Genome-wide patterns of population structure and admixture in West Africans and African Americans

Quantifying patterns of population structure in Africans and African Americans illuminates the history of human populations and is critical for undertaking medical genomic studies on a global scale. To obtain a fine-scale genome-wide perspective of ancestry, we analyze Affymetrix GeneChip 500K genotype data from African Americans (n = 365) and individuals with ancestry from West Africa (n = 203 from 12 populations) and Europe (n = 400 from 42 countries). We find that population structure within the West African sample reflects primarily language and secondarily geographical distance, echoing the Bantu expansion. Among African Americans, analysis of genomic admixture by a principal component-based approach indicates that the median proportion of European ancestry is 18.5% (25th–75th percentiles: 11.6–27.7%), with very large variation among individuals. In the African-American sample as a whole, few autosomal regions showed exceptionally high or low mean African ancestry, but the X chromosome showed elevated levels of African ancestry, consistent with a sex-biased pattern of gene flow with an excess of European male and African female ancestry. We also find that genomic profiles of individual African Americans afford personalized ancestry reconstructions differentiating ancient vs. recent European and African ancestry. Finally, patterns of genetic similarity among inferred African segments of African-American genomes and genomes of contemporary African populations included in this study suggest African ancestry is most similar to non-Bantu Niger-Kordofanian-speaking populations, consistent with historical documents of the African Diaspora and trans-Atlantic slave trade.     

The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency

Summary:  The identification of mutations in the inducible costimulator ( ICOS ) gene in nine patients with common variable immunodeficiency (CVID) was a major breakthrough. CVID is a complex, highly heterogeneous primary immunodeficiency disease, and the discovery of these mutations revealed a molecular basis. ICOS belongs to the CD28 family of costimulatory molecules and is expressed exclusively on activated T cells. It has at least three critical functions: germinal center formation, isotype class switching, and the development of memory B cells. The discovery of human ICOS deficiency showed that a monogenic disorder could account for the full spectrum of manifestations seen in childhood and adulthood-onset CVID, including autoimmune, inflammatory, and malignant disease complications, as well as recurrent infections. Moreover, this discovery showed that a disorder which had previously been perceived as a B-cell disease might in fact have its genetic origin in human T cells. In this article, we review the role of ICOS in the mammalian immune system and human disease, as well as the discovery and characteristics of patients with ICOS deficiency. Finally, we also discuss how these 'human knockouts' have contributed to our understanding of ICOS functions and have suggested potential avenues for using therapeutic ICOS manipulation to treat other diseases.     

Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses?

Transmitter-gated ion channels mediate rapid synaptic transmission in the CNS and constitute important targets for many neuroactive drugs. Inhibitory glycine receptors (GlyRs) are members of the nicotinic acetylcholine receptor superfamily and inhibit neuronal firing by opening Cl(-) channels following agonist binding. In this article, we discuss recent developments in GlyR pharmacology, delineate the receptor domains that are involved in binding of agonists and allosteric modulators, and present a molecular model of the extracellular architecture of the receptor. The recent discovery of compounds that act preferentially on specific GlyR isoforms and the differential expression of these isoforms in distinct regions of the developing and adult CNS show considerable promise towards the development of drugs that act in defined glycine-mediated pathways. In particular, compounds that can potentiate GlyR function should provide leads for novel muscle relaxants in addition to sedative and analgesic agents.     

Globulixanthones A and B,two new cytotoxic xanthones with isoprenoid groups from the root bark of Symphonia globulifera

Bioassay-guided fractionation of a root bark extract of Symphonia globulifera has yielded, in addition to stigmasterol, two new xanthones with isoprenoid units, named globulixanthones A (1) and B (2). The structures of these compounds have been elucidated by spectroscopic means. They possess significant cytotoxicity in vitro against the KB cell line.     

What is the source of mycelial fungi in expressed human milk?

The authors characterized the genera of mycelial fungi found in samples of expressed human milk received through home collection by the Human Milk Bank of the Instituto Fernandes Figueira in Rio de Janeiro. A total of 821 samples of expressed human milk were taken randomly from bottles collected at home by the milk donors themselves and were investigated for molds, yeasts, and mesophilic microorganisms. The analyses showed the occurrence of molds and yeasts in 43 (5.2%) of the samples, with counts reaching 103CFU/ml. Some 48 strains of mycelial fungi were identified by standard laboratory techniques, including: Aspergillus Niger group (6.3%), Aspergillus sp. (4.2%), Paecilomyces sp. (12.6%), Penicillium sp. (60.4%), Rhizopus sp. (2.0%), and Syncephalastrum sp. (14.5%). The authors discuss the importance of donor hands' asepsis prior to collecting human milk.     

Paracoccidioidomycosis mortality in Brazil (1980-1995)

This study analyzes 3,181 deaths from paracoccidioidomycosis in Brazil, based on 16 years of sequential data (from 1980 to 1995). During this period paracoccidioidomycosis showed considerable magnitude and low visibility, representing the eighth most common cause of death from predominantly chronic or recurrent types of infectious and parasitic diseases. It also had the highest mortality rate among the systemic mycoses. The mean annual mortality rate was 1.45 per million inhabitants, indicating a downward long-term trend (reduction of 31.28%), while spatial distribution among the different regions and States of Brazil was non-homogenous. The South (with the highest regional rate) and the Southeast showed a downward trend, while the Central West had the second highest rate in the country. At least one-fifth of Brazilian municipalities (or 22.71% of the country's total area) reported deaths from paracoccidioidomycosis. Overall nationwide mortality per area was 3.73/10,000km2. The disease was endemic in non-metropolitan areas. The majority of deaths occurred in males (84.75%), and there was a sex ratio of 562 men/100 women. The 30-59-year and over-60-year age groups were the most affected. The study showed that the mortality rate justifies classifying this disease as a major health problem in Brazil.     

Molecular Mechanisms of Inherited Ventricular Arrhythmias

Background: Inherited ventricular arrhythmias such as the long QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. The detailed pathogenetic mechanisms of inherited ventricular arrhythmias are still poorly understood because systematic investigations are difficult to perform due to low patient numbers and the lack of appropriate experimental models. However, recent advances in research and science have identified a genetic background for many of these diseases. Present Knowledge: In LQTS, various mutations in different genes encoding for cardiac potassium and sodium channel proteins have been identified ("channelopathy"), and initial progress in genotype-phenotype correlation is made. Mutations in the cardiac sodium channel gene have also been identified in a subset of patients with Brugada syndrome, whereas a genetic background has not yet been demonstrated in idiopathic VF and right ventricular outflow-tract tachycardia (RVO-VT). Very recently, mutations in the cardiac ryanodine receptor gene have been identified in CPVT and in a subgroup of patients with ARVC. Although several chromosomal loci were suggested, no other responsible genes or mutations have been found in autosomal dominant forms of ARVC. However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC. Future Perspectives: In the next years, significant progress in the genetic diagnosis pathophysiologic understanding of disease mechanisms, genotype-phenotype correlation, and the development of gene- or target-directed treatment strategies can be expected in the field of inherited ventricular arrhythmias. Conclusion: This review summarizes the current knowledge of the molecular mechanisms, including aspects of pathoanatomy, autonomic innervation, genetics, and genotype-phenotype correlations with their potential implications for diagnosis and treatment of inherited ventricular arrhythmias. Hintergrund: Angeborene ventrikuläre Arrhythmien wie QT-Syndrom (LQTS), Brugada-Syndrom, katecholamingerge polymorphe ventrikuläre Tachykardie (CPVT), idiopathisches Kammerflimmern sowie arrhythmogene rechtsventrikuläre Kardiomyopathie (ARVC) sind wesentliche Ursachen plötzlicher Herztodesfälle bei jungen Patienten. Die detaillierten pathogenetischen Mechanismen sind bislang nur in Anfängen aufgeklärt, da bei geringen Patientenzahlen und fehlenden Tiermodellen systematische Untersuchungen erschwert sind. Dennoch konnten jüngste Fortschritte in klinischer und experimenteller Forschung neue Erkenntnisse zum genetischen Hintergrund angeborener ventrikulärer Arrhythmien beitragen. Aktuelle Erkentnisse: Bei LQTS wurden in den letzten Jahren zahlreiche Mutationen in verschiedenen Genen nachgewiesen, die für Proteine kardialer Kalium- und Natriumkanäle kodieren ("Ionenkanalerkrankung"). Auch wurden erste Ergebnisse bei der Genotyp-Phänotyp-Korrelation erzielt. Mutationen im kardialen Natriumkanalgen wurden auch beim Brugada-Syndrom nachgewiesen, während bei Patienten mit idiopathischem Kammerflimmern und rechtsventrikulärer Ausflusstrakttachykardie bislang keine genetischen Veränderungen gefunden werden. Kürzlich konnten Mutationen im Gen des kardialen Ryanodinrezeptors bei Patienten mit CPVT und einer Untergruppe der ARVC nachgewiesen werden. Dagegen konnte bei anderen Formen autosomal-dominant vererbter ARVC trotz Lokalisation mehrerer chromosomaler Loci bislang kein Gendefekt identifiziert werden. Bei der rezessiv vererbten Naxos-Erkrankung, einer Sonderform der ARVC mit Koexpression von palmoplantarer Keratose, wurde unlängst eine Mutation im Plakoglobingen nachgewiesen, wodurch die potentielle Rolle genetischer Veränderungen in zytoskelettären Proteinen bei ARVC unterstrichen wird. Perspektiven: Auch in den kommenden Jahren sind entscheidende Fortschritte in der genetischen Diagnostik, dem Verständnis pathogenetischer Mechanismen, der Genotyp-Phänotyp-Korrelation und der Entwicklung von gentyporientierten Therapiestrategien bei angeborenen ventrikulären Arrythmien zu erwarten. Schlussfolgerung: Diese Übersicht fasst den aktuellen Wissensstand der molekularen Mechanismen zusammen und diskutiert dabei Aspekte von Pathoanatomie, autonomer Innervation, Genetik, und Genotyp-Phänotyp-Korrelation mit ihren potentiellen Implikationen für die Diagnostik und Therapie angeborener ventrikulärer Arrhythmien.     

QUALITY CARE ASSESSMENT AND ASSURANCE

From its beginnings in 1955, the American College of Nurse-Midwives has supported the concept of Quality Care Assessment and Assurance (QCAA) and charged its members with responsibility to involve themselves in such activities within their practice. Six tools are reviewed that represent a sound basis for the development of QCAA programs within nurse-midwifery practice, the ultimate goal being the provision of optimal health care to women and the childbearing family.