Balloon dilation of mitral stenosis in adult patients: Postmortem and percutaneous mitral valvuloplasty studies

Preliminary reports have documented the utility of percutaneous balloon valvuloplasty of the mitral valve in adult patients with mitral stenosis, but the mechanism of successful valve dilation and the effect of mitral valvuloplasty on cardiac performance have not been studied in detail. Accordingly, mitral valvuloplasty was performed in five postmortem specimens and in 18 adult patients with rheumatic mitral stenosis, using either one (25 mm) or two (18 and 20 mm) dilation balloons. Postmortem balloon dilation resulted in increased valve orifice area in all five postmortem specimens, secondary to separation of fused commissures and fracture of nodular calcium within the mitral leaflets. In no case did balloon dilation result in tearing of valve leaflets, disruption of the mitral ring or liberation of potentially embolic debris.Percutaneous mitral valvuloplasty in 18 patients with severe mitral stenosis (including 9 with a heavily calcified valve) resulted in an increase in cardiac output (4.3 ± 1.1 to 5.1 ± 1.5 liters/min, p < 0.01) and mitral valve area (0.9 ± 0.2 to 1.6 ± 0.4 cm2, p < 0.0001), and a decrease in mean mitral pressure gradient (15 ± 5 to 9 ± 4 mm Hg, p < 0.0001), pulmonary capillary wedge pressure (23 ± 7 to 18 ± 7 mm Hg, p < 0.0001) and mean pulmonary artery pressure (36 ± 12 to 33 ± 12 mm Hg, p < 0.01). Left ventriculography before and after valvuloplasty in 14 of the 18 patients showed a mild (≤1 +) increase in mitral regurgitation in five patients and no change in the remainder. Embolic phenomena were not observed in any patient.Serial radionuclide ventriculography showed an increase in left ventricular peak filling rate (2.20 ± 1.20 to 2.50 ± 1.20 end-diastolic volumes per second [EDV/s], p < 0.05). Serial echocardiography/phonocardiography showed improvement in mitral valve excursion (11 ± 6 to 14 ± 6 mm, p < 0.001), mitral EF slope (7 ± 4 to 13 ± 5, p < 0.001), left atrial diameter (5.7 ± 0.9 to 5.3 ± 0.8 cm, p < 0.001), S2-opening snap interval (0.07 ± 0.03 to 0.08 ± 0.02 second, p < 0.02) and mitral valve area (0.9 ± 0.2 to 1.5 ± 0.4 cm2, p < 0.0001). All patients were discharged from the hospital with de- creased symptoms after valvuloplasty.It is concluded that percutaneous mitral valvuloplasty can be performed in adult patients with mitral stenosis, including patients with calcific disease, and can result in significant improvement in valvular function. The mechanisms of successful dilation include commissural separation and fracture of nodular calcium

Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints

Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices

An Introduction to Temporal Graphs: An Algorithmic Perspective

A \emph{temporal graph} is, informally speaking, a graph that changes with time. When time is discrete and only the relationships between the participating entities may change and not the entities themselves, a temporal graph may be viewed as a sequence $G_1,G_2\ldots,G_l$ of static graphs over the same (static) set of nodes $V$. Though static graphs have been extensively studied, for their temporal generalization we are still far from having a concrete set of structural and algorithmic principles. Recent research shows that many graph properties and problems become radically different and usually substantially more difficult when an extra time dimension in added to them. Moreover, there is already a rich and rapidly growing set of modern systems and applications that can be naturally modeled and studied via temporal graphs. This, further motivates the need for the development of a temporal extension of graph theory. We survey here recent results on temporal graphs and temporal graph problems that have appeared in the Computer Science community

Pediatric Acupuncture: A Review of Clinical Research

Practiced in China for more than 2000 years, acupuncture has recently gained increased attention in the United States as an alternative treatment approach for a variety of medical conditions. Despite its growing prevalence and anecdotal reports of success among pediatric populations, few empirically based studies have assessed the efficacy of acupuncture for children and adolescents. This article presents a review of the current literature, including a systematic appraisal of the methodological value of each study and a discussion of potential benefits and adverse effects of acupuncture. While acupuncture holds great promise as a treatment modality for diverse pediatric conditions, a significant amount of additional research is necessary to establish an empirical basis for the incorporation of acupuncture into standard care

A Human-Curated Annotation of the Candida albicans Genome

Recent sequencing and assembly of the genome for the fungal pathogen Candida albicans used simple automated procedures for the identification of putative genes. We have reviewed the entire assembly, both by hand and with additional bioinformatic resources, to accurately map and describe 6,354 genes and to identify 246 genes whose original database entries contained sequencing errors (or possibly mutations) that affect their reading frame. Comparison with other fungal genomes permitted the identification of numerous fungus-specific genes that might be targeted for antifungal therapy. We also observed that, compared to other fungi, the protein-coding sequences in the C. albicans genome are especially rich in short sequence repeats. Finally, our improved annotation permitted a detailed analysis of several multigene families, and comparative genomic studies showed that C. albicans has a far greater catabolic range, encoding respiratory Complex 1, several novel oxidoreductases and ketone body degrading enzymes, malonyl-CoA and enoyl-CoA carriers, several novel amino acid degrading enzymes, a variety of secreted catabolic lipases and proteases, and numerous transporters to assimilate the resulting nutrients. The results of these efforts will ensure that the Candida research community has uniform and comprehensive genomic information for medical research as well as for future diagnostic and therapeutic applications

Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm

Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior–posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal–ventral patterning genes, whose expression we show to be quantitatively modulated by anterior–posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets

Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia

Evolution of pathogenicity and sexual reproduction in eight Candida genomes

Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.publishe

Frequency drift in MR spectroscopy at 3T

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B-0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites.Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC).Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p &lt; 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI.Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.</p