x 0.3 Gy exposures also agreed well with the standard linear-quadratic (LQ) model predictions based on high dose per fraction (1-6 Gy) data. In addition, effects of cellular redistribution were seen which were explained quantitatively with an extended version of the LQ model. CONCLUSIONS: These experiments were specifically designed to magnify and probe possible clinical implications of proposed "low-dose hypersensitivity" effects, in which significant deviations at low doses from the LQ model have been suggested. In fact, the results at low doses per fraction were consistent with LQ predictions based on higher dose per fraction data. This finding is in agreement with the well-documented utility of the LQ approach in estimating isoeffect doses for alternative fractionation schemes, and for brachytherapy.
Animals↗
Lifetime cognitive function and timing of the natural menopause.
BACKGROUND: There is evidence that ovarian steroids influence both reproductive aging and neural development. OBJECTIVE: We investigated the relationship between menopause and lifetime cognitive function in a prospective birth cohort study. METHODS: Participants were 1,572 women enrolled in the Medical Research Council National Survey of Health and Development (the British 1946 birth cohort). By age 50, 245 women were postmenopausal, 724 were pre- or perimenopausal, 288 had had a hysterectomy or bilateral oophorectomy, and 291 women had started taking hormone replacement therapy (HRT) before their menopause. The remaining 24 women, for various reasons, could not be classified into any of these groups. We investigated the association between cognitive function at ages 8, 11, 15, 26, and 43 years and menopause timing using Cox proportional hazard models, censoring for hysterectomy and bilateral oophorectomy, and initially for HRT use. The effect of including HRT use before menopause as an additional outcome was investigated using a competing risks analysis. RESULTS: Higher cognitive scores were associated with later menopause. The effect was strongest in childhood. This finding could not be explained by a variety of potential confounders, including early social background, physical development, education, adult social class, parity, smoking, and alcohol consumption. CONCLUSIONS: Childhood cognitive function is related to timing of the natural menopause. Both may be influenced by ovarian steroids across the life-span.
Adolescent↗
Validating aminoterminal BNP assays: a word of caution.
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Chromatography, High Pressure Liquid↗
The amino terminal regions of proBNP and proANP oligomerise through leucine zipper-like coiled-coil motifs.
We provide the first report of unique leucine zipper-like coiled-coil sequence motifs at the amino terminus (N-) of proBrain Natriuretic Peptide (proBNP) and proAtrial Natriuretic Peptide (proANP). These motifs were highly conserved across most of the known natriuretic peptide sequences from different species. Consistent with computer based modelling predictions, size exclusion (SE) chromatography analysis confirmed human and ovine N-BNP, N-ANP and human proBNP in plasma extracts to elute as high molecular weight oligomers. Synthetic model peptides corresponding to the proposed leucine zipper-like coiled-coil regions of proBNP, proANP and their related N-terminal peptides were shown to be sufficient to induce oligomerisation when assessed on size exclusion HPLC. To our knowledge, this is the first report of circulating peptides that oligomerise through leucine zipper-like coiled-coil motifs, and adds a new dimension to the field of vasoactive peptide research.
Amino Acid Sequence↗
Cognitive decline in ageing: are AAMI and AACD distinct entities?
BACKGROUND: Two sets of research diagnostic criteria, age-associated memory impairment (AAMI) and ageing-associated cognitive decline (AACD), are widely used to describe mild cognitive decline in ageing. However, the extent to which the nosological entities they represent are similar or distinct is unclear. METHODS: A sample of 111 participants without dementia but with informant evidence of cognitive decline were drawn from the EUGERIA Study of Cognitive Ageing, a population-based study in southern France. These participants were classified as either normal or with AAMI according to the criteria of Crook et al. (1986), then reclassified as normal or with AACD according to criteria recommended by Levy et al. (1994). Neuropsychological test scores were then compared in these two pairs of groups. RESULTS: Particpants were classified as either normal (N=74) or with AAMI (N=37), then reclassified as normal (N=72) or with AACD (N=39). Only 20 (54%) of participants with AAMI simultaneously met criteria for AACD, and those with AACD showed more extensive cognitive impairment than those with AAMI. CONCLUSIONS: Although there is a large overlap between AAMI and AACD, these findings suggest that AAMI and AACD refer to distinct clinical entities, the latter delineating a more severe state of impairment. This may be largely because AAMI is defined as impairment with reference to young normals, whereas AACD refers to impairment with respect to normal contemporaries.
Aged↗
Problems in cross-cultural psychogeriatric research: contacting older Turkish immigrants in the UK.
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Aged↗
Marrow-derived progenitor cell injections enhance new bone formation during distraction.
Bilateral femoral distraction was performed in rats to investigate whether injections of marrow-derived mesenchymal progenitor cells could be used to facilitate new bone formation. The cells were isolated from whole marrow of 2-6-month-old Sprague-Dawley rats. One-year-old recipient Sprague-Dawley rats were divided into five experimental groups. Rats in groups I, II, and III received injections of mesenchymal progenitor cells on days 6 (beginning), 12 (middle), and 18 (end of distraction) after surgery, respectively. Those in group IV received injections of serum and carrier gel alone, and those in group V received no injections. Distraction zones were harvested at 36 days and analyzed for new bone volume within the distraction gap by three-dimensional microcomputed tomography. Significant increases in new bone volume were observed for femora injected with marrow-derived progenitor cells compared with contralateral femora and controls (no injection). The timing of the cell injections appeared to have no effect on the experimental outcome. Histologic analyses demonstrated active formation of new trabecular bone with marked osteoblastic activity and osteoid production. No qualitative differences in histologic appearances of new bone among rats in any of the five groups were seen. The results of in vitro lysis assays indicated that donor and recipient rats were not completely syngenic, leaving some doubt as to the reasons for observed increases in new bone formation. Future work will focus on attempting to repeat these experiments in a fully syngenic rat model. This rat distraction model can be used to explore the molecular and cellular behavior of these progenitor cells in a clinically relevant in vivo environment.
Animals↗
Central venous catheter-associated thrombosis in severe haemophilia.
Significant subclavian vein thromboses associated with indwelling fully implanted (port-a-cath) devices are described in two boys with severe haemophilia A and factor VIII inhibitors. Investigations were prompted by prominent chest wall veins in one case, whereas the thrombosis was a chance finding in the other case during investigation of mechanical dislocation of the catheter tubing. Extensive collateral venous circulations were demonstrated by venography in both instances indicating that the thrombus had been present for some time. Possible contributing factors to the thromboses included desensitization therapy (both patients), high-dose FEIBA (in one patient) and use of lower doses of heparin for line flush than that recommended by some authors. Neither patient had a familial or non-familial predisposition to thrombosis.
Catheterization, Central Venous↗
Recurrence rates of ischial sores in para- and tetraplegics treated with hamstring flaps: an 8-year study.
We have collected data on the second follow-up of 27 patients who underwent musculocutaneous flap closure of their ischial pressure sores. Thirty-seven ulcers were operated on between 1988 and 1993 using the V-Y advancement hamstring musculocutaneous island flap. At the initial follow-up (mean = 20 months) in 1993, despite 33% of patients having had recurrent ulcers and 14.8% having undergone re-advancements, only 14% of patients had non-healing ulcers. In 1997, follow-up period ranged from 18 to 90 months, with a mean of 62 months. Four patients were lost to follow-up resulting in 23 patients (n = 23) for the current study. Nine patients were tetraplegic and the remaining 14 were paraplegic. Four of the 23 patients had died at follow-up therefore making the number of living patients 19 (n = 19). The total number of ulcers operated on in the current study was 29 (U = 29). Overall, ulcer and patient recurrence rates were 41.4% and 47.8% respectively. Despite this, 89.5% of patients had intact flaps at the time of follow-up. We recommend the use of the hamstring V-Y musculocutaneous flap as a reliable and safe reconstructive modality in the management of ischial pressure sores and by identifying the group of patients susceptible to ulcer recurrence we have proposed a protocol for their long-term follow-up.
Adolescent↗
The emerging tree of West Eurasian mtDNAs: a synthesis of control-region sequences and RFLPs.
Variation in the human mitochondrial genome (mtDNA) is now routinely described and used to infer the histories of peoples, by means of one of two procedures, namely, the assaying of RFLPs throughout the genome and the sequencing of parts of the control region (CR). Using 95 samples from the Near East and northwest Caucasus, we present an analysis based on both systems, demonstrate their concordance, and, using additional available information, present the most refined phylogeny to date of west Eurasian mtDNA. We describe and apply a nomenclature for mtDNA clusters. Hypervariable nucleotides are identified, and the relative mutation rates of the two systems are evaluated. We point out where ambiguities remain. The identification of signature mutations for each cluster leads us to apply a hierarchical scheme for determining the cluster composition of a sample of Berber speakers, previously analyzed only for CR variation. We show that the main indigenous North African cluster is a sister group to the most ancient cluster of European mtDNAs, from which it diverged approximately 50,000 years ago.
Africa, Northern↗
Viscoelastic characterization of mesenchymal gap tissue and consequences for tension accumulation during distraction.
Nonlinear viscoelastic analysis was used to characterize the time-dependent behavior of mesenchymal gap tissue generated during distraction osteogenesis. Six (n = 6) lengthened tibiae were harvested from New Zealand white rabbits at 18 days. This gap tissue was subjected to a series of step displacement tests of increasing magnitude, and force relaxation behavior was monitored. Isochrones in stress-strain space were fit to odd cubic functions of strain. An analytic expression, linear in both e and e3, was developed to predict stress accumulation within the gap tissue as a function of time during distraction. Stress relaxation functions were described well by two-term Prony series. The two time constants determined from mechanical testing results were consistent, suggesting the presence of two fundamental physiologic relaxation processes. Gap tissue stresses were predicted to rise considerably during early stages of lengthening when distraction magnitudes exceeded the clinical norm of 0.25 mm. These differences in tension accumulation were less pronounced by the time lengthening was completed. Specifically, these results may in part explain clinical observations of decreased bone regeneration and altered tissue proliferation and differentiation at higher distraction rates. More generally, this work provides a framework for the rigorous characterization of the viscoelastic properties of biologic tissues ordinarily exposed to step strains.
Animals↗