This report updates surveillance results for COPD in the United States. For 1999 to 2011, data from national data systems for adults aged ≥ 25 years were analyzed. In 2011, 6.5% of adults ...(approximately 13.7 million) reported having been diagnosed with COPD. From 1999 to 2011, the overall age-adjusted prevalence of having been diagnosed with COPD declined ( P = .019). In 2010, there were 10.3 million (494.8 per 10,000) physician office visits, 1.5 million (72.0 per 10,000) ED visits, and 699,000 (32.2 per 10,000) hospital discharges for COPD. From 1999 to 2010, no significant overall trends were noted for physician office visits and ED visits; however, the age-adjusted hospital discharge rate for COPD declined significantly ( P = .001). In 2010 there were 312,654 (11.2 per 1,000) Medicare hospital discharge claims submitted for COPD. Medicare claims (1999-2010) declined overall ( P = .045), among men ( P = .022) and among enrollees aged 65 to 74 years ( P = .033). There were 133,575 deaths (63.1 per 100,000) from COPD in 2010. The overall age-adjusted death rate for COPD did not change during 1999 to 2010 ( P = .163). Death rates (1999-2010) increased among adults aged 45 to 54 years ( P < .001) and among American Indian/Alaska Natives ( P = .008) but declined among those aged 55 to 64 years ( P = .002) and 65 to 74 years ( P < .001), Hispanics ( P = .038), Asian/Pacific Islanders ( P < .001), and men ( P = .001). Geographic clustering of prevalence, Medicare hospitalizations, and deaths were observed. Declines in the age-adjusted prevalence, death rate in men, and hospitalizations for COPD since 1999 suggest progress in the prevention of COPD in the United States.
The potential for age‐related trends in the stable oxygen isotope ratios of latewood alpha cellulose was investigated in samples of living oak trees and historic building timbers from the UK. When ...the series are examined individually, it is clear that the strongest trends in individual trees and timbers reflect concurrent trends in climate. Nonclimatic trends are very small and represent random noise that can be removed by averaging. If the same data are analyzed using the more conventional approach of aligning the series by ring number and fitting a regression line, so that the magnitude of the age trend is based on the slope of the mean and the statistical significance on the correlation coefficient, the results are very different. We demonstrate that this conventional approach regularly produces spurious age trends with grossly inflated probabilities, because of offsets in the mean values of series of different length. We conclude that there is no need to detrend stable oxygen isotope series from individual trees or timbers of oak from the UK and that to do so would remove important climatic information. Long isotope chronologies can safely be constructed by combining data from multiple individual trees, or by pooling material from trees prior to chemical treatment and isotopic measurement. Age‐related trends may occur in other species or in other regions, but where they have been identified using the conventional “slope of the mean” approach they should be reassessed using the “mean of the slope” approach.
Key Points
No age‐related trends are found in stable isotopes from oak tree rings based on a case study in the UK
The conventional method of trend identification can produce spurious age trends with grossly inflated probabilities
Age‐related trends may occur in other species or in other regions, but should be reassessed using the “mean of the slope” approach
The Wnt signaling pathway, named for its most upstream ligands, the Wnts, is involved in various differentiation events during embryonic development and leads to tumor formation when aberrantly ...activated. Molecular studies have pinpointed activating mutations of the Wnt signaling pathway as the cause of approximately 90% of colorectal cancer (CRC), and somewhat less frequently in cancers at other sites, such as hepatocellular carcinoma (HCC). Ironically, Wnts themselves are only rarely involved in the activation of the pathway during carcinogenesis. Mutations mimicking Wnt stimulation—generally inactivating
APC mutations or activating β-catenin mutations—result in nuclear accumulation of β-catenin which subsequently complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors to activate gene transcription. Recent data identifying target genes has revealed a genetic program regulated by β-catenin/TCF controlling the transcription of a suite of genes promoting cellular proliferation and repressing differentiation during embryogenesis, carcinogenesis, and in the post-embryonic regulation of cell positioning in the intestinal crypts. This review considers the spectra of tumors arising from active Wnt signaling and attempts to place perspective on recent data that begin to elucidate the mechanisms prompting uncontrolled cell growth following induction of Wnt signaling.
The randomised phase III clinical trial Checkmate-214 showed a survival superiority for the combination of ipilimumab and nivolumab when compared with the previous standard of care in first-line ...metastatic/advanced clear cell renal cell carcinoma (RCC) (Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. LBA5, ESMO 2017, 2017). These results change the frontline standard of care for this disease and have implications for the selection of subsequent therapies. For this reason the European Association of Urology RCC guidelines have been updated.
The European Association of Urology guidelines will be updated based on the results of the phase III Checkmate-214 clinical trial. The trial showed superior survival for a combination of ipilimumab and nivolumab (IN), compared with the previous standard of care, in intermediate- and poor-risk patients with metastatic clear cell renal cell carcinoma. When IN is not safe or feasible, alternative agents such as sunitinib, pazopanib, and cabozantinib should be considered. Furthermore, at present, the data from the trial are immature in favourable-risk patients. Therefore, sunitinib or pazopanib remains the favoured agent for this subgroup of patients.
Based on the Checkmate-214 trial, the European Association of Urology guidelines, which will be updated, recommend ipilimumab and nivolumab (IN) as the standard of care in intermediate- and poor-risk patients with metastatic clear cell renal cell carcinoma. Alternative agents such as sunitinib, pazopanib, and cabozantinib should be considered when IN is not safe or feasible. At present, in favourable-risk patients, the data from the trial are immature. Therefore, sunitinib or pazopanib remains the preferred agent in this subgroup of patients.
United Kingdom (UK) summers dominated by anti-cyclonic circulation patterns are characterised by clear skies, warm temperatures, low precipitation totals, low air humidity and more enriched oxygen ...isotope ratios (δ
18
O) in precipitation. Such conditions usually result in relatively more positive (enriched) oxygen isotope ratios in tree leaf sugars and ultimately in the tree-ring cellulose formed in that year, the converse being true in cooler, wet summers dominated by westerly air flow and cyclonic conditions. There should therefore be a strong link between tree-ring δ
18
O and the amount of summer precipitation. Stable oxygen isotope ratios from the latewood cellulose of 40 oak trees sampled at eight locations across Great Britain produce a mean δ
18
O chronology that correlates strongly and significantly with summer indices of total shear vorticity, surface air pressure, and the amount of summer precipitation across the England and Wales region of the United Kingdom. The isotope-based rainfall signal is stronger and much more stable over time than reconstructions based upon oak ring widths. Using recently developed methods that are precise, efficient and highly cost-effective it is possible to measure both carbon (δ
13
C) and oxygen (δ
18
O) isotope ratios simultaneously from the same tree-ring cellulose. In our study region, these two measurements from multiple trees can be used to reconstruct summer temperature (δ
13
C) and summer precipitation (δ
18
O) with sufficient independence to allow the evolution of these climate parameters to be reconstructed with high levels of confidence. The existence of long, well-replicated oak tree-ring chronologies across the British Isles mean that it should now be possible to reconstruct both summer temperature and precipitation over many centuries and potentially millennia.
To examine recent national trends in outpatient visits for sleep related difficulties in the United States and prescriptions for sleep medications.
Trend analysis.
Data from the National Ambulatory ...Medical Care Survey from 1999 to 2010.
Patients age 20 y or older.
The number of office visits with insomnia as the stated reason for visit increased from 4.9 million visits in 1999 to 5.5 million visits in 2010 (13% increase), whereas the number with any sleep disturbance ranged from 6,394,000 visits in 1999 to 8,237,000 visits in 2010 (29% increase). The number of office visits for which a diagnosis of sleep apnea was recorded increased from 1.1 million visits in 1999 to 5.8 million visits in 2010 (442% increase), whereas the number of office visits for which any sleep related diagnosis was recorded ranged from 3.3 million visits in 1999 to 12.1 million visits in 2010 (266% increase). The number of prescriptions for any sleep medication ranged from 5.3 in 1999 to 20.8 million in 2010 (293% increase). Strong increases in the percentage of office visits resulting in a prescription for nonbenzodiazepine sleep medications (∼350%), benzodiazepine receptor agonists (∼430%), and any sleep medication (∼200%) were noted.
Striking increases in the number and percentage of office visits for sleep related problems and in the number and percentage of office visits accompanied by a prescription for a sleep medication occurred from 1999-2010.
Ford ES, Wheaton AG, Cunningham TJ, Giles WH, Chapman DP, Croft JB. Trends in outpatient visits for insomnia, sleep apnea, and prescriptions for sleep medications among US adults: findings from the National Ambulatory Medical Care Survey 1999-2010.
Enteroendocrine cells (EECs) produce hormones such as glucagon-like peptide 1 and peptide YY that regulate food absorption, insulin secretion, and appetite. Based on the success of glucagon-like ...peptide 1-based therapies for type 2 diabetes and obesity, EECs are themselves the focus of drug discovery programs to enhance gut hormone secretion. The aim of this study was to identify the transcriptome and peptidome of human EECs and to provide a cross-species comparison between humans and mice. By RNA sequencing of human EECs purified by flow cytometry after cell fixation and staining, we present a first transcriptomic analysis of human EEC populations and demonstrate a strong correlation with murine counterparts. RNA sequencing was deep enough to enable identification of low-abundance transcripts such as G-protein-coupled receptors and ion channels, revealing expression in human EECs of G-protein-coupled receptors previously found to play roles in postprandial nutrient detection. With liquid chromatography-tandem mass spectrometry, we profiled the gradients of peptide hormones along the human and mouse gut, including their sequences and posttranslational modifications. The transcriptomic and peptidomic profiles of human and mouse EECs and cross-species comparison will be valuable tools for drug discovery programs and for understanding human metabolism and the endocrine impacts of bariatric surgery.
Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of
the Brain-Derived Neurotrophic Factor ( BDNF ) Gene
Juliette Gray 1 ,
Giles ...S.H. Yeo 1 ,
James J. Cox 2 ,
Jenny Morton 3 ,
Anna-Lynne R. Adlam 4 ,
Julia M. Keogh 1 ,
Jack A. Yanovski 5 ,
Areeg El Gharbawy 5 ,
Joan C. Han 5 ,
Y.C. Loraine Tung 1 ,
John R. Hodges 4 ,
F. Lucy Raymond 2 ,
Stephen O’Rahilly 1 and
I. Sadaf Farooqi 1
1 University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge,
U.K
2 University Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, U.K
3 West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, U.K
4 Medical Research Council, Cognition and Brain Sciences Unit, and the Department of Clinical Neurosciences, Addenbrooke’s Hospital,
Cambridge, U.K
5 Unit on Growth and Obesity, Developmental Endocrinology Branch, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, Maryland
Address correspondence and reprint requests to I. Sadaf Farooqi, University Department of Clinical Biochemistry, Cambridge
Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, CB2 2XY, U.K. E-mail: isf20{at}cam.ac.uk
Abstract
The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit
increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity,
impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region
encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF , but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared
with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe
early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin
BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.
BAC, bacterial artificial chromosome
BDNF, brain-derived neurotrophic factor
FISH, fluorescence in situ hybridization
TrkB, tropomyosin-related kinase B
Footnotes
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted August 21, 2006.
Received April 24, 2006.
DIABETES
Disruption of brain-expressed G protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identify multiple rare variants in GPR10 in people with severe obesity and in normal weight ...controls. These variants impair ligand binding and G protein-dependent signalling in cells. Transgenic mice harbouring a loss of function GPR10 variant found in an individual with obesity, gain excessive weight due to decreased energy expenditure rather than increased food intake. This evidence supports a role for GPR10 in human energy homeostasis. Therapeutic targeting of GPR10 may represent an effective weight-loss strategy.
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