tbuckley/cabot-search huggingface dataset:
Viagra: on release
Authors: A. Gregoire
Journal: BMJ (1998)

Editorial p 760 News p 765 Medicine and the media p 824 

The popular interest in Viagra (sildenafil) is not solely the result of media hype and the drug's association with sex: the demand for treatment has been enormous. Since its launch in the United States in March it has become the fastest selling drug ever.1 The demand is being met by prescription in the United States and globally through the internet and on the street, which in Europe precedes its licensing for prescription by doctors.

The level of demand was predictable, given a prevalence of erectile dysfunction of over 50% in men aged 50-70, and the unacceptability, poor effectiveness, or unavailability of existing treatments, such as implants, intracavernosal injection, intraurethral pellets, vacuum devices, and sex therapy.2 To most sufferers a tablet treatment must have seemed too good to be true.

A localised effect after oral administration is possible because of sildenafil's specificity of action. The final common pathway for sexual arousal and stimulation leading to erection is the production in cavernosal tissues of cyclic guanosine monophosphate (GMP), which relaxes the smooth muscle and permits swelling of the corpora with blood. Sildenafil is a potent and specific inhibitor of cyclic GMP …
Abstract P456: Screening Strategies and Primary Prevention Interventions for Relatives of Individuals with Coronary Heart Disease: A Systematic Review
Authors: Michael Goldfarb, Douglas Slobod, George Thanassoulis
Journal: Circulation (2014)

Introduction: Targeting relatives of individuals with coronary artery disease (CAD) may be an effective primary prevention strategy. However, a systematic review of (1) reported screening strategies to identify relatives at risk and (2) published risk factor interventions in family members has not been performed which may limit more widespread adoption. Methods: We searched PubMed, Embase and The Cochrane Library from inception to October 1, 2013 for articles describing screening strategies and primary prevention interventions targeting family members of patients with CAD. A three-part search term composed of “coronary heart disease”, “relatives” and “screening or intervention” along with related MeSH terms was designed for maximum sensitivity. Results: We identified 14 eligible articles for the analysis of screening strategies. The proband was identified most commonly during index hospitalization (n=11), but also while in a cardiac rehabilitation center (n=1) and by referral from a primary care physician (n=2). Studies in which the proband was explicitly encouraged to recruit family members were slightly more effective (participation rate of 24-91%; weighted average: 78%) than screening strategies in which the relative was only contacted by phone and/or letter (participation rate: 36-95%; weighted average: 68%). In most studies, the willingness of the proband to contact relatives for screening was high (range: 62-98%, mean 87%). Thirteen studies were identified that examined interventions in relatives of people with CAD (randomized controlled trials, n=11; prospective cohort, n=2), ranging in size from 18 to 3,981 participants. A multiple risk factor intervention was performed in 8 studies, while 3 studies looked at single risk factor intervention and 2 studies encouraged the patient to seek cardiovascular risk factor treatment from primary care physicians. Significant improvement in at least 1 modifiable cardiovascular health behavior or risk factor was observed in the intervention arm of all studies (n = 13). Conclusions: Screening strategies targeting family members achieve a high participation rate especially when the proband initiates screening. Interventions that target relatives appear to be feasible and effective in improving risk factors or health behaviours. Primary prevention delivery models targeting family members of individuals with CAD warrant further study.
Classification of clinical spirometry data using global lung initiative (GLI) and national health and nutrition examination survey (NHANES-III) models
Authors: Olinto Linares-Perdomo, Dave Collingridge, Stacy Bamberg, Denitza Blagev, Steven Howe, Robert Jensen, John Hankinson, Alan Morris
Journal: European Respiratory Journal (2013)

RATIONALE:

Pulmonary Function Testing is central to distinguishing normal from abnormal patients in Cardiac, Pulmonary, and other branches of Medicine. The National Health and Nutrition Examination Survey-III (NHANES-III) equations provide predicted normal values (Pred) and lower limits of normal (LLN) from 8 to 80 years of age. The recent Global Lung Initiative (GLI-12) equations provide values from 3 to 95 years of age. We compare clinical data classification using the NHANESIII and GLI prediction equations.

METHODS:

We used clinical data from Intermountain Medical Center and LDS Hospital patients (Salt Lake City, Utah) from 2001-2012. We analyzed data from 10-80 year old Caucasian patients. We used the NHANESIII and the GLI-12 prediction equations to calculate the Pred and LLN for FEV1, FVC, and FEV1/FVC. We compared categorizations using both approaches.

RESULTS:

We studied 17,107 spirograms from Caucasian patients (8,143 males, mean age 54.5, SD 16.1 and 8,964 females, mean 54.4, SD 15.5). Pred and LLN values were similar for both NHANES-III and GLI-12, but differences existed. These differences appear gender and height dependent. We observed small differences in normal/abnormal patient categorizations for FEV1, FVC, and FEV1/FVC when comparing NHANES-III and GLI-12 equations.

CONCLUSION:

We observed small differences between NHANES-III and GLI-12 categorization for both men and women. Differences are greatest for FVC. The GLI-12 equations categorize more PFT laboratory patients as normal than those for NHANESIII.
Abstract P159: Repeatability of Automated Determinations of the Ankle Brachial Index The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Ada Al-Qunaibet, Michelle L Snyder, David Couper, Hirofumi Tanaka, Susan Cheng, Kunihiro Matsushita, Aaron R Folsom, Gerardo Heiss
Journal: Circulation (2015)

Background: The ankle brachial index (ABI) is a noninvasive and inexpensive means to assess peripheral arterial disease (PAD) with established validity. Low ABI values are predictive of cardiovascular morbidity and all-cause mortality. Automated, oscillometric devices are commonly used to measure ABI in clinical settings and population studies for time-efficiency and to reduce observer-dependent variability. The repeatability of multi-limb systolic blood pressure (SBP) and of ABI using oscillometric devices has not been evaluated in depth. Objectives: Characterize the repeatability of limb-specific SBP and of ABI in a multi-center, community-based study of older adults. Methods: A subset of ARIC study participants (n=79; 58% women) with a mean age of 75.7 years underwent two examinations 4-8 weeks apart, using standardized protocols. SBP in the arms and ankles was measured twice in each ‘visit’ in the supine position after a 5 minute rest, using the Omron Colin VP-1000 Plus system (Omron Co., Ltd., Kyoto,...
Abstract P198: Redox Monitoring Reveals Increased Susceptibility of Whole Blood to Oxidative Stress During Hemorrhagic Shock
Authors: Nathan J White, Maryanne M Collinson, Richard A Boe, Kevin R Ward
Journal: Circulation (2008)

Introduction: The oxidation/reduction (redox) chemistry of blood during resuscitation is not well defined. Improved understanding of whole blood redox behavior would assist in developing better resuscitation monitoring and possibly reducing free radical injury both of which are PULSE initiative priorities. We use direct electrochemical measurement of equilibrium redox potential to assess the hypothesis that the overall response of blood to strong oxidant/reductant challenge is altered during shock. Methods: Five swine underwent hemorrhage to an oxygen debt (OD) of 80 cc/kg. Arterial blood was tested at baseline (BL) and after hemorrhage when OD equaled 40 and 80 cc/kg. Native redox potential was measured as the equilibrium voltage potential recorded between a freshly polished 2mm Au and standard Ag/AgCl electrode submerged in whole blood (n=34). The oxidative and reductive stress responses at each level of OD were defined as the change from native voltage potential induced by the addition of a strong oxidant (KMnO4) (n=18) or reductant (Dithiotreitol) (n=18). Mean native redox potentials and mean redox stress responses were compared for differences at increasing levels of OD using repeated measures ANCOVA. Results: Lactate increased significantly with OD (mean diff BL vs. OD=80, +4.7 mmol/L [1.3, 8.1]). No effect of OD was found on native redox potential (p value =0.233). A significant effect of OD was found on redox stress response (p value =0.0276). The redox response to oxidative stress increased from BL with increasing oxygen debt, and became significantly greater at OD=80 cc/kg (mean diff =+31.9 Rmv [3.9, 59.9]). Conclusions: Whole-blood redox potential did not change significantly even with severe shock, suggesting active redox buffering. However, our results suggest that the oxidative buffering capacity of blood may become impaired during severe shock as demonstrated by the significantly more positive redox potentials elicited by oxidative stress when OD was elevated. Impaired redox buffering during shock may exacerbate free radical injury induced by the oxidative stress of resuscitation. Monitoring the response of blood to oxidative stress may be a useful way to determine susceptibility to oxidative damage during resuscitation.
Interruption of the enterohepatic circulation of digitoxin by cholestyramine
Authors: James H. Caldwell, Charles A. Bush, Norton J. Greenberger
Journal: Journal of Clinical Investigation (1971)

Previous studies of digitalis glycoside metabolism and excretion have indicated that these compounds undergo a significant enterohepatic cycle in some species. It has been suggested that the existence of such a cycle in man contributes to the prolonged action of certain cardiac glycosides. Previous studies have demonstrated that cholestyramine binds digitoxin and digoxin in vitro and accelerates the metabolic disposition of digitoxin in rats and guinea pigs, presumably by interrupting the enterohepatic circulation. In order to assess the role of the enterohepatic circulation in the metabolism of digitalis glycosides in humans, maintenance doses of cholestyramine were administered to 7 of 15 normal human subjects beginning 8 hr after digitalization with 1.2 mg of digitoxin-(3)H. All subjects had frequent measurements of serum radioactivity, left ventricular ejection time (LVET), and electromechanical systole (QS(2)), the latter recorded as the interval from onset of Q wave to first major component of second heart sound. Measurement of the LVET and QS(2) intervals affords a sensitive index of the cardiac response to digitalis. In addition, chloroform extraction of serum was performed to separate unchanged digitoxin and active metabolites from cardioinactive metabolites of digitoxin. Cholestyramine treatment resulted in reduction in half-life to total serum radioactivity from 11.5 to 6.6 days, and in chloroform-extractable radioactivity from 6.0 to 4.5 days, as compared to controls. In addition, cholestyramine treatment was accompanied by more rapid return to base line values of digitoxin-induced changes in the LVET and QS(2) intervals. A significant positive correlation was found between QS(2) values and chloroform-extractable radioactivity, the latter reflecting unchanged digitoxin-H(3) (r=0.64; P=<0.01). The results indicate that administration of cholestyramine to digitalized human subjects accelerates the metabolic disposition of digitoxin and abbreviates the physiologic response to the glycoside. This effect is presumably mediated by interruption of the enterohepatic circulation of digitoxin by cholestyramine.
Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality
Authors: M. Slavin, S. van Hal, T.C. Sorrell, A. Lee, D.J. Marriott, K. Daveson, K. Kennedy, K. Hajkowicz, C. Halliday, E. Athan, N. Bak, E. Cheong, C.H. Heath, C. Orla Morrissey, S. Kidd, R. Beresford, C. Blyth, T.M. Korman, J. Owen Robinson, W. Meyer, S.C.-A. Chen
Journal: Clinical Microbiology and Infection (2015)
Targeting ER-Golgi homeostasis as a therapeutic strategy in lung cancer.
Authors: V. Zismanov, L. Drucker, M. Gottfried
Journal: Journal of Clinical Oncology (2010)

e21030 Background: Heat shock protein 90 (Hsp90) is a molecular chaperon essential for folding and stability of multiple oncogenes and an established target in cancer therapeutics (lung included). Misfolded proteins accumulate in the ER, induce ER stress, and activate response pathways such as the ubiquitin proteasome system (UPS), which orchestrates turnover of cellular proteins and histone deacetylases (HDACs) that critically recruit misfolded protein aggregates (un-degradable by UPS), into dedicated organelles. Indeed, Hsp90 inhibition causes unfolded proteins accumulation and ER stress. The therapeutic efficacy of such inhibition may be augmented by co-administering it with other drugs that disrupt response signals that enable ER- Golgi homeostasis. Methods: We aimed to examine the effect of combined treatment of Hsp90 antagonist with proteasome or HDAC inhibitors on human lung cancer cell lines fate (viability, proliferation, cell cycle, death, death mode) and ER-Golgi homeostasis (protein synthesis, UPR, autophagy, other Hsps, FOXO). Results: Hsp90 inhibitor (17-DMAG) co-administration with HDAC inhibitor (PTACH) or proteasome inhibitor (Velcade) yielded a synergistic increase in apoptosis of lung cancer cell lines. Reduced viability was demonstrated in all cell lines with all drug combinations except 17- DMAG and PTACH co-administered to H1299 cells. Interestingly, combined 17-DMAG and PTACH induced elevated H1299 viability despite the increased cell death. We hypothesized that this phenomenon may result from increased H1299 proliferation and in accordance determined higher levels of PCNA in treated cells. Analyses of ER stress markers (BiP, CHOP, and pJNK) in the treated cancer cells are underway. Conclusions: Our findings provide proof-of-concept that targeting ER-Golgi homeostasis is therapeutically beneficial in lung cancer cell lines. No significant financial relationships to disclose.
Abstract P6-10-12: Metformin increases survival in hormone receptor-positive, Her2-positive breast cancer patients with diabetes
Authors: Hee Jeong Kim, Hyun Wook Kwon, Jong Won Lee, Sae Byul Lee, Hee Seung Park, Sei Hyun Ahn, Hae Na Shin
Journal: Cancer Research (2015)

Abstract Purpose Metformin use has recently been observed to decrease both the rate and mortality of breast cancer. Our study was aim to determine whether metformin use is associated with survival in diabetic breast cancer patients by breast cancer subtype and systemic treatment Patients and Methods Data from the Asan Medical Center Breast Cancer Database from 1997 to 2007 were analyzed. The study cohort comprised 6,967 nondiabetic patients, 202 diabetic patients treated with metformin, and 184 diabetic patients that did not receive metformin. Patients who were divided into three groups by diabetes status and metformin use were also divided into four subgroups by hormone receptor and HER2-neu status. Results In Kaplan-Meier analysis, the metformin group had a significantly better overall and cancer specific survival outcome compared with non metformin diabetic group (P &amp;lt;0.005 for both). There was no difference in survival between the nondiabetic and metformin groups. In multivariate analysis, Compared with metformin group, patients who did not receive metformin tended to have a higher risk of metastasis with HR 5.37 (95%CI, 1.88 to 15.28) and breast cancer death with HR 6.51 (95% CI, 1.88 to 15.28) on the hormone receptor-positive and Her2-negative breast cancer. The significant survival benefit of metformin observed in diabetic patients who received chemotherapy and endocrine therapy (HR for DFS 2.14; 95% CI 1.14 to 4.04) was not seen in diabetic patients who did not receive these treatments. Conclusion Patients receiving metformin treatment when breast cancer diagnosis show a better prognosis only if they have hormone receptor-positive, HER2-positive tumors. Metformin treatment might provide a survival benefit when added to systemic therapy in diabetic patients. Citation Format: Hee Jeong Kim, Hyun Wook Kwon, Jong Won Lee, Sae Byul Lee, Hee Seung Park, Sei Hyun Ahn, Hae Na Shin. Metformin increases survival in hormone receptor-positive, Her2-positive breast cancer patients with diabetes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-12.
Single-Layer Mass Closure of Major Laparotomies by Continuous Suturing
Authors: A V Pollock, M J Greenall, Mary Evans
Journal: Journal of the Royal Society of Medicine (1979)

Surgeons who close major laparotomy incisions in a single layer (excluding skin) usually put interrupted sutures of non-absorbable monofilament material. In 305 consecutive patients we have, instead, used continuous deep-bite mass sutures with satisfactory results. The suture material, chosen at random, was either monofilament nylon, monofilament stainless steel wire or polyglycolic acid (PGA). The length of material used was measured, and this figure divided by the number of bites to give the mean distance from the cut edges at which the needle had been inserted. The ratio of length of suture material to number of bites ranged from 3-10 em (mean 5.90, s.d.I.46). There were no burst abdomens, but 26 incisonal hernias were detected within six months of operation; these were significantly associated with male sex, old age, long incisions, long operations, postoperative coughing and distension, blood transfusion and wound sepsis. Steel sutures were removed from 5 patients because of pain or sinuses, and nylon sutures from one. We conclude that laparotomy closure by a single continuous layer of sutures is satisfactory, and that there is little to choose among nylon, PGA and steel. The incidence of incisional hernias would be reduced by the elimination of wound sepsis.
Abstract 2004: S100A4 in colorectal cancer - biological function of nuclear localization
Authors: Eivind V. Egeland, Kjetil Boye, Kjersti Flatmark, Solveig J. Pettersen, Tove Oyjord, Gunhild M. Maelandsmo
Journal: Cancer Research (2014)

Abstract S100A4 is a Ca2+-binding protein promoting metastasis in several types of tumors. The protein possesses a wide variety of biological functions, and locates to different subcellular compartments including the nucleus, cytoplasm and extracellular space. Even though S100A4 is mainly localized in the latter two compartments, we have previosusly shown that the protein is localized to the nucleus in more aggressive forms of colorectal cancer (CRC) and that nuclear S100A4 has prognostic impact. This may suggest a function of nuclear S100A4 in the regulation of tumor progression and metastasis formation. The CRC cell line SW620 shows heterogeneity in nuclear S100A4 expression and in preliminary experiments we sorted cells into three distinct phases of the cell cycle using Fluorescent-activated cell sorting (FACS). When comparing the phases, the G2/M cells showed increased accumulation of nuclear S100A4 compared to cells in the G1 and S phase, respectively. Further validation was done using treatment with the cell cycle inhibitors nocodazole or thymidine, followed by subsequent release of cells. Protein expression of S100A4 at selected time points after release did also show accumulation in the nucleus around the G2/M transition making this subcellular translocation interesting for further investigation. Cancer cells are known to have a dysfunctional cell division apparatus and these results made it tempting to speculate whether S100A4 may be involved in cell cycle regulation. To further study the functional importance of the nuclear expression two different approaches were followed. First, CRC cells exclusively expressing S100A4 in the nucleus were made and used to identify downstream targets of nuclear S100A4. At the moment potential targets are being validated. Furthermore, we searched for factors known to be associated with the G2/M phase. Of great interest, the Proximity Ligation Assay (PLA) demonstrated that S100A4 and Cyclin B1, an important regulator of the G2/M transition, are within the same protein complex, and we are currently in the process of further characterizing this interaction. With clinical data linking nuclear expression of S100A4 with aggressive CRC, elucidation of the biological processes involved might unravel novel therapeutic possibilities. Citation Format: Eivind V. Egeland, Kjetil Boye, Kjersti Flatmark, Solveig J. Pettersen, Tove Oyjord, Gunhild M. Maelandsmo. S100A4 in colorectal cancer - biological function of nuclear localization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2004. doi:10.1158/1538-7445.AM2014-2004
644. How Does Measles Virus Kill Cancer Cells? Characterizing Oncolytic Measles Virus (OMV) Kinetics in a Mesenchymal Stromal Cell (MSC) Model of Cellular Transformation
Authors: A Castleton, A Dey, B Patel, J Funes, C Boshoff, M Capasso, A Fielding
Journal: Molecular Therapy (2014)
Development of pectin nanoparticles through mechanical homogenization for dissolution enhancement of itraconazole
Authors: Kanokporn Burapapadh, Hirofumi Takeuchi, Pornsak Sriamornsak
Journal: Asian Journal of Pharmaceutical Sciences (2015)

A simple method to fabricate itraconazole (ITZ)-loaded pectin nanoparticles prepared from nanoemulsion templates is described in this study. Nanoemulsions containing ITZ were prepared by a mechanical homogenization using pectin as emulsifier. After freeze-drying, the morphology, crystallinity state, thermal properties, drug dissolution and stability of the obtained pectin nanoparticles were characterized. The results demonstrated that the morphology of freeze-dried products was different, depending on the type of internal phase; the nanoparticles prepared from chloroform-based nanoemulsions were completely dried and provided a fragile characteristic. The pectin nanoparticles also demonstrated good properties in terms of redispersibility, thermal properties, drug crystallinity and dissolution. The ITZ-loaded pectin nanoparticles showed high percentage of drug dissolved (about 60–80% within 2 h), and maintained their good dissolution properties even after 1-year storage. The results suggested that freeze-dried pectin nanoparticles prepared from nanoemulsions could be used as an effective carrier for enhancement of ITZ dissolution.