Analysis of Case-Control Age-at-Onset Data Using a Modified Case-Cohort Method

Case-control designs are widely used in rare disease studies. In a typical case-control study, data are collected from a sample of all available subjects who have experienced a disease (cases) and a sub-sample of subjects who have not experienced the disease (controls) in a study cohort. Cases are oversampled in case-control studies. Logistic regression is a common tool to estimate the relative risks of the disease with respect to a set of covariates. Very often in such a study, information of ages-at-onset of the disease for all cases and ages at survey of controls are known. Standard logistic regression analysis using age as a covariate is based on a dichotomous outcome and does not efficiently use such age-at-onset (time-to-event) information. We propose to analyze age-at-onset data using a modified case-cohort method by treating the control group as an approximation of a subcohort assuming rare events. We investigate the asymptotic bias of this approximation and show that the asymptotic bias of the proposed estimator is small when the disease rate is low. We evaluate the finite sample performance of the proposed method through a simulation study and illustrate the method using a breast cancer case-control data set. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58567/1/311_ftp.pd

Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA

Localization of tenascin in human skin wounds

A total of 56 surgically treated human skin wounds with a wound age between 8h and 7 months were investigated. Tenascin was visualized by immunohistochemistry and appeared first in the wound area pericellularly around fibroblastic cells approximately 2 days after wounding. A network-like interstitial positive staining pattern was first detectable in 3-day-old skin wounds. In all wounds with an age of 5 days or more, intensive reactivity for tenascin could be observed in the lesional area (dermal-epidermal junction, wound edge, areas of bleeding). In wounds with an age of more than approximately 1.5 months no positive staining occurred in the scar tissue. In conclusion, for forensic purposes, positive staining for tenascin restricted to the pericellular area of fibroblastic cells indicates a wound age of at least 2 days. Network-like structures appear after approximately 3 days or more. Since tenascin seems to be regularly detectable in skin wounds older than 5 days, the lack of a positive reaction in a sufficient number of specimens indicates a wound age of less than 5 days. The lack of a positive reaction in the granulation tissue of wounds with advanced wound age indicates a survival time of more than about 1.5 months, but a positive staining in older wounds cannot be excluded

Pregnancy in women with pulmonary hypertension

Women with pulmonary hypertension have a high risk of morbidity and mortality during pregnancy. The inability to increase cardiac output leads to heart failure while further risks are introduced with hypercoagulability and decrease in systemic vascular resistance. There is no proof that new advanced therapies for pulmonary hypertension decrease the risk, though some promising results have been reported. However, pregnancy should still be regarded as contraindicated in women with pulmonary hypertension. When pregnancy occurs and termination is declined, pregnancy and delivery should be managed by multidisciplinary services with experience in the management of both pulmonary hypertension and high-risk pregnancies

Long-term ambient hydrocarbons exposure and incidence of ischemic stroke.

Exposure to air pollutants is known to have adverse effects on human health; however, little is known about the association between hydrocarbons in air and an ischemic stroke (IS) event. We investigated whether long-term exposure to airborne hydrocarbons, including volatile organic compounds, increased IS risk. This retrospective cohort study included 283,666 people aged 40 years or older in Taiwan. Cox proportional hazards regression analysis was used to fit single- and multiple-pollutant models for two targeted pollutants, total hydrocarbons (THC) and nonmethane hydrocarbons (NMHC), and estimated the risk of IS. Before controlling for multiple pollutants, hazard ratios (HRs) of IS with 95% confidence intervals for the overall population were 2.69 (2.64-2.74) at 0.16-ppm increase in THC and 1.62 (1.59-1.66) at 0.11-ppm increase in NMHC. For the multiple-pollutant models controlling for PM2.5, the adjusted HR was 3.64 (3.56-3.72) for THC and 2.21 (2.16-2.26) for NMHC. Our findings suggest that long-term exposure to THC and NMHC may be a risk factor for IS development

Increasing the sensitivity of NMR diffusion measurements by paramagnetic longitudinal relaxation enhancement, with application to ribosome–nascent chain complexes

The translational diffusion of macromolecules can be examined non-invasively by stimulated echo (STE) NMR experiments to accurately determine their molecular sizes. These measurements can be important probes of intermolecular interactions and protein folding and unfolding, and are crucial in monitoring the integrity of large macromolecular assemblies such as ribosome–nascent chain complexes (RNCs). However, NMR studies of these complexes can be severely constrained by their slow tumbling, low solubility (with maximum concentrations of up to 10 μM), and short lifetimes resulting in weak signal, and therefore continuing improvements in experimental sensitivity are essential. Here we explore the use of the paramagnetic longitudinal relaxation enhancement (PLRE) agent NiDO2A on the sensitivity of 15N XSTE and SORDID heteronuclear STE experiments, which can be used to monitor the integrity of these unstable complexes. We exploit the dependence of the PLRE effect on the gyromagnetic ratio and electronic relaxation time to accelerate recovery of 1H magnetization without adversely affecting storage on N z during diffusion delays or introducing significant transverse relaxation line broadening. By applying the longitudinal relaxation-optimized SORDID pulse sequence together with NiDO2A to 70S Escherichia coli ribosomes and RNCs, NMR diffusion sensitivity enhancements of up to 4.5-fold relative to XSTE are achieved, alongside ~1.9-fold improvements in two-dimensional NMR sensitivity, without compromising the sample integrity. We anticipate these results will significantly advance the use of NMR to probe dynamic regions of ribosomes and other large, unstable macromolecular assemblies

A Tree-structure Convolutional Neural Network for Temporal Features Exaction on Sensor-based Multi-resident Activity Recognition

With the propagation of sensor devices applied in smart home, activity recognition has ignited huge interest and most existing works assume that there is only one habitant. While in reality, there are generally multiple residents at home, which brings greater challenge to recognize activities. In addition, many conventional approaches rely on manual time series data segmentation ignoring the inherent characteristics of events and their heuristic hand-crafted feature generation algorithms are difficult to exploit distinctive features to accurately classify different activities. To address these issues, we propose an end-to-end Tree-Structure Convolutional neural network based framework for Multi-Resident Activity Recognition (TSC-MRAR). First, we treat each sample as an event and obtain the current event embedding through the previous sensor readings in the sliding window without splitting the time series data. Then, in order to automatically generate the temporal features, a tree-structure network is designed to derive the temporal dependence of nearby readings. The extracted features are fed into the fully connected layer, which can jointly learn the residents labels and the activity labels simultaneously. Finally, experiments on CASAS datasets demonstrate the high performance in multi-resident activity recognition of our model compared to state-of-the-art techniques.Comment: 12 pages, 4 figure

Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare long-chain fatty acid oxidation disorder (LC-FAOD) with high mortality due to cardiomyopathy or lethal arrhythmia. Triheptanoin (UX007), an investigational drug composed of synthetic medium odd-chain triglycerides, is a novel therapy in development for LC-FAOD patients. However, cases of its safe and efficacious use to reverse severe heart failure in CACT deficiency are limited. Here, we present a detailed report of an infant with CACT deficiency admitted in metabolic crisis that progressed into severe cardiogenic shock who was successfully treated by triheptanoin. The child was managed, thereafter, on triheptanoin until her death at 3 years of age from a cardiopulmonary arrest in the setting of acute respiratory illness superimposed on chronic hypercarbic respiratory failure

The Membrane-Associated Adaptor Protein DOK5 Is Upregulated in Systemic Sclerosis and Associated with IGFBP-5-Induced Fibrosis

Systemic sclerosis (SSc) is characterized by excessive fibrosis of the skin and internal organs due to fibroblast proliferation and excessive production of extracellular matrix (ECM). We have shown that insulin-like growth factor binding protein (IGFBP)-5 plays an important role in the development of fibrosis in vitro, ex vivo, and in vivo. We identified a membrane-associated adaptor protein, downstream of tyrosine kinase/docking protein (DOK)5, as an IGFBP-5-regulated target gene using gene expression profiling of primary fibroblasts expressing IGFBP-5. DOK5 is a tyrosine kinase substrate associated with intracellular signaling. Our objective was to determine the role of DOK5 in the pathogenesis of SSc and specifically in IGFBP-5-induced fibrosis. DOK5 mRNA and protein levels were increased in vitro by endogenous and exogenous IGFBP-5 in primary human fibroblasts. DOK5 upregulation required activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Further, IGFBP-5 triggered nuclear translocation of DOK5. DOK5 protein levels were also increased in vivo in mouse skin and lung by IGFBP-5. To determine the effect of DOK5 on fibrosis, DOK5 was expressed ex vivo in human skin in organ culture. Expression of DOK5 in human skin resulted in a significant increase in dermal thickness. Lastly, levels of DOK5 were compared in primary fibroblasts and lung tissues of patients with SSc and healthy donors. Both DOK5 mRNA and protein levels were significantly increased in fibroblasts and skin tissues of patients with SSc compared with those of healthy controls, as well as in lung tissues of SSc patients. Our findings suggest that IGFBP-5 induces its pro-fibrotic effects, at least in part, via DOK5. Furthermore, IGFBP-5 and DOK5 are both increased in SSc fibroblasts and tissues and may thus be acting in concert to promote fibrosis

Synchronous adenocarcinoma and carcinoid tumor of the terminal ileum in a Crohn's disease patient

BACKGROUND: Several malignancies have been described in association with inflammatory bowel diseases, the most common being adenocarcinoma. Carcinoid tumor and Crohn disease has also been previously reported, however the coexistence of both neoplasms is quite rare and the clinical diagnosis is very difficult. Here we report what we believe to be the fourth case of a mixed adenocarcinoid tumor coexisting with Crohn's disease. CASE REPORT: The patient presented with clinical and radiological features of intestinal obstruction. Laparotomy showed a stricturing lesion in the last 6 cm of the terminal ileum with proximal dilation. Only the histology of the resected surgical specimen proved the presence of a mixed adenocarcinoid tumor involving the terminal ileum. CONCLUSION: Carcinoid tumor should be suspected in elderly patients with Crohn's disease presenting with intestinal obstruction and laparotomy should be considered to exclude malignancy