Miracle-dz/UniFAR-FTUs huggingface dataset:
Defining Disease Modifying Therapy for Alzheimer's Disease.

BACKGROUND Disease-modifying therapies (DMTs) are urgently needed to treat the growing number of individuals with Alzheimer's disease (AD) or at immanent risk for AD. A definition of DMT is required to facilitate the process of DMT drug development. PROCESS This is a review of the state of the science with regard to definition and development of DMTs. RESULTS A DMT is as an intervention that produces an enduring change in the clinical progression of AD by interfering in the underlying pathophysiological mechanisms of the disease process that lead to cell death. Demonstration of DMT efficacy is garnered through clinical trial designs and biomarkers. Evidence of disease modification in the drug development process is based on trial designs such as staggered start and delayed withdrawal showing an enduring effect on disease course or on combined clinical outcomes and correlated biomarker evidence of an effect on the underlying pathophysiological processes of the disease. Analytic approaches such as showing change in slope of cognitive decline, increasing drug-placebo difference over time, and delay of disease milestones are not conclusive by themselves but support the presence of a disease modifying effect. Neuroprotection is a related concept whose demonstration depends on substantiating disease modification. No single type of evidence in itself is sufficient to prove disease modification - consistency, robustness, and variety of sources of data will all contribute to convincing stakeholders that an agent is a DMT. CONCLUSION DMT is defined by its enduring effect on processes leading to cell death. A variety of types of data can be used to support the hypothesis that disease modification has occurred.
Up‐regulation of prostaglandin biosynthesis by leukotriene C4 in elicited mice peritoneal macrophages activated with lipopolysaccharide/interferon‐γ

Leukotrienes (LT) and prostaglandins (PG) are proinflammatory mediators generated by the conversion of arachidonic acid via 5‐lipoxygenase (5‐LO) and cyclooxygenase (COX) pathways. It has long been proposed that the inhibition of the 5‐LO could enhance the COX pathway leading to an increased PG generation. We have found that in in vitro models of inflammation, such as mice‐elicited peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon‐γ (IFN‐γ), the deletion of the gene encoding for 5‐LO or the enzyme activity inhibition corresponded to a negative modulation of the COX pathway. Moreover, exogenously added LTC4, but not LTD4, LTE4, and LTB4, was able to increase PG production in stimulated cells from 5‐LO wild‐type and knockout mice. LTC4 was not able to induce COX‐2 expression by itself but rather potentiated the action of LPS/IFN‐γ through the extracellular signal‐regulated kinase‐1/2 activation, as demonstrated by the use of a specific mitogen‐activated protein kinase (MAPK) kinase inhibitor. The LT‐induced increase in PG generation, as well as MAPK activation, was dependent by a specific ligand‐receptor interaction, as demonstrated by the use of a cys‐LT1 receptor antagonist, although also a direct action of the antagonist used, on PG generation, cannot be excluded. Thus, the balance between COX and 5‐LO metabolites could be of great importance in controlling macrophage functions and consequently, inflammation and tumor promotion.
Switching control algorithm for sensor scheduling

Recently a great deal of attention has been given to the subject of wireless sensor networks (WSNs). In WSNs, networked sensor systems are spatially distributed and measurements are influenced by sensor noise. Sensor scheduling is required to achieve power saving since each sensor operates with a battery power source. In this paper, a sensor scheduling algorithm for a class of discrete-time WSNs based on switching logic of "the switching controller design strategy" is proposed. We select the hysteresis switching as Logical switching (LS).
Acute bacterial gastroenteritis: a study of adult patients with positive stool cultures treated in the emergency department

Objectives: To investigate the presenting clinical features of acute bacterial gastroenteritis in adult patients treated as outpatients in the emergency department (ED), and the pathogens responsible in this setting and population; and to identify the frequency with which positive stool culture result changes management. Method: This was a retrospective study of all patients who attended the accident and emergency department of an university affiliated hospital in Hong Kong over a 12 month period, who satisfied the following inclusion criteria: (a) age ⩾16, (b) presented with acute gastroenteritis, (c) treated as outpatients with or without observation, and (d) had positive stool cultures. Results: One hundred and thirty patients were included. Pathogens identified were Vibrio parahaemolyticus (42.3%), Samonella spp (34.6%), Plesiomonas spp (9.2%), Campylobacter spp (6.9%), Aeromonas spp (6.9%), and Shigella spp (6.2%). Mean highest body temperature was 37.5°C (95% confidence intervals (CI) 37.3 to 37.6). Bloody diarrhoea was present in 14 patients (10.8%). Mean duration of diarrhoea, from onset to the completion of stay in ED, was 2.2 days (95% CI 1.7 to 2.7). Likewise, mean duration of abdominal pain was 1.8 days (95% CI 1.5 to 2.1). Mean number of unformed stools per day was 9.3 (95% CI 8.3 to 10.3). Change of management, subsequent to the availability of positive stool culture results, was not required in 115 (88.5%) patients. Ciprofloxacin resistance occurred in eight (6.2%) cases, and seven of nine campylobacter isolates. Campylobacter positive patients had a significantly longer duration of abdominal pain (p=0.0236) and were less likely to be dehydrated (p=0.0103). Conclusions: Most patients with bacterial gastroenteritis do not present with high fever, bloody diarrhoea, or persistent diarrhoea, but generally have quite severe diarrhoea. Stool cultures do not change management for most patients. Vibrio parahaemolyticus is the commonest bacterial pathogen identified.
Randomized, Controlled Trial of a Prenatal and Postnatal Lactation Consultant Intervention on Duration and Intensity of Breastfeeding up to 12 Months

Objective. To determine whether an individualized, prenatal and postnatal, lactation consultant intervention resulted in increased cumulative intensity of breastfeeding up to 52 weeks. Design. The randomized, nonblinded, controlled trial recruited women from prenatal care. Baseline prenatal interviews covered demographic data and breastfeeding experience, intention, and knowledge. Interviews at 1, 2, 3, 4, 6, 8, 10, and 12 months after birth collected data on weekly feeding patterns, infant illness, and infant health care use. Setting. Two community health centers serving low-income, primarily Hispanic and/or black women. Participants. The analytic sample included 304 women (intervention: n = 145; control: n = 159) with ≥1 postnatal interview. Intervention. Study lactation consultants attempted 2 prenatal meetings, a postpartum hospital visit, and/or home visits and telephone calls. Control subjects received the standard of care. Outcome Measures. Cumulative breastfeeding intensity at 13 and 52 weeks, based on self-reports of weekly feeding, on a 7-level scale. Results. The intervention group was more likely to breastfeed through week 20 (53.0% vs 39.3%). Exclusive breastfeeding rates were low and did not differ according to group. In multivariate analyses, control subjects had lower breastfeeding intensity at 13 weeks (odds ratio [OR]: 1.90; 95% confidence interval [CI]: 1.13–3.20) and 52 weeks (OR: 2.50; 95% CI: 1.48–4.21). US-born control subjects had lowest breastfeeding intensity at 13 weeks (OR: 5.22; 95% CI: 2.43–11.22) and 52 weeks (OR: 5.25; 95% CI: 2.44–11.29). There were no significant differences in breastfeeding intensity among the US-born intervention, foreign-born intervention, and foreign-born control groups. Conclusions. This “best-practices” intervention was effective in increasing breastfeeding duration and intensity. Breastfeeding promotion should focus on US-born women and exclusive breastfeeding.
The effectiveness of surgery for stress incontinence in women: a systematic review.

OBJECTIVE To determine the methodological quality of studies evaluating surgery for stress incontinence, the effectiveness of different procedures and the frequency of complications associated with each procedure. MATERIALS AND METHODS Eleven randomized controlled trials, 20 non-randomized trials/prospective cohort studies and 45 retrospective cohort studies were reviewed systematically. RESULTS The methodological quality of the 31 prospective studies was generally poor. The considerable variation in inclusion criteria, surgical management and assessment of outcome precluded any statistical meta-analysis. Evidence as to the effectiveness of surgery for stress incontinence is weak; therefore, any conclusions are speculative. It appears that colposuspension may be more effective and the effect more long-lasting than that following anterior colporrhaphy and needle suspension. There is little information on the value of sling procedures. Comparisons of different ways of performing each procedure show no significant differences in outcome but this may reflect the methodological weaknesses of the studies. Valid and reliable data on the frequency of complications following surgery are lacking so the safety of the procedures is unclear. Repeat operations to correct stress incontinence are less successful than first procedures but this finding may be subject to confounding. CONCLUSIONS There is an urgent need for some large, rigorous, prospective studies of high quality. Until such studies have been completed, recommendations as to the best clinical practice cannot be based on scientific evidence. Studies need to define cases according to widely accepted criteria, including standard measures of the severity of stress incontinence, and surgical terminology for the procedures performed needs to be standardized and outcomes need to be clearly defined, valid and reliable, not confined to short-term assessment and include patients' views along with the surgeon's assessments.
Mr Darwin's shooters: on natural selection and the naturalizing of genocide

Among Charles Darwin's first writings are reports on his encounters with indigenous peoples and the violence of European colonization. When he turned to evolution, the furore over mankind's place in natural history overshadowed the problem of how ‘natural selection’ might apply in human history. It was easy, in a nineteenth-century worldview, to see the disappearance of ‘savages’ as a ‘natural’ consequence of the advance of civilization. From a later perspective, colonialism often involved genocide, only belatedly recognized as such, even after the concept came into use. Barta's essay re-examines Darwin's efforts to comprehend the extinction of peoples as a phenomenon both natural and historical, and the implications of his attempt to combine the two. It begins with his first observations, and looks for evidence of their influence in the theory of natural selection. The problems of ‘natural’ selection in human history are then traced along the paradoxical paths Darwin opened up. It becomes plain that he had an unusually sharp perception of the historical relations of genocide—economic, social, political and cultural—but confused matters by trying to integrate colonialism into an evolutionary history of civilization analogous to natural history. Always fascinated by human intervention in nature, he was also attracted by the potential of eugenics, so that a legacy intended to be cautiously scientific fed into ideologies of conquest and human selection far removed from his measured theorizing and humane ethics.
p38 MAP Kinase Is Involved in Lipopolysaccharide‐Induced Dopaminergic Neuronal Cell Death in Rat Mesencephalic Neuron‐Glia Cultures

Abstract: Immune stimulants, such as the bacterial endotoxin, lipopolysaccharide (LPS), the human immunodeficiency virus‐1 coat protein gp120, or β‐amyloid peptides, lead to glial activation and production of various immune mediators, such as nitric oxide (NO) and proinflammatory cytokines in the brain. These mediators appear to contribute to neuronal cell death in neurodegenerative diseases. However, the signaling pathways, which mediate the neurotoxic effect by the endotoxin, are not understood. The purpose of this study was to determine the role of mitogen‐activated protein kinase (MAPK) in LPS‐induced neurodegeneration using mesencephalic dopaminergic neuron/glia cultures. We have found that the p38 MAPK is important in LPS‐induced death of mesencephalic neurons in rat neuron‐glia mixed cultures. Upon treatment with 10 ng/ml LPS, the number of dopaminergic neurons decreased by 80% within 48 h, preceded by a significant production of NO by glia. Neuroprotection by selective inhibition of p38 MAPK activity paralleled a decrease in LPS‐induced inducible nitric oxide synthase (iNOS) expression. These events were significantly reduced by the selective p38 MAPK inhibitor, SB202190, but not by the inactive analogue SB202474. Inhibition of iNOS activity and NO production by treatment with GW274150 was also neuroprotective. Although the p38 MAPK inhibitor afforded significant neuroprotection from LPS toxicity in the neuron‐glia mixed culture, it failed to protect dopaminergic neurons from 6‐hydroxy‐dopamine‐induced toxicity, which acts directly on dopaminergic neurons by inducing hydroxyl radical formation from the mitochondria. The results suggest that p38 MAPK in glia plays a significant role in the LPS‐induced death of mesencephalic neurons through induction of nitric oxide synthase and resulting NO production.
The 2012 Thomas Hunt Morgan Medal

The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Thomas Hunt Morgan Medal recognizes a lifetime contribution to the science of genetics. The Genetics Society of America Medal recognizes particularly outstanding contributions to the science of genetics over the past 31 years. The George W. Beadle Medal recognizes distinguished service to the field of genetics and the community of geneticists. The Elizabeth W. Jones Award for Excellence in Education recognizes individuals or groups who have had a significant, sustained impact on genetics education at any level, from kindergarten through graduate school and beyond. The Novitski Prize recognizes an extraordinary level of creativity and intellectual ingenuity in solving significant problems in biological research through the application of genetic methods. We are pleased to announce the 2012 awards.
Design and optimization of on‐chip capillary electrophoresis

We present a systematic, experimentally validated method of designing electrokinetic injections for on‐chip capillary electrophoresis applications. This method can be used to predict point‐wise and charge‐coupled device (CCD)‐imaged electropherograms using estimates of species mobilities, diffusivities and initial sample plug parameters. A simple Taylor dispersion model is used to characterize electrophoretic separations in terms of resolution and signal‐to‐noise ratio (SNR). Detection convolutions using Gaussian and Boxcar detector response functions are used to relate optimal conditions for resolution and signal as a function of relevant system parameters including electroosmotic mobility, sample injection length, detector length scale, and the length‐to‐detector. Analytical solutions show a tradeoff between signal‐to‐noise ratio and resolution with respect to dimensionless injection width and length to the detector. In contrast, there is no tradeoff with respect to the Peclet number as increases in Peclet number favor both SNR and separation solution (R). We validate our model with quantitative epifluorescence visualizations of electrophoretic separation experiments in a simple cross channel microchip. For the pure advection regime of dispersion, we use numerical simulations of the transient convective diffusion processes associated with electrokinetics together with an optimization algorithm to design a voltage control scheme which produces an injection plug that has minimal advective dispersion. We also validate this optimal injection scheme using fluorescence visualizations. These validations show that optimized voltage scheme produces injections with a standard deviation less than one‐fifth of the width of the microchannel.
Inter-Cell Interference Sub-Space Coordination for 5G Ultra-Dense Networks

In this paper, we present an inter-cell interference subspace coordination scheme for multiple-input multiple-output communications. The method relies on downlink precoding design for distributed multi-cell multi-user networks. In the proposed method, receivers benefit from minimum-mean square error structure. Each receiver separates the received signal space into desired/interference sub-spaces. The key idea in this contribution is to employ precoding algorithms at the transmission-end with the objective of jointly projecting transmitted signal over desired subspace and aligning most of the interference onto predefined interference subspaces at the interfered receiver end. This idea works with only local channel state information available at transmitter-side and benefits from low computational complexity. Simulation results show that the proposed method offers about 28\% throughput enhancements in networks with high dominant interference regimes.
Patterns of initial management of node-negative breast cancer in two Canadian provinces. British Columbia/Ontario Working Group.

OBJECTIVE To describe the patterns of initial management of node-negative breast cancer in Ontario and British Columbia and to compare the characteristics of the patients and tumours and of the physicians and hospitals involved in management. DESIGN Retrospective, population-based, cohort study. PARTICIPANTS All 942 newly diagnosed cases of node-negative breast cancer in 1991 in British Columbia and a random sample of 938 newly diagnosed cases in Ontario in the same year. OUTCOME MEASURES Number and proportion of patients with newly diagnosed node-negative breast cancer who received breast-conserving surgery (BCS) or mastectomy and who received radiation therapy after BCS. RESULTS BCS was used in 413 cases (43.8%) in British Columbia and in 634 cases (67.6%) in Ontario (p < 0.001). After BCS, radiation therapy was received by 378 patients (91.5% of those who had undergone BCS) in British Columbia and 479 patients (75.6% of those who had undergone BCS) in Ontario (p < 0.001). In both provinces, lower patient age, smaller tumour size, a noncentral unifocal tumour, absence of extensive ductal carcinoma in situ and initial surgery by a surgeon with an academic affiliation were associated with greater use of BCS. Lower patient age and larger tumour size were associated with greater use of radiation therapy after BCS in both provinces. CONCLUSION Patient, tumour and physician factors are associated with the choice of initial management of breast cancer in these two Canadian provinces. However, the differences in management between the two provinces are only partly explained by these factors. Other possible explanations, such as the presence of provincial guidelines, differences in the organization of the health care system or differences in patient preference, require further research.
Socio–economic and Behavioural Factors Related to Caries in Twelve–Year–Old Sardinian Children

Our aim was to describe socio–economic and behavioural factors related to caries experience in school children in Sassari, Sardinia (Italy). Four hundred and three 12–year–old schoolchildren were randomly selected and their teeth clinically examined after air drying, under standard light using a plain mirror and WHO community periodontal index for treatment needs (CPITN) ballpoint probe. The clinical DMFS index was recorded following a diagnostic threshold, CPITN following the WHO indications. A questionnaire concerning oral hygiene habits (OHH), the onset of toothbrushing habits (OTH), frequency of dental check–ups (DCU), sweet food and soft drink consumption and socio–economic background factors, i.e. parents'' occupational status (SOCFAM) and parents'' age, was filled in by children and parent(s)/guardian(s). The caries prevalence was 61.6%. A positive skewness of DMFS was observed. Regarding caries, a significant linear trend (p<0.05) was found among odds ratios at each exposure level in SOCFAM, OHH, OTH and CPITN. A logistic regression model for caries was constructed using related factors. CPITN (gingival conditions) gave a significant contribution in the predictive model (p = 0.01). Gender acted as an effect modifier on CPITN, so logistic regression models were constructed for males and females separately. CPITN was the only statistically significant covariate in males and OHH the only one in females. Our results confirm a high caries prevalence and also a need for preventive and educational programmes for caries in Sardinia.
RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis

Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species–and cell type‐specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107, and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer. J. Cell. Physiol. 228: 1676–1687, 2013. © 2013 Wiley Periodicals, Inc.