tbuckley/cabot-search huggingface dataset:
Abstract 18285: Carnosine Supplementation Improves Metabolic Syndrome and Revascularization After Hindlimb Ischemia in Diet-Induced Obese Mice
Authors: Shahid P Baba, Deqing Zhang, Adjoa Boakye A Boakye, Tess Fennigan, Luping Guo, Aruni Bhatnagar, Daniel J Conklin
Journal: Circulation (2013)

Critical limb ischemia (CLI) affects more than 10 million people in U.S. as a result of peripheral arterial disease. It is an important clinical condition that leads to claudication, increased risk of peripheral limb infection, gangrene and amputation. Although surgical revascularization can facilitate blood flow, obese and type 2 diabetic (T2D) CLI patients are poor candidates for revascularization surgery, and thus, we investigated a potential alternative therapy. Carnosine is an endogenous histidyl dipeptide present in high concentrations in skeletal muscle (1-20 mM). Previous studies of T2D patients showed that carnosine level is reduced in the gastrocnemius muscle. Similarly, 12 weeks high fat diet (HFD; 60% kcal fat) fed mice had significantly lower carnosine level in the gastrocnemius muscle (1.2±0.1nmol/mg tissue) than low fat fed (LFD; 2.8±0.5 nmol/mg tissue; n=6; P&lt;0.05) as measured by LC-MS/ESI. To better understand the consequences of carnosine deficiency in obesity, we tested whether chronic supplementation of carnosine alters metabolic stress in HFD fed C57BL/6 mice. Carnosine supplementation (3g/l drinking water) for 6 weeks significantly attenuated body weight (43±1gm) and glucose tolerance in obese mice compared with untreated obese mice (49±2gm; n=12; P&lt;0.05). Because carnosine quenches reactive oxygen and carbonyl species that can limit ischemic injury we also tested if carnosine supplementation could attenuate CLI in obese mice. Doppler perfusion imaging 14 days after femoral artery ligation in obese mice showed that carnosine (1gm/l) pretreatment (1 week and continued after ligation) significantly increased hindlimb (HL) blood flow recovery in treated mice to 56±3% of the non-ischemic control limb compared to untreated mice (34±3%;n=4;P&lt;0.05).Similarly, in non-obese mice carnosine treatment also significantly increased HL blood flow recovery to (63±6%) of the non-ischemic control limb compared to untreated mice (19±3%;n=6; P&lt;0.05).These findings show that carnosine mitigates effects of diet-induced metabolic syndrome, and improves angiogenesis and thus may be a potential inexpensive and safe therapeutic for attenuating metabolic syndrome and increasing revascularization in obese patients suffering CLI.
Massive change is driven by generations X and Y
Authors: Alec Holt
Journal: BMJ (2008)

Microsoft’s HealthVault and Google Health are on the cusp, but more and massive changes may be expected in the future. It is not just health records that consumers are wanting access to. They want to know about similar patients and more information on their drug combinations. Patients like me (www.patientslikeme.com/), DoubleCheckMD (www.doublecheckmd.com/), PharmaSurveyor (www.pharmasurveyor.com), and Drug Interaction Database Online (https://druginteractions.epnet.com/) allow …
In Utero and Early-Life Conditions and Adult Health and Disease
Authors: Philippe Grandjean, Jerrold J. Heindel
Journal: New England Journal of Medicine (2008)

In their article on the developmental origin of disease, Gluckman et al. (July 3 issue) 1 state that "an altered long-term risk of disease is initially induced through adaptive responses that the fetus or infant makes to cues from the mother about her health or physical state."This rather narrow definition and the overall focus of the review leave out adverse responses due to maternal exposures to environmental chemicals, occupational hazards, drugs, tobacco smoking, or infection.These factors are likely to make a very large contribution to adult diseases of developmental origin, and they have the advantage of being potentially preventable. 2Risk assessment of environmental hazards must therefore include the effects of developmental exposures to stimulate better protection of the most vulnerable life stages.
Abstract 8551: Left Atrial Strain by Speckle Tracking Echocardiography In Patients with Heart Failure - An Independent and Incremental Predictor of Cardiac Death or Need of Heart Transplantation
Authors: Thomas Helle-Valle, Anders Opdahl, Kaspar Broch, Einar Gude, Arne Andreassen, Otto A Smiseth, Lars Gullestad
Journal: Circulation (2011)

Background: We have recently shown that left atrial (LA) stretching during atrial filling, measured as peak LA strain by speckle tracking echocardiography (STE), is a strong and independent predictor of cardiac death or heart transplantation (HTx) in patients with heart failure (HF). Furthermore, our study demonstrated that while logNT-proBNP and left ventricular ejection fraction (LVEF) were independent predictors of these end points, age, LA area and E/e’ were not. In the present study we investigate if LA strain adds predictive power to that provided by NT-proBNP and LVEF. Methods: We included 143 patients (age 54±11 years), with ischemic or dilated cardiomyopathy (NYHA II-IV, LVEF= 31±13%). Peak LA strain by STE and LVEF were measured. Time to death or HTx (Cox model) was adjusted for age, logNT-proBNP and LVEF in addition to LA strain. We computed receiver-operating characteristic (ROC) curves and tested for equality of the areas under the curve (AUC) for models with and without LA strain. Results: Median follow-up time was 3.0 years. There were 39 events and median time to event was 0.7 years (range 0.1 to 4.3). LVEF (P=0.008), logNT-proBNP (P=0.007) and LA strain (P=0.007) were independent predictors of cardiac events. When LA strain was added to age, LVEF and logNT-proBNP, AUC demonstrated significantly better predictive power (0.68±0.05 vs. 0.73±0.05, P=0.048; Figure 1). Conclusion: LA strain by STE is an independent and incremental predictor of death or need of HTx in patients with moderate to severe HF. This finding suggests that LA strain by STE may serve as a marker in the risk stratification of patients with HF.
The proteasome inhibitor PS-341 (Bortezomib) upregulates death receptor 5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite increase of c-FLIP and survivin in human lung cancer cells.
Authors: Xiangguo Liu, Ping Yue, Shuzhen Chen, Liping Hu, Sagar Lonial, Fadlo Khuri, Shi-yong Sun
Journal: Cancer Research (2007)

2406  The proteasome inhibitor PS-341 (Bortezomib or Velcade), an approved drug for treatment of patients with multiple myeloma, is currently being tested in clinical trials against various malignancies including lung cancer. Preclinical studies have demonstrated that PS-341 induces apoptosis and enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human cancer cells with undefined mechanisms. In the present study, we focused on revealing the mechanisms by which PS-341 induces apoptosis and enhances TRAIL-induced apoptosis in human lung cancer cells. PS-341 increased cleavage of caspase-8 and apoptosis. Prevention of caspase-8 activation by silencing caspase-8 expression using caspase-8 small interfering RNA (siRNA) abrogated PS-341-induced apoptosis. These results indicate that PS-341 induces caspase-8-depenent apoptosis. PS-341 induced expression of death receptor 5 (DR5) and cooperated with TRAIL to induce apoptosis in human lung cancer cells. Importantly, DR5 induction by PS-341 correlated with PS-341’s ability to induce apoptosis, whereas blockage of PS-341-induced DR5 upregulation using DR5 siRNA rendered cells less sensitive to apoptosis induced by either PS-341 or its combination with TRAIL. These results demonstrate that DR5 upregulation mediates PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis in human lung cancer cells. We exclude the involvement of c-FLIP and survivin in mediating these events because c-FLIP (i.e., FLIPS) and survivin protein levels were actually elevated upon exposure to PS-341. Reduction of c-FLIP with c-FLIP siRNA sensitized cells to PS-341-induced apoptosis, suggesting that c-FLIP elevation protects cells from PS-341-induced apoptosis. Thus, the present study highlights the important role of DR5 upregulation in PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis. (Supported by GCC Distinguished Cancer Scholar award and DOD grant W81XWH-04-1-0142-VITAL)
Abstract 4439: Insular Cortex Atrophy as an Independent Determinant of Disrupted Diurnal Rhythm of Ambulatory Blood Pressure in Elderly Hypertension
Authors: Michiaki Nagai, Satoshi Hoshide, Joji Ishikawa, Kazuyuki Shimada, Kazuomi Kario
Journal: Circulation (2008)

Recently, insular cortex (Ic) is suggested to be a key site in limbic-autonomic integration. Association of Ic damage with diurnal blood pressure (BP) variation disruption, higher level of brain natriuretic peptide (BNP) and catecholamine were reported. We examined the relationship of Ic volume with ambulatory BP measures and these biomarkers. Amubulatory BP monitoring and brain MRI were performed in 55 elderly hypertensives. Right and left Ic volumes were measured using Intensity Contour-Mapping Algorithm. BNP, adrenaline and noradrenaline concentration were evaluated. Subjects were classified into Ic-atrophy group (n=14) and non-atrophy group (n=41) based on total Ic volume (right and left side) of 12.6 cm 3 (lowest quartile). In Ic-atrophy group, 24hr (144.5 vs 134.2 mmHg, p=0.032), sleep (143.4 vs 127.2 mmHg, p=0.002) systolic BP (SBP), nocturnal SBP dipping (1.30 vs 8.54 %, p=0.027) and BNP (60.6 vs 28.1 pg/ml, p=0.008) were significantly, and noradrenaline (373.5 vs 296.5 pg/ml, p=0.084) was marginally different from those in non-atrophy group. Right Ic volume was significantly correlated with 24hr (r=−0.271, p=0.046), sleep (r=−0.420, p=0.001) SBP, nocturnal SBP dipping (r=0.311, p=0.021) and noradrenaline (r=−0.334, p=0.013), while left Ic volume with 24hr (r=−0.279, p=0.039), sleep (r=−0.498, p=0.0001) SBP, nocturnal SBP dipping (r=0.409, p=0.002) and BNP (r=−0.363, p=0.006). In multiple linear regression analysis adjusted for age, gender and body mass index, left Ic volume was significantly negatively associated with sleep SBP (p=0.008) and BNP (p=0.001), and positively with nocturnal SBP dipping (p=0.044). In elderly hypertensives, predominant left Ic atrophy was significantly associated with sleep SBP measures and BNP. Ic damage, specifically in the left side, may partly contribute to disruption of diurnal ambulatory BP rhythm as well as cardiac function via central autonomic dysregulation.
Abstract 2574: A Novel Gain-of-function KCNJ2 Mutation Associated With Short QT Syndrome Impairs Inward Rectification of Kir 2.1 Currents
Authors: Tetsuhisa Hattori, Takeru Makiyama, Masaharu Akao, Eiji Ehara, Seiko Ohno, Yukiko Nishio, Hideki Itoh, Masayuki Yokode, Takeshi Kimura, Minoru Horie
Journal: Circulation (2009)

Background: Short QT syndrome is a recently recognized disorder associated with atrial fibrillation (AF) and sudden death due to ventricular arrhythmias. Mutations in several ion channel genes have...
Fatal methadone overdose
Authors: E. W Benbow, I. S D Roberts, A. Cairns
Journal: BMJ (1996)

responders and responders, the statistical power of this analysis was low, and the authors' main conclusion is based on the responses of only 54 patients.We wonder how many of the 31 non-responders would have had to be unsatisfied with the operation to reverse the results of the statistical analysis.We suspect that it would not be many.
Interpersonal outcome of cognitive behavioral treatment for chronically suicidal borderline patients
Authors: M M Linehan, D A Tutek, H L Heard, H E Armstrong
Journal: American Journal of Psychiatry (1994)

This study reports the efficacy of a cognitive behavioral outpatient treatment on interpersonal outcome variables for patients diagnosed with borderline personality disorder.In a 1-year clinical trial, 26 female patients with borderline personality disorder were randomly assigned to either dialectical behavior therapy or a treatment-as-usual comparison condition. All subjects met criteria of DSM-III-R and Diagnostic Interview for Borderline Patients for borderline personality disorder and were chronically suicidal.In both the intent-to-treat and treatment completion groups, dialectical behavior therapy subjects had significantly better scores on measures of anger, interviewer-rated global social adjustment, and the Global Assessment Scale and tended to rate themselves better on overall social adjustment than treatment-as-usual subjects.These results suggest that dialectical behavior therapy is a promising psychosocial intervention for improving interpersonal functioning among severely dysfunctional patients with borderline personality disorder.
Abstract 11325: Prediction of Diabetes in the Framingham Offspring Study
Authors: Ernst J Schaefer, Charles C White, Masumi Ai, Seiko Otokozawa, Katsuyuki Nakajima, Katalin Horvath, Bela F Asztalos, Peter W Wilson, L Adrienne Cupples
Journal: Circulation (2013)

Introduction: Diabetes mellitus, defined as a fasting serum glucose of > 125 mg/dL, is a leading cause of heart disease, kidney failure, blindness, and neuropathy. Lifestyle modification with calor...
Abstract 10125: A Fibrin Patch-based Enhanced Delivery of Human Embryonic Stem Cell-derived Vascular Cell Transplantation Improves Cardiac Function in Postinfarction LV Remodeling
Authors: Qiang Xiong, Katherine L Hill, Qinglu Li, Piradeep Suntharalingam, Abdul Mansoor, Xiaohong Wang, Mohammad N Jameel, Pengyuan Zhang, Cory Swingen, Dan S Kaufman, Jianyi Zhang
Journal: Circulation (2010)
High CD30 Ligand Expression by Epithelial Cells and Hassal's Corpuscles in the Medulla of Human Thymus
Authors: Paola Romagnani, Francesco Annunziato, Roberto Manetti, Carmelo Mavilia, Laura Lasagni, Cinzia Manuelli, Gabriella B. Vannelli, Vittorio Vanini, Enrico Maggi, Cinzia Pupilli, Sergio Romagnani
Journal: Blood (1998)
Involvement of ROS generation and induction of NADPH oxidases in decitabine-induced apoptosis in leukemia cells
Authors: Tamer Fandy, Anchalee Jiemjit, Steven Gore
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2268 

Decitabine (DAC) is currently FDA approved for the treatment of myelodysplastic syndrome and clinical trials demonstrated its efficacy in the treatment of different leukemias. However, the exact mechanism behind its clinical efficacy is still unclear. Cytotoxicity and apoptosis induction may contribute to the clinical efficacy of DAC and therefore understanding its mechanisms of cytotoxicity will be important for predicting patients’ response and for optimal combination with other cytotoxic drugs. We previously reported the decrease in DAC-induced apoptosis in leukemia cells upon co-treatment with the reactive oxygen species (ROS) scavenger; N-acetylcysteine (NAC), indicating ROS involvement in apoptosis induction. ROS generation was assessed by the fluorescent dye CM-H2DCFDA in 3 leukemia cell lines after DAC treatment for different time points (1, 3, 6, 24 and 48h); ROS generation was delayed, detectable after 24 and 48 h only. Superoxide anion generation was also detected by the fluorescent dye dihydroethidium, after 24 and 48 h but not at earlier time points. To investigate the significance of this ROS generation in DAC-induced apoptosis, NAC significantly decreased the loss in mitochondrial membrane potential (MMP) after DAC treatment, indicating the involvement of ROS in MMP loss. Inhibition of JNK, a downstream target of ROS, by the specific JNK inhibitor SP600125 also decreased the loss in MMP. Moreover, glutathione depletion by buthionine sulfoximine (BSO) significantly increased apoptosis induction by DAC. NADPH oxidases (NOX) are a family of enzymes responsible for the generation of superoxide anion. DAC induced mRNA expression of NOX2 and NOX4 (semi-quantitative RT-PCR), although NOX2 possesses no putative CpG island around its promoter region. In conclusion, DAC-induced ROS generation in leukemia cells leads to MMP disruption and subsequent apoptosis. This feature is potentially independent of DNA methyltransferase inhibition and needs to be considered when evaluating the mechanism of clinical efficacy and planning rational drug combinations.
Effect of Heparin Surface Modification of Polymethylmethacrylate Intraocular Lenses on Signs of Postoperative Inflammation after Extracapsular Cataract Extraction
Authors: Dott. Marco Borgioli, Douglas J. Coster, Richard F.T. Fan, John Henderson, Karl W. Jacobi, Graham R. Kirkby, Yoon-Kee Lai, José L. Menezo, Michel Montard, Jürgen Strobel, Josef Wollensak
Journal: Ophthalmology (1992)
The New Chemistry: A Showcase for Modern Chemistry and its Applications
Authors: Jeremy Playfer
Journal: BMJ (2001)

Ed Nina Hall Cambridge University Press, £30, pp 493 ISBN 0521 45224 4 Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> Medicine and chemistry are intimately related. One extreme view of doctors is as infantrymen firing molecules developed by chemists at targets ordained by molecular biologists. Even the most holistic practitioner accepts that chemical literacy is essential. As medical education shifts from foundationalism to problem oriented learning, chemistry remains a mandatory A level. Having not studied chemistry formally for over 30 years, I was drawn to this attractively produced book, hoping to refresh my knowledge. I discovered an uncompromising yet pleasurable return to basics, well illustrated by the first chapter, … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
Circulatory adjustments at birth: their importance in congenital heart disease.
Authors: Rudolph Am
Journal: Circulation (1969)

Normal physiological changes which occur in the circulatory system of infants at birth was described.  The relevancy of these changes for understanding the hemodynamic responses and disturbances which accompany congenital heart lesions in the newborn was emphasized.  During the transference of gas from the placenta to the lung there is a 1) decrease in pulmonary vascular resistance; 2) an increase in total systemic vascular resistance and 3) closure of the ductus arteriosus the ductus venosus and the foramen ovale.
Abstract #1467: Taxol modulates apoptosis-related intracellular calcium changes in breast cancer cells depending on extracellular calcium concentrations
Authors: Zhi Pan, Lauren Gollahon
Journal: Cancer Research (2009)

Taxol employs apoptosis to induce cell death in breast cancer treatment. Our previous study showed that the main intracellular Ca2+ pool, the endoplasmic reticulum (ER), provides a direct target for Taxol. Taxol-induced ER Ca2+ release resulted in a cytosolic Ca2+ increase and promoted subsequent apoptosis. However, the role of the extracellular Ca2+ pool in this process remains unclear. This study characterizes Taxol-induced Ca2+ changes in breast cancer cells under normal and extracellular Ca2+-free concentrations. The dynamic Ca2+ changes induced by Taxol were determined in living cultured breast cancer cells using Fluo4-AM Ca2+ dye. We showed Taxol at a clinically-relevant dose of 2.5 \#956;M, directly induced a rapid cytosolic Ca2+ increase, which promoted apoptosis. However, when Taxol was added into Ca2+ free medium, the cells did not show any increase. Instead, a rapid 40% decrease in the cytosolic Ca2+ level was observed. This interesting phenomenon indicates that Taxol affects Ca2+ homeostasis through different mechanisms dependent upon extracellular Ca2+ concentrations, thus differentially affecting subsequent apoptosis. In order to investigate where the cytosolic Ca2+ fluctuated upon Taxol addition, thapsigargin (TG), a highly specific ER Ca2+ pump inhibitor that blocks ER uptake, was applied to Ca2+-free medium. Results showed that the amplitude of the TG-induced cytosolic Ca2+ increase was much lower in the Taxol treated group with Ca2+ levels quickly decreasing below the basal level. Since the pump appeared to be irreversibly blocked by TG, it is unlikely that Ca2+ was pumped back into the ER. Therefore, the most likely reason for the continued rapid cytosolic decrease was an enhanced Ca2+ efflux. This was further confirmed when the extracellular Ca2+ replenishment only induced a 70% cytosolic Ca2+ elevation in the Taxol treated group followed by a sharp decrease below basal levels without any sustained plateau, indicating that Ca2+effluxeven overcame extracellular Ca2+ influx. To confirm these results, the extracellular Ca2+ chelator BAPTA was added, inducing apoptosis. This indicates that extracellular Ca2+ is required for the survival of breast cancer cells. Taxol combined treatment inhibited this extracellular Ca2+ depletion-induced apoptosis, which can be explained by Taxol enhanced-Ca2+ efflux. In summary, Taxol modulates Ca2+ homeostasis depending on extracellular Ca2+ concentrations, thus applying either stimulatory or inhibitory effects on subsequent apoptosis.These interesting results suggest that extracellular Ca2+ concentrations need to be carefully considered in Taxol treatment of breast cancer.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1467.
Characteristics of rituximab-resistant B-NHL clones: deficiencies in rituximab-mediated changes in lipid raft microdomains and cell signaling
Authors: Ali R. Jazirehi, Christine Bezombes, Guy Laurant, Massimo Libra, Benjamin Bonavida
Journal: Cancer Research (2006)

4657   The chimeric mouse anti-human CD20 mAb Rituximab, alone or combined with chemotherapy, has significant anti-lymphoma activity. A subset of patients does not respond initially or following treatment with rituximab. In order to investigate the mechanism of rituximab resistance, we have developed rituximab-resistant (RR) clones of Ramos and Daudi cells following culture with increasing concentrations of rituximab and limiting dilution analysis of single cells. The CD20+ expressing RR clones failed to respond to rituximab-mediated CDC, cytostasis, chemo-sensitization, cross-linked rituximab-mediated apoptosis (Jazirehi and Bonavida, Oncogene, 24:2121-43, 2005). Studies were undertaken to examine the underlying mechanism of rituximab resistance in the clones. The RR clones showed over-expression of the complement inhibitor CD59. In the wild type cells, treatment with rituximab resulted in a rapid and transient increase in acid-sphingomyelinase activity concomitant with cellular ceramide generation in lipid rafts. Rituximab treated cells externalized both acid sphingomyelinase and ceramide which co-localized with the CD20 receptor (Bezombes, et al., Blood,104:1166-73, 2004). Preliminary results show that rituximab-induced acid sphingomyelinase translocation and ceramide generation at the cell surface is reduced in RR clones compared to parental clones. We further analyzed possible mutations in the CD20 coding sequence. There was no difference in mutations between the parental and RR clones. Since lipid rafts serve as signaling platforms, thus, it seems that resistance to rituximab in these clones is due to a defect of the sphingomyelin-ceramide pathway. RR clones exhibit hyperactivation of the ERK1/2 and NF-kB survival signaling pathways concomitant with overexpression of Bcl-xL, Bcl-2, and Mcl-1. Treatment of RR clones with specific pharmacological inhibitors of these pathways sensitized the RR clones to various chemotherapeutic drugs (e.g., CDDP, Vincristine, Adrimycin, Taxol, Etoposide) and significant synergy in apoptosis was achieved. These findings demonstrate that the development of resistance to rituximab treatment may result from alteration of the cell signaling mediated by rituximab and failure to mobilize the lipid rafts on the cell membrane and the failure to inhibit downstream survival signaling pathways. In addition, the findings suggest the potential therapeutic application of combining sensitizing agents and conventional therapeutic drugs in the treatment of rituximab and drug-resistant B-NHL. This study was supported in part by a philanthropic contribution from the JCCC/Rosenfield Fund under the direction of David Leveton.