The impact of daily mean air temperature on the proportion of time in hypoglycemia in 2,582 children and adolescents with type 1 diabetes - Is this association clinically relevant?

OBJECTIVES: To study the potential association between increases in daily mean air temperature and time below range (TBR <54 mg/dl) and time above range (TAR >250 mg/dl) in children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Individuals with type 1 diabetes <21 years with information on daily glucose profiles from the diabetes prospective follow-up study (DPV) were included (n = 2582). Further inclusion criteria were age at least 6 months at diabetes onset, diabetes duration for at least one year and treatment years 2020-2021. Mean daily air temperature and other meteorological parameters from 78 measurement stations in Germany were linked to the individual glucose sensor profile via the five-digit postcode areas of residency. We used multivariable repeated measures fractional logistic regression models with a compound symmetry covariance structure to study the association between a 1 °C increase in daily mean temperature and time in specific glucose ranges. RESULTS: A 1 °C increase in daily mean temperature was associated with an acute (Odds Ratio (OR) 1.009 (95%-CI 1.007, 1.011)) and up to 7 days delayed (OR 1.003 (1.001, 1.005)) increase in TBR <54 mg/dl. Moreover, an acute decrease in TAR >250 mg/dl (OR 0.997 (0.996, 0.997)) was found. CONCLUSIONS: Results of the DPV registry showed small, but statistically significant changes in TBR and TAR in association with a short-term temperature increase. Higher blood flow and faster insulin absorption might be one possible mechanism. In times of increasing temperature fluctuations meteorological impacts on time in range could become even more relevant.

6LiF:ZnS(Ag) Neutron Detector Performance Optimized Using Waveform Recordings and ROC Curves.

We used Gaussian separation and receiver operating characteristic (ROC) curves to optimize the neutron sensitivity and gamma rejection of an ultra-thin 6LiF:ZnS(Ag)-scintillator-based neutron detector paired with a silicon photomultiplier (SiPM). We recorded the waveforms while operating the detector in a monochromatic cold neutron beam and in the presence of isotopic 137Cs and 60Co gamma sources. We used a two-window charge comparison (CC) pulse-shape discrimination (PSD) technique to distinguish the neutron capture events from other types of signals. By feeding the recorded waveforms through variants of this algorithm, it was possible to optimize the duration of the integration windows [(0-100 ns) for the prompt window and (100-2300 ns)] for the delayed window. We then computed the detector's ROC curve from waveform recordings and compared that with the experimental performance. We also used this procedure to compare a series of detector configurations to select the optimal bias voltage for the SiPM photosensor.

Studies of the Corneocytary Pathway Across the Stratum Corneum. Part I: Diffusion of Amino Acids Into the Isolated Corneocytes.

Amino acids (AAs), important constituents of natural moisturizing factors (NMFs) of the skin are decreased in diseased conditions such as psoriasis and atopic dermatitis. No study so far investigated the uptake of AAs into isolated corneocytes (COR). The present study was performed using 19 AAs, including taurine (TAU), to measure their amount diffused into the COR and binding of these AAs to keratin. Incubation of alanine, aspartic acid, asparagine, glutamine, glutamic acid, histidine, proline, serine and TAU with the isolated COR showed uptake after 24 h of 51.6, 95.4, 98.6, 94.1, 95.6, 90.1, 94.6, 72.9 and 57.8 %, respectively, into the COR but no binding with keratin. Uptake of TAU was validated by time dependent in-vitro diffusion models 'without COR and 'with COR'. The time dependent curve fitting showed that in in-vitro diffusion model 'without COR' there was no change in the total concentration of TAU until 72 hours, while in diffusion model 'with COR' the total conc. decreased to 37.8 % after 72 hours. The Pearson's correlation coefficient 'r' between the conc. curves of both in-vitro diffusion models was -0.54 that was an evidence of significant amount of TAU uptake by the COR. AAs as part of the NMFs have a great potential to be diffused into the COR. This property of the AAs can be employed in further dermatological research on diseased or aged skin conditions with NMFs deficiency.

No change in type 2 diabetes prevalence in children and adolescents over 10 years: Update of a population-based survey in South Germany.

Objective of this study was to analyze prevalence changes in type 2 diabetes (T2D) among children and adolescents over the last 10 years. We performed a cross-sectional survey in Baden-Württemberg (BW), Germany, by using a written questionnaire and comparing these results with T2D prevalence data from the same area retrieved in 2004/2005. In 2016, 50 patients with T2D under 20 years of age were registered in BW, Germany, which corresponds to a prevalence rate of 2.42 per 100 000 (95% confidence interval [CI]: 1.75-3.09). The prevalence rate found in the same geographic area 10 years prior was 2.30 per 100 000 (95% CI: 1.70-2.90). Overall, 70% of T2D patients of this age group were treated by adult diabetologists. Concisely the prevalence of T2D in children and adolescents is still low in South Germany, remaining practically unchanged over the past decade.

Synergistic benefits between stormwater management measures and a new pricing system for stormwater in the City of Hamburg.

Hamburg is a growing metropolitan city. The increase in sealed surfaces of about 0.36% per year and the subsequent increased runoff impacts on the city's wastewater infrastructure. Further potential risks to the drainage infrastructure arise also from effects of climate change, e.g. increased intensity and frequency of heavy rainfalls. These challenges were addressed in the Rain InfraStructure Adaption (RISA) project conducted 2009-2015 by HAMBURG WASSER and the State Ministry for Environment and Energy, supported by several municipal stakeholders. RISA addressed intensifying conflicts in the context of urban development and stormwater management at that time. Major results of the project are improvements and recommendations for adequate consideration of stormwater management issues during urban planning as well as new funding mechanisms for stormwater management measures. The latter topic resulted in the introduction of a separated stormwater charge based on the amount of sealed area connected to the sewer system of each property. For both undertakings - the RISA project and the introduction of the separated stormwater charge - a novel, comprehensive, digital database was built. Today, these geographical information system (GIS)-based data offer various scale-independent analysis and information opportunities, which facilitate the day-to-day business of HAMBURG WASSER and stormwater management practice in Hamburg.

Pharmacokinetics and safety of an 8 week continuous treatment with once-daily versus twice-daily inhalation of tobramycin in cystic fibrosis patients.

OBJECTIVES: We evaluated the pharmacokinetics, safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution (TIS) in 29 cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. PATIENTS AND METHODS: In this randomized, multicentre, open-label, two-period crossover study, TIS (300 mg/5 mL) was administered via PARI eFlow(®) rapid once daily and twice daily each for 8 weeks. Serum pharmacokinetics of these two regimens was analysed. Tobramycin levels were determined before the morning dose and at 30, 60 and 90 min after the end of nebulization in the middle and at the end of each 8 week cycle. At these timepoints, trough and peak serum tobramycin concentrations (Cmax, mg/L) as well as the area under the curve for 0-90 min of tobramycin (AUC0-90min) were assessed in order to evaluate the risk of systemic toxicity. Safety parameters and forced expiratory volume in 1 s (FEV1) were assessed. RESULTS: For once-daily treatment, tobramycin levels were 10% higher after 8 weeks compared with 4 weeks (AUC0-90min ratio = 1.096, 90% CI = 0.860-1.396, P = 0.5237). For twice-daily treatment, tobramycin levels after 8 weeks showed a 40% decrease compared with 4 weeks (AUC0-90min ratio = 0.608, 90% CI = 0.461-0.802, P = 0.0055). The AUC0-90min ratio at 8 weeks (once daily versus twice daily) did not differ significantly (AUC0-90min ratio = 0.749, 90% CI = 0.514-1.092, P = 0.2009). The mean FEV1 did not differ markedly compared between treatment periods or with baseline. No audiological or nephrotoxic side effects were noted. CONCLUSIONS: Continuous treatment with TIS (once daily or twice daily) over 8 weeks appears to be safe and tolerable.

Probing Quantum Capacitance in a 3D Topological Insulator.

We measure the quantum capacitance and probe thus directly the electronic density of states of the high mobility, Dirac type two-dimensional electron system, which forms on the surface of strained HgTe. Here we show that observed magnetocapacitance oscillations probe-in contrast to magnetotransport-primarily the top surface. Capacitance measurements constitute thus a powerful tool to probe only one topological surface and to reconstruct its Landau level spectrum for different positions of the Fermi energy.

Prebiotic-supplemented partially hydrolysed cow's milk formula for the prevention of eczema in high-risk infants: a randomized controlled trial.

BACKGROUND: Prevention guidelines for infants at high risk of allergic disease recommend hydrolysed formula if formula is introduced before 6 months, but evidence is mixed. Adding specific oligosaccharides may improve outcomes. OBJECTIVE: To evaluate whether partially hydrolysed whey formula containing oligosaccharides (0.8 g/100 ml) (pHF-OS) can prevent eczema in high-risk infants [ISRCTN65195597]. METHODS: We conducted a parallel-group, multicentre, randomized double-blind controlled trial of pHF-OS vs standard cow's milk formula. Infants with a family history of allergic disease were randomized (stratified by centre/maternal allergy) to active (n = 432) or control (n = 431) formula until 6 months of age if formula was introduced before 18 weeks. Primary outcome was cumulative incidence of eczema by 12 months in infants randomized at 0-4 weeks (375 pHF-OS, 383 control). Secondary outcomes were cumulative incidence of eczema by 12 or 18 months in all infants randomized, immune markers at 6 months and adverse events. RESULTS: Eczema occurred by 12 months in 84/293 (28.7%) infants allocated to pHF-OS at 0-4 weeks of age, vs 93/324 (28.7%) control (OR 0.98 95% CI 0.68, 1.40; P = 0.90), and 107/347 (30.8%) pHF-OS vs 112/370 (30.3%) control in all infants randomized (OR 0.99 95% CI 0.71, 1.37; P = 0.94). pHF-OS did not change most immune markers including total/specific IgE; however, pHF-OS reduced cow's milk-specific IgG1 (P < 0.0001) and increased regulatory T-cell and plasmacytoid dendritic cell percentages. There was no group difference in adverse events. CONCLUSION: pHF-OS does not prevent eczema in the first year in high-risk infants. The immunological changes found require confirmation in a separate cohort.

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study.

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

The national incidence and clinical picture of SLE in children in Australia - a report from the Australian Paediatric Surveillance Unit.

OBJECTIVES: The objectives of this paper are to prospectively determine the incidence of paediatric systemic lupus erythematosus (pSLE) in Australia as well as describe the demographics, clinical presentation and one-year outcome. STUDY DESIGN: Newly diagnosed cases of pSLE were ascertained prospectively from October 2009 to October 2011 through the Australian Paediatric Surveillance Unit (a national monthly surveillance scheme for notification of childhood rare diseases) as well as national subspecialty groups. Questionnaires were sent to notifying physicians at presentation and at one year. RESULTS: The annual incidence rate was 0.32 per 10(5) children aged less than 16 years. The incidence was significantly higher in children of Asian or Australian Aboriginal and Torres Strait Islander parents. Approximately one-third of children underwent a renal biopsy at presentation and 7% required dialysis initially although only one child had end-stage kidney disease (ESKD) at one-year follow-up. CONCLUSION: The incidence of pSLE in Australia is comparable to that worldwide with a significantly higher incidence seen in children of Asian and Australian Aboriginal and Torres Strait Islander backgrounds. Renal involvement is common but progression to ESKD, at least in the short term, is rare.

Sequential use of double-balloon catheter and oral misoprostol versus oral misoprostol alone for induction of labour at term (CRBplus trial): a multicentre, open-label randomised controlled trial.

OBJECTIVE: To evaluate the efficacy of inducing labour using a double-balloon catheter and oral misoprostol sequentially, in comparison with oral misoprostol alone. DESIGN: A multicentre randomised controlled trial. SETTING: Five hospitals in Germany. POPULATION: A total of 326 pregnant women with an unfavourable cervix undergoing labour induction at term. METHODS: Women were randomly assigned according to a computer-generated allocation sequence to sequential use of double-balloon catheter and oral misoprostol (study group) or oral misoprostol alone (control group). In the study group, the double-balloon catheter was used the first day before starting oral misoprostol the second day. MAIN OUTCOME MEASURES: The primary outcome measure was the induction-to-delivery interval, and a further outcome parameter was delivery within 48 hours. RESULTS: The median times for induction of labour until delivery were 32.4 hours in the study group and 22.5 hours in the control group (P = 0.004). This difference was not seen when evaluating according to parity (nulliparous, P = 0.19; parous, P = 0.06). The rate of vaginal delivery within 48 hours did not differ between both groups. The number of applications of misoprostol (two versus three, P < 0.001) and the dose of misoprostol used was lower in the study group (100 versus 200 µg, P < 0.001). In the study group, there were more Apgar scores of <7 at 5 minutes (8 versus 1, P = 0.04). CONCLUSIONS: The use of a double-balloon catheter on the first day, before starting oral misoprostol on the second day, did not improve the induction to delivery interval and the rate of delivery within 48 hours, in comparison with oral misoprostol alone.

A novel intronic splice site deletion of the IL-2 receptor common gamma chain results in expression of a dysfunctional protein and T-cell-positive X-linked Severe combined immunodeficiency.

X-linked severe combined immunodeficiency is caused by mutations in the IL-2 receptor common gamma chain and classically presents in the first 6 months of life with predisposition to bacterial, viral and fungal infections. In most instances, affected individuals are lymphopenic with near complete absence of T cells and NK cells. We report a boy who presented at 12 months of age with Pneumocystis jiroveci pneumonia and a family history consistent with X-linked recessive inheritance. He had a normal lymphocyte count including the presence of T cells and a broad T-cell-receptor diversity, as well as normal surface expression of the common gamma chain (CD132) protein. He however had profound hypogammaglobulinaemia, and IL-2-induced STAT5 phosphorylation was absent. Sequencing of IL-2RG demonstrated a 12-base pair intronic deletion close to the canonical splice site of exon 5, which resulted in a variety of truncated IL2RG mRNA species. A review of the literature identified 4 other patients with T-cell-positive X-SCID, with the current patient being the first associated with an mRNA splicing defect. This case raises the question of how a dysfunctional protein incapable of mediating STAT5 phosphorylation might nonetheless support T-cell development. Possible explanations are that STAT5-mediated signal transduction may be less relevant to IL7-receptor-mediated T-cell development than are other IL7R-induced intracellular transduction pathways or that a low level of STAT5 phosphorylation, undetectable in the laboratory, may be sufficient to support some T-cell development.

Quantitative analysis of flavanones and chalcones from willow bark.

Willow bark extracts are used for the treatment of fever, pain and inflammation. Recent clinical and pharmacological research revealed that not only the salicylic alcohol derivatives, but also the polyphenols significantly contribute to these effects. Quantitative analysis of the European Pharmacopoeia still focuses on the determination of the salicylic alcohol derivatives. The objective of the present study was the development of an effective quantification method for the determination of as many flavanone and chalcone glycosides as possible in Salix purpurea and other Salix species as well as commercial preparations thereof. As Salix species contain a diverse spectrum of the glycosidated flavanones naringenin, eriodictyol, and the chalcone chalconaringenin, a subsequent acidic and enzymatic hydrolysis was developed to yield naringenin and eriodictyol as aglycones, which were quantified by HPLC. The 5-O-glucosides were cleaved with 11.5% TFA before subsequent hydrolysis of the 7-O-glucosides with an almond ß-glucosidase at pH 6-7. The method was validated with regard to LOD, LOQ, intraday and interday precision, accuracy, stability, recovery, time of hydrolysis, robustness and applicability to extracts. All 5-O- and 7-O-glucosides of naringenin, eriodictyol and chalconaringenin were completely hydrolysed and converted to naringenin and eriodictyol. The LOD of the HPLC method was 0.77 µM of naringenin and 0.45 µM of eriodictyol. The LOQ was 2.34 µM of naringenin and 1.35 µM for eriodictyol. The method is robust with regard to sample weight, but susceptible concerning enzyme deterioration. The developed method is applicable to the determination of flavanone and chalcone glycosides in willow bark and corresponding preparations.

Type 1 Diabetes Mellitus in the First Years of Life - Onset, Initial Treatment, and Early Disease Course.

OBJECTIVE: This study investigated the onset and the choice of treatment in children with very early onset of type 1 diabetes mellitus (T1D). METHODS: The study included 5,763 patients from the German Diabetes Patient Follow-up registry with onset of T1D in the first 4 years of life from January 2010 - June 2022. The analysis included diabetes-specific parameters, anthropometric data, and mode of treatment at onset, within the first and second year of T1D. Three groups were compared according to age at onset (G1: 223 patients 6-<12 months, G2: 1519 patients 12-<24 months, G3: 4001 patients 24-48 months). RESULTS: In 12.3% of all cases in childhood and adolescence, the incidence of diabetes in the first 4 years of life was rare. At the onset, clinical status was worse and diabetic ketoacidosis (DKA) rates were higher in G1 and G2 (52.3% and 46.5%, respectively) compared to G3 (27.3% (p<0.001)). G1 and G2 were significantly more likely to be treated with insulin pump therapy (CSII) 2 years after onset (98.1% and 94.1%, respectively)) compared to G3 (85.8%, p<0.001). Median HbA1c after 2 years did not differ between groups (G1: 7.27% (56.0 mmol/mol), G2: 7.34% (56.7 mmol/mol) and G3: 7.27% (56.0 mmol/mol)) or when comparing CSII vs MDI. The rate of severe hypoglycemia (SH) and DKA during the first 2 years of treatment did not differ among the three groups, ranging from 1.83-2.63/100 patient-years (PY) for DKA and 9.37-24.2/100 PY for SH. Children with T1D under 4 years of age are more likely to be diagnosed with celiac disease but less likely to have thyroiditis than older children with T1DM. CONCLUSIONS: Young children with T1D had high rates of DKA at onset and were predominantly treated with insulin pump therapy during the first 2 years. The median HbA1c for all three groups was<7.5% (58 mmol/mol) without increased risk of SH or DKA. The use of continuous glucose monitoring (CGM) was not associated with lower HbA1c in children under 48 months.

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Interlayer excitons in MoSe2/2D perovskite hybrid heterostructures - the interplay between charge and energy transfer.

van der Waals crystals have opened a new and exciting chapter in heterostructure research, removing the lattice matching constraint characteristics of epitaxial semiconductors. They provide unprecedented flexibility for heterostructure design. Combining two-dimensional (2D) perovskites with other 2D materials, in particular transition metal dichalcogenides (TMDs), has recently emerged as an intriguing way to design hybrid opto-electronic devices. However, the excitation transfer mechanism between the layers (charge or energy transfer) remains to be elucidated. Here, we investigate PEA2PbI4/MoSe2 and (BA)2PbI4/MoSe2 heterostructures by combining optical spectroscopy and density functional theory (DFT) calculations. We show that band alignment facilitates charge transfer. Namely, holes are transferred from TMDs to 2D perovskites, while the electron transfer is blocked, resulting in the formation of interlayer excitons. Moreover, we show that the energy transfer mechanism can be turned on by an appropriate alignment of the excitonic states, providing a rule of thumb for the deterministic control of the excitation transfer mechanism in TMD/2D-perovskite heterostructures.

Analysis of FTO gene variants with obesity and glucose homeostasis measures in the multiethnic Insulin Resistance Atherosclerosis Study cohort.

OBJECTIVE: Previous studies have replicated the association of variants within FTO (fat mass- and obesity-associated) intron 1 with obesity and adiposity quantitative traits in populations of European ancestry. Non-European populations, however, have not been so intensively studied. The goal of this investigation was to examine the association of FTO single-nucleotide polymorphisms (SNPs), prominent in the literature in a multiethnic sample of non-Hispanic White American (n=458), Hispanic American (n=373) and African American (n=288) subjects from the Insulin Resistance Atherosclerosis Study (IRAS). This cohort provides the unique ability to evaluate how variation within FTO influences measures of adiposity and glucose homeostasis in three different ethnicities, which were ascertained and examined using a common protocol. DESIGN: A total of 26 FTO SNPs were genotyped, including those consistently associated in the literature (rs9939609, rs8050136, rs1121980, rs1421085, rs17817449 and rs3751812), and tested for association with adiposity and glucose homeostasis traits. RESULTS: For the adiposity phenotypes, these and other SNPs were associated with body mass index (BMI) in both non-Hispanic Whites (P-values ranging from 0.015 to 0.048) and Hispanic Americans (P-values ranging from 7.1 × 10(-6) to 0.027). In Hispanic Americans, four other SNPs (rs8047395, rs10852521, rs8057044 and rs8044769) still showed evidence of association after multiple comparisons adjustment (P-values ranging from 5.0 × 10(-5) to 5.2 × 10(-4)). The historically associated BMI SNPs were not associated in the African Americans, but rs1108102 was associated with BMI (P-value of 5.4 × 10(-4)) after accounting for multiple comparisons. For glucose homeostasis traits, associations were seen with acute insulin response in non-Hispanic Whites and African Americans. However, all associations with glucose homeostasis measures were no longer significant after adjusting for multiple comparisons. CONCLUSION: These results replicate the association of FTO intron 1 variants with BMI in non-Hispanic Whites and Hispanic Americans but show little evidence of association in African Americans, suggesting that the effect of FTO variants on adiposity phenotypes shows genetic heterogeneity dependent on ethnicity.

KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma.

A major controversy regarding Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) is whether or not it is a ubiquitous infection of humans. Immunoassays based on KSHV- and Epstein-Barr virus (EBV)-coinfected cell lines show that most US AIDS-KS patients have specific antibodies to KSHV-related antigens. We have developed a sensitive indirect immunofluorescence assay (IFA) based on an EBV-negative, KSHV-infected cell line, BCP-1. When we used this IFA assay, KSHV-related antibodies were found in 71-88% of serum samples from US, Italian and Ugandan AIDS-KS patients, as well as all serum samples examined from HIV-seronegative KS patients. Although none of the US blood donors examined were KSHV seropositive by IFA, intermediate and high seroprevalence rates were found in Italian and Ugandan control populations. Antibody kinetics showed that more than half of the AIDS-KS patients who were examined IgG-seroconverted before KS development, and antibody levels did not decline after seroconversion. For these patients, seropositivity rates increased linearly with time, suggesting that the rate of infection was constant and that the risk of developing KS once infected with KSHV is not highly dependent on the duration of infection. These data strongly suggest that KSHV is not ubiquitous in most populations and that the virus may be under strict immunologic control in healthy KSHV-infected persons.

Candidate loci for insulin sensitivity and disposition index from a genome-wide association analysis of Hispanic participants in the Insulin Resistance Atherosclerosis (IRAS) Family Study.

AIMS/HYPOTHESIS: The majority of type 2 diabetes genome-wide association studies (GWAS) to date have been performed in European-derived populations and have identified few variants that mediate their effect through insulin resistance. The aim of this study was to evaluate two quantitative, directly assessed measures of insulin resistance, namely insulin sensitivity index (S(I)) and insulin disposition index (DI), in Hispanic-American participants using an agnostic, high-density single nucleotide polymorphism (SNP) scan, and to validate these findings in additional samples. METHODS: A two-stage GWAS was performed in Hispanic-American samples from the Insulin Resistance Atherosclerosis Family Study. In Stage 1, 317,000 SNPs were assessed using 229 DNA samples. SNPs with evidence of association with glucose homeostasis and adiposity traits were then genotyped on the entire set of Hispanic-American samples (n = 1,190). This report focuses on the glucose homeostasis traits: S(I) and DI. RESULTS: Although evidence of association did not reach genome-wide significance (p = 5 x 10(-7)), in the combined analysis SNPs had admixture-adjusted p values of p (ADD) = 0.00010-0.0020 with 8 to 41% differences in genotypic means for S(I) and DI. CONCLUSIONS/INTERPRETATION: Several candidate loci were identified that are nominally associated with S(I) and/or DI in Hispanic-American participants. Replication of these findings in independent cohorts and additional focused analysis of these loci is warranted.