Biomedical subjects
Publications and source records attributed to L Murray.
Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.
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Attention-deficit hyperactivity disorder (ADHD) is a common disorder among children and adolescents with reported prevalence rates of between 3 and 10%. Recent reports suggest that a multimodal treatment approach is preferable to address many symptoms of ADHD and its associated problems for the children, the family, and the school. Stimulant medications remain the mainstay of treatment and are highly effective in more than 75% of patients. Improvement in the core symptoms of inattention, impulsivity, and hyperactivity are most noticeable. Recently approved extended release preparation of methylphenidate will allow once a day dosing. Reports of effectiveness of some non-stimulant medications such as bupropion, especially for adolescents, appear promising. A number of behavioral and psychosocial interventions can be used effectively as part of multimodal approach to address many ADHD-related problems. This article provides an update on practical information on the treatment of children and adolescents with ADHD who do not have other associated psychiatric disorders.
Stroke mortality and morbidity remain high despite downward trends in incidence and case fatality. Population-based longitudinal studies which include collection of risk factor data are required for a better understanding of stroke aetiology. From a representative cohort of men from South Wales and South-west England, followed up for a median of 17 y, details of possible cerebrovascular events were collected from questionnaires, hospital admission data, general practitioner records, death certificates, radiology records and post-mortem reports. Radiology records, and strokes and transient ischaemic attacks were independently validated. There were 433 strokes and 163 transient ischaemic attacks identified during follow-up. Of these, 333 were the first ever in a lifetime strokes of which 139 were definite ischaemic, 20 were haemorrhagic and 168 were probable ischaemic strokes. The crude incidence rate for stroke was 445 (95% confidence interval 398-493) per 100 000 person years. The age-standardised rates for 10 y age-bands were: 45-54 y 91 (10-172); 55-64 y 351 (269-432) and 65-74 y 855 (669-1040). The 30 d case-fatality rate was 21.0% (70/333) for all strokes and 19.2% (60/312) for ischaemic strokes. For transient ischaemic attacks the age-standardised incidence rates for the same 10 y age bands were 92 (4-179), 111 (64-157), and 273 (167-80), respectively. These rates for stroke transient ischaemic attack are likely to be accurate given the high ascertainment of events in this representative population of middle-aged men. Such studies, reporting reliable measures of cerebrovascular events, are important for measuring burden of disease, and for analysis of risk factor associations to help improve understanding of stroke aetiology and inform preventive efforts.
Reduction of stroke burden requires preventive interventions targeted at important risk factors. This report presents the analysis of risk factors for ischaemic stroke from a representative cohort of middle aged men from South Wales and south-west England. Data on risk factors were collected through validated questionnaires and physical and clinical measurements. Details of possible cerebrovascular events were retrieved, classified into ischaemic, haemorrhagic and uncertain subtypes, and validated. The ratio of definite ischaemic to definite haemorrhagic strokes was calculated. This showed that the vast majority of strokes of unknown subtype were likely to ischaemic. After exclusion of known haemorrhagic strokes and subarrachnoid haemorrhages the remaining strokes were labelled ischaemic. Hazard ratios for possible risk factors were calculated for all ischaemic, and for fatal and non-fatal strokes. There were 293 ischaemic strokes. Statistically significant age-adjusted hazard ratios were: 1.50 (95% confidence interval 1.16-1.95) for being in a manual social class, 1.82 (1.24-2.67) if smoking >15 cigarettes/d at enrollment, 1.19 (1.13-1.24) and 1.23 (1.14-1.34) per 10 mmHg increase in systolic and diastolic blood pressure, respectively, 0.67 (0.46-0.96) for the top quintile high density lipoprotein-cholesterol:cholesterol ratio compared to the bottom quintile, 2.04 (1.40-2.99) for presence of angina, 3.90 (2.01-7.58) for presence of atrial fibrillation, and 3.35 (1.90-5.80) for presence of diabetes. Risk factors were more strongly associated with fatal than non-fatal strokes. Multivariate analyses revealed that, while there was some attenuation of the effect of social class, angina and elevated BP, the risks from atrial fibrillation and diabetes were increased.
PURPOSE: The purpose of this study was to examine the independence and relative strengths of association between coronary heart disease (CHD) risk status and both body fatness and cardiorespiratory (C-R) fitness in 12- and 15-yr-old adolescents. METHODS: The study cohort consisted of 1015 schoolchildren aged 12 and 15 yr (251 12-yr-old boys, 258 12-yr-old girls, 252 15-yr-old boys, and 254 15-yr-old girls), representing a 2% random sample of each population group. For each child, height, weight, sexual maturity (pubertal status), skin-fold thicknesses (4 sites), blood pressure (random zero sphygmomanometer), nonfasting serum total, and high density lipoprotein (HDL)-cholesterol and C-R fitness (20-m shuttle run; 20-MST) were determined under standardized conditions. Socioeconomic status and habitual physical activity were also determined from questionnaire information. Multiple regression analyses were carried out to examine relationships between five CHD risk factors, and fitness and fatness and to examine the relative strengths of fitness and fatness on CHD risk status, correcting for potential confounding variables. RESULTS: Our main findings were: 1) Relationships between fatness and CHD risk factors are invariably stronger than between fitness and the same risk factors. For example, partially adjusted standardized regression coefficients for 12-yr-old boys revealed significant relationships between all five CHD risk factors and fatness, compared with three of five for fitness. The corresponding figures for 12-yr-old girls were three of five (fatness) and one of five (fitness). Broadly similar results were apparent for 15-yr-olds. 2) Although relationships between fitness and CHD risk factors do not survive further adjustment for fatness, the relationships between fatness and CHD risk are more robust and are unaffected by further adjustment for fitness. CONCLUSION: Our results indicate that the observed relationships between C-R fitness and CHD risk status in adolescents are mediated by fatness, whereas the observed relationships with fatness are independent of fitness. Primary prevention of CHD during childhood should therefore concentrate upon preventing or reversing undue weight gain.
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BACKGROUND: Vascular remodeling occurs in the skeletal muscle of patients with severe congestive heart failure (CHF); this remodeling is mediated in part by increased activity of the renin-angiotensin system. Animal models suggest that in the vasculature, angiotensin II receptor type 2 (AT2-R) expression may be upregulated in pathological states associated with vascular remodeling. The therapeutic effects of an AT1-R antagonist may, therefore, be in part due to increased plasma angiotensin II levels, which stimulate AT2-R. However, whether AT2-R is expressed in the skeletal muscle vasculature of patients with severe CHF is unknown. METHODS AND RESULTS: The steady-state transcript levels of the AT1-R and AT2-R genes were analyzed by reverse transcription-polymerase chain reaction in RNA samples prepared from the skeletal muscle of 12 patients with severe CHF (f1.gif" BORDER="0">O(2)<10 mL. kg(-1). min(-1)) and 5 age-matched healthy subjects who underwent vastus lateralis biopsies. Human fetal skeletal muscle RNA served as a positive control for the expression of AT1-R and AT2-R gene transcripts. Transcripts from the AT1-R gene were detected readily in all samples. In contrast, transcripts from the AT2-R gene were only detected in fetal skeletal muscle samples and could not be detected in the skeletal muscle vasculature of healthy subjects or that of CHF patients, who were treated with either angiotensin-converting enzyme inhibitors or AT1-R antagonists. CONCLUSIONS: The AT2-R gene is not expressed in the skeletal muscle of patients with CHF. In the absence of detectable AT2-R gene transcripts, the AT2-R pathway is unlikely to contribute to the effects of AT1-R antagonists on the skeletal muscle vasculature in patients with severe CHF.
Absence of durable high-level expression of transgenes from Moloney murine leukemia (Mo-MuLV) retroviral vectors has been a hurdle in bringing effective gene therapy to the clinic. In this study we have analyzed transgene expression among the progeny of mobilized hematopoietic stem cells (HSCs), comparing Mo-MuLV and mouse stem cell virus (MSCV) vectors, with or without addition of a scaffold attachment region (SAR) from the human interferon beta gene. Retroviral (RV) vector supernatant quality was assessed by comparing NGFR transgene expression by HEL cells, and transgene delivery and expression by CD34(+) cells 72 hr after transduction, using real-time PCR and FACS analysis. This is the first description of the effect of SAR within both Mo-MuLV and MSCV vector backbones on long-term RV transgene expression among in vivo HSC progeny in HSC repopulation assays (SCID-hu bone and NOD/SCID). After transduction of mobilized CD34(+) cells with MSCV-SAR vector, transgene expression was observed among a mean of 10% of donor HSC progeny in the SCID-hu bone (range, 0.6-43%). The predominant effect of SAR was to increase the mean fluorescence intensity (MFI) of transgene expression among HSC progeny in both in vivo bone repopulation models (three- to fourfold), and after long-term stromal cultures (twofold).
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Because cystinotic patients are polyuric and may have severe proteinuria, each of which is a potential risk factor for graft thrombosis, preemptive transplantation for them is questionable. The objectives of this study were to characterize the changes in urine volume and protein excretion at various stages of cystinosis, determine whether there is serologic evidence of hypercoagulability, and review the clinical experience in renal transplantation in cystinotic children. The records of cystinotic patients followed at the Montreal Children's Hospital between 1992 and 1998 were reviewed. Urinary volume, protein excretion, and coagulation markers were collected to determine the glomerular filtration rate (GFR) >50 ml/min/1.73 m2, <20 ml/min/1.73 m2, before and after starting dialysis. In addition, graft failure and graft thrombosis rates were obtained from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database. Urinary volume and protein excretion remained elevated throughout different phases of the disease. Coagulation factors were within normal limits for all patients. In the NAPRTCS database there were four thromboses among the 114 patients transplanted cystinotic patients. All these occurred in cadaveric grafts and only one occurred after preemptive transplantation. Despite polyuria and severe proteinuria, children with cystinosis do not appear to be at an increased risk of graft failure or graft thrombosis.
Lipids are a major constituent of myelin and apolipoprotein E (apoE) plays a key role in lipid transport. We therefore hypothesized that apoE is involved in the processes of demyelination and remyelination. Furthermore as there is a biologically significant polymorphism in the APOE gene, the APOE genotype may influence the course of multiple sclerosis (MS). Specifically, as there is reduced affinity of the apoE E2 isoform for receptors on glial cells, we hypothesized that remyelination is impaired in individuals with the apoE epsilon2 allele. We determined the apoE genotypes of 71 archival cases of multiple sclerosis and 41 controls, reviewed the neurohistology, and performed apoE immunohistochemistry. ApoE immunoreactivity was increased in demyelinated areas compared with control white matter. ApoE immunostaining was markedly increased in areas of active demyelination, specifically in macrophages and astrocytes. The APOE allele frequencies of the cases of MS (epsilon2 = 0.06, epsilon3 = 0.8, epsilon4 = 0.13) resembled those of controls. Evidence of remyelination was identified in 25/ 71 MS cases (35%): in 25/64 patients (39%) without an epsilon2 allele and 0/7 (0%) patients with an epsilon2 allele (p < 0.05). In conclusion, we provide evidence that apoE is involved in the trafficking of lipid in MS and, although the number of cases with this allele was small, remyelination may be defective in patients with the APOE epsilon2 allele.
A truncated first cytosolic domain of type V adenylyl cyclase (VC(1)) and a truncated second cytosolic domain of type II adenylyl cyclase (IIC(2)) were used alone and in the readily reversible complex (VC(1).IIC(2)) to evaluate interactions with each other and with reversible and irreversible P-site ligands. Enzyme activity was used to assess formation and dissolution of VC(1).IIC(2). The data suggest that binding of 2',5'-dideoxy-3'-ATP to VC(1) and IIC(2) prevented formation of VC(1).IIC(2) and that 2',5'-dideoxy-3'-ATP dissociation occurred slowly. To enable configuration specific cross-linking to the catalytic site, 2',5'-dideoxyadenosine 3'-[gamma-(1-methylimidazole)-triphosphate] (gamma-MetIm-2', 5'-dd-3'-ATP) and 2',5'-dd-adenosine 3'-(gamma-azidoanilido)-triphosphate (gamma-azidoanilido-2', 5'-dd-3'-ATP) were synthesized, the former also as its gamma-(32)P-labeled analog. gamma-Azidoanilido-2',5'-dd-3'-ATP exhibited an inhibitory potency comparable with that of 2', 5'-dd-3'-ATP. gamma-MetIm-2',5'-dd-[gamma-(32)P]3'-ATP labeled the individual VC(1) and IIC(2) domains comparably and covalently to approximately 20% within 1 h. Formation of VC(1).IIC(2) resulted in reduced labeling of VC(1) but enhanced labeling of IIC(2). The data imply that formation of the catalytically active VC(1).IIC(2) complex affects the interaction of each domain with the 2', 5'-dd-3'-ATP, the binding of which also affects the interaction between the two cytosolic domains, leading to a pseudo-irreversible inhibition.
We have investigated the ability of several cytokine combinations to improve retrovirus-mediated transduction of human primitive hematopoietic progenitors (PHPs) from mobilized peripheral blood (MPB). Retroviral infection of CD34+ cells was performed by culture on fibronectin fragment CH-296 (RetroNectin, RN), using the truncated human nerve growth factor receptor (NGFR) as the transgene reporter. Transgene expression among progeny of PHPs was assayed by FACS analysis after long-term stromal culture (LTC). Transgene delivery to PHPs was assessed by PCR of individual stromal culture-derived methylcellulose colonies (LTC-CFCs). Compared with interleukin 3 (IL-3), IL-6, and leukemia inhibitory factor (LIF), the combination of thrombopoietin (TPO), Flt3 ligand (FL), and Kit ligand (KL) effected a 73-fold increase in NGFR expression among CD34+ cells (to 14%) and a 14-fold increase in NGFR expression among total cells (to 10%) after LTC. In addition, a 2.4-fold increase in neo gene marking of LTC-CFCs was observed. A preclinical study comparing the effect of high-speed centrifugation ("spinoculation") or culture on RN during exposure to retroviral particles in teflon cell culture bags showed no difference in the efficiency of transduction of PHPs between these two methods.
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BACKGROUND: Post-partum depression in the developing world has received little research attention, and its association with disturbances in the mother-infant relationship is unknown. AIMS: To determine the prevalence of post-partum depression and associated disturbances in the mother-infant relationship in Khayelitsha, a South African peri-urban settlement. METHOD: The mental state of 147 women who had delivered two months previously was assessed, and the quality of their engagement with their infants was determined. RESULTS: The point prevalence of DSM-IV major depression was found to be 34.7%. Maternal depression was associated with poor emotional and practical support from the partner. It was also associated with insensitive engagement with the infants. CONCLUSIONS: The rate of post-partum depression in Khayelitsha was around three times that found in British post-partum samples, and these depressions were strongly associated with disturbances in the mother-infant relationship.
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A community sample of depressed and well mothers, recruited at 2 months postpartum and assessed through to 18 months, was followed up at 5 years. The quality of mother-child interactions was assessed, as was the children's behavioural and social adjustment, using maternal reports and observations of child behaviour during free play at school. Several aspects of child outcome were found to be associated with postnatal depression, even when taking account of current adverse circumstances (maternal depression and parental conflict). These included the child's behaviour with the mother, the presence of behavioural disturbance at home, and the content and social patterning of play at school. These associations with postnatal depression were independent of the child's gender. The child's relationship with the mother appeared to be mediated by the quality of infant attachment at 18 months. The mother's behaviour with her child was more affected by current difficulties, in particular by conflict with the child's father. Together these findings suggest that, while maternal behaviour varies with changing circumstances, exposure to maternal depression in the early postpartum months may have an enduring influence on child psychological adjustment.