Impaired nicotinamide adenine dinucleotide synthesis in pyruvate kinase- deficient human erythrocytes: a mechanism for decreased total NAD content and a possible secondary cause of hemolysis

Erythrocytes from individuals with pyruvate kinase (PK) deficiency have approximately half the total (oxidized and reduced) nicotinamide adenine dinucleotide (NAD) of normal erythrocytes. In order to elucidate the mechanism(s) for the decrease in total NAD, we examined NAD synthesis in intact erythrocytes. It is demonstrated that NAD synthesis is impaired in PK-deficient erythrocytes to a degree that is dependent on the PK activity and adenosine 5'-triphosphate (ATP) concentration of these cells. After incubation in the presence of fluoride, which simulates the characteristics of PK deficiency by inhibiting enolase, normal erythrocytes had impaired NAD synthesis and decreased ATP concentrations. Fluoride did not inhibit NAD synthesis in a hemolysate system that is not dependent on glycolysis for ATP generation. These data suggest that fluoride does not inhibit the enzymes of NAD synthesis and that impairment of NAD synthesis by fluoride is mediated by decreased ATP formation. Thus, it is concluded that impaired NAD synthesis in PK-deficient erythrocytes is caused by decreased ATP formation due to the PK deficiency. Since the rate of glycolysis is limited by the availability of NAD+, it is suggested that impaired NAD synthesis causes further ATP depletion and thereby may enhance hemolysis in PK-deficient erythrocytes.     

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAbeta knockout NOD mice

A line of nonobese diabetic (NOD) mice expressing the human diabetes-associated HLA-DQ8 transgene in the absence of mouse IAbeta failed to show spontaneous insulitis or diabetes, but rather developed dilated cardiomyopathy, leading to early death from heart failure. Pathology in these animals results from an organ- and cell-specific autoimmune response against normal cardiomyoctes in the atrial and ventricular walls, as well as against very similar myocytes present in the outermost muscle layer surrounding the pulmonary veins. Progression of the autoimmune process could be followed by serial ECG measurements; irradiation of young animals significantly delayed disease progression, and this effect could be reversed by adoptive transfer of splenocytes taken from older animals with complete heart block. Disease progression could also be blocked by cyclosporin A treatment, but was accelerated by injection of complete Fruend's adjuvant. The constellation of findings of spontaneously arising destructive focal lymphocytic infiltrates within the myocardium, rising titers of circulating anticardiac autoantibodies, dilation of the cardiac chambers, and gradual progression to end-stage heart failure bears a striking resemblance to what is seen in humans with idiopathic dilated cardiomyopathy, a serious and often life-threatening medical condition. This transgenic strain provides a highly relevant animal model for human autoimmune myocarditis and postinflammatory dilated cardiomyopathy.     

Associations of Angiopoietins With Heart Failure Incidence and Severity

BackgroundAngiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.Methods and ResultsIn a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.ConclusionsAng2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.     

Loss to follow-up among youth accessing outpatient HIV care and treatment services in Kisumu,Kenya

Youth are particularly vulnerable to acquiring HIV, yet reaching them with HIV prevention interventions and engaging and retaining those infected in care and treatment remains a challenge. We sought to determine the incidence rate of loss to follow-up (LTFU) and explore socio-demographic and clinical characteristics associated with LTFU among HIV-positive youth aged 15–21 years accessing outpatient care and treatment clinics in Kisumu, Kenya. Between July 2007 and September 2010, youth were enrolled into two different HIV care and treatment clinics, one youth specific and the other family oriented. An individual was defined as LTFU when absent from the HIV treatment clinic for ≥?4 months regardless of their antiretroviral treatment status. The incidence rate of LTFU was calculated and Cox regression analysis used to identify factors associated with LTFU. A total of 924 youth (79% female) were enrolled, with a median age of 20 years (IQR 18–21). Over half, (529 (57%)), were documented as LTFU, of whom 139 (26%) were LTFU immediately after enrolment. The overall incidence rate of LTFU was 52.9 per 100 person-years (p-y). Factors associated with LTFU were pregnancy during the study period (crude HR 0.68, 95% CI 0.53–0.89); CD4 cell count >350 (adjusted hazard ratios (AHR) 0.59, 95% CI 0.39–0.90); not being on antiretroviral therapy (AHR 4.0, 95% CI 2.70–5.88); and non-disclosure of HIV infection status (AHR 1.43, 95% CI 1.10–1.89). The clinic of enrolment, age, marital status, employment status, WHO clinical disease stage and education level were not associated with LTFU. Interventions to identify and enrol youth into care earlier, support disclosure, and initiate ART earlier may improve retention of youth and need further investigation. Further research is also needed to explore the reasons for LTFU from care among HIV-infected youth and the true outcomes of these patients.     

Novel insights into the effects of diabetes on gastric motility

Recent data from the Diabetes Control and Complications Trial/Epidemiology of Diabetic Interventions and Complications cohort indicate that the disease burden of gastroparesis in diabetes remains high, consistent with the outcome of cross-sectional studies in type 1 and 2 diabetes. An improved understanding of the pathogenesis of diabetic gastroparesis at the cellular level has emerged in the last decade, particularly as a result of initiatives such as the National Institute of Health funded Gastroparesis Clinical Research Consortium in the US. Management of diabetic gastroparesis involves dietary and psychological support, attention to glycaemic control, and the use of prokinetic agents. Given that the relationship between upper gastrointestinal symptoms and the rate of gastric emptying is weak, therapies targeted specifically at symptoms, such as nausea or pain, are important. The relationship between gastric emptying and postprandial glycaemia is complex and inter-dependent. Short-acting glucagon-like peptide-1 agonists, that slow gastric emptying, can be used to reduce postprandial glycaemic excursions and, in combination with basal insulin, result in substantial reductions in glycated haemoglobin in type 2 patients.     

A 25-Year Longitudinal Evaluation of Gastric Emptying in Diabetes

OBJECTIVE

To evaluate the natural history of gastric emptying in diabetes.

RESEARCH DESIGN AND METHODS

Thirteen patients with diabetes (12, type 1; 1, type 2) had measurements of gastric emptying, blood glucose levels, glycated hemoglobin, upper gastrointestinal symptoms, and autonomic nerve function at baseline and after 24.7 ± 1.5 years.

RESULTS

There was no change in gastric emptying of either solids (% retention at 100 min) (baseline 58.5 ± 5% vs. follow-up 51.9 ± 8%; P = 0.35) or liquids (50% emptying time) (baseline 29.8 ± 3 min vs. follow-up 34.3 ± 6 min; P = 0.37). Gastric emptying of solid at follow-up was related to emptying at baseline (r = 0.56, P < 0.05). At follow-up, blood glucose concentrations were lower (P = 0.006), autonomic function deteriorated (P = 0.03), and gastrointestinal symptoms remained unchanged (P = 0.17).

CONCLUSIONS

In unselected patients with diabetes, gastric emptying appears remarkably stable over 25 years.There is limited information about the natural history of gastric emptying in diabetes (1–3). We have reported that gastric emptying and symptoms changed little after 12 years of follow-up, possibly because a deterioration in autonomic function was counteracted by better glycemic control (4). We reexamined patients from the same cohort after 25 years.     

Factors influencing decision‐making processes for unwell residents in residential aged care: Hospital transfer or Residential InReach referral?

Objective

To investigate decision‐making around hospital transfer and/or referral of residents to a Residential InReach (RiR) service in north‐eastern metropolitan Melbourne, Australia, from the perspectives of residential aged care facility (RACF) staff, general practitioners (GPs) and RiR registered nurses (RNs).

Methods

Thirty‐one staff from eight RACFs, five GPs and four RiR RNs participated in individual or group interviews.

Results

Residential aged care facility staff and GPs valued and relied upon RiR to manage unwell residents. Thematic analysis identified RiR utilisation was driven by the following: (i) complexity of decision‐making processes in RACFs; (ii) variability in facility‐based medical and nursing care; and (iii) impact of RiR service outcomes on patients and referrers.

Conclusion

Availability of timely and appropriate medical and nursing care in RACFs was reported to influence transfers to the hospital and/or referrals to RiR. RiR was used to complement or substitute usual care available to residents. Further research and improvements in RACF and RiR resources are required.

     

急性和慢性呼吸道炎症疾病激肽形成机制探讨

目的探讨急性和慢性呼吸道炎症过程中激肽的生成途径和机制。方法测定支气管肺癌伴阻塞性肺炎,慢性支气管炎和健康对照组支气管肺泡灌洗液（ＢＡＬＦ）凝胶过滤前后激肽、激肽形成酶活性（ＴＡＭＥｅａ）,血浆血管舒缓素（ＰＫ）和α２巨球蛋白（α２Ｍ）,并进一步鉴定ＴＡＭＥｅａ性质。结果急、慢性组ＴＡＭＥｅａ和激肽水平与健康对照组比较差异有显著性（Ｐ＜０００１,Ｐ＜０．０１）,但两组间差异无显著性（Ｐ＞００５）;急性组ＰＫ和α２Ｍ与慢性组比较差异有显著性（Ｐ＜０００１）。凝胶过滤结果显示：急性组ＢＡＬＦ的ＴＡＭＥｅａ最高峰位于分子量约８０００００处,与第一个α２Ｍ峰重叠,而慢性组的最高峰位于４００００处。ＴＡＭＥｅａ抑制试验证实８０００００处的ＴＡＭＥｅａ来自于ＰＫ;而４００００处的ＴＡＭＥｅａ主要来源于组织血管舒缓素（ＴＫ）。结论急性呼吸道炎症的ＴＡＭＥｅａ主要来自血浆的ＰＫ;而慢性呼吸道炎症则以局部组织腺体分泌的ＴＫ为主。     

Differences in hypertension between blacks and whites: an overview

Hypertension is more prevalent and severe in urban black populations compared to whites, and is associated with a greater degree of target-organ damage for any given blood pressure level. In general, compared to whites, blacks respond well to diuretics and calcium channel blockers and less well to beta-blockers and ACE inhibitors. The exact mechanisms that contribute to differences in blood pressure between blacks and whites are still not fully understood, given the multi-factorial aetiology of essential hypertension. Various lines of evidence suggest black patients are more salt sensitive than whites, which is due to a tendency to retain sodium in the kidney. Inherent differences in ionic transport mechanisms, the renal epithelial sodium channel, the reninangiotensin-aldosterone system and vasoactive substances may be a partial explanation, but analysis is compounded by disparate socio-economic conditions between blacks and whites. At present, there is no complete explanation for these differences and further research is required.     

Spatial heterogeneity of mesopredator release within an oceanic island system

Predator–prey communities are ubiquitous in ecology, but introduced predators can drive native species to extinction within island systems, prompting the eradication of such exotics. Ecological theory predicts that elimination of top-introduced predators from islands can lead to the counterintuitive decline of native prey populations through the ecological release of smaller introduced species in a process termed “mesopredator release.” We show, in accordance with mesopredator release theory and counter to conservation goals for a New Zealand island reserve, that initial eradication of cats on Little Barrier Island led to reduced breeding success of Cook's petrels, which also are vulnerable to predation by a mesopredator, the Pacific rat. The rat's impact on prey productivity varied with elevation within the island. Rat eradication was followed by a rise in petrel productivity, in support of both ecological theory and practical conservation management goals. It appears that interactions among introduced predators, native prey, and environmental gradients can drive counterintuitive and spatially heterogeneous responses to predator eradications from islands. Location-specific, ecosystem-level understanding is essential for predicting the outcomes of such restoration management techniques.