Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) are present in the peripheral blood and liver of chronically infected patients. The current study was performed to study the relationship between the strength of the CTL response, liver disease severity, and viral load. The results may be summarized as follows: first, using CTL precursor frequency (CTLpf) analysis to quantitate the peripheral blood CTL response, chronically infected patients were less strongly sensitized to a panel of well-defined HCV epitopes than they were to an epitope within the influenza matrix protein. Second, HCV-specific CTLpf did not correlate with disease activity or viral load in the majority of patients on a cross-sectional basis, although it did increase in three patients concomitant with sharp increases in liver disease. Finally, interferon therapy did not enhance the CTLpf against the HCV epitopes studied in these patients, indicating that its antiviral effect is independent of the CTL response. Since the HCV-specific CTLpf in the blood is actually quite low, the CTL may contribute to ongoing liver disease in these patients while being quantitatively inadequate to destroy all of the infected hepatocytes, thereby facilitating HCV persistence and contributing to chronic liver disease.     

Long-wavelength GaInNAs(Sb) lasers on GaAs

The boom in fiber-optic communications has caused a high demand for GaAs-based lasers in the 1.3-1.6-μm range. This has led to the introduction of small amounts of nitrogen into InGaAs to reduce the bandgap sufficiently, resulting in a new material that is lattice matched to GaAs. More recently, the addition of Sb has allowed further reduction of the bandgap, leading to the first demonstration of 1.5-μm GaAs-based lasers by the authors. Additional work has focused on the use of GaAs, GaNAs, and now GaNAsSb barriers as cladding for GaInNAsSb quantum wells. We present the results of photoluminescence, as well as in-plane lasers studies, made with these combinations of materials. With GaNAs or GaNAsSb barriers, the blue shift due to post-growth annealing is suppressed, and longer wavelength laser emission is achieved. Long wavelength luminescence out to 1.6 μm from GaInNAsSb quantum wells, with GaNAsSb barriers, was observed. In-plane lasers from these samples yielded lasers operating out to 1.49 μm, a minimum threshold current density of 500 A/cm² per quantum well, a maximum differential quantum efficiency of 75%, and pulsed power up to 350 mW at room temperature     

Torsemide: a new loop diuretic

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of torsemide are reviewed. Torsemide belongs to the pyridine-sulfonylurea class of loop diuretics. Its primary site of activity is the thick ascending limb of the loop of Henle, where it blocks active reabsorption of sodium and chloride, resulting in diuresis, natriuresis, and other effects. Torsemide has high bioavailability, a relatively long half-life, and a prolonged duration of activity. It is highly protein bound. Clinical trials indicate that torsemide is effective in the treatment of hypertension and of edema and other symptoms in patients with chronic renal failure (CRF), hepatic dysfunction, or congestive heart failure (CHF). Torsemide has infrequent, mild, and transient adverse effects; among the most common are orthostatic hypotension, fatigue, dizziness, and nervousness. The recommended initial oral dosages of torsemide are 10-20 mg/day for CHF, 20 mg/day for CRF, 5 mg/day for hypertension, and 5-10 mg/day (in combination with a potassium-sparing diuretic or aldosterone antagonist) for hepatic cirrhosis. In most patients, the pharmacokinetic advantages of torsemide over other loop diuretics are unlikely to translate into a substantial edge in clinical outcomes, and in practice there may be no cost advantages. Although torsemide does not offer major advantages over other loop diuretics, it may be of benefit in patients who do not respond to or cannot tolerate other agents.     

The oxygen and carbon monoxide reactions of heme oxygenase

The O2 and CO reactions with the heme, alpha-hydroxyheme, and verdoheme complexes of heme oxygenase have been studied. The heme complexes of heme oxygenase isoforms-1 and -2 have similar O2 and CO binding properties. The O2 affinities are very high, KO2 = 30-80 microM-1, which is 30-90-fold greater than those of mammalian myoglobins. The O2 association rate constants are similar to those for myoglobins (kO2' = 7-20 microM-1 s-1), whereas the O2 dissociation rates are remarkably slow (kO2 = 0.25 s-1), implying the presence of very favorable interactions between bound O2 and protein residues in the heme pocket. The CO affinities estimated for both isoforms are only 1-6-fold higher than the corresponding O2 affinities. Thus, heme oxygenase discriminates much more strongly against CO binding than either myoglobin or hemoglobin. The CO binding reactions with the ferrous alpha-hydroxyheme complex are similar to those of the protoheme complex, and hydroxylation at the alpha-meso position does not appear to affect the reactivity of the iron atom. In contrast, the CO affinities of the verdoheme complexes are >10,000 times weaker than those of the heme complexes because of a 100-fold slower association rate constant (kCO' approximately 0. 004 microM-1 s-1) and a 300-fold greater dissociation rate constant (kCO approximately 3 s-1) compared with the corresponding rate constants of the protoheme and alpha-hydroxyheme complexes. The positive charge on the verdoporphyrin ring causes a large decrease in reactivity of the iron.     

Presence of Epstein-Barr virus in lymphoepithelioma-like carcinoma of the middle ear

AIM: To examine the association of Epstein-Barr virus (EBV) with carcinoma of the ear. METHODS: Five non-keratinising squamous cell carcinomas and two undifferentiated carcinomas of the ear were examined. In situ hybridisation was used to localised EBV-encoded RNAs (EBER). Immunohistochemical methods to detect LMP-1 and EBNA2 were performed in the EBER positive cases. RESULTS: Two cases were EBER positive, including one non-keratinising and one undifferentiated carcinoma. Both showed identical morphology to those arising from the nasopharynx, with abundant lymphoid stroma. They were both negative for LMP-1 and EBNA2. CONCLUSIONS: EBV associated carcinoma with the morphology of lymphoepithelioma can also arise from the middle ear.     

Relationship of provider characteristics to outcomes, process, and costs of care for community-acquired pneumonia

OBJECTIVES: The authors describe the relation of provider characteristics to processes, costs, and outcomes of medical care for elderly patients hospitalized for community-acquired pneumonia. METHODS: Using Medicare claims data, Medicare beneficiaries discharged from Pennsylvania hospitals during 1990 with community-acquired pneumonia were identified. Claims data were used to ascertain mortality, readmissions, use of procedures and physician consultations, and the costs of care. The relationship of these measures to provider characteristics was analyzed using regression techniques to adjust for patient characteristics, including comorbidity and microbial etiology. RESULTS: Among 22,294 pneumonia episodes studied, 30-day mortality was 17.0%. After adjusting for patient characteristics, 30-day mortality and readmission rates were unrelated to hospital teaching status or urban location or to physician specialty. Use of procedures and physician consultations was more common and costs were 11% higher among patients discharged from teaching hospitals compared with nonteaching hospitals. Similarly, costs were 15% higher at urban hospitals compared with rural hospitals. General internists and medical subspecialists used more procedures and had higher costs than family practitioners. CONCLUSIONS: Processes and costs of care for community-acquired pneumonia varied by provider characteristics, but neither mortality nor readmission rates did. These differences cannot be explained by clinical variables in the database. Further studies should determine whether less costly patterns of care for pneumonia, and perhaps other conditions, could replace more costly ones without compromising patient outcomes.     

Acadesine extends the window of protection afforded by ischaemic preconditioning in conscious rabbits

OBJECTIVE: Ischaemic preconditioning protects myocardium from infarction if the reperfusion interval between the brief and prolonged ischaemic intervals is less than 1 h. In anaesthetised rabbits acadesine (5-amino-4-imidazolecarboxamide riboside, AICAR), an adenosine enhancer which increases tissue adenosine during ischaemia, prolongs the window of protection to 2 h. The aim of this study was to try to determine the maximum extension of this window of protection, using chronically instrumented, unsedated rabbits. METHODS: Rabbits were instrumented with a balloon occluder around a major branch of the left coronary artery for reversible coronary occlusion. Five to seven days after surgery all animals underwent a 30 min coronary occlusion. Animals were randomised to one of seven groups: (1) No additional treatment (control); (2) Ischaemic preconditioning with 5 min regional ischaemia followed by 10 min reperfusion before the 30 min coronary occlusion; (3) and (4) Ischaemic preconditioning followed by 2 or 4 h of reperfusion before the 30 min occlusion, respectively; (5) Treatment with acadesine (2.5 mg.kg-1.min-1 intravenously for 5 min and then 0.5 mg.kg-1.min-1 beginning 45 min before and continuing until 30 min after release of the 30 min occlusion) without ischaemic preconditioning; (6) and (7) Treatment with the higher dose of acadesine for 5 min beginning 35 min before the 5 min ischaemic period, and then the lower dose continuing until 30 min after release of the 30 min coronary occlusion in rabbits with 4 or 6 h reperfusion intervals, respectively. RESULTS: Rabbits with ischaemic preconditioning with 10 min reperfusion preceding the 30 min coronary occlusion (group 2) had only 5.6(SEM 1.1)% infarction of the ischaemic zone. Ischaemic preconditioning followed by 2 h reperfusion (group 3) offered continued protection [18.2(2.2)% infarction] as compared to control animals [37.7(2.6)% infarction]. However, protection waned if ischaemic preconditioning was followed by 4 h reperfusion (group 4) [36.7(3.0)% infarction]. Additionally, treatment with acadesine alone did not modify infarct size (group 7) [39.5(4.0)%], but acadesine largely restored the protection of ischaemic preconditioning despite a 4 h reperfusion interval (group 5) [20.4(3.0)% infarction, P < 0.01 v control]. However, when reperfusion was extended to 6 h (group 6) acadesine could no longer restore protection [36.2(0.9)% infarction]. CONCLUSIONS: The protection afforded by a 5 min ischaemic preconditioning period lasts from 2 to 4 h in the awake, unsedated rabbit, and acadesine can extend the duration of this window of protection to at least 4 h but not to 6 h.     

The effect of Pseudomonas aeruginosa infection on clinical parameters in steady-state bronchiectasis

STUDY OBJECTIVE: To investigate the effect of Pseudomonas aeruginosa infection on clinical parameters in Chinese patients with noncystic fibrosis and steady-state bronchiectasis. DESIGN: Prospective, cross-sectional clinicomicrobiological study with informed consent. SETTING: Consecutive outpatient recruitment from a specialist bronchiectasis respiratory clinic. PATIENTS: Outpatients (n = 100; 62 women; 55.1+/-16.7 years old; FEV1/FVC 1.4+/-0.7/2.1+/-0.9 L), who had stable respiratory symptoms for more than 3 weeks. MEASUREMENTS AND RESULTS: Respiratory pathogens isolated from the sputum were: Pseudomonas aeruginosa (33), Haemophilus influenzae (10), Moraxella catarrhalis (2), other Gram-negative bacilli (5), Streptococcus pneumoniae (6), Staphylococcus aureus (5), mycobacteria (3), and yeast (1). Clinical parameters in patients with positive isolation of P aeruginosa were compared with those without the organism in the sputum culture (non-P aeruginosa). In the P aeruginosa group, the FEV1/FVC ratio and sputum volume were lower (p < 0.005) and higher (p < 0.0001), respectively, than those of the non-P aeruginosa group. The FEV1/FVC ratio (< 60%) and sputum volume (grading > 5) were independently associated with a positive sputum isolation of P aeruginosa with odds ratios of 3.1 (confidence interval [CI] 1.2 to 8.4; p < 0.01) and 4.7 (CI 1.6 to 13.3; p < 0.001), respectively. CONCLUSIONS: P aeruginosa is the predominant respiratory pathogen isolated in the sputum of Chinese patients with steady-state bronchiectasis, and its isolation is associated with high sputum output (> or = 75th quartile) and moderately severe airflow obstruction (FEV1/FVC < 60%).