Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes.

Severe combined deficiency of the 2-oxoacid dehydrogenases, associated with a defect in lipoate synthesis and accompanied by defects in complexes I, II, and III of the mitochondrial respiratory chain, is a rare autosomal recessive syndrome with no obvious causative gene defect. A candidate locus for this syndrome was mapped to chromosomal region 2p14 by microcell-mediated chromosome transfer in two unrelated families. Unexpectedly, analysis of genes in this area identified mutations in two different genes, both of which are involved in [Fe-S] cluster biogenesis. A homozygous missense mutation, c.545G>A, near the splice donor of exon 6 in NFU1 predicting a p.Arg182Gln substitution was found in one of the families. The mutation results in abnormal mRNA splicing of exon 6, and no mature protein could be detected in fibroblast mitochondria. A single base-pair duplication c.123dupA was identified in BOLA3 in the second family, causing a frame shift that produces a premature stop codon (p.Glu42Argfs(∗)13). Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic isoform of NFU1 and with isoform 1, but not isoform 2 of BOLA3 restored both respiratory chain function and oxoacid dehydrogenase complexes. NFU1 was previously proposed to be an alternative scaffold to ISCU for the biogenesis of [Fe-S] centers in mitochondria, and the function of BOLA3 was previously unknown. Our results demonstrate that both play essential roles in the production of [Fe-S] centers for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases, and for the assembly of the respiratory chain complexes.

Burden of community-acquired and nosocomial rotavirus gastroenteritis in the pediatric population of Western Europe: a scoping review.

BACKGROUND: Rotavirus affects 95% of children worldwide by age 5 years and is the leading cause of severe dehydrating diarrhea. The objective of this review was to estimate the burden of rotavirus gastroenteritis (RVGE) in the Western European pediatric population. METHODS: A comprehensive literature search (1999-2010) was conducted in PubMed and other sources (CDC; WHO, others). Data on the epidemiology and burden of RVGE among children < 5 years-old in Western Europe --including hospital-acquired disease--were extracted. RESULTS: 76 studies from 16 countries were identified. The mean percentage of acute gastroenteritis (AGE) cases caused by rotavirus ranged from 25.3%-63.5% in children < 5 years of age, peaking during winter. Incidence rates of RVGE ranged from 1.33-4.96 cases/100 person- years. Hospitalization rates for RVGE ranged from 7% to 81% among infected children, depending on the country. Nosocomial RVGE accounted for 47%-69% of all hospital-acquired AGE and prolonged hospital stays by 4-12 days. Each year, RVGE incurred $0.54- $53.6 million in direct medical costs and $1.7-$22.4 million in indirect costs in the 16 countries studied. Full serotyping data was available for 8 countries. G1P[8], G2P[4], G9P[8], and G3P[8] were the most prevalent serotypes (cumulative frequency: 57.2%- 98.7%). Serotype distribution in nosocomial RVGE was similar. CONCLUSIONS: This review confirms that RVGE is a common disease associated with significant morbidity and costs across Western Europe. A vaccine protecting against multiple serotypes may decrease the epidemiological and cost burden of RVGE in Western Europe.

Burden of rotavirus gastroenteritis in the Middle Eastern and North African pediatric population.

BACKGROUND: Rotavirus gastroenteritis (RVGE) is the most common cause of severe childhood diarrhea worldwide. Objectives were to estimate the burden of RVGE among children less than five years old in the Middle East (Bahrain, Iran, Iraq, Israel, Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Syria, UAE, Yemen), North Africa (Algeria, Egypt, Libya, Morocco, Tunisia) and Turkey. METHODS: A comprehensive literature search was conducted in major databases on the epidemiology and burden of rotavirus among children less than five years old between 1999 and 2009. Data from each country was extracted and compared. RESULTS: The search identified 43 studies. RVGE was identified in 16-61% of all cases of acute gastroenteritis, with a peak in the winter. RVGE-related hospitalization rates ranged from 14% to 45%, compared to 14%-28% for non-RVGE. Annually, RVGE caused up to 112 fatalities per 100,000 in certain countries in the region. Hospitalization costs ranged from $1.8 to $4.6 million annually, depending on the country. The most recent literature available showed that G1P[8] was the most prevalent genotype combination in 8 countries (range 23%-56%). G2P[4] was most prevalent in 4 countries (26%-48%). G9P[8] and G4P[8] were also frequently detected. CONCLUSIONS: RVGE is a common disease associated with significant morbidity, mortality, and economic burden. Given the variety and diverse rotavirus types in the region, use of a vaccine with broad and consistent serotype coverage would be important to help decrease the burden of RVGE in the Middle East and North Africa.

Burden of rotavirus gastroenteritis in the pediatric population in Central and Eastern Europe: serotype distribution and burden of illness.

BACKGROUND: Rotaviral gastroenteritis (RVGE) is the leading cause of severe diarrhea in children under five years of age worldwide. This comprehensive review aims to estimate the burden of RVGE among children in Central and Eastern Europe. METHODS: An extensive search of the biomedical literature (1999-2009) was conducted in major databases. Studies pertaining to the epidemiology and burden of rotavirus in Central and Eastern Europe were captured and data from each country was systematically extracted and compared. RESULTS: This literature search captured 38 studies pertaining to RVGE infection in the region. Among children under 15 years of age, RVGE accounted for between 22.0% and 55.3% of all cases of acute gastroenteritis per year. For most countries RVGE was most common in the winter months, although it was reported year round in Bulgaria. Geographical comparison of genotyping data revealed that three genotype combinations, G1P[8], G4P[8], and G2P[4] were present in all countries for which full genotyping data was available. Genotype predominance varied on a season to season basis within each country. Only limited data was available for healthcare resource utilization, and economic burden for this region. CONCLUSIONS: RVGE is a common disease associated with significant morbidity, and mortality. While three genotype combinations currently predominate in the region, the dominance of a certain serotype can change dramatically from year to year and from country to country. A vaccination program with broad serotype coverage may help to decrease the burden of RVGE in Central and Eastern Europe.

A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy.

NADH:ubiquinone oxidoreductase (complex I) deficiency is a common cause of mitochondrial oxidative phosphorylation disease. It is associated with a wide range of clinical phenotypes in infants, including Leigh syndrome, cardiomyopathy, and encephalomyopathy. In at least half of patients, enzyme deficiency results from a failure to assemble the holoenzyme complex; however, the molecular chaperones required for assembly of the mammalian enzyme remain unknown. Using whole genome subtraction of yeasts with and without a complex I to generate candidate assembly factors, we identified a paralogue (B17.2L) of the B17.2 structural subunit. We found a null mutation in B17.2L in a patient with a progressive encephalopathy and showed that the associated complex I assembly defect could be completely rescued by retroviral expression of B17.2L in patient fibroblasts. An anti-B17.2L antibody did not associate with the holoenzyme complex but specifically recognized an 830-kDa subassembly in several patients with complex I assembly defects and coimmunoprecipitated a subset of complex I structural subunits from normal human heart mitochondria. These results demonstrate that B17.2L is a bona fide molecular chaperone that is essential for the assembly of complex I and for the normal function of the nervous system.

Ischaemic stroke and bleeding rates in 'real-world' atrial fibrillation patients.

Stroke prevention guidelines recommend oral anticoagulants (OAC) for atrial fibrillation (AF) patients at moderate/high risk of stroke, and antiplatelet or no therapy for those at low/moderate risk. Outcomes for AF patients receiving antiplatelet/no therapy in 'real-life' clinical practice were explored. This study compared clinical event rates (stroke/bleeding) for AF patients treated with OAC therapy, antiplatelets or no therapy in usual clinical practice to event rates in OAC-treated AF patients from optimally-monitored 'real-life' settings (anticoagulation clinics). We searched biomedical literature (1994-2010) using PubMed to identify 'real-world' studies of clinical event rates for AF patients receiving OAC therapy, antiplatelets, or no therapy; event rates were extracted for each treatment and setting. We identified 136 studies of thromboembolic events and 86 of bleeding events. Ischaemic stroke rates (30 studies) were higher for AF patients receiving no therapy (median: 4.45/100 person-years; range: 0.25-5.9) or antiplatelet-therapy (median: 4.45/100 person-years; range: 2.0-10) compared to OAC-treated patients monitored in anticoagulation clinics (median: 1.72/100 person-years; range: 0.97-2.00), or from a non-specialized setting (median 1.66/100 person-years; range: 0-4.9). Major bleeding rates (32 studies) for patients receiving antiplatelet/no therapy were similar to OAC-treated patients from both clinical settings. As in randomised clinical trials, AF patients in 'real-world' clinical practice receiving antiplatelet/no therapy have higher rates of ischaemic stroke than OAC-treated patients. Antiplatelet/no therapy was associated with similar bleeding rates to OAC therapy. Increasing utilisation of anticoagulants in clinical practice could improve patient outcomes.

Characterization of the proportion of untreated and antiplatelet therapy treated patients with atrial fibrillation.

Despite the efficacy of oral anticoagulants for stroke prevention in atrial fibrillation (AF), evidence suggests that many patients with AF who should be treated with vitamin K antagonists (VKAs) are treated with antiplatelet therapy or remain untreated. The aims of this study were to determine the proportion of patients with AF in each treatment category in clinical practice and to ascertain whether treatment is appropriate for stroke risk. An extensive search of the biomedical research published since 1994 was performed. Studies delineating the treatment of patients with AF were captured. Seventy-eight studies pertaining to the treatment of patients with AF were identified; 56 studies, containing data from 1980 to 2007, met the inclusion criteria. Over time, the use of VKA therapy for stroke prevention increased, while the proportion of untreated patients decreased; antiplatelet use remained static. Looking at the more recent data, (collected from 2000 onward), the proportion of patients receiving no therapy ranged from 4% to 48% (median 18%), antiplatelet therapy from 10% to 56% (median 30%), and VKA therapy from 9% to 86% (median 52%). Although most studies showed a decrease in the proportion of antiplatelet-treated and untreated patients with increasing stroke risk (12 of 14 studies), many patients at moderate or high risk for stroke were not treated according to guidelines. In conclusion, this review shows that up to 56% of patients with AF are treated with antiplatelet therapy, and up to 48% receive no therapy regardless of stroke risk level. This may reflect the inconvenience associated with VKA use, inadequate assessment of stroke risk, or poor adherence to treatment guidelines.

Underuse of oral anticoagulants in atrial fibrillation: a systematic review.

BACKGROUND: Atrial fibrillation is associated with substantial mortality and morbidity from stroke and thromboembolism. Despite an efficacious oral anticoagulation therapy (warfarin), atrial fibrillation patients at high risk for stroke are often under-treated. This systematic review compares current treatment practices for stroke prevention in atrial fibrillation with published guidelines. METHODS: Literature searches (1997-2008) identified 98 studies concerning current treatment practices for stroke prevention in atrial fibrillation. The percentage of patients eligible for oral anticoagulation due to elevated stroke risk was compared with the percentage treated. Under-treatment was defined as treatment of <70% of high-risk patients. RESULTS: Of 54 studies that reported stroke risk levels and the percentage of patients treated, most showed underuse of oral anticoagulants for high-risk patients. From 29 studies of patients with prior stroke/transient ischemic attack who should all receive oral anticoagulation according to published guidelines, 25 studies reported under-treatment, with 21 of 29 studies reporting oral anticoagulation treatment levels below 60% (range 19%-81.3%). Subjects with a CHADS(2) (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score >or=2 also were suboptimally treated, with 7 of 9 studies reporting treatment levels below 70% (range 39%-92.3%). Studies (21 of 54) using other stroke risk stratification schemes differ in the criteria they use to designate patients as "high risk," such that direct comparison is not possible. CONCLUSIONS: This systematic review demonstrates the underuse of oral anticoagulation therapy for real-world atrial fibrillation patients with an elevated risk of stroke, highlighting the need for improved therapies for stroke prevention in atrial fibrillation.

Cost-effectiveness of pneumococcal polysaccharide vaccination in adults: a systematic review of conclusions and assumptions.

Streptococcus pneumoniae infections in adults are associated with substantial morbidity, mortality, and costs. A literature review was conducted to identify strengths and limitations of the cost-effectiveness of pneumococcal polysaccharide vaccine studies. A comparative analysis of the impact of model parameters on cost-effectiveness ratios was complemented by systematic assessment of the studies. We identified 11 economic evaluations of pneumococcal polysaccharide vaccine (PPV-23) in adults. In general, all 11 studies found that vaccination with PPV-23 is a cost-effective, and in some cases a cost-saving strategy for the prevention of invasive pneumococcal disease (IPD). The systematic assessment indicated that the results of the cost-effectiveness studies of PPV-23 are influenced by the values applied to vaccine efficacy, IPD incidence and case-fatality.

Identification and characterization of a common set of complex I assembly intermediates in mitochondria from patients with complex I deficiency.

Deficiencies in the activity of complex I (NADH: ubiquinone oxidoreductase) are an important cause of human mitochondrial disease. Complex I is composed of at least 46 structural subunits that are encoded in both nuclear and mitochondrial DNA. Enzyme deficiency can result from either impaired catalytic efficiency or an inability to assemble the holoenzyme complex; however, the assembly process remains poorly understood. We have used two-dimensional Blue-Native/SDS gel electrophoresis and a panel of 11 antibodies directed against structural subunits of the enzyme to investigate complex I assembly in the muscle mitochondria from four patients with complex I deficiency caused by either mitochondrial or nuclear gene defects. Immunoblot analyses of second dimension denaturing gels identified seven distinct complex I subcomplexes in the patients studied, five of which could also be detected in nondenaturing gels in the first dimension. Although the abundance of these intermediates varied among the different patients, a common constellation of subcomplexes was observed in all cases. A similar profile of subcomplexes was present in a human/mouse hybrid fibroblast cell line with a severe complex I deficiency due to an almost complete lack of assembly of the holoenzyme complex. The finding that diverse causes of complex I deficiency produce a similar pattern of complex I subcomplexes suggests that these are intermediates in the assembly of the holoenzyme complex. We propose a possible assembly pathway for the complex, which differs significantly from that proposed for Neurospora, the current model for complex I assembly.