tbuckley/cabot-search huggingface dataset:
Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome
Authors: M G Dunlop
Journal: Gut (2002)

Within groups of patients with colorectal cancer who report a family history of cancer, it is possible to identify cases associated with defined genetic susceptibility syndromes. These syndromes account for a small, but appreciable, proportion of all cases of colorectal cancer and are characterised by very high absolute cancer risk. There is usually evidence of germline transmission of a dominant gene associated with bowel cancer susceptibility, but there is frequently an excess of other cancer types in the family. Genes responsible for these syndromes have been identified, although some families have been identified where linkage to all known genes has been formally excluded. Hence, it is likely that there are other dominant genes that have yet to be identified. This implies that at risk people can be identified in two ways; empirically on the basis of family history or clinical and pathological criteria, or by molecular analysis of the respective gene. Although there are other rare syndromes associated with colorectal cancer risk, in the interests of clarity this guideline is restricted to discussion of hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), juvenile polyposis (JP), and Peutz-Jeghers syndrome (PJS). The syndromes are defined and summarised in Online Inheritance in Man (OMIM), for which the OMIM ID numbers are given for each syndrome and the respective URL in the appendix.

The molecular aetiology for each of these syndromes is listed in appendix 1. It has been shown that some people who carry pathogenic mutations of one of the causative genes do not have a strong family history of colorectal cancer. Hence, it is essential to define people at risk either by family history that fulfils inclusion criteria or those carrying a mutation in the respective gene. Screening and surveillance issues for these families must be considered separately from that recommended …
Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.
Authors: A K Das, C H Becerra, W Yi, J Y Lu, A N Siakotos, K E Wisniewski, S L Hofmann
Journal: Journal of Clinical Investigation (1998)

Mutations in a newly described lysosomal enzyme, palmitoyl-protein thioesterase (PPT), were recently shown to be responsible for an autosomal recessive neurological disorder prevalent in Finland, infantile neuronal ceroid lipofuscinosis. The disease results in blindness, motor and cognitive deterioration, and seizures. Characteristic inclusion bodies (granular osmiophilic deposits [GROD]) are found in the brain and other tissues. The vast majority of Finnish cases are homozygous for a missense mutation (R122W) that severely affects PPT enzyme activity, and the clinical course in Finnish children is uniformly rapidly progressive and fatal. To define the clinical, biochemical, and molecular genetic characteristics of subjects with PPT deficiency in a broader population, we collected blood samples from U.S. and Canadian subjects representing 32 unrelated families with neuronal ceroid lipofuscinosis who had GROD documented morphologically. We measured PPT activity and screened the coding region of the PPT gene for mutations. In 29 of the families, PPT deficiency was found to be responsible for the neurodegenerative disorder, and mutations were identified in 57 out of 58 PPT alleles. One nonsense mutation (R151X) accounted for 40% of the alleles and was associated with severe disease in the homozygous state. A second mutation (T75P) accounted for 13% of the alleles and was associated with a late onset and protracted clinical course. A total of 19 different mutations were found, resulting in a broader spectrum of clinical presentations than previously seen in the Finnish population. Symptoms first appeared at ages ranging from 3 mo to 9 yr, and about half of the subjects have survived into the second or even third decades of life.
Common Estrogen Receptor Polymorphism Augments Effects of Hormone Replacement Therapy on E-Selectin but Not C-Reactive Protein
Authors: David M. Herrington, Timothy D. Howard, K. Bridget Brosnihan, Donald P. McDonnell, Xiaolin Li, Gregory A. Hawkins, David M. Reboussin, Jianfeng Xu, Siqun L. Zheng, Deborah A. Meyers, Eugene R. Bleecker
Journal: Circulation (2002)

Background — The estrogen receptor-α (ER-α) IVS1-401 polymorphism identifies a group of women (≈20%) who have augmented effects of hormone replacement therapy (HRT) on levels of HDL cholesterol. This study sought to determine if this augmentation extends to HRT regulation of E-selectin and C-reactive protein (CRP) and to explore possible mechanisms by which this polymorphism might influence estrogen action. Methods and Results — Serum levels of soluble E-selectin and CRP were measured at baseline and 1 year in 264 postmenopausal women randomized to treatment with oral conjugated equine estrogen (0.625 mg/d), estrogen plus progestin (medroxyprogesterone acetate 2.5 mg/d), or placebo. Women with the ER-α IVS1-401 C/C genotype receiving HRT had nearly a 2-fold greater reduction in E-selectin compared with C/T or T/T women ( P for interaction=0.02). In contrast, there was no augmentation of the HRT-associated increase in CRP among the C/C women compared with C/T or T/T women ( P for interaction=0.54). Of luciferase reporter constructs containing sequences spanning the IVS1-401 T/C polymorphism, expression of the construct containing the C allele was enhanced &gt;10-fold, with cotransfection of a constitutively expressed B-myb vector. In contrast, B-myb resulted in only a 2.5-fold increase in expression of the T allele construct. Conclusions — Women with the ER-α IVS1-401 C/C genotype have greater reductions in E-selectin but no further increases in CRP with HRT. The C allele produces a functional binding site for the transcription factor B-myb. The impact of this polymorphism on ER-α transcription and other estrogen-sensitive intermediate and clinical end points has not yet been established.
The Response of the US Centers for Disease Control and Prevention to the Obesity Epidemic
Authors: William H. Dietz
Journal: Annual Review of Public Health (2015)

The recognition of the obesity epidemic as a national problem began in 1999 with the Centers for Disease Control and Prevention's (CDC's) publication of a series of annual state-based maps that demonstrated the rapid changes in the prevalence of obesity. Increasing rates of obesity had been noted in earlier CDC studies, but the maps provided evidence of a rapid, nationwide increase. The urgent need to respond to the epidemic led to the identification of state targets and the first generation of interventions for obesity prevention and control. The CDC's role was to provide setting- and intervention-specific guidance on implementing these strategies, and to assess changes in targeted policies and behaviors. The CDC's efforts were augmented by Congressional funding for community initiatives to improve nutrition and increase physical activity. Complementary investments by Kaiser Permanente, the Robert Wood Johnson Foundation, and the Institute of Medicine improved the evidence base and provided policy recommendations that reinforced the need for a multisectoral approach. Legislative, regulatory, and voluntary initiatives enacted by President Obama's administration translated many of the strategies into effective practice. Whether current efforts to address obesity can be sustained will depend on whether they can be translated into greater grass-roots engagement consistent with a social movement.
A Small-Molecule Enhancer of Signal Transducer and Activator of Transcription 1 Transcriptional Activity Accentuates the Antiproliferative Effects of IFN-γ in Human Cancer Cells
Authors: Rebecca A. Lynch, Julia Etchin, Traci E. Battle, David A. Frank
Journal: Cancer Research (2007)

The transcription factor signal transducer and activator of transcription (STAT) 1 can mediate antiproliferative and proapoptotic effects in cancer cells, and a number of mechanisms have been found whereby STAT1 signaling is attenuated in tumors thereby increasing their malignant behavior. Thus, enhancing gene transcription mediated by STAT1 may be an effective approach to cancer therapy. A high-throughput screen was developed to identify molecules that could enhance STAT1-dependent gene expression. Through this approach, it was found that 2-(1,8-naphthyridin-2-yl)phenol (2-NP) caused a 2-fold increase in STAT1-dependent reporter gene expression compared with that seen with maximally effective concentrations of IFN-gamma alone. This effect was specific to STAT1 because 2-NP had no effect on unrelated transcription factors such as nuclear factor (NF) kappaB or the highly homologous transcription factor STAT3. STAT1-dependent gene activation was enhanced by this compound in a variety of human and murine cell lines and was independent of the stimulus used. Furthermore, 2-NP enhanced the expression of the bona fide endogenous STAT1 target gene interferon regulatory factor 1. 2-NP increased the duration of STAT1 tyrosine phosphorylation in response to IFN-gamma, and this may underlie its enhancement of STAT1-dependent transcription. Reflecting the fact that STAT1 can exert tumor-suppressive effects, 2-NP enhanced the ability of IFN-gamma to inhibit the proliferation of human breast cancer and fibrosarcoma cells. Tumor cells lacking STAT1 were unaffected by either IFN-gamma or 2-NP. These findings indicate that enhancement of STAT1 transcriptional activity may have utility in anticancer therapies, and that cell-based screens for modulators of transcription factor function can be a useful approach for drug discovery.
Leu 7<sup>+</sup>, Leu 11a<sup>−</sup> acute T‐lymphoblastic leukemia having low K cell activity and NO NK cell activity
Authors: Roberto P. Falcäo, Sebastiäo J. Ismael
Journal: American Journal of Hematology (1987)

The phenotypic and functional features of the leukemic blasts from a child with T-acute lymphoblastic leukemia (T-ALL) were studied. The leukemic cells lacked the usual markers of T-cell lineage (T3-, T11-, E-sheep-) although they displayed some T-lymphocyte markers (T6+, T8+, T9+, T10+) and were T gamma-. Furthermore, these cells had a strong reaction with anti-Leu 7 but were negative to anti-Leu 11a antibody and exhibited low K cell activity, no NK activity, and showed virtually no response to PHA. These leukemic cells probably represented the leukemic counterpart of the Leu 7+, Leu 11a- subset that has been demonstrated in the peripheral blood of normal individuals.
Arthritis development in germ free mice deficient for reactive oxygen species
Authors: Kajsa Wing, Annika Samuelsson, Sven Pettersson, Rikard Holmdahl
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The Ncf1 protein is a subunit of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase complex, which is responsible for producing the precursors of reactive oxygen species (ROS). ROS is mainly used to kill invading pathogens and a defect in the NADPH oxidase complex therefore leads to a diminished resistance to bacterial and fungal infections in humans, a disorder called chronic granulomatous disease. Interestingly, mice and rats with a mutated Ncf1 gene are more sensitive to arthritis induction compared to wild type littermates. However, Ncf1 mutant mice are also more prone to infections, which could affect arthritis incidence and severity. To dissect the immune regulatory role of ROS from its role in pathogen control, Ncf1 mutant mice were bred in germ free condition and investigated for collagen induced arthritis (CIA). <h3>Methods</h3> Ncf1 mutant mice and wild type controls both on B10Q background were bred in the germ free facility at Karolinska Institute. 10–14 week old mice were immunised with rat collagen type II (CII) emulsified in complete freunds adjuvant and boosted 35 days later (Stockholm ethical committee license number N66/10). At the end of the experiment mice were killd and investigated by histopathology and for T and B cell responses to CII. <h3>Results</h3> Naïve Ncf1 mutant mice did not have noticeable differences in the composition of leucocytes nor did they have signs of activation in lymph nodes and spleen as judged by flow cytometry. After CIA boost both male and female Ncf1 mutant mice developed arthritis with higher incidence compared to wild type controls. CII reactive T cells produced both interferon-γ and interleukin-17 in an enzyme-linked immunosorbent spot assay and titres of anti-CII antibodies were detected in the serum. <h3>Conclusion</h3> The arthritis susceptibility in ROS deficient mice is not dependant on persistent bacterial infections but occurs also in an aseptic environment. This indicates that ROS has an important immune regulatory role on T cell priming and/or the inflammatory response in the joint.
Kallidin- and Bradykinin-Degrading Pathways in Human Heart
Authors: Jorma O. Kokkonen, Antti Kuoppala, Juhani Saarinen, Ken A. Lindstedt, Petri T. Kovanen
Journal: Circulation (1999)

Background —Since kinins kallidin (KD) and bradykinin (BK) appear to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of kinin-degrading enzymes should potentiate such effects. Indeed, it is believed that this mechanism is partly responsible for the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. In the heart, enzymes other than ACE may contribute to local degradation of kinins. The purpose of this study was to investigate which enzymes are responsible for the degradation of KD and BK in human heart tissue. Methods and Results —Cardiac membranes were prepared from the left ventricles of normal (n=5) and failing (n=10) hearts. The patients had end-stage congestive heart failure as the result of coronary heart disease or idiopathic dilated cardiomyopathy. Heart tissue was incubated with KD or BK in the presence or absence of enzyme inhibitors. We found no difference in the enzymes responsible for kinin metabolism or their activities between normal and failing hearts. Thus KD was mostly converted into BK by the aminopeptidase M–like activity. When BK was used as substrate, it was converted into an inactive metabolite BK-(1-7) mostly (80% to 90%) by the neutral endopeptidase (NEP) activity, with ACE unexpectedly playing only a minor role. The low enzymatic activity of ACE in the cardiac membranes, compared with that of NEP, was not due to chronic ACE inhibitor therapy, because the cardiac ACE activities of patients, whether receiving ACE inhibitors or not, and of normal subjects were all equal. Conclusions —The present in vitro study shows that in human cardiac membranes, the most critical step in kinin metabolism, that is, inactivation of BK, appears to be mediated mostly by NEP. This observation suggests a role for NEP in the local control of BK concentration in heart tissue. Thus inhibition of cardiac NEP activity could be cardioprotective by elevating the local concentration of BK in the heart.
Genetic and Environmental Contributions to Cardiovascular Risk Factors in Mexican Americans
Authors: Braxton D. Mitchell, Candace M. Kammerer, John Blangero, Michael C. Mahaney, David L. Rainwater, Bennett Dyke, James E. Hixson, Richard D. Henkel, R. Mark Sharp, Anthony G. Comuzzie, John L. VandeBerg, Michael P. Stern, Jean W. MacCluer
Journal: Circulation (1996)

The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes.Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure.These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.
THROWING SPORT IMPROVES SHOULDER PROPRIOCEPTION
Authors: P Lubiatowski, P Kaczmarek, P Ogrodowicz, P Dudzinski, L Romanowski
Journal: British Journal of Sports Medicine (2014)

Background Proprioception is a specialized variation of the sensory modality of touch that includes the sensation of joint motion and joint position. It is an essential part of shoulder stability and neuromuscular control. It is controversial whether throwing sports and sports training effects shoulder proprioception. Objective To analyse the shoulder proprioceptive abilities of professional handball players. Design Prospective study with control group and descriptive analysis. Setting Elite division handball players. Participants 70 professional handball players from top national league and 25 healthy volunteers as control. Interventions Shoulder proprioception was evaluated by measuring error of active reproduction of joint position (EARJP). Own construction electronic goniometer (Propriometer) with accuracy of 0,1 o was used for measurements. Both dominant and non-dominant shoulders were evaluated. EARJP was measured in 4 directions and 3 positions for each direction: flexion and abduction (60 o , 90 o , 120 o ), external and internal rotation (30 o , 45 o , 60 o ). Three repetitions for each position were performed to obtain an average EARJP for every subject and position. Results Based on statistical analysis there was significantly better proprioceptive control (lower EARJP) in throwing versus non throwing and throwing versus control group shoulder. No difference in proprioception when comparing dominant and non-dominant shoulders in control group. Higher reference angles correlated with better proprioception. Increased external rotation correlated with better shoulder control in mid range of external rotation. Conclusions Throwing sport affects neuromuscular shoulder control. Handball players show significantly better proprioceptive abilities when compared to control normal population. Throwing shoulder has better neuromuscular control then the opposite one.
A High-Fidelity Electronic Stethoscope
Authors: Denis Abenson
Journal: JAMA (1971)

<h3>To the Editor.—</h3> Electronic stethoscopes have not achieved widespread popularity, despite their increasing compactness, because of distortion and high background noise. Physicians complain of the need to reeducate their ears to interpret the new and unfamiliar sounds. By contrast, the heart sound amplifiers incorporated in laboratory instruments such as phonocardiographs generally have excellent characteristics and contain elaborate filter systems. We removed one of these amplifiers from a multichannel recorder and adapted it for bedside and office use by simply enclosing it in a light wooden carrying case with an on-off switch and battery power supply (four 11.2-v mercury cells) (Figure). The unit accepts both contact and aircoupled microphones and is provided with a bandpass (70 to 700 hertz) as well as a Leathem filter. It gives ample volume and has proved very satisfactory in operation.
Sex Hormone–Binding Globulin and the Free Androgen Index Are Related to Cardiovascular Risk Factors in Multiethnic Premenopausal and Perimenopausal Women Enrolled in the Study of Women Across the Nation (SWAN)
Authors: Kim Sutton-Tyrrell, Rachel P. Wildman, Karen A. Matthews, Claudia Chae, Bill L. Lasley, Sarah Brockwell, Richard C. Pasternak, Donald Lloyd-Jones, Mary Fran Sowers, Javier I. Torréns
Journal: Circulation (2005)

Background— Recent clinical trials have shifted attention away from estrogens and toward androgens and sex hormone–binding globulin (SHBG) as potential mediators of increasing cardiovascular (CV) risk in women at midlife. Methods and Results— The correlation between reproductive hormones and CV risk factors was evaluated in a multiethnic (white, black, Hispanic, Chinese, and Japanese) sample of 3297 premenopausal and perimenopausal women. Testosterone and estradiol (E 2 ) were evaluated along with SHBG and the free androgen index (FAI), the amount of testosterone not bound by SHBG. Low SHBG and high FAI were strongly and consistently related to elevated CV risk factors (higher insulin, glucose, and hemostatic and inflammatory markers and adverse lipids) even after controlling for body mass index ( P &lt;0.001 for all). Low levels of E 2 were associated with elevated CV risk factors to a lesser degree. These observations were consistent across the 5 ethnic groups. Compared with whites, blacks had higher levels of SHBG and lower levels of FAI, and Chinese had lower levels of SHBG and higher levels of FAI. Conclusions— Low SHBG and high FAI are strongly associated with CV risk factors in racially diverse women, and thus, androgens likely play a role in the CV risk profile of perimenopausal women.
Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action
Authors: Ankita Roy, Lama Al-Qusairi, Bridget F. Donnelly, Caroline Ronzaud, Allison L. Marciszyn, Fan Gong, Y.P. Christy Chang, Michael B. Butterworth, Núria M. Pastor-Soler, Kenneth R. Hallows, Olivier Staub, Arohan R. Subramanya
Journal: Journal of Clinical Investigation (2015)

The thiazide-sensitive NaCl cotransporter (NCC) is important for renal salt handling and blood-pressure homeostasis. The canonical NCC-activating pathway consists of With-No-Lysine (WNK) kinases and their downstream effector kinases SPAK and OSR1, which phosphorylate NCC directly. The upstream mechanisms that connect physiological stimuli to this system remain obscure. Here, we have shown that aldosterone activates SPAK/OSR1 via WNK1. We identified 2 alternatively spliced exons embedded within a proline-rich region of WNK1 that contain PY motifs, which bind the E3 ubiquitin ligase NEDD4-2. PY motif–containing WNK1 isoforms were expressed in human kidney, and these isoforms were efficiently degraded by the ubiquitin proteasome system, an effect reversed by the aldosterone-induced kinase SGK1. In gene-edited cells, WNK1 deficiency negated regulatory effects of NEDD4-2 and SGK1 on NCC, suggesting that WNK1 mediates aldosterone-dependent activity of the WNK/SPAK/OSR1 pathway. Aldosterone infusion increased proline-rich WNK1 isoform abundance in WT mice but did not alter WNK1 abundance in hypertensive Nedd4-2 KO mice, which exhibit high baseline WNK1 and SPAK/OSR1 activity toward NCC. Conversely, hypotensive Sgk1 KO mice exhibited low WNK1 expression and activity. Together, our findings indicate that the proline-rich exons are modular cassettes that convert WNK1 into a NEDD4-2 substrate, thereby linking aldosterone and other NEDD4-2–suppressing antinatriuretic hormones to NCC phosphorylation status.