Managing information overload on the Web with collaborative filtering

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1996.Includes bibliographical references (leaves 102-103).by Winnie H. Liang.M.Eng

Pharmacodynamic analysis of the furosemide-probenecid interaction in man

Pharmacodynamic analysis of the furosemide-probenecid interaction in man. Probenecid pretreatment in man increased the overall response to furosemide in contrast to animal studies in which probenecid decreased response by inhibiting proximal renal tubular secretion of furosemide to its active site. We administered i.v. 40mg of furosemide to eight normal volunteers with and without probenecid pretreatment and measured serum and urinary furosemide concentrations by high performance liquid chromatography to determine the mechanism of probenecid's effect. Probenecid pretreatment significantly increased serum furosemide concentration. Urinary furosemide excretion rate paralleled urinary sodium excretion rate; both were initially decreased but were later increased by probenecid pretreatment. Probenecid pretreatment decreased renal and nonrenal clearance of furosemide (1.04 ± 0.31 vs. 0.29 ± 0.06 ml/kg/min, P < 0.05; and 1.00 ± 0.18 vs. 0.27 ± 0.03 ml/kg/min, P < 0.004, respectively). Although probenecid inhibited renal clearance for the duration of the study, accumulation of furosemide in serum from concomitant effects on nonrenal clearance allowed more furosemide to appear in the urine at later times, increasing response. This analysis demonstrated the importance of probenecid's effects on nonrenal elimination of furosemide in determining the overall response to furosemide. The relationship between furosemide concentrations and response depicted a sigmoid dose-response curve. Probenecid shifted the serum dose-response relationship to the right but did not affect the relationship between urinary furosemide excretion rate and response, demonstrating the importance of the urinary (as opposed to serum) concentration-response relationship of furosemide in normal man. This relationship will provide a valuable tool for assessing response to diuretics in various disease states where resistance to diuretics occurs.Analyse pharmacodynamique de l'interaction furosémide-probénécide chez l'homme. Le pré-traitement par le probénécide chez l'homme augmente la réponse globale au furosémide par opposition aux études chez l'animal où le probénécide diminue cette réponse en inhibant la sécrétion tubulaire proximale de furosémide. Nous avons administré i.v. 40mg de furosémide par voie à huit volontaires normaux, avec ou sans pré-traitement par le probénécide, et mesuré les concentrations de furosémide sériques et urinaires par chromatographie liquide à haute résolution afin d'étudier le mécanisme de l'effet du probénécide. Le pré-traitement par le probénécide augmente significativement la concentration sérique de furosémide. L'excrétion urinaire de furosémide est parallèle à l'excrétion urinaire de sodium. Ces deux dernières sont initialement diminuées mais ultérieurement augmentées par le pré-traitement au moyen de probénécide. Le pré-traitement par le probénécide diminue les clearances rénale et non-rénale du furosémide (1,04 ± 0,31 vs. 0,29 ± 0,06 ml/kg/min, P < 0,05; et 1,00 ± 0,18 vs. 0,27 ± 0,03 ml/kg/min, P < 0,004, respectivement). Bien que le probénécide diminue la clearance rénale pendant la durée de l'étude, l'accumulation sérique de furosémide due aux effets sur la clearance non rénale permet l'apparition dans l'urine de quantités plus importantes à des temps ultérieurs, ce qui augmente la réponse. Cette analyse démontre l'importance des effets du probénécide sur l'élimination non rénale de furosémide dans le déterminisme de la réponse globale au furosémide. La relation entre les concentrations de furosémide et la réponse décrit une courbe dose-réponse sigmoïde. Le probénécide déplace la courbe dose-réponse sérique vers la droite mais n'affecte pas la relation entre l'excrétion urinaire de furosémide et la réponse, ce qui démontre l'importance de la relation entre la concentration urinaire (à la différence de la concentration sérique) et la réponse. Cette relaition fournit un instrument utile pour évaluer la réponse aux diurétiques dans divers états où la résistance à ces drogues est observée

Sirtuin 3 Attenuates Amyloid-Beta Induced Neuronal Hypometabolism

Alzheimer\u27s disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy

Cerebral small vessel disease burden is associated with poststroke depressive symptoms: A 15-month prospective study

Objective: All types of cerebral small vessel disease (SVD) markers including lacune, white matter hyperintensities (WMH), cerebral microbleeds, and perivascular spaces were found to be associated with poststroke depressive symptoms (PDS). This study explored whether the combination of the four markers constituting an overall SVD burden was associated with PDS. Methods: A cohort of 563 patients with acute ischemic stroke were followed over a 15-month period after the index stroke. A score of _7 on the 15-item Geriatric Depression Scale was defined as clinically significant PDS. Scores of the four SVD markers ascertained on magnetic resonance imaging were summed up to represent total SVD burden. The association between SVD burden and PDS was assessed with generalized estimating equation models. Results: The study sample had a mean age of 67.0 _ 10.2 years and mild-moderate stroke [National Institutes of Health Stroke Scale score: 3, interquartile, 1–5]. PDS were found in 18.3%, 11.6%, and 12.3% of the sample at 3, 9, and 15 months after stroke, respectively. After adjusting for demographic characteristics, vascular risk factors, social support, stroke severity, physical and cognitive functions, and size and locations of stroke, the SVD burden was associated with an increased risk of PDS [odds ratio = 1.30; 95% confidence interval = 1.07–1.58; p = 0.010]. Other significant predictors of PDS were time of assessment, female sex, smoking, number of acute infarcts, functional independence, and social support. Conclusion: SVD burden was associated with PDS examined over a 15-month follow-up in patients with mild to moderate acute ischemic stroke

Understanding substance misuse amongst the mentally ill: an investigation of the context of, and motivations for, drug and alcohol use in an in-patient sample of individuals with psychotic illness

Background: Dual diagnosis (substance misuse and mental illness) is recognised as a significant clinical problem. However there is little evidence contributing to the understanding of what motivates people with psychotic illnesses to use drugs and alcohol, and in what social context. There is still less evidence concerning the correlates of dual diagnosis in in-patient settings including the relationship between mental health service settings and the initiation and maintenance of substance misuse. This study reports the prevalence, social context of, and motivations for substance use in a sample of in-patients with psychotic illnesses.;Methods and measures: Staff on 9 acute mental health wards and 2 psychiatric intensive care units in North London used a Clinician Drug and Alcohol Use Rating Scale to assess whether working age in-patients with psychotic illness also met the criteria for harmful alcohol or drug use, or dependence during the preceding six months. Those meeting the criteria for harmful use or dependence were then approached to participate in the study. Participants were interviewed and asked to report on the nature, extent, social context and attributions of their substance use, and whether they had continued to use whilst an in-patient. Measures used included an Inventory of Alcohol and Drug Use Situations, a Self-Medication Questionnaire, a demographic schedule and a structured set of questions concerning substance use history and it's relationship to mental health service settings.;Results: All working age adult in-patients (264) were screened for a current or recent substance use disorder. One hundred and twenty nine individuals met the study criteria (48.9%), whilst a further 39 (15%) had a substance use history, but no associated impairment of these, 102 agreed to take part in the study (response rate 79%). Those with dual diagnosis were younger on average and more likely to be male, than those with psychosis alone. The majority (76%) suffered from schizophrenia and were detained under the Mental Health Act (1983), with 19% being street homeless. A wide range of substances including opiates, stimulant substances and khat were used by participants, but alcohol, cannabis and cocaine (respectively) were the most frequently used substances. Eighty one percent of the participants reported using on the ward during their current admission, with almost half of the participants buying substances from other in-patients. Methods of using reflected the wide range of substance use reported, and included intravenous injection, chasing, and smoking. A third of participants reported feeling pressurised to buy, or use substances with other in-patients. For the majority substance use was clearly a social activity with three quarters of the participants reporting that they typically used or drank with others. Sixteen percent of the participants reported typically using with other mental health service users. Two principal components analyses of use situations and self medication data each revealed three factors, explaining 68% and 66% of the variance respectively. All factors had high mean scores, and elicited motivations for substance use. They were (use related to): negative personal and social states (48% variance), pleasant social conditions (13% variance), reward (7% variance), social interaction and boredom (41%) social acceptance (14% variance), and medication side effects (9% variance). An exploratory cluster analysis aimed at identifying sub-groups with distinctive patterns of motivations for use. Scores within clusters varied, with the membership of one cluster scoring highly on all factor items while other cluster members scored low on several items, clearly influencing their motivations for use. This exploratory analysis gives some indication that there are a number of distinctive patterns of use, including people who use in a wide range of situations with a variety of motivations, those who primarily use for relief of unpleasant feelings and social anxiety, and those whose use is predominantly social.;Conclusions: Substance misuse is a common problem in users of adult mental health services, and innovative solutions to understand and address these problems are needed. Although it was uncommon for individuals to directly medicate the symptoms of their illness with substances, their motivations for use reflected a range of social difficulties, isolation and other affective problems. Further investigation of demographic variables and substance use motivations in a larger sample may be an effective way of delineating sub groups with distinct motivations and of developing treatment strategies which take these motivations into account

Cell–cell Interaction Underlies Formation of Fluid in the Male Reproductive Tract of the Rat

The epithelia lining the epididymides of many species consists of several cell types. We have provided evidence that the basal cells are essential to the integrated functions of the epithelium. Basal cells, but not principal cells, and other cells in the epididymis express TRPC3 and COX-1. We have isolated basal cells from intact rat epididymis using antibody-coated Dynabeads and subjected them to whole-cell patch-clamp measurement of nonselective cation channel activity, a feature of TRPC3 protein, and Fluo-3 fluorescence measurement of intracellular Ca2+ concentration. The results show that a nonselective cation current blockable by La3+ (0.1 mM), Gd3+ (0.1 mM), or SKF96365 (20 μM) could be activated by lysylbradykinin (200 nM). In cells loaded with Fluo-3, addition of lysylbradykinin (100 nM) caused a sustained increase of intracellular Ca2+. This effect was blocked by Gd3+ (0.1 mM) or SKF96365 (20 μM) and was not observed in Fluo-3–loaded principal cells. Stimulation of basal cell/principal cell cocultures with lysylbradykinin (200 nM) evoked in principal cells a current with CFTR-Cl− channel characteristics. Isolated principal cells in the absence of basal cells did not respond to lysylbradykinin but responded to PGE2 (100 nM) with activation of a CFTR-like current. Basal cells, but not principal cells, released prostaglandin E2 when stimulated with lysylbradykinin (100 nM). The release was blocked by SKF96365 (20 μM) and BAPTA-AM (0.05 or 0.1 mM). Confluent cell monolayers harvested from a mixture of disaggregated principal cells and basal cells responded to lysylbradykinin (100 nM) and PGE2 (500 nM) with an increase in electrogenic anion secretion. The former response was dependent on prostaglandin synthesis as piroxicam blocked the response. However, cell cultures obtained from principal cells alone responded to PGE2 but not to bradykinin. These results support the notion that basal cells regulate principal cells through a Ca2+ and COX signaling pathway

Identifying the Alteration Patterns of Brain Functional Connectivity in Progressive Mild Cognitive Impairment Patients: A Longitudinal Whole-Brain Voxel-Wise Degree Analysis

Patients with mild cognitive impairment (MCI) are at high risk for developing Alzheimer’s disease (AD), while some of them may remain stable over decades. The underlying mechanism is still not fully understood. In this study, we aimed to explore the connectivity differences between progressive MCI (PMCI) and stable MCI (SMCI) individuals on a whole-brain scale and on a voxel-wise basis, and we also aimed to reveal the differential dynamic alternation patterns between these two disease subtypes. The resting-state functional magnetic resonance images of PMCI and SMCI patients at baseline and year-one were obtained from the Alzheimer’s Disease Neuroimaging Initiative dataset, and the progression was determined based on a three-year follow-up. A whole-brain voxel-wise degree map that was calculated based on graph-theory was constructed for each subject, and then the cross-sectional and longitudinal analyses on the degree maps were performed between PMCI and SMCI patients. In longitudinal analyses, compared with SMCI group, PMCI group showed decreased long-range degree in the left middle occipital/supramarginal gyrus, while the short-range degree was increased in the left supplementary motor area and middle frontal gyrus and decreased in the right middle temporal pole. A significant longitudinal alteration of decreased short-range degree in the right middle occipital was found in PMCI group. Taken together with previous evidence, our current findings may suggest that PMCI, compared with SMCI, might be a severe presentation of disease along the AD continuum, and the rapidly reduced degree in the right middle occipital gyrus may have indicative value for the disease progression. Moreover, the cross-sectional comparison results and corresponding receiver-operator characteristic-curves analyses may indicate that the baseline degree difference is not a good predictor of disease progression in MCI patients. Overall, these findings may provide objective evidence and an indicator to characterize the progression-related brain connectivity changes in MCI patients

Evaluation of pre-analytical factors affecting plasma DNA analysis.

Pre-analytical factors can significantly affect circulating cell-free DNA (cfDNA) analysis. However, there are few robust methods to rapidly assess sample quality and the impact of pre-analytical processing. To address this gap and to evaluate effects of DNA extraction methods and blood collection tubes on cfDNA yield and fragment size, we developed a multiplexed droplet digital PCR (ddPCR) assay with 5 short and 4 long amplicons targeting single copy genomic loci. Using this assay, we compared 7 cfDNA extraction kits and found cfDNA yield and fragment size vary significantly. We also compared 3 blood collection protocols using plasma samples from 23 healthy volunteers (EDTA tubes processed within 1 hour and Cell-free DNA Blood Collection Tubes processed within 24 and 72 hours) and found no significant differences in cfDNA yield, fragment size and background noise between these protocols. In 219 clinical samples, cfDNA fragments were shorter in plasma samples processed immediately after venipuncture compared to archived samples, suggesting contribution of background DNA by lysed peripheral blood cells. In summary, we have described a multiplexed ddPCR assay to assess quality of cfDNA samples prior to downstream molecular analyses and we have evaluated potential sources of pre-analytical variation in cfDNA studies

Evaluation of a village-based digital health kiosks program: A protocol for a cluster randomized clinical trial

Background To address disparities in healthcare quality and access between rural and urban areas in China, reforms emphasize strengthening primary care and digital health utilization. Yet, evidence on digital health approaches in rural areas is lacking. Objective This study will evaluate the effectiveness of Guangdong Second Provincial General Hospital's Digital Health Kiosk program, which uses the Dingbei telemedicine platform to connect rural clinicians to physicians in upper-level health facilities and provide access to artificial intelligence-enabled diagnostic support. We hypothesize that our interventions will increase healthcare utilization and patient satisfaction, decrease out-of-pocket costs, and improve health outcomes. Methods This cluster randomized control trial will enroll clinics according to a partial factorial design. Clinics will be randomized to either a control arm with clinician medical training, a second arm additionally receiving Dingbei telemedicine training, or a third arm with monetary incentives for patient visits conducted through Dingbei plus all prior interventions. Clinics in the second and third arm will then be orthogonally randomized to a social marketing arm that targets villager awareness of the kiosk program. We will use surveys and Dingbei administrative data to evaluate clinic utilization, revenue, and clinician competency, as well as patient satisfaction and expenses. Results We have received ethical approval from Guangdong Second Provincial General Hospital (IRB approval number: GD2H-KY IRB-AF-SC.07-01.1), Peking University (IRB00001052-21007), and the University of North Carolina at Chapel Hill (323385). Study enrollment began April 2022. Conclusions This study has the potential to inform future telemedicine approaches and assess telemedicine as a method to address disparities in healthcare access. Trial registration number: ChiCTR210005387