SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes

AIMS/HYPOTHESIS: Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus. METHODS: We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts. RESULTS: In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p?=?0.00045, p (36tests)?=?0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p?=?0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p?=?0.0040), but the association did not remain after Bonferroni correction (p (36tests)?=?0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease. CONCLUSIONS/INTERPRETATION: A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.

A universal measure of chaotropicity and kosmotropicity

Diverse parameters, including chaotropicity, can limit the function of cellular systems and thereby determine the extent of Earth's biosphere. Whereas parameters such as temperature, hydrophobicity, pressure, pH, Hofmeister effects, and water activity can be quantified via standard scales of measurement, the chao-/kosmotropic activities of environmentally ubiquitous substances have no widely accepted, universal scale. We developed an assay to determine and quantify chao-/kosmotropicity for 97 chemically diverse substances that can be universally applied to all solutes. This scale is numerically continuous for the solutes assayed (from +361kJkg^-1mol^-1 for chaotropes to -659kJkg^-1mol^-1 for kosmotropes) but there are key points that delineate (i) chaotropic from kosmotropic substances (i.e. chaotropes =+4; kosmotropes =-4kJkg^-1mol^-1); and (ii) chaotropic solutes that are readily water-soluble (log P<1.9) from hydrophobic substances that exert their chaotropic activity, by proxy, from within the hydrophobic domains of macromolecular systems (log P>1.9). Examples of chao-/kosmotropicity values are, for chaotropes: phenol +143, CaCl₂ +92.2, MgCl₂ +54.0, butanol +37.4, guanidine hydrochloride +31.9, urea +16.6, glycerol [>6.5M] +6.34, ethanol +5.93, fructose +4.56; for kosmotropes: proline -5.76, sucrose -6.92, dimethylsulphoxide (DMSO) -9.72, mannitol -6.69, trehalose -10.6, NaCl -11.0, glycine -14.2, ammonium sulfate -66.9, polyethylene glycol- (PEG-)1000 -126; and for relatively neutral solutes: methanol, +3.12, ethylene glycol +1.66, glucose +1.19, glycerol [<5M] +1.06, maltose -1.43 (kJkg^-1mol^-1). The data obtained correlate with solute interactions with, and structure-function changes in, enzymes and membranes. We discuss the implications for diverse fields including microbial ecology, biotechnology and astrobiology.

'Ascendency's ... last big jamboree':Big house society in Northern Ireland 1921-69

Thie examines the continuing role that the landed class enjoyed in Northern Ireland in contrast to the experience of their fellow landlords in the rest of Ireland following Partition. It argues that the senses of tradition and continuity which the unionist population in particular attributed to the old landed elite gave them an important role in bolstering the newly created state of Northern Ireland. In turn this allowed them to continue acting as a social elite long after the economic and political foundations of their ascendancy had been removed.

Cord blood erythropoietin, pH, PaO2 and haematocrit following caesarean section before labour

We have investigated the relationship between erythropoietin (Epo) and pH, PaO2 and haematocrit in 100 cord blood samples obtained at Caesarean section prior to labour. Of 82 term (> 37 weeks) infants, 64 were appropriately grown (10th-90th centiles), and their mean cord serum Epo and cord blood Epo was 23 +/- 8 mU/ml (mean +/- SD). Strong inverse correlations were found between cord serum Epo and cord blood pH (r = -0.74; p <0.0001), and between cord serum Epo and cord blood PaO2 (r = -0.55; p <0.0001), but not between cord serum Epo and cord haematocrit (r = 0.02; p <0.9). For the 18 preterm babies (gestation 32.4 +/- 4.1 weeks, birth weight 1,820 +/- 476 g), the Epo level was 36 +/- 8 mU/ml, which was not significantly greater than for the term babies. Strong inverse correlations were again found between Epo and pH (r = -0.87; p <0.0001) and Epo and PaO2 (r = -0.69; p <0.002). Babies from complicated pregnancies (intra-uterine growth retardation, pre-eclampsia, antepartum haemorrhage, diabetes mellitus and fetal distress) tended to have higher Epo levels. Thirteen babies had Epo levels > 40 mU/ml, and 11 (85%) of these required neonatal intensive care. Cord serum Epo correlates better with oxygen tension and pH at birth than with fetal growth and haematocrit, which are measures of chronic stress to the fetus.

Neonatal Ultrasound Results Following Very Preterm Birth Predict Adolescent Behavioral and Cognitive Outcome

This study investigated the association between different neonatal ultrasonographic classifications and adolescent cognitive, educational, and behavioral outcomes following very preterm birth. Participants included a group of 120 adolescents who were born very preterm (33 weeks of gestation), subdivided into three groups according to their neonatal cerebral ultrasound (US) classifications: (a) normal (N = 69), (b) periventricular hemorrhage (PVH, N = 37), and (c) PVH with ventricular dilatation (PVH + DIL, N = 14), and 50 controls. The cognitive functions assessed were full-scale IQ, phonological and semantic verbal fluency, and visual-motor integration. Educational outcomes included reading and spelling; behavioral outcomes were assessed with the Rutter Parents' Scale and the Premorbid Adjustment Scale (PAS). Adolescent outcome scores were compared among the four groups. A main effect for group was observed for full-scale IQ, Rutter Parents' Scale total scores, and PAS total scores, after controlling for gestational age, socioeconomic status and gender, with the PVH + DIL group showing the most impaired scores compared to the other groups. The current results demonstrate that routine neonatal ultrasound classifications are associated with later cognitive and behavioral outcome. Neonatal ultrasounds could aid in the identification of subgroups of children who are at increased risk of neurodevelopmental problems. These at risk subgroups could then be referred to appropriate early intervention services.

Antibacterial Effect of Human Mesenchymal Stem Cells is Mediated in Part from Secretion of the Antimicrobial Peptide LL-37

Recent in vivo studies indicate that mesenchymal stem cells (MSCs) may have beneficial effects in the treatment of sepsis induced by bacterial infection. Administration of MSCs in these studies improved survival and enhanced bacterial clearance. The primary objective of this study was to test the hypothesis that human MSCs possessed intrinsic antimicrobial properties. We studied the effect of human MSCs derived from bone marrow on the bacterial growth of Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. MSCs as well as their conditioned medium (CM) demonstrated marked inhibition of bacterial growth in comparison with control medium or normal human lung fibroblasts (NHLF). Analysis of expression of major antimicrobial peptides indicated that one of the factors responsible for the antimicrobial activity of MSC CM against Gram-negative bacteria was the human cathelicidin antimicrobial peptide, hCAP-18/LL-37. Both m-RNA and protein expression data showed that the expression of LL-37 in MSCs increased after bacterial challenge. Using an in vivo mouse model of E. coli pneumonia, intratracheal administration of MSCs reduced bacterial growth (in colony-forming unit) in the lung homogenates and in the bronchoalveolar lavage (BAL) fluid, and administration of MSCs simultaneously with a neutralizing antibody to LL-37 resulted in a decrease in bacterial clearance. In addition, the BAL itself from MSC-treated mice had a greater antimicrobial activity in comparison with the BAL of phosphate buffered saline (PBS)-treated mice. Human bone marrow-derived MSCs possess direct antimicrobial activity, which is mediated in part by the secretion of human cathelicidin hCAP-18/ LL-37.

Coordination of palliative cancer care in the community: "unfinished business"

Goal: This study assessed the degree to which services in south-central Ontario, Canada, were coordinated to meet the supportive care needs of palliative cancer patients and their families. Participants and method: Programs within the region that were identified as providing supportive care to palliative cancer patients and their families were eligible to participate in the study. Program administrators participated in a semi-structured interview and direct-care providers completed a survey instrument. Main results: Administrators from 37 (97%) of 38 eligible programs and 109 direct-care providers representing 26 (70%) programs participated in the study. Most administrator and direct-care respondents felt that existing services in the community were responsive to palliative care patients' individual needs. However, at a system level, most respondents in both groups felt that required services were not available and that resources were inadequate. The most frequently reported unmet supportive care need identified by both respondent groups was psychological/social support. Most administrator (69%) and direct-care (64%) respondents felt that palliative care services were not available when needed. The majority of administrator and direct-care respondents were satisfied with the exchange of patient information within and between programs, although direct-care staff identified a deficit in information transferred on palliative care patients' social/psychological status. Conclusions: The study demonstrated the value of a theory-based approach to evaluate the coordination of palliative cancer care services. The findings revealed that service programs faced significant challenges in their efforts to provide coordinated care. © 2009 Springer-Verlag.

A comparison of self-report and health care provider data to assess surveillance definitions of influenza-like illness in outpatients

Objective: Several surveillance definitions of influenza-like illness (ILI) have been proposed, based on the presence of symptoms. Symptom data can be obtained from patients, medical records, or both. Past research has found that agreements between health record data and self-report are variable depending on the specific symptom. Therefore, we aimed to explore the implications of using data on influenza symptoms extracted from medical records, similar data collected prospectively from outpatients, and the combined data from both sources as predictors of laboratory-confirmed influenza. Methods: Using data from the Hutterite Influenza Prevention Study, we calculated: 1) the sensitivity, specificity and predictive values of individual symptoms within surveillance definitions; 2) how frequently surveillance definitions correlated to laboratory-confirmed influenza; and 3) the predictive value of surveillance definitions. Results: Of the 176 participants with reports from participants and medical records, 142 (81%) were tested for influenza and 37 (26%) were PCR positive for influenza. Fever (alone) and fever combined with cough and/or sore throat were highly correlated with being PCR positive for influenza for all data sources. ILI surveillance definitions, based on symptom data from medical records only or from both medical records and self-report, were better predictors of laboratory-confirmed influenza with higher odds ratios and positive predictive values. Discussion: The choice of data source to determine ILI will depend on the patient population, outcome of interest, availability of data source, and use for clinical decision making, research, or surveillance. © Canadian Public Health Association, 2012.

Interobserver Reliability of Radiologists' Interpretations of Mobile Chest Radiographs for Nursing Home-Acquired Pneumonia

Objectives: To determine the interobserver reliability of radiologists' interpretations of mobile chest radiographs for nursing home-acquired pneumonia. Design: A cross-sectional reliability study. Setting: Nursing homes and an acute care hospital. Participants: Four radiologists reviewed 40 mobile chest radiographs obtained from residents of nursing homes who met a clinical definition of lower respiratory tract infections. Measurements: Radiologists were asked to interpret radiographs with respect to the film quality; presence, pattern, and extent of an infiltrate; and the presence of a pleural effusion or adenopathy. Interrater reliability was evaluated using the intraclass correlation coefficient derived from a 2-way random effects model. Results: On average the radiologists reported that 6 of the 40 films were of very good or excellent quality and 16 of the 40 were of fair or poor quality. When the finding of an infiltrate was dichotomized (0 = no; 1 = possible, probable, or definite) all 4 radiologists agreed on 21 of the 37 chest radiographs. The intraclass correlation coefficient for the presence or absence of infiltrates was 0.54 (95% confidence intervals [CI] 0.38 to 0.69). For the 14 radiographs where infiltrates were observed by all radiologists, intraclass correlation coefficients for the presence of pleural effusions was 0.08 (95% CI -0.10 to 0.41), hilar adenopathy 0.54 (95% CI 0.29 to 0.79), and mediastinal adenopathy 0.49 (95% CI 0.21 to 0.76). Conclusion: In conclusion, the interrater agreement among radiologists for mobile chest radiographs in establishing the presence or absence of an infiltrate can be judged to be "fair." Treatment decisions need to include clinical findings and should not be made based on radiographic findings alone. © 2006 American Medical Directors Association.

Influence of YAG laser posterior capsulotomy on preexisting glaucoma

Purpose. To evaluate the effects of a YAG laser posterior capsulotomy on intraocular pressure (IOP) in glaucoma patients. Methods. We retrospectively studied 69 patients who underwent posterior capsulotomy following cataract or combined cataract-glaucoma surgery and who had a minimum follow-up of six months. We assessed IOP control, number of glaucoma medications required, and need for additional glaucoma surgery following capsulotomy as clinical outcomes. We defined an "unfavorable result" as: a =5 mm Hg sustained rise in IOP, a need for additional glaucoma medications, and/or a need for additional glaucoma surgery. We calculated Kaplan-Meier event rate curves for these "unfavorable results." Mean follow-up was 24.4 ± 12.3 months. Results. 6.3% of patients had an IOP rise of =5 mm Hg one hour post capsulotomy. The actuarial (Kaplan-Meier) rate of any "unfavorable result" was 11.6% at 4 months, 38.1% at 12 months, 46.1% at 24 months, and 52.1% at 36 months following capsulotomy. Conclusions. Progression of glaucoma after YAG capsulotomy is common and may be accelerated by the laser procedure.

Predicting the need for insulin therapy in late onset (40-69 years) diabetes mellitus

A six-year prospective study of 144 newly diagnosed, symptomatic diabetic patients aged 40-69 years showed that 21 (15%) required insulin therapy, commencing 1-61 months after diagnosis. The plasma insulin response to oral glucose was assessed at the time of diagnosis. All 12 patients with very low peak insulin response (less than or equal to 6 mU/l) required insulin therapy. Thirty-six patients had an intermediate insulin response (greater than 6 less than or equal to 18 mU/l); of these, 7 with a mean weight 88% (range 73-96%) of average body weight required insulin, while 29 with a mean weight 117% (range 98-158%) of average body weight, did not. Ninety-six patients had a peak insulin response (greater than 18 mU/l); 2 patients whose weights were 96% and 100% of average body weight, required insulin, while the remainder did not. Consideration of initial body weight and peak insulin response provides a useful prediction of the eventual need for insulin.

Comment on "On the Uniqueness of Stable Marriage Matchings" [Economic Letters 69(1):1-8, 2000]

We prove with the help of a counterexample that Lemma 6 and Corollary 7 from Eeckhout [1] are incorrect.