Detection of abnormal calf muscle metabolism in patients with heart failure using phosphorus-31 nuclear magnetic resonance

Patients with heart failure frequently report leg fatigue during exercise. At present, however, there is no objective method of detecting leg muscle abnormalities in such patients. To determine if phosphorus-31 nuclear magnetic resonance spectroscopy can provide such information, this technique was used to compare calf responses to stair climbing and plantarflexion in 20 patients with heart failure (peak oxygen consumption (VO2) of 13.6 +/- 5 ml/kg/min, ejection fraction 20 +/- 5%) and 9 age-matched normal subjects. Work was quantified by measuring VO2. At rest, both groups exhibited similar inorganic phosphorus to phosphocreatine (Pi/PCr) ratios (patients with heart failure 0.21 +/- 0.07, normal subjects 0.21 +/- 0.06, difference not significant) and pH levels (patients with heart failure 7.06 +/- 0.17, normal subjects 7.05 +/- 0.11, difference not significant). In both normal subjects and patients with heart failure, exercise resulted in a progressive rise in Pi/PCr as VO2 increased. However, examination of the relation of VO2 versus Pi/PCr revealed steeper slopes in patients with heart failure during both stair climbing and plantar-flexion. Neither form of exercise decreased calf pH in normal subjects. In the patients with heart failure, significant decreases in pH were noted during the highest work level of plantarflexion (pH of heart failure patients 6.86 +/- 0.20, pH of normal subjects 7.07 +/- 0.14, p less than 0.01). Metabolic recovery time was also prolonged in the patients with heart failure versus normal subjects (3.3 +/- 0.8 vs 2.1 +/- 0.5 minutes, respectively, p less than 0.002). These findings indicate that phosphorus-31 nuclear magnetic resonance provides objective evidence of leg muscle abnormalities in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activity of fleroxacin alone and in combination with clindamycin or metronidazole in experimental intra-abdominal abscesses.

To assess the potential efficacy of fleroxacin in combination with clindamycin or metronidazole in mixed aerobic and anaerobic infections, we used a rat model of intra-abdominal abscesses in which the inoculum consisted of pooled rat feces mixed with BaSO4. Two hours after bacterial challenge, antimicrobial therapy was begun intravenously with regimens designed to stimulate human pharmacokinetics. A combination of clindamycin and gentamicin was included as an established treatment regimen. After 8.5 days of therapy, final bacterial counts in abscesses showed that fleroxacin alone or combined with metronidazole or clindamycin effectively eradicated Escherichia coli, with bacterial densities of < or = 2.84 +/- 0.1, < or = 2.9 +/- 0.1, and < or = 2.9 +/- 0.1 (mean +/- standard error of the mean) log10 CFU/g, respectively. The addition of either clindamycin or metronidazole to fleroxacin substantially enhanced the effectiveness of the regimens against Bacteroides fragilis, with bacterial counts of < or = 3.0 +/- 0.1 or < or = 2.9 +/- 0.1 log10 CFU/g, respectively, versus 9.2 +/- 0.2 log10 CFU/g for fleroxacin alone. The combination of metronidazole and fleroxacin also resulted in a significantly greater reduction of peptostreptococci and Bacteroides thetaiotaomicron than fleroxacin alone (< or = 2.9 +/- 0.1 versus 6.1 +/- 0.9 log10 CFU/g and 3.3 +/- 0.4 versus 8.3 +/- 0.1 log10 CFU/g, respectively). Except for those of B. fragilis, counts of other anaerobes were reduced to a greater extent by metronidazole plus fleroxacin than by clindamycin plus fleroxacin, although differences were not always significant. Metronidazole plus fleroxacin was at least as active a clindamycin plus gentamicin against all species and was significantly more active against Clostridium spp. No regimen effectively eradicated enterococci from the abscesses. These results suggest that the addition of either metronidazole or clindamycin would effectively enhance the spectrum of fleroxacin for treatment of mixed aerobic and anaerobic infections.     

Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States.

Three hundred fifty-two blood culture isolates of viridans group streptococci obtained from 43 U.S. medical centers during 1993 and 1994 were characterized. Included were 48 isolates of "Streptococcus milleri," 219 S. mitis isolates, 29 S. salivarius isolates, and 56 S. sanguis isolates. High-level penicillin resistance (MIC, > or = 4.0 micrograms/ml) was noted among 13.4% of the strains; for 42.9% of the strains, penicillin MICs were 0.25 to 2.0 micrograms/ml (i.e., intermediate resistance). In general, amoxicillin was slightly more active than penicillin. The rank order of activity for five cephalosporins versus viridans group streptococci was cefpodoxime = ceftriaxone > cefprozil = cefuroxime >> cephalexin. The percentages of isolates resistant (MIC, > or = 2 micrograms/ml) to these agents were 15, 17, 18, 20, and 96, respectively. The rates of resistance to erythromycin, tetracycline, and trimethoprim-sulfamethoxazole were 12 to 38%. Resistance to either chloramphenicol or ofloxacin was uncommon (i.e., < 1%). In general, among the four species, S. mitis was the most resistant and "S. milleri" was the most susceptible.     

Circulatory improvement after hydralazine or isosorbide dinitrate administration in patients with heart failure: Effect on metabolic responses to submaximal exercise

Hydralazine and isosorbide dinitrate can increase the cardiac output during submaximal exercise in patients with heart failure but whether this increase improves oxygen delivery to underperfused exercising muscle is uncertain. To investigate this question, we measured three systemic markers of skeletal muscle oxygen availability—exercise V?O₂, mixed venous lactate concentration and oxygen debt—during submaximal exercise in 15 patients with heart failure both before and after hydralazine (nine patients) or isosorbide dinitrate (eight patients) administration. Hydralazine increased the cardiac output during exercise from 4.9 ± 1.2 liter/min to 6.5 ± 1.8 liter/min (p < 0.01) but had no effect on exercise V?O₂ (control, 531 ± 135 ml/min; hydralazine, 489 ± 102 ml/min), peak lactate concentration (control, 18.3 ± 4.2 mg/dl; hydralazine, 17.9 ± 3.6 mg/dl) or oxygen debt (control, 474 ± 213 ml; hydralazine, 465 ± 170 ml) (all p > 0.10). Isosorbide dinitrate increased the cardiac output during exercise from 4.6 ± 0.9 liter/min to 5.3 ± 0.8 liter/min (p < 0.01) but also did not change exercise V?O₂ (control, 488 ± 62 ml/min; isosorbide, 473 ± 44 ml/min), peak lactate concentration (control, 19.2 ± 6.0 mg/dl; isosorbide, 21.4 ± 8.2 mg/dl) or oxygen debt (control, 522 ± 154 ml; isosorbide, 445 ± 147 ml) (all p > 0.10). We conclude that short-term administration of hydralazine or nitrates to patients with heart failure can substantially improve circulatory function during exercise but that this improvement probably does not enhance skeletal muscle nutritional flow.     

Vasodilatory behavior of skeletal muscle arterioles in patients with nonedematous chronic heart failure

During maximal upright exercise, blood flow to working skeletal muscle is frequently reduced in patients with nonedematous chronic heart failure. It has been speculated that this reduced muscle flow may be caused in part by an intrinsic impairment of skeletal muscle vasodilatory capacity. To test this hypothesis, forearm blood flow and resistance were compared during forearm exercise and in response to transient forearm ischemia (10 min) in 22 patients with heart failure and in 11 normal subjects. During forearm exercise, both groups exhibited comparable forearm blood flows (ml/min/100 ml) (0.2 W: normal 5.9 +/- 3.1, heart failure 6.5 +/- 2.8; 0.4 W: normal 8.2 +/- 5.5, heart failure 8.2 +/- 3.6; 0.6 W: normal 11.5 +/- 6.8, heart failure 11.8 +/- 4.8 [all p = NS]) and forearm vascular resistance (mm Hg/ml/min/100 ml) (0.2 W: normal 23.1 +/- 12.4, heart failure 18.5 +/- 7.8; 0.4 W: normal 16.9 +/- 7.7, heart failure 14.7 +/- 6.4; 0.6 W: normal 13.1 +/- 7.7, heart failure 10.3 +/- 4.1 [all p = NS]). Ten minutes of forearm ischemia, an intervention that produces maximal forearm vasodilation, also resulted in comparable forearm vascular resistances in both groups (normal 4.1 +/- 2.4, heart failure 3.8 +/- 1.3 mm Hg/ml/min/100 ml/p = NS). These data suggest that skeletal muscle vasodilatory capacity is not intrinsically impaired in patients with nonedematous chronic heart failure.     

First endoscopic-histologic follow-up in patients with body-predominant atrophic gastritis: when should it be done?

BACKGROUND: Body-predominant atrophic gastritis is considered a risk factor for gastric cancer and carcinoid. Timing of follow-up for patients with this disorder has not been defined. This study was undertaken to determine the optimal time for the first endoscopic/histologic follow-up in patients with body-predominant atrophic gastritis. METHODS: Forty-two patients with body-predominant atrophic gastritis were randomly assigned to 1 of 2 follow-up intervals: group A (n = 22) at 24 months and group B (n = 20) at 48 months. At baseline and follow-up patients underwent gastroscopy at which biopsies were obtained from the antrum and body for histopathology and evaluation for enterochromaffin-like cells. RESULTS: In group A patients, 2 antral hyperplastic polyps (9.1%) were present at baseline and 4 antral hyperplastic polyps (18.2%) were found at follow-up. In group B patients, baseline gastroscopy revealed 2 antral hyperplastic polyps (10%) and follow-up 2 antral hyperplastic polyps (10%) and 1 carcinoid tumor (5%) in the body. Atrophy and intestinal metaplasia scores in gastric body and antral mucosa in both groups did not change significantly between baseline and follow-up, except an increase in antral mucosa atrophy in group B patients (p = 0.02) was revealed. CONCLUSIONS: The results of this study indicate that performing the first follow-up in patients with body-predominant atrophic gastritis need not be earlier than at 4 years after diagnosis. This interval is satisfactory for detection of potential neoplastic lesions.     

Gemcitabine sensitizes lung cancer cells to Fas/FasL system‐mediated killing

Gemcitabine is a chemotherapy agent commonly used in the treatment of non‐small cell lung cancer (NSCLC) that has been demonstrated to induce apoptosis in NSCLC cells by increasing functionally active Fas expression. The aim of this study was to evaluate the Fas/Fas ligand (FasL) system involvement in gemcitabine‐induced lung cancer cell killing. NSCLC H292 cells were cultured in the presence or absence of gemcitabine. FasL mRNA and protein were evaluated by real‐time PCR, and by Western blot and flow cytometry, respectively. Apoptosis of FasL‐expressing cells was evaluated by flow cytometry, and caspase‐8 and caspase‐3 activation by Western blot and a colorimetric assay. Cytotoxicity of lymphokine‐activated killer (LAK) cells and malignant pleural fluid lymphocytes against H292 cells was analysed in the presence or absence of the neutralizing anti‐Fas ZB4 antibody, by flow cytometry. Gemcitabine increased FasL mRNA and total protein expression, the percentage of H292 cells bearing membrane‐bound FasL (mFasL) and of mFasL‐positive apoptotic H292 cells, as well as caspase‐8 and caspase‐3 cleavage. Moreover, gemcitabine increased CH11‐induced caspase‐8 and caspase‐3 cleavage and proteolytic activity. Cytotoxicity of LAK cells and pleural fluid lymphocytes was increased against gemcitabine‐treated H292 cells and was partially inhibited by ZB4 antibody. These results demonstrate that gemcitabine: (i) induces up‐regulation of FasL in lung cancer cells triggering cell apoptosis via an autocrine/paracrine loop; (ii) induces a Fas‐dependent apoptosis mediated by caspase‐8 and caspase‐3 activation; (iii) enhances the sensitivity of lung cancer cells to cytotoxic activity of LAK cells and malignant pleural fluid lymphocytes, partially via Fas/FasL pathway. Our data strongly suggest an active involvement of the Fas/FasL system in gemcitabine‐induced lung cancer cell killing.     

Contemporary percutaneous treatment of saphenous vein graft stenosis: immediate and late outcomes

PURPOSE: The aim of this study was to evaluate the immediate and long-term outcomes following percutaneous treatment of an unselected series of saphenous vein graft (SVG) lesions. METHODS AND RESULTS: Consecutive interventions on 129 saphenous vein graft lesions in 101 patients were reviewed. Stents were implanted in 114 lesions (88%), which included the use of polytetrafluoroethylene-covered stents in 22 lesions (17%) and abciximab in 20 patients (20%). Angiographic success was achieved in 125 lesions (97%). In-hospital major adverse cardiac events (MACE) occurred in 11 patients (11%), with myocardial infarction being the most frequent event. Treatment of degenerated SVG lesions and SVG lesions with larger reference diameters correlated with the incidence of in-hospital MACE [odds ratio (OR) = 7.69 and 2.65, respectively; 95% confidence interval (CI) = 1.80Eth 32.8 and 0.99Eth 7.10, respectively)]. Clinical follow-up was achieved in all patients at 25 +/- 21 months. Successful revascularization to all three distributions of the major coronary arteries negatively correlated [relative risk (RR) = 0.43; 95% CI = 0.20Eth 0.92)], while treatment of a degenerated SVG positively correlated (RR = 1.92; 95% CI = 1.05Eth 3.51) with the occurrence of follow-up MACE. A final effective blood supply to the anterior wall and a higher left ventricular ejection fraction was found to negatively correlate with the occurrence of follow-up death (RR = 0. 20 and 0.61, respectively; 95% CI = 0.06Eth 0.60 and 0.41Eth 0.90, respectively). CONCLUSION: Treatment of SVG lesions continues to be associated with a high incidence of myocardial infarction, particularly in cases of degenerated SVG lesions. An effective blood supply to the anterior wall and a higher left ventricular ejection fraction were protective for the occurrence of death during the follow-up period.