Vitamin D Status Over Time and Cognitive Function in Norwegian Older Adults: A Prospective Cohort of the HUNT Study.

BACKGROUND: There is conflicting evidence regarding the association between vitamin D status and cognitive function in population studies. The use of one-time vitamin D measurement in cognitive health studies may not reflect long-term vitamin D status in the body. OBJECTIVE: We aimed to examine the relationship of vitamin D status measured over time with the risk of neurocognitive disorders (NCDs) in Norwegian older adults. DESIGN: Prospective cohort study. SETTING: Regional, Trøndelag Health Study. PARTICIPANTS: This study followed a random cohort of 717 participants from HUNT2 (1995-97) and HUNT3 (2006-08) to HUNT4 70+ (2017-19). The mean age at HUNT4 70+ was 77.7 years. METHODS: Seasonal-standardized serum 25-hydroxyvitamin D [25(OH)D] levels in HUNT2 and HUNT3 were averaged and used as either a categorical variable (<50 and ≥50 nmol/L) or a continuous variable (per 25 nmol/L decrease). In the cohort aged 70 years or over (HUNT4 70+), NCDs consisting of mild cognitive impairment (MCI) and dementia were diagnosed by clinical experts according to the DSM-5 criteria. Logistic and linear regression models were used to estimate odds ratios (ORs) and regression coefficients (beta) with 95% confidence intervals (CIs) to assess the relationship between 25(OH)D levels and the risk of NCDs or the Montreal Cognitive Assessment (MoCA) score. RESULTS: In total, 347 (48.4%) had NCDs in HUNT4, with 33.3% having MCI and 15.1% having dementia. Compared with participants with serum 25(OH)D ≥50 nmol/L, those with 25(OH)D <50 nmol/L had a similar risk of NCDs (OR 1.05, 95% CI 0.76 to 1.46). No association was observed with the risk of MCI (OR 1.01, 95% CI 0.71 to 1.44) or dementia (OR 1.16, 95% CI 0.70 to 1.92), respectively. In a subsample of participants evaluated with the MoCA (n=662), a 25 nmol/L decrease in serum 25(OH)D was not associated with a change in MoCA score (beta 0.33, 95% CI -0.17 to 0.85). CONCLUSION: Vitamin D insufficiency defined by two times measurements of serum 25(OH)D with a 10-year interval was not associated with the risk of NCDs in a cohort of older Norwegian adults. Future studies utilizing multiple vitamin D measurements with a longer follow-up duration and larger sample size are warranted.

[Impacts of glycemic variability on the relationship between time in range and estimated glycated hemoglobin in patients with type 1 diabetes mellitus].

Objective: This study is to investigate the relationship between time in range (TIR) and glucose management indicator (GMI), and the impact of glycemic variability (GV) on their relationship in patients with type 1 diabetes mellitus (T1DM). Methods: The CGM data were collected from a multicenter randomized clinical trial of adults (≥18 years old) with T1DM, including 83 T1DM patients, respectively from the Third Affiliated Hospital of Sun Yat-sen University (72 cases), Drum Tower Hospital Affiliated to Nanjing University School of Medicine (2 cases), and the First Affiliated Hospital of University of Science and Technology of China (9 cases). All subjects wore the iProTM2 system for 14 days at baseline (0-2 weeks), 3 months (12-14 weeks), and 6 months (24-26 weeks). Data derived from iProTM2 sensor was used to calculate CGM parameters. Correlation between TIR and GMI was explored according to different stratification of glycemic variability assessed by glucose coefficient of variation (CV). Predicted TIR in the fixed GMI value was calculated via the linear regression equations performed in the respective interquartile group of CV. Results: From November 2017 to June 2021, a total of 233 CGM data were collected with 83 collected from baseline, 80 from the 3-month follow-up, 70 from the 6-month follow-up. Patients including 27 males had a median (Q1, Q3) age of 30.69 (25.22, 38.43) years, with a diabetes duration of 10.05(4.46, 13.92) years. The median (Q1, Q3) and effective wearing time of available CGM data was 13.92 (13.02, 14.00) days and 91.61% (84.96%, 95.94%), and the value of TIR, GMI and CV was 60.34%±13.03%, 7.14%±0.61% and 41.01%±7.64%, respectively. There was a strong negative correlation between TIR and GMI (r=-0.822, P<0.001). Multiple linear regression analysis showed that the predictive value of TIR calculated from a given GMI was 8.352% higher when CV was up to standard (36%) than that when CV was down to standard. Based on the multiple linear regression equations generated from quartiles of CV, the predicted TIR value was decreased across the ascending quartiles with 69.98 % in the lowest quartile of CV (≤35.91%), 64.57 % in 25th-50th quartile of CV (35.91%75th quartile, CV>45.86%) when GMI was set as 7%. Conclusions: There is a strong correlation between TIR and GMI in adult patients with T1DM in patients with type 1 diabetes mellitus. CV influenced the relationship between TIR and GMI.

Treatments targeting autophagy ameliorate the age-related macular degeneration phenotype in mice lacking APOE (apolipoprotein E).

Age-related macular degeneration (AMD) is a leading cause of vision loss with recent evidence indicating an important role for macroautophagy/autophagy in disease progression. In this study we investigate the efficacy of targeting autophagy for slowing dysfunction in a mouse model with features of early AMD. Mice lacking APOE (apolipoprotein E; B6.129P2-Apoetm1UncJ/Arc) and C57BL/6 J- (wild-type, WT) mice were treated with metformin or trehalose in the drinking water from 5 months of age and the ocular phenotype investigated at 13 months. Control mice received normal drinking water. APOE-control mice had reduced retinal function and thickening of Bruch's membrane consistent with an early AMD phenotype. Immunohistochemical labeling showed reductions in MAP1LC3B/LC3 (microtubule-associated protein 1 light chain 3 beta) and LAMP1 (lysosomal-associated membrane protein 1) labeling in the photoreceptors and retinal pigment epithelium (RPE). This correlated with increased LC3-II:LC3-I ratio and alterations in protein expression in multiple autophagy pathways measured by reverse phase protein array, suggesting autophagy was slowed. Treatment of APOE-mice with metformin or trehalose ameliorated the loss of retinal function and reduced Bruch's membrane thickening, enhancing LC3 and LAMP1 labeling in the ocular tissues and restoring LC3-II:LC3-I ratio to WT levels. Protein analysis indicated that both treatments boost ATM-AMPK driven autophagy. Additionally, trehalose increased p-MAPK14/p38 to enhance autophagy. Our study shows that treatments targeting pathways to enhance autophagy have the potential for treating early AMD and provide support for the use of metformin, which has been found to reduce the risk of AMD development in human patients.Abbreviations:AMD: age-related macular degeneration; AMPK: 5' adenosine monophosphate-activated protein kinase APOE: apolipoprotein E; ATM: ataxia telangiectasia mutated; BCL2L1/Bcl-xL: BCL2-like 1; DAPI: 4'-6-diamidino-2-phenylindole; ERG: electroretinogram; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCL: ganglion cell layer; INL: inner nuclear layer; IPL: inner plexiform layer; IS/OS: inner and outer photoreceptor segments; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; OCT: optical coherence tomography; ONL: outer nuclear layer; OPs: oscillatory potentials; p-EIF4EBP1: phosphorylated eukaryotic translation initiation factor 4E binding protein 1; p-MAPK14/p38: phosphorylated mitogen-activated protein kinase 14; RPE: retinal pigment epithelium; RPS6KB/p70 S6 kinase: ribosomal protein S6 kinase; SQSTM1/p62: sequestosome 1; TP53/TRP53/p53: tumor related protein 53; TSC2: TSC complex subunit 2; WT: wild type.

Risk Factors for Stroke Based on the National Health and Nutrition Examination Survey.

OBJECTIVES: To explore the risk factors for stroke by using National Health and Nutrition Examination Survey (NHANES). METHODS: A total of 19384 cases from the NHANES database during 2005 to 2016 were included in this study, of which 661 were stroke patients, with a weighted prevalence of 2.60%. Univariate and multivariate logistic regression analysis was used to analyze possible risk factors for stroke. RESULTS: The risk of stroke was 1.839 times higher in subjects with diabetes than in those without diabetes, P<0.001. An average increase of 1 ug/dL in blood lead was associated with a 1.082-fold increase in stroke risk, P<0.001. Subjects with mild-, moderate-, and moderately severe or severe depression had a 1.567-fold, 1.836-fold, and 3.279-fold higher risk than those without depression respectively, P<0.001. The risk of stroke in subjects with sleep disorders was 1.622 times higher than those without sleep disorders, P<0.001. CONCLUSIONS: Patients with diabetes, lower household income (<$2000), PHQ-9 depression score (5-27), trouble sleep, older age and higher concentration of blood lead are associated with a higher risk of stroke.

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin suppresses male reproductive functions in their adulthood.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant in the environment. The developmental period is more sensitive to TCDD and there is a possibility that maternal exposure to TCDD may affect in adulthood. Adult female Wistar rats were exposed to 0.5, 1.0, and 2.0 µg/kg TCDD during the critical stage of organogenesis, that is, on GD15. The results revealed a significant decrease in indices of reproductive organ weight in adult male rats exposed to prenatal TCDD, and dose-dependent reduction in epididymal sperm reserves, percent motile, and viable sperm with an increase in percent morphological abnormal sperm. Polymerase chain reaction analysis revealed downregulated expression levels of steroidogenic markers such as steroidogenic acute regulatory, cholesterol side-chain cleavage, and 3ß- and 17ß-hydroxysteroid dehydrogenase (HSDs) in experimental rats. Immunofluorescence sections portrayed reduced distribution of 3ß- and 17ß-HSD proteins in testes of experimental rats. Furthermore, spermatogenic markers (acid phosphatase, alkaline phosphatase, lactate dehydrogenase, and sorbitol dehydrogenase) were significantly altered in the testes. Serum levels of testosterone, follicle stimulating hormones, and luteinizing hormone were significantly decreased. Testicular levels of hydrogen peroxide and lipid peroxidation were significantly elevated with a decline in superoxide dismutase, catalase, glutathione peroxidase activities, and total thiol levels. Moreover, histological and morphometric examination of testicular cross-sections depicted degenerative changes. Male fertility assessment in adult rats revealed a significant decrease in mating index, fertility index, and mean number of pre- and postimplantations with an increase in pre- and postimplantation losses in rats cohabited with in utero TCDD-exposed adult males. In conclusion, the findings of this study provided clear evidence that maternal exposure to TCDD during the critical stage of development results in suppressed reproductive health in adulthood.

Publisher Correction: Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3).

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.

Oral bisphosphonate use and lung cancer incidence among postmenopausal women.

Background: Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI. Patients and methods: The association between oral bisphosphonate use and lung cancer risk was examined in 151 432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates. Results: After a mean follow-up of 13.3 years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio = 0.91; 95% confidence intervals, 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (hazard ratio = 0.57, 95% confidence interval, 0.39-0.84; P < 0.01). Conclusion: In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.

Nanosecond Laser Treatment for Age-Related Macular Degeneration Does Not Induce Focal Vision Loss or New Vessel Growth in the Retina.

Purpose: Subthreshold, nanosecond pulsed laser treatment shows promise as a treatment for age-related macular degeneration (AMD); however, the safety profile needs to be robustly examined. The aim of this study was to investigate the effects of laser treatment in humans and mice. Methods: Patients with AMD were treated with nanosecond pulsed laser at subthreshold (no visible retinal effect) energy doses (0.15-0.45 mJ) and retinal sensitivity was assessed with microperimetry. Adult C57BL6J mice were treated at subthreshold (0.065 mJ) and suprathreshold (photoreceptor loss, 0.5 mJ) energy settings. The retinal and vascular responses were analyzed by fundus imaging, histologic assessment, and quantitative PCR. Results: Microperimetry analysis showed laser treatment had no effect on retinal sensitivity under treated areas in patients 6 months to 7 years after treatment. In mice, subthreshold laser treatment induced RPE loss at 5 hours, and by 7 days the RPE had retiled. Fundus imaging showed reduced RPE pigmentation but no change in retinal thickness up to 3 months. Electron microscopy revealed changes in melanosomes in the RPE, but Bruch's membrane was intact across the laser regions. Histologic analysis showed normal vasculature and no neovascularization. Suprathreshold laser treatment did not induce changes in angiogenic genes associated with neovascularization. Instead pigment epithelium-derived factor, an antiangiogenic factor, was upregulated. Conclusions: In humans, low-energy, nanosecond pulsed laser treatment is not damaging to local retinal sensitivity. In mice, treatment does not damage Bruch's membrane or induce neovascularization, highlighting a reduced side effect profile of this nanosecond laser when used in a subthreshold manner.

The Role of Angiotensin II/AT1 Receptor Signaling in Regulating Retinal Microglial Activation.

Purpose: This study explored whether the proangiogenic factor Angiotensin II (AngII) had a direct effect on the activation state of microglia via the Angiotensin type 1 receptor (AT1-R). Methods: Microglial dynamic activity was investigated in live retinal flatmounts from adult Cx3Cr1+/GFP mice under control, AngII (5 µM) or AngII (5 µM) + candesartan (0.227 µM) conditions. The effects of intravitreal administration of AngII (10 mM) were also investigated at 24 hours, with retinae processed for immunocytochemistry, flow cytometry, or inflammatory quantitative PCR arrays. Results: We found FACS isolated retinal microglia expressed AT1-R. In retinal flatmounts, microglia showed characteristic movement of processes under control conditions. Perfusion of AngII induced an immediate change in process length (-42%, P < 0.05) and activation state of microglia that was ameliorated by AT1-R blockade, suggesting a direct effect of AngII on microglia via the AT1-R. Intravitreal injection of AngII induced microglial activation after 24 hours, which was characterized by increased soma size (23%, P < 0.001) and decreased process length (20%, P < 0.05). Further analysis indicated a significant decrease in the number of microglial contacts with retinal neurons (saline 15.6 ± 2.31 versus AngII 7.8 ± 1.06, P < 0.05). Retinal cytokine and chemokine expression was modulated, indicative of an inflammatory retinal phenotype. Conclusions: We show that retinal microglia express AT1-R and their activation state is significantly altered by the angiogenic factor, AngII. Specifically, AngII may directly activate AT1-Rs on microglia and contribute to retinal inflammation. This may have implications for diseases like diabetic retinopathy where increases in AngII and inflammation have been shown to play an important role.

Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death.

Goldberg-Shprintzen syndrome is a poorly understood condition characterized by learning difficulties, facial dysmorphism, microcephaly, and Hirschsprung disease. GOSHS is due to recessive mutations in KIAA1279, which encodes kinesin family member 1 binding protein (KIF1BP, also known as KBP). We examined the effects of inactivation of Kif1bp in mice. Mice lacking Kif1bp died shortly after birth, and exhibited smaller brains, olfactory bulbs and anterior commissures, and defects in the vagal and sympathetic innervation of the gut. Kif1bp was found to interact with Ret to regulate the development of the vagal innervation of the stomach. Although newborn Kif1bp -/- mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed. The data show an essential in vivo role for KIF1BP in axon extension from some neurons, and the reduced size of the olfactory bulb also suggests additional roles for KIF1BP. Our mouse model provides a valuable resource to understand GOSHS.

Loss of Function of P2X7 Receptor Scavenger Activity in Aging Mice: A Novel Model for Investigating the Early Pathogenesis of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7-null mice had thickening of Bruchs membrane and retinal pigment epithelium dysfunction. By 18 months of age, P2X7-null mice displayed phenotypic characteristics consistent with early AMD, including Bruchs membrane thickening, retinal pigment epithelium cell loss, retinal functional deficits, and signs of subretinal inflammation. Our present study shows that loss of function of the P2X7 receptor in mice induces retinal changes representing characteristics of early AMD, providing a valuable model for investigating the role of scavenger receptor function and the immune system in the development of this age-related disease.

Prenatal Iron Deficiency and Auditory Brainstem Responses at 3 and 10 Months: A Pilot Study.

PURPOSE: To examine whether prenatal iron deficiency delays auditory brainstem response (ABR) maturation in infancy. METHODS: One hundred and fifteen full-term healthy Chinese infants with maternal and cord blood haemoglobin and serum ferritin determinations were recruited into this study. Forty-eight infants received ABR testing at 3 months, and 45 infants were tested at 10 months. Comparison of the ABR variables were made between infants with and those without evidence of prenatal iron deficiency (maternal 3rd trimester haemoglobin <110 g/L, cord blood ferritin <75 µg/L); or anaemia at 10 months (haemoglobin <110 g/L). RESULTS: Latencies for wave V and wave III-V and I-V intervals were prolonged at 3 months in infants of anaemic mothers (effect sizes 1.02-1.19 SD). At 10 months, infants with low cord blood serum ferritin (indicating low iron stores at birth) showed longer wave I latency and possibly wave V latency also, besides demonstrating a smaller wave V amplitude (effect sizes 0.58-0.62 SD). Infants with low ferritin at birth and anemia at 10 months had longer wave III-V latency than other groups. CONCLUSION: In full-term healthy infants, prenatal iron deficiency appears to have adverse effects on the developing central nervous system and auditory system as assessed by ABRs at 3 and/or 10 months.

Serum 25-hydroxyvitamin D levels and self-reported allergic rhinitis in Norwegian adults - The HUNT Study.

BACKGROUND: The role of low vitamin D status in the development of allergic rhinitis is unclear. We aimed to investigate the relationship between serum 25-hydroxyvitamin D [25(OH)D] and incidence of allergic rhinitis in adults. METHODS: The study included a random sample from an adult population who participated in the second and third surveys of the Nord-Trøndelag Health Study (HUNT) in Norway (HUNT2, 1995-1997 and HUNT3, 2006-2008). Serum 25(OH)D levels were measured in blood samples collected at baseline. Among 1351 adults who did not report allergic rhinitis at baseline, incident allergic rhinitis was identified by participant report of having or having had allergic rhinitis or hay fever at follow-up. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated after adjustment for age, smoking, physical activity, socioeconomic status, family history of allergy, body mass index, and season. The analyses were stratified by sex due to its significant interaction with 25(OH)D levels (P < 0.02). RESULTS: Over an average of 11 years, 9% of men and 15% of women developed allergic rhinitis. Among men, serum 25(OH)D level <50 nM was associated with an increased risk of incident allergic rhinitis (AOR 2.55; 95% CI 1.01-6.49); each 25 nM reduction in 25(OH)D level was associated with an AOR of 1.84 (95% CI 1.18-2.87). In women, however, the association was opposite, with AOR being 0.83 (95% CI 0.66-1.05) for each 25 nM reduction in serum 25(OH)D level. CONCLUSIONS: Vitamin D appears to play different roles in the development of allergic rhinitis among men and women.

The associations of anxiety and depression symptoms with weight change and incident obesity: The HUNT Study.

OBJECTIVE: To investigate the associations of anxiety and depression symptoms with weight change and incident obesity in men and women. DESIGN: We conducted a prospective cohort study using the Norwegian Nord-Trøndelag Health Study (HUNT). SUBJECTS: The study cohort included 25 180 men and women, 19-55 years of age from the second survey of the HUNT (1995-1997). MEASUREMENTS: Anxiety and depression symptoms were measured using the Hospital Anxiety and Depression Scale. Weight change was determined for the study period of an average 11 years. Incident obesity was new-onset obesity classified as having a body mass index of 30.0 kg m(2) at follow-up. The associations of anxiety or depression with weight change in kilograms (kg) was estimated using linear regression models. Risk ratios (RRs) for incident obesity associated with anxiety or depression were estimated using log-binomial regression. RESULTS: In men, any anxiety or depression was associated with an average 0.81 kg (95% confidence interval (CI) 0.27-1.34) larger weight change after 11 years compared with those without such symptoms (mean weight change: 5.04 versus 4.24 kg). Women with any anxiety or depression had an average 0.98 kg (95% confidence interval (CI) 0.49-1.47) larger weight change compared with those without such symptoms (mean weight change: 5.02 versus 4.04 kg). Participants with any anxiety or depression had a significantly elevated cumulative incidence of obesity (men: RR 1.37, 95% CI 1.13-1.65; women: RR 1.18, 95% CI 1.00-1.40). CONCLUSION: We found that symptoms of anxiety and depression were associated with larger weight change and an increased cumulative incidence of obesity in both men and women.

A call for standardized naming and reporting of human ESC and iPSC lines.

Human embryonic and induced pluripotent stem cell lines are being generated at a rapid pace and now number in the thousands. We propose a standard nomenclature and suggest the use of a centralized database for all cell line names and a minimum set of information for reporting new derivations.

Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation.

BACKGROUND: Early antibiotic use has been postulated to increase the development of allergic disease. Antibiotic use results from infection. Early infection may play a confounding role in the relationship between antibiotic use and allergic disease. OBJECTIVE: We aimed to investigate the relationship between antibiotic use during the first year of life and the development of allergic diseases in a birth cohort study, and also to carefully address the confounding effect of early respiratory infection. METHODS: Three thousand three hundred and six children were included in this study who participated in investigations at all occasions of 2 months, 1, 4 and 8 years of age. Data on antibiotic use and respiratory infections were collected at the age of 1 year. Diagnoses of allergic diseases at 4 and 8 years of age were derived from the follow-up questionnaires. RESULTS: During the first year of life, 43% (n=1420) of the children received antibiotics and 32% (n=1046) of the children had at least one type of respiratory infection among pneumonia, bronchitis and otitis. In univariate logistic regression analysis and after adjustment for early life factors, antibiotic use during the first year of life was associated with wheeze, asthma, eczema and food hypersensitivity at 4 years of age. After adjustment for the above respiratory infections during the first year of life, only the associations with wheeze and asthma at age 4 years remained statistically significant. These associations became non-significant in a subgroup analysis in children without early allergic signs. At age 8 years, antibiotic use during the first year of life was significantly associated with wheeze and eczema after adjustment for early life factors. The significant associations at age 8 years faded away following further adjustment for the respiratory infections. CONCLUSION: Our study indicated that the association between early antibiotic use and later allergic disease could at least partially be explained by early respiratory infection.

International stem cell registries.

Rapid advances in stem cell research have led to the derivation of hundreds of human embryonic stem (hES) cell lines in centers throughout the world, as well as the development of new technologies for producing pluripotent stem cells. These cell lines have unique characteristics and were derived using a variety of ethical guidelines. Stem cell registries have been developed in order to collect, organize, and disseminate cell line-specific information. In this review, we describe the current state of the field by providing an overview of the unique qualities and mandates of the three major stem cell registries: the European hES Cell Registry, the Registry of hES Cell Line Provenance developed by the International Society for Stem Cell Research, and the International Stem Cell Registry of hES and induced pluripotent stem cell lines established at the University of Massachusetts Medical School. While each registry has its own unique mandate and features, there is some overlap in the goals and information provided. This review discusses the challenges and prospects for an integrated approach in which all three registries effectively collaborate to minimize duplication and facilitate information exchange within the stem cell community.

Pluripotency: toward a gold standard for human ES and iPS cells.

With the advent of technologies for the derivation of embryonic stem cells and reprogrammed stem cells, use of the term "pluripotent" has become widespread. Despite its increased scientific and political importance, there are ambiguities with this designation and a common standard for experimental approaches that precisely define this state in human cells remains elusive. Recent studies have revealed that reprogramming may occur via many pathways which do not always lead to pluripotency. In addition, the pluripotent state itself appears to be highly dynamic, leading to significant variability in the results of molecular studies. Establishment of a stringent set of criteria for defining pluripotency will be vital for biological studies and potential clinical applications in this rapidly evolving field. In this review, we explore the various definitions of pluripotency, examine the current status of pluripotency testing in the field and provide an analysis of how these assays have been used to establish pluripotency in the scientific literature.