Molecular basis of altered red blood cell membrane properties in Southeast Asian ovalocytosis: role of the mutant band 3 protein in band 3 oligomerization and retention by the membrane skeleton

Southeast Asian ovalocytosis (SAO) is an asymptomatic trait characterized by rigid, poorly deformable red cells that resist invasion by several strains of malaria parasites. The underlying molecular genetic defect involves simple heterozygous state for a mutant band 3 protein, which contains a deletion of amino acids 400 through 408, linked with a Lys 56-to-Glu substitution (band 3-Memphis polymorphism). To elucidate the contribution of the mutant SAO band 3 protein to increased SAO red blood cell (RBC) rigidity, we examined the participation of the mutant SAO band 3 protein in increased band 3 attachment to the skeleton and band 3 oligomerization. We found first that SAO RBC skeletons retained more band 3 than normal cells and that this increased retention preferentially involved the mutant SAO band 3 protein. Second, SAO RBCs contained a higher percentage of band 3 oligomer-ankyrin complexes than normal cells, and these oligomers were preferentially enriched by the mutant SAO protein. At the ultrastructural level, the increased oligomer formation of SAO RBCs was reflected by stacking of band 3-containing intramembrane particles (IMP) into longitudinal strands. The IMP stacking was not reversed by treating SAO RBCs in alkaline pH (pH 11), which is known to weaken ankyrin-band 3 interactions, or by removing the cytoplasmic domain of band 3 from SAO membranes with trypsin. Finally, we found that band 3 protein in intact SAO RBCs exhibited a markedly decreased rotational mobility, presumably reflecting the increased oligomerization and the membrane skeletal association of the SAO band 3 protein. We propose that the mutant SAO band 3 has an increased propensity to form oligomers, which appear as longitudinal strands of IMP and exhibit increased association with membrane skeleton. This band 3 oligomerization underlies the increase in membrane rigidity by precluding membrane skeletal extension, which is necessary for membrane deformation.     

The Effects of Aldosterone Synthase Inhibition on Aldosterone and Cortisol in Patients With Hypertension: A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

J Clin Hypertens (Greenwich). 2012; 14:580–587. © 2012 Wiley Periodicals, Inc. Blockade of the renin‐angiotensin‐aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose‐ and time‐dependent effect of LCI699 on both aldosterone and ACTH‐stimulated cortisol. Based on exposure‐response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.     

Awareness of HIV/AIDS among primary school pupils in north central region of Nigeria

ObjectiveTo determine the knowledge of HIV/AIDS among primary school pupils in north central area of Nigeria.Methods2000 randomly selected primary school pupils in and around eastern part of Idoma area of Benue state were interviewed using an open-ended questionnaire. Data analysis was done with EPI-INFO 2000. The Chi-square test was used for statistical analysis and the 0.05 level of significance was adopted.ResultsA totle of 1010 males and 990 females at ages between five and sixteen years were drawn from 10 primary schools in the area. Pupils in the higher classes were more knowledgeable and sex difference was not statistically significant. Certain misconceptions were noted.ConclusionsThere is need for health education for all cadres of primary school pupils in the area, which will increase the awareness of the disease.     

牙科医生对口腔卫生服务体系的评价

目的 :分析牙科医生的日常工作量和牙医对口腔卫生服务的态度评价 ,有助于口腔卫生服务体系的制定和评价。方法 :根据武汉市卫生部门登记在册的牙科医生 ,采用整群抽样的方法随机选择 2 5 0名牙科医生进行开放式问卷调查。结果 :所调查的 2 5 0名样本中 ,5 2 %为女性 ,牙科医生平均工作年限为 11.6年 ,平均使用 0 .8台牙椅 ,每位牙医平均每天看 15个病人。主要工作时间用于充填治疗和拔牙。 93 %的牙医认为中国口腔卫生服务强调治疗而忽视预防保健。结论 :口腔卫生服务应重视口腔预防保健     

Positron emission tomographic scanning demonstrates a presynaptic dopaminergic lesion in Lytico-Bodig. The amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam

We performed positron emission tomography using 18F-6-fluorodopa on four Guamanians with an amyotrophic lateral sclerosis syndrome, eight Guamanians with parkinsonism, and seven clinically normal Guamanians; the results were compared with those of nine Vancouver control subjects. The Guamanian subjects had all been exposed to similar Chamorro lifestyles. The scans were analyzed using a graphic method that calculates a constant for whole striatal 18F-6-fluorodopa uptake. The parkinsonian subjects all had significantly reduced striatal 18F-6-fluorodopa uptake. The group with amyotrophic lateral sclerosis had significantly reduced uptake that was intermediate between that of the control group and the parkinsonian group. Two Guamanian normal subjects had reduced striatal 18F-6-fluorodopa uptake. The nigrostriatal dopaminergic lesion in Guamanian parkinsonism is similar to that found in idiopathic parkinsonism. The nigrostriatal lesions in the subjects with amyotrophic lateral sclerosis and the Guamanian normal subjects are examples of subclinical neuronal damage demonstrable in living subjects with positron emission tomography.     

Chagas' disease diagnosis: evaluation of several tests in blood bank screening

Blood transfusion is one of the principal routes of transmission of Chagas' disease, a major endemic disease in Latin America. Methods for blood screening are not accurate and may yield false results that lead to high social and economic costs. This study compares two methods of diagnosing Chagas' disease (indirect immunofluorescence and hemagglutination) and several enzyme-linked immunosorbent assays (ELISAs) with regard to specificity and sensitivity, by using human sera with known serologic and parasitologic characteristics, as well as samples with discrepant results on conventional serologic tests. An ELISA using recombinant antigens showed no cross-reactivity with sera that were positive for other diseases. All evaluated ELISAs performed well, and their use may lead to a reduction of more than 50 percent in the number of discordant sera. Further improvements are needed in view of the complexity of the serologic diagnosis of Chagas' disease.     

Satellite and Mobile Wireless Transmission of Focused Assessment with Sonography in Trauma

Objectives: Focused assessment with sonography in trauma (FAST) can define life‐threatening injuries in austere settings with remote real‐time review by experienced physicians. This study evaluates vest‐mounted microwave, satellite, and LifeLink communications technology for image clarity and diagnostic accuracy during remote transmission of FAST examinations. Methods: Using a SonoSite, FAST was obtained on three patients with pericardial and intraperitoneal effusions and two control subjects in a remotely located U.S. Army Combat Support Hospital. A miniature vest‐mounted video transmitter attached to the SonoSite sent wireless ultrasound video 20 m to a receiving antenna. The signal was then transferred over VSAT satellite systems at 512 kilobaud per second (kbps), INMARSAT satellite systems at 64 kbps, and over LifeLink on a moving ambulance through a metropolitan wireless traffic–management network. Clarity and absence or presence of effusions were recorded by 15 staff emergency physicians. Results: Average sensitivity, specificity, and accuracy were 87% (95% confidence interval [CI] = 79% to 95%), 85% (95% CI = 81% to 89%), and 86% (95% CI = 82% to 90%) for the Premier Wireless Vest; 98% (95% CI = 97% to 99%), 83% (95% CI = 75% to 91%), and 86% (95% CI = 82% to 90%) for VSAT; 95% (95% CI = 94% to 96%), 70% (95% CI = 58% to 82%), and 75% (95% CI = 70% to 80%) for INMARSAT; and 82% (95% CI = 73% to 91%), 83% (95% CI = 74% to 92%), and 82% (95% CI = 78% to 86%) for LifeLink with clarity of 3.0 (95% CI = 2.7 to 3.3), 2.9 (95% CI = 2.6 to 3.2), 1.3 (95% CI = 1.2 to 1.4), and 2.1 (95% CI = 1.8 to 2.4), respectively. Conclusions: Accuracy correlated with clarity. Roaming vest transmission of FAST provides interpretable, diagnostic imagery at the distances used in this study. VSAT provided the best clarity and diagnostic value with the lighter, more portable INMARSAT serving a lesser role for remote clinical interpretation. LifeLink performed well, and further infrastructure improvements may increase clarity and accuracy.     

Successful treatment of Fusarium keratitis with cornea transplantation and topical and systemic voriconazole

A case of invasive Fusarium keratitis in a previously healthy male patient was treated successfully with cornea transplantation and systemic and topical voriconazole after treatment failure with topical amphotericin B and systemic itraconazole. Topical voriconazole was well tolerated, and, in conjunction with the oral administration, it resulted in a high level of the drug in the anterior chamber of the eye (which was 160% of the plasma drug level).     

A novel homozygous mutation at the GAA gene in Mexicans with early-onset Pompe disease

Glycogen-storage disease type II, also named Pompe disease, is caused by the deficiency of the enzyme acid alpha-glucosidase, which originates lysosomal glycogen accumulation leading to progressive neuromuscular damage. Early-onset Pompe disease shows a debilitating and frequently fulminating course. To date, more than 300 mutations have been described; the majority of them are unique to each affected individual. Most early-onset phenotypes are associated with frameshift mutations leading to a truncated alpha-glucosidase protein with loss of function. Founder effects are responsible from many cases from few highprevalence world regions. Herein we described two apparently unrelated cases affected with classical early-onset Pompe disease, both pertaining to a small region from Central Mexico (the State of San Luis Potosí), the same novel homozygous frameshift mutation at gene GAA (c.1987delC) was demonstrated in both cases. This GAA gene deletion implies a change of glutamine to serine at codon 663, and a new reading frame that ends after 33 base pairs, which leads to the translation of a truncated protein. This report contributes to widen the knowledge on the effect of pathogenic mutations in Pompe disease. Here we postulate the existence of a founder effect.Key words: Early-onset Pompe disease, Acid maltase deficiency, Founder effectGlycogen storage disease type II (Online Mendelian Inheritance in Man, OMIM, accession number 232300), also called Pompe disease, was described by Johannes C. Pompe in 1932. The disorder is caused by a deficiency of the enzyme acid alpha-glucosidase (acid maltase, EC 3.2.1.20, Swiss) which originates lysosomal glycogen accumulation leading to lysosomal swelling, cellular damage and dysfunction (1-3). Affected individuals develop progressive neuromuscular damage, showing a debilitating and frequently fulminating course on the classical, early-onset type of the disease. Other main findings are hypertrophic cardiomyopathy, hypotonia, hepatomegaly, macroglossia, feeding problems and breath difficulty. Currently it is recognized that the late form of Pompe disease has a very variable phenotype that can be confused with a wide range of neuromuscular, pulmonary and cardiovascular diseases with mild, moderate or severe symptoms that present either alone or combined (4-6).Pompe disease has an autosomal recessive inheritance and it is caused by more than 300 mutations that occur all over the gene coding for acid alpha-glucosidase (GAA) located at locus 17q25.2q25.3. The molecular phenomenon responsible of the different types of clinical expression occur by the presence of two either homozygous or compound heterozygous pathogenic mutations in early-onset Pompe cases, whereas late-onset Pompe have one variant and one pathogenic mutation (7). The majority of disease-causing mutations are unique; nonetheless, relatively frequent mutations have been described in certain populations with a possible founder effect traced from the original mutated carrier to the newly occurring cases. Affected cases have been described worldwide with a few high-prevalence regions like South-Africa, Taiwan and Holland (1, 8-10).Herein, we described two unrelated cases affected with classical early-onset Pompe disease, both pertaining to the same small Mexican region, with the same novel homozygous frameshift mutation at gene GAA (c.1987delC), identified by complete gene sequencing.     

The arterial wall: a new pharmacological and therapeutic target*

Summary— In recent years, two key concepts having numerous interrelationships were advanced for the understanding of various cardiovascular diseases: the “endothelial dysfunction” and the “arterial remodelling”. Both endothelial dysfunction and arterial remodelling occur in various pathologies including essential hypertension, heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extra-cellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extra-cellular matrix.