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Objectives To investigate whether demographic (age and education) adjustments for the Mini‐Mental State Examination ( MMSE ) attenuate mean score discrepancies between African‐American and Caucasian adults and whether demographically adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African‐American adults over unadjusted MMSE scores. Design Cross‐sectional study. Setting Community‐dwelling adults participating in the Mayo Clinic A lzheimer's Disease Patient Registry and A lzheimer's Disease Research Center. Participants Three thousand two hundred fifty‐four adults (2,819 Caucasian, 435 African American) aged 60 and older. Measurements MMSE score at study entry. Results African‐American adults had significantly lower unadjusted MMSE scores (23.0 ± 7.4) than Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly derived weights. Controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. In African‐American adults, an age‐ and education‐adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African‐American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia. Conclusion Age, dementia severity at study entry, and quality of educational experience are important explanatory factors in understanding the existing discrepancies in MMSE performance between Caucasian and African‐American adults. These findings support the use of unadjusted MMSE scores when screening older African Americans for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.

Marine fish drink seawater and eliminate excess salt by active salt transport across gill and gut epithelia. Euryhaline pufferfish ( Takifugu obscurus , mefugu) forms a CaCO3 precipitate on the luminal gut surface after transitioning to seawater. NBCe1 (Slc4a4) at the basolateral membrane of intestinal epithelial cell plays a major role in transepithelial intestinal HCO3− secretion and is critical for mefugu acclimation to seawater. We assayed fugu-NBCe1 (fNBCe1) activity in the Xenopus oocyte expression system. Similar to NBCe1 found in other species, fNBCe1 is an electrogenic Na+/HCO3− cotransporter and sensitive to the stilbene inhibitor DIDS. However, our experiments revealed several unique and distinguishable fNBCe1 transport characteristics not found in mammalian or other teleost NBCe1-orthologs: electrogenic Li+/ nHCO3− cotransport; HCO3− independent, DIDS-insensitive transport; and increased basal intracellular Na+ accumulation. fNBCe1 is a voltage-dependent Na+/ nHCO3− cotransporter that rectifies, independently from the extracellular Na+ or HCO3− concentration, around −60 mV. Na+ removal (0Na+ prepulse) is necessary to produce the true HCO3−-elicited current. HCO3− addition results in huge outward currents with quick current decay. Kinetic analysis of HCO3− currents reveals that fNBCe1 has a much higher transport capacity (higher maximum current) and lower affinity (higher Km) than human kidney NBCe1 (hkNBCe1) does in the physiological range (membrane potential = −80 mV; [HCO3−] = 10 mM). In this state, fNBCe1 is in favor of operating as transepithelial HCO3− secretion, opposite of hkNBCe1, from blood to the luminal side. Thus, fugu-NBCe1 represents the first ortholog-based tool to study amino acid substitutions in NBCe1 and how those change ion and voltage dependence.

ABSTRACT Most of an intravenous dose of species C adenovirus serotype 5 (Ad5) is destroyed by liver Kupffer cells. In contrast, another species C virus, Ad6, evades these cells to mediate more efficient liver gene delivery. Given that this difference in Kupffer cell interaction is mediated by the hypervariable (HVR) loops of the virus hexon protein, we genetically modified each of the seven HVRs of Ad5 with a cysteine residue to enable conditional blocking of these sites with polyethylene glycol (PEG). We show that these modifications do not affect in vitro virus transduction. In contrast, after intravenous injection, targeted PEGylation at HVRs 1, 2, 5, and 7 increased viral liver transduction up to 20-fold. Elimination or saturation of liver Kupffer cells did not significantly affect this increase in the liver transduction. In vitro , PEGylation blocked uptake of viruses via the Kupffer cell scavenger receptor SRA-II. These data suggest that HVRs 1, 2, 5, and 7 of Ad5 may be involved in Kupffer cell recognition and subsequent destruction. These data also demonstrate that this conditional genetic-chemical mutation strategy is a useful tool for investigating the interactions of viruses with host tissues.

Fourth branchial pouch anomalies are rare congenital disorders of the neck and are a consequence of abnormal development of the branchial apparatus during embryogenesis. Failure to appropriately recognize these anomalies may result in misdiagnosis, insufficient treatment, and continued recurrence. Here, we present an unique presentation of two cases, describe their diagnosis, clinical course, and management, and review the literature regarding these interesting anomalies.

AbstractGene‐set analyses have been widely used in gene expression studies, and some of the developed methods have been extended to genome wide association studies (GWAS). Yet, complications due to linkage disequilibrium (LD) among single nucleotide polymorphisms (SNPs), and variable numbers of SNPs per gene and genes per gene‐set, have plagued current approaches, often leading to ad hoc “fixes.” To overcome some of the current limitations, we developed a general approach to scan GWAS SNP data for both gene‐level and gene‐set analyses, building on score statistics for generalized linear models, and taking advantage of the directed acyclic graph structure of the gene ontology when creating gene‐sets. However, other types of gene‐set structures can be used, such as the popular Kyoto Encyclopedia of Genes and Genomes (KEGG). Our approach combines SNPs into genes, and genes into gene‐sets, but assures that positive and negative effects of genes on a trait do not cancel. To control for multiple testing of many gene‐sets, we use an efficient computational strategy that accounts for LD and provides accurate step‐down adjustedP‐values for each gene‐set. Application of our methods to two different GWAS provide guidance on the potential strengths and weaknesses of our proposed gene‐set analyses.

Antibody-mediated rejection (AMR) (humoral rejection) of cardiac allografts remains difficult to diagnose and treat. Interest in AMR of cardiac allografts has increased over the last decade as it has become apparent that untreated humoral rejection threatens graft and patient survival. An international and multidisciplinary consensus group has formulated guidelines for the diagnosis and treatment of AMR and established that identification of circulating or donor-specific antibodies is not required and that asymptomatic AMR, that is, biopsy-proven AMR without cardiac dysfunction is a real entity with worsened prognosis. Strict criteria for the diagnosis of cardiac AMR have not been firmly established, although the diagnosis relies heavily on tissue pathological findings. Therapy remains largely empirical. We review an unfortunate experience with one of our patients and summarize recommended criteria for the diagnosis of AMR and potential treatment schemes with a focus on current limitations and the need for future research and innovation.

Abstract Multiple myeloma (MM) is malignancy of isotype-switched, BM-localized plasma cells that frequently results in bone destruction, BM failure, and death. Important molecular subgroups are identified by three classes of recurrent immunoglobulin gene translocations and hyperdiploidy, both of which affect disease course. From a clinical standpoint, it is critical to identify MM patients carrying the t(4;14) translocation, which is present in 15% of myelomas and is associated with dysregulation of WHSC1/MMSET and often FGFR3. These patients should all receive bortezomib as part of their initial induction treatment because this has been shown to significantly prolong survival. In contrast, patients with translocations affecting the MAF family of transcription factors, del17p, or gene-expression profiling (GEP)–defined high-risk disease appear to have a worse prognosis that is not dramatically improved by any intervention. These patients should be enrolled in innovative clinical trials. The remaining patients with cyclin D translocations or hyperdiploidy do well with most therapies, and the goal should be to control disease while minimizing toxicity.

Abstract High-dose melphalan (HDM) plus stem cell transplantation is an effective treatment for light-chain amyloidosis (AL), but is associated with high treatment-related mortality in patients with cardiac involvement. We studied 187 patients with cardiac involvement with AL who underwent HDM between 1996 and 2008. The median age was 57 years and the median time from diagnosis to HDM was 3.6 months. Half of the patients received reduced-dose melphalan (100-160 mg/m2). The median overall survival (OS) was 66 months, 54 months from diagnosis and HDM, respectively, and 91 patients (49%) were alive at the last follow-up 52 months (median) from HDM. Thirty patients (16%) died within 100 days of transplantation; only low serum albumin predicted early deaths. Overall, hematologic response (HR) and cardiac responses were seen in 66% and 41% of patients, respectively. The median OS for patients with and without HR was not reached and 22 months, respectively (P < .01); and for those with any decrease and no decrease in N-terminal-pro-brain natriuretic peptide was not reached and 26 months, respectively (P < .01). In multivariate analysis of baseline factors, only reduced-dose melphalan predicted shorter OS. HDM is feasible in patients with cardiac amyloidosis, and achievement of HR and organ response is associated with improved survival.

Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR ( FCAR ) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced ( P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).