Marvin Reid

Glutathione in disease.

Altered glutathione metabolism in association with increased oxidative stress has been implicated in the pathogenesis of many diseases. However, whether strategies aimed at restoring glutathione concentration and homeostasis are effective in ameliorating or modifying the natural history of these states is unknown. In this review we discuss the pathogenic role for altered glutathione metabolism in such diseases as protein energy malnutrition, seizures, Alzheimers disease, Parkinsons disease, sickle cell anaemia, chronic diseases associated with ageing and the infected state. In addition, we discuss the efficacy of glutathione precursors in restoring glutathione homeostasis both in vitro and in vivo.

Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso‐occlusive crises in patients with sickle cell disease: a phase III randomized, placebo‐controlled, double‐blind study of the gardos channel blocker senicapoc (ICA‐17043)

Red blood cell (RBC) hydration is regulated in part by the Ca2+‐activated K+ efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo‐controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty‐five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0·38 vs. 0·31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups.

Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation

BACKGROUND Aging is associated with oxidative stress, but underlying mechanisms remain poorly understood. OBJECTIVE We tested whether glutathione deficiency occurs because of diminished synthesis and contributes to oxidative stress in aging and whether stimulating glutathione synthesis with its precursors cysteine and glycine could alleviate oxidative stress. DESIGN Eight elderly and 8 younger subjects received stable-isotope infusions of [2H(2)]glycine, after which red blood cell (RBC) glutathione synthesis and concentrations, plasma oxidative stress, and markers of oxidant damage (eg, F(2)-isoprostanes) were measured. Elderly subjects were restudied after 2 wk of glutathione precursor supplementation. RESULTS Compared with younger control subjects, elderly subjects had markedly lower RBC concentrations of glycine (486.7 ± 28.3 compared with 218.0 ± 23.7 μmol/L; P < 0.01), cysteine (26.2 ± 1.4 compared with 19.8 ± 1.3 μmol/L; P < 0.05), and glutathione (2.08 ± 0.12 compared with 1.12 ± 0.18 mmol/L RBCs; P < 0.05); lower glutathione fractional (83.14 ± 6.43% compared with 45.80 ± 5.69%/d; P < 0.01) and absolute (1.73 ± 0.16 compared with 0.55 ± 0.12 mmol/L RBCs per day; P < 0.01) synthesis rates; and higher plasma oxidative stress (304 ± 16 compared with 346 ± 20 Carratelli units; P < 0.05) and plasma F(2)-isoprostanes (97.7 ± 8.3 compared with 136.3 ± 11.3 pg/mL; P < 0.05). Precursor supplementation in elderly subjects led to a 94.6% higher glutathione concentration, a 78.8% higher fractional synthesis rate, a 230.9% higher absolute synthesis rate, and significantly lower plasma oxidative stress and F(2)-isoprostanes. No differences in these measures were observed between younger subjects and supplemented elderly subjects. CONCLUSIONS Glutathione deficiency in elderly humans occurs because of a marked reduction in synthesis. Dietary supplementation with the glutathione precursors cysteine and glycine fully restores glutathione synthesis and concentrations and lowers levels of oxidative stress and oxidant damages. These findings suggest a practical and effective approach to decreasing oxidative stress in aging.

Protein metabolism in severe childhood malnutrition

Abstract The major clinical syndromes of severe childhood malnutrition (SCM) are marasmus (non-oedematous SCM), kwashiorkor and marasmic-kwashiorkor (oedematous SCM). Whereas treatment of marasmus is straightforward and the associated mortality is low, kwashiorkor and marasmic-kwashiorkor are difficult to treat and have high morbidity and mortality rates. Despite extensive research, the pathogenic factors which cause a child to develop the oedematous instead of the non-oedematous form of SCM in response to food deprivation are still not clear. Over the years, two attractive hypotheses have been put forward. The first proposed that a dysadaptation in protein metabolism was involved and the second proposed that free radical damage of cellular membranes might be involved. To address aspects of these hypotheses, in this article we have reviewed work done by our group and by others on protein metabolism and pro-oxidant/anti-oxidant homeostasis in children with the oedematous and non-oedematous syndromes of SCM. A significant finding is that when there is chronic food deprivation children with non-oedematous SCM can maintain body protein breakdown at the same rate as when they are well nourished, but children with oedematous SCM cannot. The slower protein breakdown rate of children with oedematous SCM reduces the supply of most amino acids, resulting in decreased availability for the synthesis of plasma proteins involved in nutrient transport and the acute phase response to infection. Another consistent finding is that children with oedematous SCM have oxidative stress as there is evidence of oxidant-induced cellular damage and impaired synthesis of the primary cellular anti-oxidant glutathione.

Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

Background Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis. Design and Methods Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions. Results Results showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age. Conclusions Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.

Growth, body composition, and the onset of puberty: longitudinal observations in Afro-Caribbean children

CONTEXT Childhood growth and body composition may influence the onset of puberty. OBJECTIVE We examined the effects of birth size, growth rates throughout childhood, and body composition on the onset of puberty in Afro-Caribbean children. DESIGN AND SETTING This was a longitudinal birth cohort study (the Vulnerable Windows Cohort Study) in Jamaica. SUBJECTS AND MEASUREMENTS The anthropometry (weight, height, skinfold measurements, and waist circumference) of 259 children was measured at birth, at 6 wk, every 3 months to 2 yr, and then every 6 months. Tanner staging for puberty and orchidometry were performed every 6 months starting at approximately age 8 yr. Bioelectrical impedance was done at age 11 yr. RESULTS In the girls, thelarche, pubarche, and menarche occurred at median ages of 8.8, 9.9, and 12.0 yr, respectively. Pubarche in boys occurred at a median age of 11.3 yr when the median testicular volume was 2.8 ml. Faster weight gain during infancy (age 0-6 months) and childhood, but not birth size, was associated with more advanced puberty (P values <0.05). Fat mass at age 8 yr was associated with more advanced puberty (P values <0.001) in both sexes. At age 11 yr, lean mass, but not fat mass, was associated with more advanced puberty (P values <0.001). CONCLUSION These data support the hypothesis that faster growth throughout childhood, especially with fat mass accretion, is associated with more advanced puberty apart from menarche. With the onset of puberty, lean mass accretion significantly increases.

Newborn sickle cell disease screening: the Jamaican experience (1995–2006):

Objectives: The aim of this study was to evaluate the existing newborn sickle haemoglobinopathy screening programme in Jamaica. Methods: A retrospective analysis of infants screened during the period 8 November 1995 to 22 July 2006 was performed. Patient data for analyses was restricted to patients with homozygous (Hb SS) sickle cell disease. Published data from the Jamaican Sickle Cell Cohort Study was used to make comparisons with the study sample. Results: The study sample consisted of 435 patients with Hb SS disease. Acute chest syndrome was the most common clinical (non-death) event accounting for ∼50% of all events. Acute splenic sequestration, no longer a significant cause of mortality, was responsible for ∼32% of clinical events. Seven deaths (1.8%) occurred during the study period compared with 17.6% to the same age in the Jamaican Sickle Cell Cohort Study. There was a lower proportion of hospital admissions and episodes of serious illness in the study group compared with controls. Conclusions: Survival estimates for the study sample showed improvement compared with the Jamaican Sickle Cell Cohort Study. This study continues to demonstrate the benefits of, and as such shows support for, newborn screening and early interventions in sickle cell disease. In addition, it highlights some of the areas for continued focus and research development. Although the current system is providing an essential and beneficial service, the study emphasizes the need for newborn screening programmes to be comprehensive care systems to be fully effective.

Venous incompetence, poverty and lactate dehydrogenase in Jamaica are important predictors of leg ulceration in sickle cell anaemia

Clinical features and potential risk factors for chronic leg ulceration (duration >6 months) in homozygous sickle cell (SS) disease were examined in 225 subjects in the Jamaican Cohort Study. Potential risk factors included the number of HBA genes, steady state haematology, serum lactate dehydrogenase (LDH), venous incompetence, and socio‐economic status. Chronic ulcers occurred in 53 subjects with the highest risk of ulcer development at 18 years. The prevalence was 29·5% and cumulative incidence 16·7%. Gender or α‐thalassaemia trait did not affect the incidence of leg ulcer. Ulceration was associated with lower haemoglobin, red cell count, fetal haemoglobin, and socio‐economic status and higher reticulocyte count, platelet count, serum LDH and venous incompetence in univariate analyses. Venous incompetence [Hazard Ratio (HR) 3·0–4·0] and socio‐economic status (HR 0·8) were most consistently associated with leg ulceration on multivariate analysis. Regression models incorporating serum LDH suggested this to be a stronger predictor than haematological indices. The prevalence of ulcers at 30% is less than previous estimates in Jamaica, probably reflecting the lack of ascertainment bias in the Cohort Study, and also a real secular decline. In Jamaica, venous incompetence, low socio‐economic status, and high serum LDH were the strongest predictors of chronic ulceration.

Discrepancies between clinical and postmortem diagnoses in Jamaica: a study from the University Hospital of the West Indies

Aims: It has previously been shown that the low necropsy request rate at the University Hospital of the West Indies (UHWI) in Jamaica (35.3%) results primarily from clinicians’ confidence in clinical diagnoses and laboratory investigations. This study aimed to determine the rates of discrepancy between clinical and necropsy diagnoses at the UHWI, because many previous studies from other institutions have shown persistent high rates of discrepancy, despite advances in medical investigative technology over the past several years. Methods: Data were extracted retrospectively from consecutive necropsies performed at the UHWI over a two year period. The data were analysed to determine the categories and rates of discrepancy, and to determine the relation between discrepancy rates and age, sex, type and number of diagnoses for each patient, hospital service, and length of hospitalisation. Results: Necropsies were performed on 446 patients; 348 were suitable for further analysis. The overall discrepancy rate was 48.4% and the diagnoses with the highest individual discrepancy rates were pneumonia (73.5%), pulmonary thromboembolism (68.3%), and myocardial infarction (66.7%). Males and older patients were more likely to have discrepant diagnoses. There was a high frequency of discrepancies in patients who died within 24 hours of admission, but there was no consistent relation between length of hospitalisation and discrepancy rate. Conclusions: The high discrepancy rates documented at the UHWI are similar to those reported globally. This study supports previous attestations that the necropsy remains a vital tool for determining diagnostic accuracy, despite modern modalities of clinical investigation and diagnosis.

Prevention of striae gravidarum with cocoa butter cream

To determine whether cocoa butter cream is effective in preventing striae gravidarum.