Jefferson College

BACKGROUND: We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays. METHODS: A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker-defibrillator. The primary composite end point was the time to death from or hospitalization for any cause. RESULTS: As compared with optimal pharmacologic therapy alone, cardiac-resynchronization therapy with a pacemaker decreased the risk of the primary end point (hazard ratio, 0.81; P=0.014), as did cardiac-resynchronization therapy with a pacemaker-defibrillator (hazard ratio, 0.80; P=0.01). The risk of the combined end point of death from or hospitalization for heart failure was reduced by 34 percent in the pacemaker group (P<0.002) and by 40 percent in the pacemaker-defibrillator group (P<0.001 for the comparison with the pharmacologic-therapy group). A pacemaker reduced the risk of the secondary end point of death from any cause by 24 percent (P=0.059), and a pacemaker-defibrillator reduced the risk by 36 percent (P=0.003). CONCLUSIONS: In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.

BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).

BACKGROUND: Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes. METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later. RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who underwent standard balloon angioplasty (96.1 percent vs. 89.6 percent, P = 0.011), a larger immediate increase in the diameter of the lumen (1.72 +/- 0.46 vs. 1.23 +/- 0.48 mm, P < 0.001), and a larger luminal diameter immediately after the procedure (2.49 +/- 0.43 vs. 1.99 +/- 0.47 mm, P < 0.001). At six months, the patients with stented lesions continued to have a larger luminal diameter (1.74 +/- 0.60 vs. 1.56 +/- 0.65 mm, P = 0.007) and a lower rate of restenosis (31.6 percent vs. 42.1 percent, P = 0.046) than those treated with balloon angioplasty. There were no coronary events (death; myocardial infarction; coronary-artery bypass surgery; vessel closure, including stent thrombosis; or repeated angioplasty) in 80.5 percent of the patients in the stent group and 76.2 percent of those in the angioplasty group (P = 0.16). Revascularization of the original target lesion because of recurrent myocardial ischemia was performed less frequently in the stent group than in the angioplasty group (10.2 percent vs. 15.4 percent, P = 0.06). CONCLUSIONS: In selected patients, placement of an intracoronary stent, as compared with balloon angioplasty, results in an improved rate of procedural success, a lower rate of angiographically detected restenosis, a similar rate of clinical events after six months, and a less frequent need for revascularization of the original coronary lesion.

Standardization of terminology used to describe the pattern and course of MS is essential for mutual understanding between clinicians and investigators. It is particularly important in design of, and recruitment for, clinical trials statistically powered for expected outcomes for given patient populations with narrowly defined entry criteria. For agents that prove safe and effective for MS, knowledge of the patient populations in definitive clinical trials assists clinicians in determining who may ultimately benefit from use of the medication. An international survey of clinicians involved with MS revealed areas of consensus about some terms classically used to describe types of the disease and other areas for which there was lack of consensus. In this report, we provide a summary of the survey results and propose standardized definitions for the most common clinical courses of patients with MS.

Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. However, the mechanisms linking obesity to insulin resistance and diabetes in humans remain largely unknown. In this study we examined the expression pattern of TNF-alpha mRNA in adipose tissues from 18 control and 19 obese premenopausal women by Northern blot analysis. TNF-alpha protein concentrations in plasma and in conditioned medium of explanted adipose tissue were measured by ELISA. Furthermore, the effects of weight reduction by dietary treatment of obesity on the adipose expression of TNF-alpha mRNA were also analyzed in nine premenopausal obese women, before and after a controlled weight-reduction program. These studies demonstrated that obese individuals express 2.5-fold more TNF-alpha mRNA in fat tissue relative to the lean controls (P < 0.001). Similar increases were also observed in adipose production of TNF-alpha protein but circulating TNF-alpha levels were extremely low or undetectable. A strong positive correlation was observed between TNF-alpha mRNA expression levels in fat tissue and the level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance. Finally, body weight reduction in obese subjects which resulted in improved insulin sensitivity was also associated with a decrease in TNF-alpha mRNA expression (45%, P < 0.001) in fat tissue. These results suggest a role for the abnormal regulation of this cytokine in the pathogenesis of obesity-related insulin resistance.

Background— Dual-chamber (DDDR) pacing preserves AV synchrony and may reduce heart failure (HF) and atrial fibrillation (AF) compared with ventricular (VVIR) pacing in sinus node dysfunction (SND). However, DDDR pacing often results in prolonged QRS durations (QRSd) as the result of right ventricular stimulation, and ventricular desynchronization may result. The effect of pacing-induced ventricular desynchronization in patients with normal baseline QRSd is unknown. Methods and Results— Baseline QRSd was obtained from 12-lead ECGs before pacemaker implantation in MOST, a 2010-patient, 6-year, randomized trial of DDDR versus VVIR pacing in SND. Cumulative percent ventricular paced (Cum%VP) was determined from stored pacemaker data. Baseline QRSd &lt;120 ms was observed in 1339 patients (707 DDDR, 632 VVIR). Cum%VP was greater in DDDR versus VVIR (90% versus 58%, P =0.001). Cox models demonstrated that the time-dependent covariate Cum%VP was a strong predictor of HF hospitalization in DDDR (hazard ratio [HR], 2.99 [95% CI, 1.15 to 7.75] for Cum%VP &gt;40%) and VVIR (HR 2.56 [95% CI, 1.48 to 4.43] for Cum%VP &gt;80%). The risk of AF increased linearly with Cum%VP from 0% to 85% in both groups (DDDR, HR 1.36 [95% CI, 1.09, 1.69]; VVIR, HR 1.21 [95% CI 1.02, 1.43], for each 25% increase in Cum%VP). Model results were unaffected by adjustment for known baseline predictors of HF hospitalization and AF. Conclusions— Ventricular desynchronization imposed by ventricular pacing even when AV synchrony is preserved increases the risk of HF hospitalization and AF in SND with normal baseline QRSd.

The hypoxia-inducible factor 1 transcriptional activator complex (HIF-1) is involved in the activation of the erythropoietin and several other hypoxia-responsive genes. The HIF-1 complex is composed of two protein subunits: HIF-1β/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed, and HIF-1α, which is not present in normal cells but induced under hypoxic conditions. The HIF-1α subunit is continuously synthesized and degraded under normoxic conditions, while it accumulates rapidly following exposure to low oxygen tensions. The involvement of the ubiquitin-proteasome system in the proteolytic destruction of HIF-1 in normoxia was studied by the use of specific inhibitors of the proteasome system. Lactacystin and MG-132 were found to protect the degradation of the HIF-1 complex in cells transferred from hypoxia to normoxia. The same inhibitors were able to induce HIF-1 complex formation when added to normoxic cells. Final confirmation of the involvement of the ubiquitin-proteasome system in the regulated degradation of HIF-1α was obtained by the use ofts20TG R cells, which contain a temperature-sensitive mutant of E1, the ubiquitin-activating enzyme. Exposure of ts20 cells, under normoxic conditions, to the non-permissive temperature induced a rapid and progressive accumulation of HIF-1. The effect of proteasome inhibitors on the normoxic induction of HIF-1 binding activity was mimicked by the thiol reducing agentN-(2-mercaptopropionyl)-glycine and by the oxygen radical scavenger 2-acetamidoacrylic acid. Furthermore,N-(2-mercaptopropionyl)-glycine induced gene expression as measured by the stimulation of a HIF-1-luciferase expression vector and by the induction of erythropoietin mRNA in normoxic Hep 3B cells. These last findings strongly suggest that the hypoxia induced changes in HIF-1α stability and subsequent gene activation are mediated by redox-induced changes. The hypoxia-inducible factor 1 transcriptional activator complex (HIF-1) is involved in the activation of the erythropoietin and several other hypoxia-responsive genes. The HIF-1 complex is composed of two protein subunits: HIF-1β/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed, and HIF-1α, which is not present in normal cells but induced under hypoxic conditions. The HIF-1α subunit is continuously synthesized and degraded under normoxic conditions, while it accumulates rapidly following exposure to low oxygen tensions. The involvement of the ubiquitin-proteasome system in the proteolytic destruction of HIF-1 in normoxia was studied by the use of specific inhibitors of the proteasome system. Lactacystin and MG-132 were found to protect the degradation of the HIF-1 complex in cells transferred from hypoxia to normoxia. The same inhibitors were able to induce HIF-1 complex formation when added to normoxic cells. Final confirmation of the involvement of the ubiquitin-proteasome system in the regulated degradation of HIF-1α was obtained by the use ofts20TG R cells, which contain a temperature-sensitive mutant of E1, the ubiquitin-activating enzyme. Exposure of ts20 cells, under normoxic conditions, to the non-permissive temperature induced a rapid and progressive accumulation of HIF-1. The effect of proteasome inhibitors on the normoxic induction of HIF-1 binding activity was mimicked by the thiol reducing agentN-(2-mercaptopropionyl)-glycine and by the oxygen radical scavenger 2-acetamidoacrylic acid. Furthermore,N-(2-mercaptopropionyl)-glycine induced gene expression as measured by the stimulation of a HIF-1-luciferase expression vector and by the induction of erythropoietin mRNA in normoxic Hep 3B cells. These last findings strongly suggest that the hypoxia induced changes in HIF-1α stability and subsequent gene activation are mediated by redox-induced changes. Mammalian cells are able to sense oxygen tension and turn on a series of genes in response to the lack of oxygen. The best characterized of these hypoxia-regulated genes is the one coding for erythropoietin (Epo), 1The abbreviations used are: Epo, erythropoietin; HIF-1, hypoxia-inducible factor 1; ARNT, aryl hydrocarbon receptor nuclear translocator; NMPG, N-(2-mercaptopropionyl)-glycine; PAS, PER-ARNT-SIM; Ac, acetyl; Z, benzyloxycarbonyl; E1, Ub-activating enzyme.1The abbreviations used are: Epo, erythropoietin; HIF-1, hypoxia-inducible factor 1; ARNT, aryl hydrocarbon receptor nuclear translocator; NMPG, N-(2-mercaptopropionyl)-glycine; PAS, PER-ARNT-SIM; Ac, acetyl; Z, benzyloxycarbonyl; E1, Ub-activating enzyme. the growth factor that regulates red cell production (reviewed in Ref. 1Ratcliffe P.J. Ebert B.L. Firth J.D. Gleadle J.M. Maxwell P.H. Nagao M. O'Rourke J.F. Pugh C.W. Wood S.M. Kidney Int. 1997; 51: 514-526Abstract Full Text PDF PubMed Scopus (45) Google Scholar). The hypoxia response of the Epo gene is controlled by an enhancer element located in the 3′-flanking region of the gene (2Beck I. Ramirez S. Weinmann R. Caro J. J. Biol. Chem. 1991; 266: 15563-15566Abstract Full Text PDF PubMed Google Scholar, 3Semenza G.L. Nejfelt M.K. Chi S.M. Antonarakis S.E. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 5680-5684Crossref PubMed Scopus (704) Google Scholar, 4Pugh C.W. Tan C.C. Jones R.W. Ratcliffe P.J. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 10553-10557Crossref PubMed Scopus (225) Google Scholar). Transcriptional activation of the enhancer is mediated by a hypoxia-inducible DNA-binding protein complex termed HIF-1, which binds to the site-1 sequences of the enhancer (5Semenza G.L. Wang G.L. Mol. Cell. Biol. 1992; 12: 5447-5454Crossref PubMed Scopus (2174) Google Scholar, 6Beck I. Weinmann R. Caro J. Blood. 1993; 82: 704-711Crossref PubMed Google Scholar). Similar enhancer elements, also involving the binding of HIF-1, have been identified in other hypoxia-responsive genes, such as those coding for vascular endothelial growth factor (7Levy A.P. Levy N.S. Wegner S. Goldberg M.A. J. Biol. Chem. 1995; 270: 13333-13340Abstract Full Text Full Text PDF PubMed Scopus (877) Google Scholar), glucose transporter-1, and several glycolytic enzymes (8Firth J.D. Ebert B.L. Pugh C.W. Ratcliffe P.J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6496-6500Crossref PubMed Scopus (443) Google Scholar, 9Semenza G.L. Roth P.H. Fang H.-M. Wang G.L. J. Biol. Chem. 1994; 269: 23757-23763Abstract Full Text PDF PubMed Google Scholar, 10Ebert B.L. Firth J.D. Ratcliffe P.J. J. Biol. Chem. 1995; 270: 29083-29089Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar). All these genes also respond like Epo, to cobalt ions and iron chelators, suggesting a common mechanism for oxygen sensing and gene activation. The recent cloning of the protein components of the HIF-1 complex identified two subunits, HIF-1α and HIF-1β, which belong to the subfamily of basic helix-loop-helix transcription factors containing a PAS (PER-ARNT-SIM) motif (11Wang G.L. Jiang B.-H. Rue E.A. Semenza G.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5510-5514Crossref PubMed Scopus (4995) Google Scholar). The HIF-1α subunit is a new member of the family, whereas HIF-1β corresponds to the known aryl hydrocarbon receptor nuclear translocator (ARNT) protein. Hypoxia induces the formation of HIF-1 complex by a process that requires protein synthesis (5Semenza G.L. Wang G.L. Mol. Cell. Biol. 1992; 12: 5447-5454Crossref PubMed Scopus (2174) Google Scholar). The mechanisms by which cells sense the lack of oxygen and initiate the hypoxic response are currently unknown. However, significant indirect evidence suggests that redox-mediated processes are likely involved in this step. Treatment of cells with hydrogen peroxide greatly reduces HIF-1 formation and Epo mRNA expression in response to hypoxic stimulation (12Fandrey J. Frede S. Jelkmann W. Biochem. J. 1994; 303: 507-510Crossref PubMed Scopus (224) Google Scholar, 13Wang G.L. Jiang B.-H. Semenza G.L. Biochem. Biophys. Res. Commun. 1995; 212: 550-556Crossref PubMed Scopus (158) Google Scholar). Since oxygen radicals and superoxide formation are very dependent on oxygen availability, their reduced formation under hypoxic conditions could serve as the initial signal in oxygen sensing. Of the components of the HIF-1 complex, ARNT protein is constitutively expressed in all cells while HIF-1α is present only in hypoxic cells. Thus, HIF-1 complex formation appears to be determined primarily by the abundance of the HIF-1α subunit. The observation that hypoxia does not modify HIF-1α mRNA levels suggested that HIF-1α protein content is regulated at the level of its mRNA translation or by changes in its rate of degradation (14Salceda S. Beck I. Caro J. Arch. Biochem. Biophys. 1996; 334: 389-394Crossref PubMed Scopus (83) Google Scholar). Indeed, Huang et al. (15Huang L.E. Arany Z. Livingston D.M. Bunn H.F. J. Biol. Chem. 1996; 271: 32253-32259Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar) recently reported that HIF-1α protein is highly unstable under normoxic conditions and that hypoxia significantly prolonged its half-life, thus allowing its accumulation and the formation of the complex. The mechanisms involved in the rapid degradation of HIF-1α under normoxic conditions and the signals involved in the stabilization process by hypoxia, are currently unknown. The results presented here indicate that the rapid degradation of HIF-1α under normoxic conditions is mediated by the ubiquitin-proteasome system and its stabilization is probably induced by redox-mediated changes. Hep 3B and B-1 cells were cultured in minimal essential medium (Life Technologies, Inc., Grand Island, NY) supplemented with 10% heat-inactivated fetal bovine serum (Hyclone, Logan, UT), penicillin (100 units/ml), and streptomycin (100 μg/ml) (Life Technologies, Inc.). Cells were maintained at 37 °C in an atmosphere of 5% CO2. Hep 3B cells were obtained from the American Tissue Culture Collection. The B-1 cell line is a Hep 3B-derived cell line which was stably transfected with an expression vector containing luciferase cDNA under the control of a minimal Epo promoter (330-base pair SfaNI-XbaIII fragment) and the hypoxia responsive enhancer from the human Epo gene (150-base pair ApaI/PstI fragment). The response of these cells to hypoxia, cobalt, and desferrioxamine has been reported (16Salceda S. Beck I. Srinivas V. Caro J. Kidney Int. 1997; 51: 556-559Abstract Full Text PDF PubMed Scopus (59) Google Scholar). For hypoxic stimulation cells were flushed with a gas mixture containing 0.5% O2, 5% CO2 and balanced N2 as already described (2Beck I. Ramirez S. Weinmann R. Caro J. J. Biol. Chem. 1991; 266: 15563-15566Abstract Full Text PDF PubMed Google Scholar). The BALB/c 3T3 andts20TG R (17Chowdary D.R. Dermody J.J. Jha K.K. Ozer H.L. Mol. Cell. Biol. 1994; 14: 1997-2003Crossref PubMed Scopus (266) Google Scholar) cell lines were provided by Dr. Harvey L. Ozer, Department of Microbiology and Molecular Genetics, UMDNJ, New Jersey Medical School, Newark, New Jersey. Both cell lines were maintained at 35 °C in a humidified incubator with 10% CO2 in Dulbecco's modified Eagle's medium (Life Technologies, Inc.) supplemented with 10% fetal bovine serum and antibiotics as described above. The permissive and non-permissive temperatures for the ts20TG R mutant cell line are 35 and 39 °C, respectively. For inhibitor experiments, calpain inhibitors I and II (Calbiochem-Novabiochem Corp., La Jolla, CA) were dissolved in ethanol. MG-132 (Peptides International, Inc., Knoxville, KY), E-64d (Sigma), interleukin-1β-converting enzyme inhibitor II (BACHEM Bioscience, Inc., King of Prussia, PA), and lactacystin (provided by Dr. S. Ōmura from The Kitasato Institute, Tokyo, Japan) (18Ōmura S. Fujimoto T. Otoguro K. Matsuzaki K. Moriguchi R. Tanaka H. Sasaki Y. J. Antibiot. ( Tokyo ). 1991; 44: 113-116Crossref PubMed Scopus (532) Google Scholar) were dissolved in dimethyl sulfoxide. Control cells were untreated or treated with dimethyl sulfoxide or ethanol. No differences in binding activity were found among these samples. Catalase, AD-1, and NMPG were from Sigma. Nuclear extracts were prepared from normal or treated cells as described previously (14Salceda S. Beck I. Caro J. Arch. Biochem. Biophys. 1996; 334: 389-394Crossref PubMed Scopus (83) Google Scholar). Electrophoretic mobility shift assay was performed by incubating 7 μg of nuclear extract with32P-labeled double-stranded oligonucleotide probe as described previously (6Beck I. Weinmann R. Caro J. Blood. 1993; 82: 704-711Crossref PubMed Google Scholar). For supershift assays, 1 μl of polyclonal antiserum raised in rabbits against recombinant HIF-1α or ARNT (1:5 dilution) were added to the nuclear extracts and incubated for 2 h on ice prior to adding labeled probe. Antibodies were kindly provided by Drs. G. L. Semenza (The Johns Hopkins University, School of Medicine, Baltimore, Maryland) and C. A. Bradfield (Department of Oncology, Medical School, University of Wisconsin-Madison, Madison, Wisconsin). A normal rabbit serum (preimmune) served as a negative antibody control. All cell extracts were prepared and analyzed using the Luciferase Assay System (Promega, Madison, WI). Briefly, 35-mm plates were washed twice with cold 1 × phosphate-buffered saline and 100 μl of 1 × lysis buffer was then added to the cells. Samples were collected and 5-μl aliquots were assayed using luciferase assay reagent. Luminescence was measured in a TD 20/20 luminometer (Promega), and results expressed as relative light units per μg of total protein. Protein concentrations were determined by a commercial kit (Bio-Rad), using bovine serum albumin as the standard. Total RNA was extracted by utilizing the as described by and Biochem. PubMed Scopus Google Scholar). For μg of total RNA was in a transferred to and by were in buffer at was performed in the same containing 1 × of probe at the same were washed twice with 2 × at temperature and with × at °C by exposure to probe was obtained from a human cDNA as already described C.W. Tan C.C. Jones R.W. Ratcliffe P.J. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 10553-10557Crossref PubMed Scopus (225) Google Scholar) and labeled with using a translation kit (Life Technologies, Inc.). by Wang et al. (11Wang G.L. Jiang B.-H. Rue E.A. Semenza G.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5510-5514Crossref PubMed Scopus (4995) Google Scholar) that following of hypoxia is a rapid of HIF-1α protein and HIF-1 complex with a of the of proteolytic degradation in this rapid a series of inhibitors with enzyme Nuclear extracts were obtained from Hep 3B cells with hypoxia for h and then transferred to normoxia for an inhibitors were added the last of the hypoxic for lactacystin that it was added 1 h the and while in normoxia. in the shift in from hypoxia to normoxia a rapid of the HIF-1 complex which was by the of the in normoxia. of the inhibitor to a inhibitor this whereas a and a highly specific The from hypoxia to normoxia and the of inhibitors effect on the expression of binding activity 1 The effect of calpain inhibitor which also has activity against the and the lack of effect of E-64d suggested that the ubiquitin-proteasome system was likely involved in HIF-1 The of the proteasome was using the inhibitors and the as in in this is the lack of effect of the an inhibitor of enzyme of proteasome inhibitors on HIF-1 binding of as in shift using HIF-1 probe. of hypoxic of normoxia are: and shift in utilizing The results indicate that the rapid of HIF-1 complex of hypoxia could be by the use of these inhibitors could also induce the formation of HIF-1 complex in normoxic cells. For this Hep 3B cells were incubated under normoxic conditions for h in the of inhibitors and their nuclear extracts assayed for HIF-1 activity by shift in calpain inhibitor and to a calpain inhibitor and the formation of HIF-1 complex in normoxic cells, whereas and E-64d effect these effect on of the of HIF-1α and ARNT in the induced was obtained by supershift utilizing specific against protein subunits, as in C. using that lactacystin the level of in transfected normoxic cells. Srinivas and J. The of changes in HIF-1 induction was studied in normoxic Hep 3B cells to the agentN-(2-mercaptopropionyl)-glycine in of cells with NMPG for h induced HIF-1 complex, while effect was in A effect of NMPG on the proteasome system was by the that NMPG not the expression of whereas the proteasome inhibitors induced it in the of HIF-1α and ARNT in the complex. the effect of NMPG on gene activation a Hep 3B-derived cell line stably transfected with a luciferase expression vector containing a minimal Epo promoter and a These cells have been to respond to hypoxia by luciferase expression in a (16Salceda S. Beck I. Srinivas V. Caro J. Kidney Int. 1997; 51: 556-559Abstract Full Text PDF PubMed Scopus (59) Google Scholar). Exposure of B-1 cells to concentrations of NMPG for h a stimulation of luciferase as in A. Similar results were found when the oxygen radical scavenger 2-acetamidoacrylic was used A effect NMPG and hypoxia is in B-1 cells were to NMPG at or 0.5% for The effect of NMPG was also mimicked by the of which and its confirmation of the effect of NMPG on gene expression was obtained by of RNA obtained from normoxic Hep 3B cells treated with NMPG for as in the proteasome inhibitors not Epo No changes in HIF-1α mRNA levels were found in untreated or hypoxia, proteasome and Hep 3B cells of is the in the degradation of by the proteasome system. a basic protein of found in all cells, be to in an Ub-activating enzyme this in the formation of an the involvement of the ubiquitin-proteasome in the proteolytic degradation of HIF-1α under normoxic conditions a BALB/c cell containing a temperature-sensitive mutant of (17Chowdary D.R. Dermody J.J. Jha K.K. Ozer H.L. Mol. Cell. Biol. 1994; 14: 1997-2003Crossref PubMed Scopus (266) Google Scholar). Cells cultured under the permissive temperature a whereas the shift to the non-permissive temperature For these experiments, ts20 cells were cultured under normoxic conditions at 35 and 39 °C for and h and nuclear extracts were obtained and for HIF-1 complex formation by shift in cells at 35 °C not HIF-1, whereas the shift to the non-permissive temperature a progressive accumulation of the complex. No were on binding against HIF-1α and ARNT the of the complex as HIF-1. Similar with the 3T3 cell line induction of HIF-1 with the temperature Hypoxia of the Epo and other genes are mediated by the binding of a hypoxia-inducible complex (HIF-1) to a hypoxia-responsive process requires protein synthesis (5Semenza G.L. Wang G.L. Mol. Cell. Biol. 1992; 12: 5447-5454Crossref PubMed Scopus (2174) Google Scholar) and is also dependent on as it is by several inhibitors (16Salceda S. Beck I. Srinivas V. Caro J. Kidney Int. 1997; 51: 556-559Abstract Full Text PDF PubMed Scopus (59) Google Scholar, G.L. Jiang B.-H. Semenza G.L. Biochem. Biophys. Res. Commun. 1995; PubMed Scopus Google Scholar). The protein components of this complex were recently and characterized as to the PAS of the basic helix-loop-helix of transcription factors (11Wang G.L. Jiang B.-H. Rue E.A. Semenza G.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5510-5514Crossref PubMed Scopus (4995) Google Scholar). of the protein HIF-1β, is the already known ARNT, the of the aryl hydrocarbon receptor protein. ARNT protein is constitutively expressed in normal cells and its level is not by hypoxic conditions. the the other HIF-1α, a new member of that family, is not expressed in normoxic cells, but accumulates rapidly under hypoxic conditions. Since HIF-1α mRNA is constitutively present in normoxic cells, the lack of HIF-1α protein is the of a lack of translation of the mRNA or the of a rapid degradation of the protein. A recent by al. (15Huang L.E. Arany Z. Livingston D.M. Bunn H.F. J. Biol. Chem. 1996; 271: 32253-32259Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar) that the of the HIF-1α protein is in normoxic conditions and is prolonged hypoxic The mechanisms for the rapid degradation of the protein were not Control of gene expression by regulated of transcription factors has been recently described to be an and mechanism of gene transcription (reviewed in Ref. H.L. Biol. 1996; PubMed Scopus Google Scholar). all transcription factors are degraded as of the of the stability of factors is of control at a very rapid rate and has the other of its cells on the and the proteasome for the degradation of for degradation are modified by the of of a basic to specific (reviewed in Ref. W. Biochem. Sci. 1996; Full Text PDF PubMed Scopus Google Scholar). The process requires several the one utilizing E1, an enzyme that a thiol the of regulated in the of HIF-1α, a series of inhibitors with proteolytic enzyme The cells were by hypoxia and the effect of the inhibitors on the rate of degradation of the HIF-1 complex was by shift These that controlled was involved in HIF-1 formation and that it was mediated by the proteasome it was by a highly specific inhibitor of the proteasome L. L. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). No significant effect was with the use of inhibitors or with inhibitors of enzyme the proteolytic system The lack of involvement of this last was by the use of a stably transfected cell line the protein J. T. G. Res. 1997; Google Scholar), which HIF-1 activation The of in the induction of HIF-1 was then studied in normoxic cells. These that induced HIF-1 complex formation in a to hypoxic confirmation of the involvement of the ubiquitin-proteasome system in the of HIF-1α protein levels and HIF-1 complex formation was obtained the use of a cell line containing a temperature-sensitive mutant of the ubiquitin-activating enzyme. These cell lines were in H. L. and to the degradation of (17Chowdary D.R. Dermody J.J. Jha K.K. Ozer H.L. Mol. Cell. Biol. 1994; 14: 1997-2003Crossref PubMed Scopus (266) Google Scholar). ts20 cells were cultured under normoxic conditions at the permissive temperature HIF-1 was whereas a shift to 39 °C a rapid accumulation of the complex. The HIF-1α protein contain several in other have been in degradation M. Biochem. Sci. 1996; Full Text PDF PubMed Scopus Google Scholar). However, the sequences that HIF-1α have not been is of to that proteasome induced HIF-1 complex formation in normoxic cells, not gene However, this is likely to a effect of these inhibitors lactacystin a in expression of the luciferase gene and the stimulation of its expression by cobalt, and hypoxia not is not HIF-1 complex formation is and for transcriptional activation. previously reported by Semenza et G.L. Jiang B.-H. R. A. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar) that of HIF-1α in normoxic conditions is to transcription of 1 its hypoxia response The mechanisms of oxygen sensing and the mechanisms by which hypoxia induces stabilization of the HIF-1α protein are currently unknown. The by several of an effect of on HIF-1 formation and Epo gene expression suggested that changes are likely to be involved in oxygen sensing signal Huang et al. (15Huang L.E. Arany Z. Livingston D.M. Bunn H.F. J. Biol. Chem. 1996; 271: 32253-32259Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar) recently reported that of the thiol reducing and hypoxia induced gene activation. The effect with the reducing thiol NMPG on HIF-1 formation and Epo gene activation in normoxic cells a that changes involved in the hypoxic The of the radicals that these signals and the mechanism of of the reducing are not A effect on HIF-1α the reducing already in their reduced changes could modify HIF-1α by the activity of and J. have that the induction of HIF-1 by NMPG could be by evidence suggest that radicals are in signal The of radicals in cells is strongly by the that 2-acetamidoacrylic the luciferase activity in cells under normoxic conditions. as as other have been described to with and superoxide and radicals M. 1993; PubMed Scopus Google Scholar). was recently reported that a J.M. M.A. A. J. Biochem. 1997; PubMed Scopus Google Scholar). have been described and in the of the mechanism for activation appears to on the of B.L. S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). dependent changes of the degradation rate of by the proteasome system was recently reported to be dependent on the of M. 1997; PubMed Scopus Google Scholar). Since protein is a in HIF-1 the of in HIF-1α stabilization is a Dr. H. L. Ozer for the BALB/c 3T3 and ts20TG R cells and Dr. M. Institute, Medical University, for the stably transfected cell line the Drs. G. L. Semenza and C. A. Bradfield for the HIF-1α and Dr. S. Ōmura for of for for and R. for are to Dr. S. for the

PURPOSE: This longitudinal study was designed to examine changes in medical students' empathy during medical school and to determine when the most significant changes occur. METHOD: Four hundred fifty-six students who entered Jefferson Medical College in 2002 (n = 227) and 2004 (n = 229) completed the Jefferson Scale of Physician Empathy at five different times: at entry into medical school on orientation day and subsequently at the end of each academic year. Statistical analyses were performed for the entire cohort, as well as for the "matched" cohort (participants who identified themselves at all five test administrations) and the "unmatched" cohort (participants who did not identify themselves in all five test administrations). RESULTS: Statistical analyses showed that empathy scores did not change significantly during the first two years of medical school. However, a significant decline in empathy scores was observed at the end of the third year which persisted until graduation. Findings were similar for the matched cohort (n = 121) and for the rest of the sample (unmatched cohort, n = 335). Patterns of decline in empathy scores were similar for men and women and across specialties. CONCLUSIONS: It is concluded that a significant decline in empathy occurs during the third year of medical school. It is ironic that the erosion of empathy occurs during a time when the curriculum is shifting toward patient-care activities; this is when empathy is most essential. Implications for retaining and enhancing empathy are discussed.

BACKGROUND AND METHODS: Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS: Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS: In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.

PURPOSE: To test the hypothesis that physicians' empathy is associated with positive clinical outcomes for diabetic patients. METHOD: A correlational study design was used in a university-affiliated outpatient setting. Participants were 891 diabetic patients, treated between July 2006 and June 2009, by 29 family physicians. Results of the most recent hemoglobin A1c and LDL-C tests were extracted from the patients' electronic records. The results of hemoglobin A1c tests were categorized into good control (<7.0%) and poor control (>9.0%). Similarly, the results of the LDL-C tests were grouped into good control (<100) and poor control (>130). The physicians, who completed the Jefferson Scale of Empathy in 2009, were grouped into high, moderate, and low empathy scorers. Associations between physicians' level of empathy scores and patient outcomes were examined. RESULTS: Patients of physicians with high empathy scores were significantly more likely to have good control of hemoglobin A1c (56%) than were patients of physicians with low empathy scores (40%, P < .001). Similarly, the proportion of patients with good LDL-C control was significantly higher for physicians with high empathy scores (59%) than physicians with low scores (44%, P < .001). Logistic regression analyses indicated that physicians' empathy had a unique contribution to the prediction of optimal clinical outcomes after controlling for physicians' and patients' gender and age, and patients' health insurance. CONCLUSIONS: The hypothesis of a positive relationship between physicians' empathy and patients' clinical outcomes was confirmed, suggesting that physicians' empathy is an important factor associated with clinical competence and patient outcomes.

Given its rarity, drug-related hepatotoxicity may not be seen during the initial clinical trials of a new medication. After approval, when many more patients are exposed, toxic effects that are very infrequent may emerge. This review explains the difficulties in identifying the cause of hepatotoxic effects in such situations and provides clinical guidance with regard to the detection, evaluation, and possible prevention of drug-related hepatotoxicity.

The present study was designed to develop a brief instrument to measure empathy in health care providers in patient care situations. Three groups participated in the study: Group 1 consisted of 55 physicians, Group 2 was 41 internal medicine residents, and Group 3 was composed of 193 third-year medical students. A 90-item preliminary version of the Empathy scale was developed based on a review of the literature and distributed to Group 1 for feedback. After pilot testing, a revised and shortened 45-item version of the instrument was distributed to Groups 2 and 3. A final version of the Jefferson Scale of Physician Empathy containing 20 items based on statistical analyses was constructed. Psychometric findings provided support for the construct validity, criterion-related validity (convergent and discriminant), and internal consistency reliability (coefficient alpha) of the scale scores.

BACKGROUND: The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. METHODS: In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. RESULTS: Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). CONCLUSIONS: The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).

CONTEXT: It has been reported that medical students become more cynical as they progress through medical school. This can lead to a decline in empathy. Empirical research to address this issue is scarce because the definition of empathy lacks clarity, and a tool to measure empathy specifically in medical students and doctors has been unavailable. OBJECTIVE: To examine changes in empathy among medical students as they progress through medical school. MATERIALS AND SUBJECTS: A newly developed scale (Jefferson Scale of Physician Empathy [JSPE], with 20 Likert-type items) was administered to 125 medical students at the beginning (pretest) and end (post-test) of Year 3 of medical school. This scale was specifically developed for measuring empathy in patient care situations and has acceptable psychometric properties. METHODS: In this prospective longitudinal study, the changes in pretest/post-test empathy scores were examined by using t-test for repeated measure design; the effect size estimates were also calculated. RESULTS: Statistically significant declines were observed in 5 items (P < 0.01) and the total sores of the JSPE (P < 0.05) between the 2 test administrations. CONCLUSIONS: Although the decline in empathy was not clinically important for all of the statistically significant findings, the downward trend suggests that empathy could be amenable to change during medical school. Further research is needed to identify factors that contribute to changes in empathy and to examine whether targeted educational programmes can help to retain, reinforce and cultivate empathy among medical students for improving clinical outcomes.

BACKGROUND: Infantile Krabbe's disease produces progressive neurologic deterioration and death in early childhood. We hypothesized that transplantation of umbilical-cord blood from unrelated donors before the development of symptoms would favorably alter the natural history of the disease among newborns in whom the disease was diagnosed because of a family history. We compared the outcomes among these newborns with the outcomes among infants who underwent transplantation after the development of symptoms and with the outcomes in an untreated cohort of affected children. METHODS: Eleven asymptomatic newborns (age range, 12 to 44 days) and 14 symptomatic infants (age range, 142 to 352 days) with infantile Krabbe's disease underwent transplantation of umbilical-cord blood from unrelated donors after myeloablative chemotherapy. Engraftment, survival, and neurodevelopmental function were evaluated longitudinally for four months to six years. RESULTS: The rates of donor-cell engraftment and survival were 100 percent and 100 percent, respectively, among the asymptomatic newborns (median follow-up, 3.0 years) and 100 percent and 43 percent, respectively, among the symptomatic infants (median follow-up, 3.4 years). Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-moderate delays in expressive language and mild-to-severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement. CONCLUSIONS: Transplantation of umbilical-cord blood from unrelated donors in newborns with infantile Krabbe's disease favorably altered the natural history of the disease. Transplantation in babies after symptoms had developed did not result in substantive neurologic improvement.

CONTEXT: Empathy is a major component of a satisfactory doctor-patient relationship and the cultivation of empathy is a learning objective proposed by the Association of American Medical Colleges (AAMC) for all American medical schools. Therefore, it is important to address the measurement of empathy, its development and its correlates in medical schools. OBJECTIVES: We designed this study to test two hypotheses: firstly, that medical students with higher empathy scores would obtain higher ratings of clinical competence in core clinical clerkships; and secondly, that women would obtain higher empathy scores than men. MATERIALS AND SUBJECTS: A 20-item empathy scale developed by the authors (Jefferson Scale of Physician Empathy) was completed by 371 third-year medical students (198 men, 173 women). METHODS: Associations between empathy scores and ratings of clinical competence in six core clerkships, gender, and performance on objective examinations were studied by using t-test, analysis of variance, chi-square and correlation coefficients. RESULTS: Both research hypotheses were confirmed. Empathy scores were associated with ratings of clinical competence and gender, but not with performance in objective examinations such as the Medical College Admission Test (MCAT), and Steps 1 and 2 of the US Medical Licensing Examinations (USMLE). CONCLUSIONS: Empathy scores are associated with ratings of clinical competence and gender. The operational measure of empathy used in this study provides opportunities to further examine educational and clinical correlates of empathy, as well as stability and changes in empathy at different stages of undergraduate and graduate medical education.

Treatment of prostate cancer cell lines expressing bcl-2 with taxol induces bcl-2 phosphorylation and programmed cell death, whereas treatment of bcl-2-negative prostate cancer cells with taxol does not induce apoptosis. bcl-2 phosphorylation seems to inhibit its binding to bax since less bax was observed in immunocomplex with bcl-2 in taxol-treated cancer cells. These findings support the use of the anticancer drug taxol for the treatment of bcl-2-positive prostate cancers and other bcl-2-positive malignancies, such as follicular lymphoma.

Cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with obesity and type 2 diabetes mellitus, and recent work has elucidated several potential mechanisms by which increased adiposity enhances cardiovascular risk. Excess adipose tissue, especially in certain compartments, leads to reduced insulin sensitivity in metabolically responsive tissues, which is frequently associated with a set of cardiovascular risk factors, including hyperinsulinemia, hypertension, dyslipidemia, and glucose intolerance. Increasing attention has also been paid to the direct vascular effects of plasma proteins that originate from adipose tissue, especially adiponectin, which exhibits potent antiinflammatory and antiatherosclerotic effects. This brief review will summarize recent work on the vascular actions of adiponectin, which complements the growing body of information on its insulin-sensitizing effects in glucose and lipid metabolism. Adiponectin is now a recognized component of a novel signaling network among adipocytes, insulin-sensitive tissues, and vascular function that has important consequences for cardiovascular risk.

American medicine is in the midst of a professional evolution driven by a refocusing of medicine's regard for the patient's viewpoint. Historically, medicine has been largely physician centered, but physicians have begun to incorporate patients' perspectives in ways that increasingly matter. Some call this shift "patient-centered" care. In support of the view that this refocusing reflects a broad professional shift, we describe the evolution to patient-centered care in many areas of medicine: patient care, health-related law, medical education, research, and quality assessment.

A woman visits the doctor for her six-week postpartum evaluation. She reports that she cannot sleep even if her baby sleeps. She cries daily and worries constantly. She does not feel hungry and is not eating regularly. Making decisions is overwhelming. How should she be evaluated and treated?