Case-control study of the alpha-synuclein interacting protein gene and Parkinson's disease.

We conducted a case-control study of the alpha-synuclein-interacting protein gene (SNCAIP, also known as synphilin-1) and Parkinson's disease (PD). A total of 319 PD cases and 195 controls were genotyped for four SNCAIP variants, including a microsatellite repeat in intron 4 and three restriction fragment length polymorphisms (RFLP) proximal to the 5' terminal of exons 1, 4, and 6. None of the variants were found associated with PD overall. Global score statistics were not significant for four, three, and two loci haplotypes. All four loci were in linkage disequilibrium for cases, controls, or both groups combined (P < 0.0001). Recursive partitioning showed no interactions between variants of the SNCAIP gene and variants of the alpha-synuclein gene (SNCA) or the parkin (PARK2) gene.     

Complex interactions in Parkinson's disease: a two-phased approach.

The identification of pathogenic mutations in the three genes alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson's disease (PD). In addition, polymorphisms of these three genes have been shown to be independently associated with PD. In a sample of 298 unrelated PD cases and 185 controls, we applied a two-phased approach of recursive partitioning and logistic regression analyses to explore complex interactions. For women only, we observed an epistatic interaction of UCHL1 and alpha-synuclein genotypes with significant effects on PD risk (odds ratio = 2.42; P = 0.003). Our findings are consistent with the hypothesis that PD is a multigenic disorder of the UPS.     

Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene

Plasma amyloid beta protein (Abeta42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Abeta aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Abeta. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Abeta42 and LOAD. PLAU SNP compound genotypes composed of haplotype pairs showed significant association with AD in three independent case-control series. PLAU SNP haplotypes associated significantly with plasma Abeta42 in 10 extended LOAD families. One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L). We analyzed PLAU_1 for association with AD in six case-control series and 24 extended LOAD families. The CT and TT PLAU_1 genotypes showed association (P=0.05) with an overall estimated odds ratio of 1.2 (1.0-1.5). The CT and TT genotypes of PLAU_1 were also associated with significant age-dependent elevation of plasma Abeta42 in 24 extended LOAD families (P=0.0006). In knockout mice lacking the PLAU gene, plasma--but not brain--Abeta42 as well as Abeta40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Abeta42, LOAD and variants in the IDE or VR22 region. These results provide strong evidence that PLAU or a nearby gene is involved in the development of LOAD. PLAU_1 is a plausible pathogenic mutation that could act by increasing Abeta42, but additional biological experiments are required to show this definitively.     

Prevalence and patterns of resistance of Streptococcus pneumoniae strains isolated from carriers attending day care centers in the area of Athens

The prevalence and patterns of Streptococcus pneumoniae resistance to antibiotics was examined in 146 nasopharyngeal carrier strains obtained during April and May, 1997, from 382 healthy children attending eight day care centers (DCCs) in the area of Athens. Reduced susceptibility to at least one antibiotic was found in 32.6% as follows: penicillin 11.4% (intermediate), cefotaxime 0.8% (intermediate), trimethoprim-sulfamethoxazole 22.7%, erythromycin 13.6%, tetracycline 11.4%, chloramphenicol 8.3%. Most of the nonsusceptible to penicillin isolates belonged to serogroups 23, 9, and 19. Multidrug resistance was detected in 11.4% of S. pneumoniae isolates including five penicillin nonsusceptible serogroup 23 strains. More than half of the multidrug resistant strains were susceptible to penicillin and belonged to serogroups 6 (4), 23 (1), 19 (1), and 1(1). Strains that belonged to the same serogroup/serotype and had identical resistance patterns appeared to cluster in some DCCs. Antibiotic use in the previous month was associated with reduced susceptibility to penicillin (p = 0.007) and multidrug resistance (p = 0.012). In conclusion, a moderate prevalence of reduced susceptibility to penicillin in pneumococcal carrier strains was found in our community. Multidrug resistance was common and was often associated with susceptibility to penicillin. Several distinct patterns of resistance were observed, suggesting the spread of resistant clones to our country.     

Immunogenicity and side‐effects of the inactivated hepatitis A vaccine in periodic fever,aphthous stomatitis,pharyngitis, and adenitis patients

The aim of this study was to compare the immunogenicity and side‐effects of hepatitis A virus (HAV) vaccination between periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) patients and healthy controls who have not been previously exposed to HAV. A prospective observational study was carried out of 28 PFAPA patients and 76 controls who received two doses of the vaccine. Immunogenicity was expressed as seroconversion and seroprotection rates; mean HAV‐immunoglobulin G concentration was measured at 0, 1, 7 and 18 months. Side‐effects were defined as incidence of adverse events and the effect of vaccination on PFAPA symptoms. All participants were seronegative and seroconverted at 1 month. One month after primary vaccination, 92.9% of PFAPA patients and 77.6% of the controls attained seroprotection, while the rates increased to 100% and 96.1%, respectively, 1 month after the second dose. Seroprotection rates remained adequate 1 year after completion of vaccination. In conclusion, two doses of the inactivated HAV vaccine are well‐tolerated and effective in children with PFAPA.     

Urothelial eddies in papillary urothelial neoplasms: a distinct morphologic pattern with low risk for progression

We encountered an undescribed histologic feature of papillary urothelial neoplasms: “urothelial eddy”, which was histologically reminiscent of squamous eddy of irritated follicular keratosis of the skin. A review of 756 patients with transurethral resection of bladder tumor revealed 10 patients (1.3%) of papillary urothelial neoplasms with urothelial eddies. All cases were male with a median age of 65 years. Urothelial eddies were characterized by small ovoid nests of ovoid to spindle cells arranged in an onion-skin pattern with fine cytoplasmic processes within wide intercellular space. The cytoplasmic processes mimicked intercellular bridges but ultrastructurally were cytoplasmic microvillous projections. They were of papillary urothelial neoplasm of low malignant potential in seven patients and low-grade urothelial carcinoma in three patients. Nine patients presented as non-invasive tumor and one patient showed microinvasion within papillary stalks. Six patients showed an inverted growth pattern. Their immunoprofile was more similar to that of conventional urothelial carcinoma rather than squamous cell carcinoma: high expressions of GATA3, S100P, uroplakin III, and cytokeratin 7; and low expressions of high molecular weight cytokeratin and p53. The Ki-67 labeling index was low (mean and median values, 2% each). During the follow-up period (mean, 88.7 months), four patients, including the microinvasive patient, showed recurrence with the same grade and stage but neither progressed into muscle-invasive tumor nor caused death. Our results suggest that urothelial eddy is a rare aberrant histology of papillary urothelial neoplasms with indolent behavior and should be discriminated from squamous differentiation of urothelial carcinoma, which has a poor prognosis.     

Biology‐Driven Gene‐Gene Interaction Analysis of Age‐Related Cataract in the eMERGE Network

Bioinformatics approaches to examine gene‐gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge‐driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty‐three SNP‐SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)–rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell‐to‐cell adhesion signaling, cell‐cell junction organization, and cell‐cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP‐SNP models, which included signal transduction and PI3K‐Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology‐driven method, applicable for any genome‐wide association study dataset.     

Association of frailty with short-term outcomes,organ support and resource use in critically ill patients

Purpose

Frail patients are known to experience poor outcomes. Nevertheless, we know less about how frailty manifests itself in patients’ physiology during critical illness and how it affects resource use in intensive care units (ICU). We aimed to assess the association of frailty with short-term outcomes and organ support used by critically ill patients.

Methods

Retrospective analysis of prospective collected data from 93 ICUs in Brazil from 2014 to 2015. We assessed frailty using the modified frailty index (MFI). The primary outcome was in-hospital mortality. Secondary outcomes were discharge home without need for nursing care, ICU and hospital length of stay (LOS), and utilization of ICU organ support and transfusion. We used mixed logistic regression and competing risk models accounting for relevant confounders in outcome analyses.

Results

The analysis consisted of 129,680 eligible patients. There were 40,779 (31.4%) non-frail (MFI?=?0), 64,407 (49.7%) pre-frail (MFI?=?1–2) and 24,494 (18.9%) frail (MFI?≥?3) patients. After adjusted analysis, frailty was associated with higher in-hospital mortality (OR 2.42, 95% CI 1.89–3.08), particularly in patients admitted with lower SOFA scores. Frail patients were less likely to be discharged home (OR 0.36, 95% CI 0.54–0.79) and had higher hospital and ICU LOS than non-frail patients. Use of all forms of organ support (mechanical ventilation, non-invasive ventilation, vasopressors, dialysis and transfusions) were more common in frail patients and increased as MFI increased.

Conclusions

Frailty, as assessed by MFI, was associated with several patient-centered endpoints including not only survival, but also ICU LOS and organ support.