tbuckley/cabot-search huggingface dataset:
On the Use of Familial Aggregation in Population-Based Case Probands for Calculating Penetrance
Authors: Colin B Begg
Journal: JNCI Journal of the National Cancer Institute (2002)

Estimating the lifetime risk associated with (i.e., the penetrance of) genetic abnormalities that predispose individuals to cancer is important for genetic counseling. (Penetrance may be estimated from the degree of familial aggregation of cancer, that is, the extent to which cancers cluster in families.) Early penetrance studies of BRCA1 and BRCA2 mutations used high-risk families with multiple cases of breast cancer, a study design that led to very high penetrance estimates. However, such studies were subject to potential ascertainment biases. To offset such biases, recent studies have used data from family members of probands ascertained from population-based incident cases of cancer. The use of case probands is, however, also subject to bias because all risk factors are over-represented in case patients. To draw attention to this problem, literature on the penetrance of breast cancer in BRCA1 and BRCA2 carriers is reviewed.A theory is presented to show that the use of case probands is itself biased, leading to inflated penetrance estimates. The strategy is unbiased only if all carriers share an identical risk. Any unexplained heterogeneity of risk caused by unknown genetic or shared environmental factors within families leads to an inflated estimate of penetrance.Eight published studies using population-based methods are reviewed. All but one of the family-based studies used case probands.Penetrance estimates from case proband studies must be inflated if other factors influence breast cancer risk in addition to the specific genetic abnormality. Thus, women with such genetic abnormalities and a strong family history of breast cancer are likely to possess a much higher risk for breast cancer than women with such abnormalities but without a strong family history. Methodologic techniques to improve the prediction of cancer risk are needed.
Development of Renal Disease in People at High Cardiovascular Risk
Authors: Johannes F. E. Mann, Hertzel C. Gerstein, Qi-Long Yi, Eva M. Lonn, Byron J. Hoogwerf, Andrew Rashkow, Salim Yusuf
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. In people with diabetes, renal disease tends to progress from microalbuminuria to clinical proteinuria to renal insufficiency. Little evidence has been published for the nondiabetic population. This study retrospectively analyzed changes of proteinuria over 4.5 yr in the HOPE (Heart Outcomes and Prevention Evaluation) study, which compared ramipril's effects to placebo in 9297 participants, including 3577 with diabetes and 1956 with microalbuminuria. This report is restricted to 7674 participants with albuminuria data at baseline and at follow-up. Inclusion criteria were known vascular disease or diabetes plus one other cardiovascular risk factor, exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (>1+), and serum creatinine >2.3 mg/dl (200 μM). Baseline microalbuminuria predicted subsequent clinical proteinuria for the study participants overall (adjusted odds ratio [OR], 17.5; 95% confidence interval [CI], 12.6 to 24.4), in participants without diabetes (OR, 16.7; 95% CI, 8.6 to 32.4), and in participants with diabetes (OR, 18.2; 95% CI, 12.4 to 26.7). Any progression of albuminuria (defined as new microalbuminuria or new clinical proteinuria) occurred in 1859 participants; 1542 developed new microalbuminuria, and 317 participants developed clinical proteinuria. Ramipril reduced the risk for any progression (OR, 0.87; 95% CI, 0.78 to 0.97; P = 0.0146). People without and with diabetes who are at high risk for cardiovascular disease are also at risk for a progressive rise in albuminuria. Microalbuminuria itself predicts clinical proteinuria in nondiabetic and in diabetic people. Ramipril prevents or delays the progression of albuminuria. E-mail: [email protected]
Changes in Locus-specific V(D)J Recombinase Activity Induced by Immunoglobulin Gene Products during B Cell Development
Authors: Andrei Constantinescu, Mark S. Schlissel
Journal: The Journal of Experimental Medicine (1997)

The process of V(D)J recombination is crucial for regulating the development of B cells and for determining their eventual antigen specificity. Here we assess the developmental regulation of the V(D)J recombinase directly, by monitoring the double-stranded DNA breaks produced in the process of V(D)J recombination. This analysis provides a measure of recombinase activity at immunoglobulin heavy and light chain loci across defined developmental stages spanning the process of B cell development. We find that expression of a complete immunoglobulin heavy chain protein is accompanied by a drastic change in the targeting of V(D)J recombinase activity, from being predominantly active at the heavy chain locus in pro-B cells to being exclusively restricted to the light chain loci in pre-B cells. This switch in locus-specific recombinase activity results in allelic exclusion at the immunoglobulin heavy chain locus. Allelic exclusion is maintained by a different mechanism at the light chain locus. We find that immature, but not mature, B cells that already express a functional light chain protein can undergo continued light chain gene rearrangement, by replacement of the original rearrangement on the same allele. Finally, we find that the developmentally regulated targeting of V(D)J recombination is unaffected by enforced rapid transit through the cell cycle induced by an Eμ-myc transgene.
Glutathione monoethyl ester ameliorates caerulein-induced pancreatitis in the mouse.
Authors: B A Neuschwander-Tetri, L D Ferrell, R J Sukhabote, J H Grendell
Journal: Journal of Clinical Investigation (1992)

Studies in animal models suggest that oxygen radicals may be important in the pathogenesis of acute pancreatitis. Because glutathione is an essential component of the defense against radical-mediated cellular injury, we investigated whether pancreatic glutathione content is influenced by inducing acute pancreatitis and whether augmenting the intracellular supply of glutathione would alter the course of pancreatitis. Caerulein, a decapeptide cholecystokinin analogue, induces acute necrotizing pancreatitis in mice when given in high doses (50 micrograms/kg per h) over a period of 6 h. The pancreatic glutathione content (total, GSH + GSSG) in mice treated with high-dose caerulein fell to 17% of normal within 4 h of beginning caerulein and recovered toward normal after discontinuing caerulein treatment. Mice treated with glutathione monoethyl ester (20 mmol/kg 1 h before caerulein, 10 mmol/kg 3 and 7 h after starting caerulein) were found to have blunted depletion of pancreatic glutathione, diminished histologic evidence of pancreatitis (necrosis, inflammation, and vacuolization), and lower serum amylase values compared with mice treated with caerulein alone. These findings suggest that the profound depletion of pancreatic glutathione caused by hyperstimulation of the pancreas with caerulein is critically important in the pathogenesis of acute caerulein-induced pancreatitis.
Acute Sore Throat
Authors: W. S. Adams
Journal: BMJ (1956)

Background: Snail medic (Medicago scutellata L.) seeds exhibit a significantly higher content of a trypsin inhibitor than other Medicago species. This inhibitor belongs to the Bowman-Birk family of serine protease inhibitors (BBI) and exhibits a good sequence homology with the BBI from soybean, while presenting some differences. It has been suggested that BBIs have antitumoral and radio-protective activity. Materials and Methods: In order to assess whether the inhibitor from Medicago scutellata (MsTI) seeds show similar properties to those of BBI from soybean with respect to potentiation of cisplatin-induced cytotoxicity, we evaluated the effects of MsTI on cisplatin-induced cell killing in MCF7 human breast carcinoma cells and HeLa human cervical carcinoma cells. Results: The 24-hour treatment of MsTI in the cell culture medium decreased the clonogenic survival of MCF7 and HeLa cells in a dose-dependent manner and enhanced cisplatininduced cytotoxicity. The presence of MsTI during the entire incubation period reduced the D<sub>37</sub> of cisplatin by 40% in both the cell lines. Conclusion: MsTI could be an useful agent for the potentiation of cisplatin-mediated cancer treatment.
Self-Organization and the Self-Assembling Process in Tissue Engineering
Authors: Kyriacos A. Athanasiou, Rajalakshmanan Eswaramoorthy, Pasha Hadidi, Jerry C. Hu
Journal: Annual Review of Biomedical Engineering (2013)

In recent years, the tissue engineering paradigm has shifted to include a new and growing subfield of scaffoldless techniques that generate self-organizing and self-assembling tissues. This review aims to cogently describe this relatively new research area, with special focus on applications toward clinical use and research models. Particular emphasis is placed on providing clear definitions of self-organization and the self-assembling process, as delineated from other scaffoldless techniques in tissue engineering and regenerative medicine. Significantly, during formation, self-organizing and self-assembling tissues display biological processes similar to those that occur in vivo. These processes help lead to the recapitulation of native tissue morphological structure and organization. Notably, functional properties of these engineered tissues, some of which are already in clinical trials, also approach native tissue values. This review endeavors to provide a cohesive summary of work in this field and to highlight the potential of self-organization and the self-assembling process for providing cogent solutions to currently intractable problems in tissue engineering.
Public Reporting of Discharge Planning and Rates of Readmissions
Authors: Ashish K. Jha, E. John Orav, Arnold M. Epstein
Journal: New England Journal of Medicine (2009)

A reduction in hospital readmissions may improve quality and reduce costs. The Centers for Medicare and Medicaid Services has initiated a national effort to measure and publicly report on the conduct of discharge planning. We know little about how U.S. hospitals perform on the current discharge metrics, the factors that underlie better performance, and whether better performance is related to lower readmission rates.
Histological and immunohistochemical study of the gall bladder lesion in primary sclerosing cholangitis.
Authors: G P Jeffrey, W D Reed, S Carrello, K B Shilkin
Journal: Gut (1991)

The histological features and type of mononuclear cell infiltrate in gall bladders from six patients with primary sclerosing cholangitis were studied using routine staining techniques and immunohistochemistry. Control studies were performed using the gall bladders from six patients (age and sex matched) with chronic cholecystitis and four with primary biliary cirrhosis. A range of histological abnormalities was present in gall bladders from patients with primary sclerosing cholangitis including a mild to moderate degree of epithelial hyperplasia, pseudogland formation, and mononuclear cell infiltrate of the epithelium; moderate to severe chronic inflammatory cell infiltrate and fibrosis affecting the superficial and deep layers of the gall bladder wall; and minimal smooth muscle hypertrophy. These abnormalities were non-specific and were also present in gall bladders from patients with chronic cholecystitis and primary biliary cirrhosis. Vasculitis and granulomas were not present in the patients with primary sclerosing cholangitis. Immunohistochemistry showed that the superficial and deep mononuclear cell infiltrate in primary sclerosing cholangitis gall bladders was composed predominantly of lymphocytes, in contrast to chronic cholecystitis where macrophages were found in similar or greater numbers. Moreover, T lymphocytes (activated and resting) were present throughout the lymphocytic infiltrate and were apposed to the base and interdigitated between the biliary epithelial cells in significantly greater numbers than in chronic cholecystitis gall bladders. B lymphocytes were present only in lymphoid follicles. Comparative studies using liver biopsy specimens from three of the primary sclerosing cholangitis patients showed a similar T lymphocyte portal tract infiltrate. We conclude that a number of non-specific chronic inflammatory histological abnormalities were present in primary sclerosing cholangitis gall bladders. Immunohistochemistry found other features that were present in this disease - a predominantly lymphocytic mononuclear cell infiltrate of the superficial and deep layers of the gall bladder wall and the presence of T lymphocytes that infiltrated the biliary epithelial cells. These findings support the hypothesis that aberrant cell mediated immune mechanisms may play a role in the pathogenesis of both the intrahepatic and extrahepatic lesions in primary sclerosing cholangitis.
Efficacy of carbocystein as add-on therapy for adults with light to moderate occupational COPD
Authors: Olyga Vasilyeva, Andrey Gusakov, Natalya Kravchenko
Journal: European Respiratory Journal (2014)

Background The main symptoms of COPD are dyspnoe, cough and phlegm production. GOLD 2014 recommends to include carbocystein as a mucoregulative drug in treatment patients with severe COPD. Carbocystein (CS)is a mucolytic drug, which reduces the viscosity of sputum. Undoubtedly it can be useful for elimination of dust particles and relieving the symptoms of COPD caused by gas, vapors and toxic agents. In this study we compared basis therapy (BT) alone and use of CS as addition to BT in order to evaluate the combined effect in patients with light to moderate COPD, still working in dusty trades.

Methods 46 patients with light to moderate COPD, who used LABA and muscarinic receptor antagonist, were submitted to medical examination, questionnaire (SWORD), MRC and CAT score scales and dynamics of sputum expectoration, spirography (measuring FVC, FEV1, FEV1/FVC) before and after the addition therapy with CS (2,7 mg per day) during 30 days. 20 patients received BT alone.

Results There were no dynamic of CAT score in BT group but 29 patients (63%) in CS group move from moderate to low impact by CAT score. About 20% (9 patients) move from MRC1 to MRC0 group after 30 days with CS therapy. In CS group we observed positive dynamic of FEV, but it was no statistically significant. Also we note positive dynamics of FEV1/FVC ratio at the end of 20 days with CS in 13% (6 patients). 14 patients (30.4%) fell reduction in the intensity of coughing and improvement expectoration of phlegm.

Conclusion Our data suggest that Carbocystein is rather effective in improving expectoration of sputum and reducing of cough intensity in patients with light to moderate COPD due to work-related dust particles.
How do elderly patients decide where to go for major surgery? Telephone interview survey
Authors: Lisa M Schwartz, Steven Woloshin, John D Birkmeyer
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To learn how patients in Medicare, the US medical insurance programme that covers elderly patients, made decisions about where to undergo major surgery and how they would make future decisions. <b>Design</b> National telephone interview study. <b>Setting</b> United States. <b>Participants</b> 510 randomly selected Medicare beneficiaries who had undergone an elective, high risk procedure about 3 years earlier—abdominal aneurysm repair (n = 103), heart valve replacement surgery (n = 96), or resection of the bladder (n = 119), lung (n = 128), or stomach (n = 64) for cancer. Response rates were 48% among eligible survivors and 68% among those able to participate. <b>Results</b> Although all participants could choose where to have surgery, only 55% said there was an alternative hospital in their area where they could have gone. Overall, only 10% of respondents seriously considered going elsewhere for surgery. Few respondents (11%) looked for information to compare hospitals. Almost all respondents thought their hospital and surgeon had good reputations (94% and 88%, respectively), beliefs mostly determined by what their referring doctors said. When asked how much various factors would influence their advice to a friend about choosing where to go for major surgery, surgeon reputation was the most influential (78% said it would influence their advice "a lot"), followed by the hospital having "nationally recognised" surgeons (63%), and then various performance data (surgeon volume (58%), nurse:patient ratios (49%), number of operations carried out by the hospital (48%), and hospital operative mortality (45%)). Forty per cent said they would act on mortality data, indicating that they would switch from their initial choice of hospital to a different one if its mortality was a percentage point lower (that is, 3% <i>v</i> 4%). <b>Conclusion</b> Some respondents claimed they would switch hospital for elective surgery on the basis of mortality data. Since most respondents relied on their referring physician9s opinion to decide where to have surgery, surgical performance data ought to be accessible to referring physicians.
Congestive Heart Failure in Renal Transplant Recipients
Authors: Claudio Rigatto, Patrick Parfrey, Robert Foley, Carol Negrijn, Carrie Tribula, John Jeffery
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Cardiovascular disease (CVD) is the major cause of death in renal transplant recipients (RTR). Several cohort studies have examined CVD in RTR, but none have addressed the development of congestive heart failure (CHF). CHF would hypothetically be a frequent and prognostically important event in RTR. A retrolective cohort study was, therefore, conducted in two Canadian centers to describe the incidence, risk factors for, and interrelationships between de novo CHF, de novo ischemic heart disease (IHD), and mortality in 638 consecutive adult RTR who were free of cardiac disease at 1 yr posttransplant. Detailed clinic and hospital records were available for 99% of patients. Median follow-up was 7 yr (range, 1 to 28 yr). De novo CHF occurred as frequently as de novo IHD (1.26 versus 1.22 events/100 patient-years, respectively) and appeared to carry a similar prognosis (relative risk for death, 1.78 [confidence interval, 1.21 to 2.61] for CHF versus 1.50 [1.05 to 2.13] for IHD). The incidence of CHF was considerably higher than that in the Framingham cohort, whereas the incidence of IHD was not, suggesting that renal transplantation might correspond more to a state of “accelerated heart failure” than to “accelerated atherosclerosis.” Age, diabetes, gender, BP, and anemia were identified as independent risk factors for de novo CHF, whereas age, diabetes, gender, BP, and rejection were independent risk factors for de novo IHD. Optimal strategies for treatment of BP and anemia in RTR will need to be determined in randomized controlled trials.
Refining Therapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: T Stands for Trastuzumab, Tumor Size, and Treatment Strategy
Authors: Harold J. Burstein, Eric P. Winer
Journal: Journal of Clinical Oncology (2009)

The clinical importance of breast cancer subsets is now well established; we know that one size won’t fit all. In fact, we are well into the era of parsing subsets of subsets, and the major challenges are to refine therapies within each tumor subtype to tailor treatments based on tumor risk, treatment benefit, and likely adverse effects of therapy. For patients with estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative breast cancers, the current challenge centers on defining which patients benefit from the addition of chemotherapy to endocrine therapy. For those with triple-negative (or basaloid) tumors, the challenge is to optimize our chemotherapy regimens while searching for targeted drugs that might dramatically improve outcomes. Finally, for the 15% to 20% of patients with HER2-overexpressing tumors, the success of trastuzumab has fastforwarded our efforts and has led to a dramatic improvement in clinical outcomes. The thoughtful and thorough review by Spector and Blackwell outlines several important ongoing areas of investigation that should better elucidate the precise mechanisms of action for trastuzumab and clarify which tumors markers besides HER2 overexpression most clearly predict benefit from trastuzumab; it also suggests related signaling pathways, such as PI3K and hsp90, that may account for trastuzumab resistance in both the adjuvant and metastatic settings and that can be targeted with newly available pharmacologic agents. Meanwhile, clinicians wrestle with practical day-to-day questions of how best to use trastuzumab, questions that remain unanswered from the landmark clinical trials of adjuvant trastuzumab therapy. The pivotal studies generally concentrated on patients with relatively high-risk, HER2-positive breast cancers and node-positive tumors. There has been only limited information on node-negative cancer outcomes, although the results have suggested comparable proportionate risk reduction as in node-positive patients. The randomized trials provided no data on small tumors (ie, cancers 1 cm) with negative lymph nodes. Although almost all of the data reported are with 1 year of trastuzumab administration, one study (Finland Herceptin [FinHER] study) delivered only 9 weeks of treatment, whereas another study (Herceptin Adjuvant Trial [HERA]) studied up to 2 years of trastuzumab. Three reports in this issue of Journal of Clinical Oncology raise questions about who should receive trastuzumab and how best to administer this drug. SMALL, NODE-NEGATIVE, HER2-POSITIVE TUMORS
Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia
Authors: Shinji Kishi, Wenjian Yang, Benoit Boureau, Stanislas Morand, Soma Das, Peixian Chen, Edwin H. Cook, Gary L. Rosner, Erin Schuetz, Ching-Hon Pui, Mary V. Relling
Journal: Blood (2003)
Influence of an essential fatty acid deficient diet on absorption of topical hydrocortisone in the rat
Authors: B. LAMBREY, W. SCHALLA, N. KAIL, J.P. LAHMY, H. SCHAEFER
Journal: British Journal of Dermatology (1987)

Using a rat dermatosis model, produced by dietary essential fatty acid deficiency (EFAD), which is characterized by histological changes and elevated transepidermal water loss, changes in skin permeability were studied using [14C]-hydrocortisone (HC). Skin, serum and urinary levels of HC were measured, and absorption and excretion of HC in EFAD rats compared with that in control rats on a normal diet. This animal model has demonstrated the importance of the functional integrity of the horny layer in skin penetration.