tbuckley/cabot-search huggingface dataset:
Deciphering the genesis and fate of amyloid β-protein yields novel therapies for Alzheimer disease
Authors: Dennis J. Selkoe
Journal: Journal of Clinical Investigation (2002)

The biogenesis of AβWhen APP was first cloned, the 40-and 42-residue Aβ peptides were found to comprise the last 28 amino acids of its large, N-terminal ectodomain plus the first 12 or 14 residues of its single transmembrane (TM) domain (Figure 1).This location predicted that the proteolytic cleavage creating the C-terminus of Aβ required some previous disruption of the membrane to allow access by the responsible protease (dubbed γ-secretase) into the phospholipid bilayer.It was therefore widely assumed that Aβ production was not a primary event in AD but rather followed neuronal membrane injury.The subsequent discovery that both Aβ1-40 and Aβ1-42 peptides are constitutive products of cellular metabolism and occur in normal biological fluids throughout life disproved this notion (reviewed in ref.3).The normal scission of APP near the middle of its TM domain to create Aβ provided an initial example of the mechanism that came to be recognized as regulated intramembrane proteolysis (4).The unusual protease that effects this cleavage will be discussed below.APP is a type 1 membrane glycoprotein that undergoes N-and O-linked glycosylation during its trafficking through the secretory pathway.At steady state, a small subset of APP molecules is found on the plasma membrane, and these can undergo ectodomain shedding by a proteolytic activity called α-secretase (Figure 1).The disintegrin metalloproteinases ADAM 10 and ADAM 17 can serve as α-secretases for APP (5,6).The 83-residue C-terminal fragment (C83) retained in the membrane can then undergo constitutive cleavage by γ-secretase to release the p3 peptide (residues 17-40/42
Macrophage plasticity and polarization in liver homeostasis and pathology
Authors: Antonio Sica, Pietro Invernizzi, Alberto Mantovani
Journal: Hepatology (2013)

Resident and recruited macrophages are key players in the homeostatic function of the liver and in its response to tissue damage. In response to environmental signals, macrophages undergo polarized activation to M1 or M2 or M2-like activation states. These are extremes of a spectrum in a universe of activation states. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of mononuclear phagocytes. Resident and recruited macrophages are a key component of diverse homeostatic and pathological responses of hepatic tissue. Polarized macrophages interact with hepatic progenitor cells, integrate metabolic adaptation, mediate responses to infectious agents, orchestrate fibrosis in a yin-yang interaction with hepatic stellate cells, and are a key component of tumor-promoting inflammation. A better understanding of macrophage diversity and plasticity in liver homeostasis and pathology may pave the way to innovative diagnostic and therapeutic approaches.
Inpatient management of acute COPD: a cause for concern?
Authors: M Rudolf
Journal: Thorax (2003)

Inpatient mortality rates for patients with COPD vary with the type of hospital

British guidelines for the management of chronic obstructive pulmonary disease (COPD) were first published in 1997.1 Over the subsequent 6 years there has been an enormous increase in our understanding of the underlying causes and mechanisms of acute exacerbations of COPD,2–4 as well as the realisation that, in addition to being a major cause of morbidity and mortality, acute exacerbations place an enormous burden on healthcare resources.

COPD is the third largest cause of respiratory death in the UK after pneumonia and cancer, causing over 30 000 deaths per year. Age adjusted emergency admission rates for COPD in the UK rose by more than 50% between 1991 and 2000, and about one quarter of all hospital inpatient bed days used for treating acute respiratory disease are for COPD,5 amounting to nearly one million hospital bed days per year.6

With such a significant proportion of inpatient resources being consumed by acute exacerbations of COPD, understanding how well and effectively they are managed in hospital becomes a matter of much more than academic interest. In order to obtain information …
Functional constraints against variations on molecules from the tissue level: slowly evolving brain-specific genes demonstrated by protein kinase and immunoglobulin supergene families.
Authors: K. Kuma, N. Iwabe, T. Miyata
Journal: Molecular Biology and Evolution (1995)

In the protein kinase family, the basic function of kinase domain is similar among members. According to the standard view of functional constraint, the molecular evolutionary rate depends on functional and structural features characteristic of individual molecules (local constraint). Thus the evolutionary rate of the kinase domain is expected to be similar for different members. Contrary to this expectation, a comparison of the evolutionary rates revealed a wide difference among members; it amounts to about 100 times difference between the maximum and minimum rates. A similar result was also found in members of the immunoglobulin (Ig) family. In addition, significant correlations in evolutionary rate were observed between the kinase domain and the Ig-like domain in the receptor protein tyrosine kinases and between the kinase domain and the SH domain in the nonreceptor-type kinases. Furthermore, the evolutionary rates of family members that are expressed tissue specifically differ widely, depending on their tissue distribution: members expressed in the brain evolve with significantly slower rates than those expressed in the immune system. These results strongly suggest the presence of an alternative constraint (global constraint) against changes on molecules derived from higher levels like tissues or organs.
The new BTS/SIGN asthma guidelines: where evidence leads the way
Authors: B G Higgins
Journal: Thorax (2003)

Announcing the publication of the new BTS/SIGN asthma guidelines as a supplement to this issue of Thorax .

It is 12 years since the first British guidelines on asthma management in adults were published as two papers in the BMJ .1,2 The British Thoracic Society (BTS) guidelines were rewritten in 19933 with additional advice on childhood asthma, and further updated in 1995.4 Elsewhere, the Scottish Intercollegiate Guidelines Network (SIGN) published their guideline on the hospital management of asthma in 19965 based on the BTS work, and subsequently published on the primary care management of asthma in 19986 and the management of acute asthma in 1999.7 While the BTS versions have been among the most widely implemented of all clinical guidelines, there has been an increasing need to update them using evidence-based methodology and covering all aspects of asthma care. With this issue of Thorax the new British guidelines on the management of asthma8 produced jointly by the BTS and SIGN are published in a separate supplement. The development process has involved individuals from all relevant professional groups involved in asthma care in the UK. Initial literature searches based on key questions produced over 15 000 abstracts and all relevant published papers up to the end of September 2001 were considered. What changes has this evidence-based review brought?

For those familiar with the previous guideline, the striking features will be the change in style and the increased size of the new version. The design will be more familiar to those working in Scotland since it follows the basic pattern of all SIGN publications. It is important—and hopefully interesting—for readers to be able to link the recommendations in the guideline to the supporting evidence, and the format of the guidelines follows naturally from this. …
Fecundity and Twinning Rates as Measures of Fertility Before Diagnosis of Germ-Cell Testicular Cancer
Authors: L. Richiardi, O. Akre, S. M. Montgomery, M. Lambe, U. Kvist, A. Ekbom
Journal: JNCI Journal of the National Cancer Institute (2004)

Previous studies have suggested an association between subfertility and testicular cancer by using fecundity and semen characteristics to measure fertility. The occurrence of twinning in offspring may be used to investigate male reproductive health, because dizygotic twinning is reduced by male subfertility. We therefore assessed number of children and offspring twinning rates among 4592 Swedish patients with testicular cancer and 12 254 control subjects. Before diagnosis, case patients had a decreased number of children (for testicular cancer, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.62 to 0.81; at least three children compared with no children), with a lower frequency of dizygotic twinning (for unlike-sex twins, OR for the father having testicular cancer = 0.49, 95% CI = 0.22 to 1.08). The ratio of unlike-sex to same-sex twins was 0.22 among children of case patients and 0.66 among children of control subjects (adjusted P =.03, two-sided Wald test). We also found an increased occurrence of twinning after diagnosis, probably attributable to treatment for iatrogenic subfertility. Our study strongly supports evidence of an association between subfertility and the subsequent risk for testicular cancer.
Angiogenesis as a strategic target for prostate cancer therapy
Authors: Yong Li, Paul J. Cozzi
Journal: Medicinal Research Reviews (2009)

Abstract It is becoming increasingly clear that angiogenesis plays a crucial role in prostate cancer (CaP) survival, progression, and metastasis. Tumor angiogenesis is a hallmark of advanced cancers and an attractive treatment target in multiple solid tumors. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy in CaP, the rational design of targeted therapeutics is possible. This review summarizes the recent advancements that have improved our understanding of the role of angiogenesis in CaP metastasis and the potential therapeutic efficacy of inhibiting angiogenesis in this disease. Current therapeutic options for patients with metastatic hormone‐refractory CaP are very limited. Targeting vasculature is a developing area, which shows promise for the control of late stage and recurrent CaP disease and for overcoming drug resistance. We discuss angiogenesis and its postulated mechanisms and focus on the regulation of angiogenesis in CaP progression and the therapeutic beneficial effects associated with targeting of the CaP vasculature to overcome the resistance to current treatments and CaP recurrence. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 1, 23–66, 2010
Biochemical differentiation in bile duct cestodes and their marsupial hosts.
Authors: P R Baverstock, M Adams, I Beveridge
Journal: Molecular Biology and Evolution (1985)

Isozyme electrophoresis was used to assess possible cospeciation of parasites (cestodes of the Progamotaenia festiva complex) and their hosts (Australian diprotodont marsupials) and to compare the extent of interspecific genetic diversity of the parasites and their hosts. On the basis of morphology, there are three species in the complex, although electrophoresis revealed 14 distinct genetic types, most of which were host specific, although there were three cases of apparent host switching. The evolutionary relationships among the parasites were only partially concordant with those among the hosts. Moreover, the extent of electrophoretic diversity among the parasites was much higher than that among hosts.
An Isolated Cardiac Conduction Disease Maps to Chromosome 19q
Authors: Anne de Meeus, Edouard Stephan, Sophie Debrus, Marie-Kamala Jean, Jacques Loiselet, Jean Weissenbach, Jacques Demaille, Patrice Bouvagnet
Journal: Circulation Research (1995)

Isolated cardiac conduction disease is an autosomal dominant defect that includes various combinations of bundle branch or fascicular blocks. These defects can cause sudden death due to a complete heart block. We used a genome-wide screening approach with polymorphic (CA)n repeat markers to determine the chromosomal position of the gene defect implicated in this disorder. The analyses were carried out on a large Lebanese kindred, which included individuals with either a complete or incomplete right bundle branch block (RBBB) with a vertical-axis deviation (< or = -30 or > or = +100). Linkage to the disease locus was detected with the polymorphic marker D19S604 on the q arm of chromosome 19 (19q13.3) with a multipoint lod score of 7.18. Additionally, we were able to exclude the flanking loci D19S606 and D19S571, which are 13 cM apart because of recombination events in three affected individuals. The histidine-rich calcium-binding protein gene is found in this region and is an attractive candidate gene on the basis of its physiological properties and a tight linkage. There is no expansion in two exon 1 regions known for a variable number of triplet repeats.
The prevention of catastrophic head and spine injuries in high school and college sports
Authors: R C Cantu, F O Mueller
Journal: British Journal of Sports Medicine (2009)

The incidence of catastrophic injuries in sports at the high school and college levels is low, <0.5 per 100 000 participants, but even one is too many.1 Permanent paralysis, brain damage and death should not be associated with teenagers and young adults participating in high school and college athletics. Catastrophic injury is devastating not only to the injured athlete, but also to the athlete’s family, school and community.

Many of these injuries can be prevented by utilising proper data collection and proper medical care and safety precautions such as implementing safer rules, proper conditioning and coaching techniques.

While there are some sports with a higher incidence of catastrophic injury than others, there are also some sports with higher injury rates per 100 000 participants. For example, American football has the greatest number of catastrophic injuries, but it also has the greatest number of participants. Gymnastics, ice hockey, and cheerleading have higher rates per 100 000 participants than American football, but fewer participants and thus fewer total injuries. Table 1 gives the participation numbers for high school and college sports from the autumn of 1982 to the spring of 2008, and table 2 gives the injury rates per 100 000 participants.

View this table:

Table 1 
Participation figures for 1982–3 and 2007–8



View this table:

Table 2 
Direct injuries per 100 000 participants



Emphasis should be placed on the fact that no matter how low the incidence levels or rates per number of participants are, an increased effort should be placed on prevention of catastrophic injuries.

The collection of American football death data began in 1931, when the American Football Coaches Association initiated the first Annual Survey of Football Fatalities.2 The research has been carried out on a national level every year except for 1942 and has been conducted at the University of North Carolina, Chapel Hill since 1965. The title of the survey …
Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons
Authors: Qiuli Liang, Xiaosen Ouyang, Lonnie Schneider, Jianhua Zhang
Journal: Molecular Neurodegeneration (2011)

Huntington's disease is caused by aggregation of mutant huntingtin (mHtt) protein containing more than a 36 polyQ repeat. Upregulation of macroautophagy was suggested as a neuroprotective strategy to degrade mutant huntingtin. However, macroautophagy initiation has been shown to be highly efficient in neurons whereas lysosomal activities are rate limiting. The role of the lysosomal and other proteases in Huntington is not clear. Some studies suggest that certain protease activities may contribute to toxicity whereas others are consistent with protection. These discrepancies may be due to a number of mechanisms including distinct effects of the specific intermediate digestion products of mutant huntingtin generated by different proteases. These observations suggested a critical need to investigate the consequence of upregulation of individual lysosomal enzyme in mutant huntingtin accumulation and toxicity.In this study, we used molecular approaches to enhance lysosomal protease activities and examined their effects on mutant huntingtin level and toxicity. We found that enhanced expression of lysosomal cathepsins D and B resulted in their increased enzymatic activities and reduced both full-length and fragmented huntingtin in transfected HEK cells. Furthermore, enhanced expression of cathepsin D or B protected against mutant huntingtin toxicity in primary neurons, and their neuroprotection is dependent on macroautophagy.These observations demonstrate a neuroprotective effect of enhancing lysosomal cathepsins in reducing mutant huntingtin level and toxicity in transfected cells. They highlight the potential importance of neuroprotection mediated by cathepsin D or B through macroautophagy.
Block grants. New federalism or hot potatoes?
Authors: F. R. Woolley
Journal: JAMA (1982)

PASSAGE of the Omnibus Reconciliation Act (OBRA) of 1981 may have the most far-reaching impact on health care provision and consumption in this country of any legislation since the Medicare and Medicaid amendments to the Social Security Act. Intending to transfer federal funds directly to states for distribution and control, the OBRA included nine block grants, four of which relate directly to the provision of health care. These grants consolidate 22 existing programs and provide for at least a 25% reduction in program funding. The general areas for these new block grants include (1) maternal and child health; (2) alcohol and drug abuse and mental health; (3) primary care, which includes The Community Health Services program; and (4) preventive health and health services.  The potential impact of block grants is directly proportional to the extent to which the federal government has influenced both the supply and demand for health care
Ventricular arrhythmias associated with long-term endurance sports: what is the evidence?
Authors: Hein Heidbuchel, David L Prior, André La Gerche
Journal: British Journal of Sports Medicine (2012)

Athletic performance tests the limits of the human body and mind. Awe-inspiring achievements is what makes sports so fascinating. It is well appreciated however that top-level sports may sometimes overtax the body, and can lead to injuries, most notably of musculo-skeletal nature. This paper defends the thesis that the heart can also develop sports injuries at the ventricular level. We will elaborate on our hypothesis, originally put forward in 2003, that intense endurance activities put a particularly high strain on the right ventricle (RV), which over time, may lead to a proarrhythmic state resembling right (or less often) left ventricular cardiomyopathy. This can develop even in the absence of underlying demonstrable genetic abnormalities, probably just as a result of excessive RV wall stress during exercise. The syndrome of 'exercise-induced arrhythmogenic RV cardiomyopathy' may easily be overlooked. Sports cardiologists, like orthopaedic specialists, should be prepared to realise that excessive sports activity can lead to cardiac sports injuries in some, which will help to council on safe participation in all.
Cell-Biologic and Functional Analyses of Five New Aquaporin-2 Missense Mutations that Cause Recessive Nephrogenic Diabetes Insipidus
Authors: Nannette Marr, Daniel G. Bichet, Susan Hoefs, Paul J. M. Savelkoul, Irene B. M. Konings, Fabrizio de Mattia, Michael P. J. Graat, Marie-Franc[COMBINING CEDILLA]oise Arthus, Michele Lonergan, T. Mary Fujiwara, Nine V. A. M. Knoers, Daniel Landau, William J. Balfe, Alexander Oksche, Walter Rosenthal, Dominik Müller, Carel H. van Os, Peter M. T. Deen
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Mutations in the Aquaporin-2 gene, which encodes a renal water channel, have been shown to cause autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Most AQP2 missense mutants in recessive NDI are retained in the endoplasmic reticulum (ER), but AQP2-T125M and AQP2-G175R were reported to be nonfunctional channels unimpaired in their routing to the plasma membrane. In five families, seven novel AQP2 gene mutations were identified and their cell-biologic basis for causing recessive NDI was analyzed. The patients in four families were homozygous for mutations, encoding AQP2-L28P, AQP2-A47V, AQP2-V71M, or AQP2-P185A. Expression in oocytes revealed that all these mutants, and also AQP2-T125M and AQP2-G175R, conferred a reduced water permeability compared with wt-AQP2, which was due to ER retardation. The patient in the fifth family had a G>A nucleotide substitution in the splice donor site of one allele that results in an out-of-frame protein. The other allele has a nucleotide deletion (c652delC) and a missense mutation (V194I). The routing and function of AQP2-V194I in oocytes was not different from wt-AQP2; it was therefore concluded that c652delC, which leads to an out-of-frame protein, is the NDI-causing mutation of the second allele. This study indicates that misfolding and ER retention is the main, and possibly only, cell-biologic basis for recessive NDI caused by missense AQP2 proteins. In addition, the reduced single channel water permeability of AQP2-A47V (40%) and AQP2-T125M (25%) might become of therapeutic value when chemical chaperones can be found that restore their routing to the plasma membrane.
Smoking, Use of Moist Snuff, and Risk of Chronic Inflammatory Diseases
Authors: Cecilia Carlens, Maria-Pia Hergens, Johan Grunewald, Anders Ekbom, Anders Eklund, Caroline Olgart Höglund, Johan Askling
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Cigarette smoking is emerging as a strong risk factor in the otherwise unknown etiology of chronic inflammatory diseases. Whether the same applies also to smokeless tobacco remains unknown. Nicotine is a powerful modifier of the inflammatory response. By comparing risks associated with tobacco smoking and with smokeless tobacco, the role of nicotine in the development of chronic inflammation may be evaluated.To assess and compare the risks of rheumatoid arthritis (RA), ulcerative colitis (UC), Crohn's disease (CD), sarcoidosis, and multiple sclerosis (MS) associated with cigarette smoking and with the use of Swedish moist snuff.We performed a cohort study of 277,777 males within a cohort of Swedish construction workers who had provided information about tobacco use in 1978-1993. Cross-linkage to the nationwide Swedish Hospital Discharge Register provided information about the occurrence of RA, UC, CD, sarcoidosis, and MS through 2004.Age-adjusted relative risks (RRs) associated with smoking and moist snuff, respectively, were estimated by Cox regression. Ever-smoking was associated with an increased risk for RA (RR, 2.1; 95% confidence interval [CI], 1.7-2.5), CD (RR, 1.5; 95% CI, 1.2-1.8), MS (RR, 1.9; 95% CI, 1.4-2.6), and UC (RR, 1.3; 95% CI, 1.1-1.5, confined to ex-smokers), and a decreased risk of sarcoidosis (RR, 0.5; 95% CI, 0.4-0.5). By contrast, ever-use of moist snuff, adjusted for smoking, was not associated with RA (RR, 1.0; 95% CI, 0.9-1.2), UC (RR, 1.1; 95% CI, 0.9-1.2), CD (RR, 0.9; 95% CI, 0.8-1.1), sarcoidosis (RR, 1.1; 95% CI, 0.8-1.5), or MS (RR, 1.0; 95% CI, 0.8-1.4).Smokeless tobacco does not increase the risk of chronic inflammatory diseases, suggesting that inhaled nonnicotinic components of cigarette smoke are more important than nicotine itself in the etiology of these diseases.