Chronic hepatitis C in patients with persistently normal alanine transaminase levels.

BACKGROUND & AIMS: Many patients with chronic hepatitis C virus (HCV) have persistently normal serum alanine transaminase (ALT) levels. We compared characteristics of chronic hepatitis C patients with patients with normal and elevated ALT levels using data from 3 randomized phase III trials of peginterferon alfa-2a (40 kDa). METHODS: The characteristics of 480 patients with normal ALT values (on >or=3 occasions without any increases in ALT level over a 6- to 18-month period) and 1993 patients with elevated ALT levels were compared. Sixty-eight of the 480 patients with normal ALT levels were randomized to no treatment and monitored for 72 weeks. RESULTS: More patients with normal ALT levels than patients with elevated ALT levels were women (59% vs 32%; P<.01). The serum HCV RNA titer was significantly lower in patients with normal ALT levels (P<.01 vs in patients with elevated ALT levels). Patients with normal ALT levels had significantly lower inflammation and fibrosis scores on liver biopsy examination than patients with elevated ALT levels, but almost two-thirds had portal fibrosis and 10% had bridging fibrosis. No correlation between baseline ALT activity, HCV RNA level, and liver histology was observed in patients with normal ALT levels. During the 72-week follow-up period, ALT activity elevated above the upper limit of normal in 53% of the untreated patients with normal levels of ALT. None became HCV RNA undetectable. CONCLUSIONS: Chronic hepatitis C patients with normal ALT levels should be evaluated in a similar manner as patients with elevated ALT levels because they are at risk for developing significant liver disease. The decision to treat with peginterferon alfa and ribavirin should be based on multiple factors, rather than on ALT levels alone.     

Hemodynamic analysis of descending versus ascending aortomyoplasty, and comparison with intra-aortic balloon pump

Objective: Descending and ascending aortomyoplasty are two surgical procedures intended to induce hemodynamic benefits similar to those of the intra-aortic-balloon-pump (IABP). To date, there have been no studies comparing the two surgical techniques. The objective of this study was to compare coronary blood flow augmentation and afterload reduction as produced by descending and ascending aortomyoplasty counterpulsation Methods: Twenty-two mongrel dogs (18–35 kg) underwent IABP application (n=7), descending (n=8), or ascending (n=7) aortomyoplasty. Left anterior descending (LAD) coronary artery blood flow was measured using a Transonic Doppler flow probe. Left ventricular pressure as well as aortic pressures proximal and distal to either the aortomyoplasty site or the IABP position were monitored continuously. Results: Descending aortomyoplasty induced higher elevation in the LAD blood flow during assisted beats (27% from 10.8±4 to 13.8±6 ml/min, P<0.001) than that induced by either ascending aortomyoplasty (19% from 11.7±5 to 14±5 ml/min, P<0.001) or IABP counterpulsation (18% from 8.6±3 to 10.2±4 ml/min, P<0.001). Conversely, while ascending aortomyoplasty reduced the left ventricular end-diastolic pressure by 16% (from 60±18 to 50±22 mmHg, P<0.001), similar to the 16% after load reduction achieved by the IABP counterpulsation, descending aortomyoplasty failed to induce afterload reduction. Conclusions: Descending aortomyoplasty produces higher coronary blood flow augmentation than either ascending aortomyoplasty or IABP. However, afterload reduction comparable to that achieved by IABP was observed only with ascending aortomyoplasty and not with descending aortomyoplasty.     

Determination of 3,4-dihydroxyphenylalanine (DOPA) in plasma and cerebrospinal fluid by high performance liquid chromatography with electrochemical detection

We report a reliable method for determining DOPA levels in plasma and cerebrospinal fluid. The method is based on complete conversion of DOPA to dopamine and quantification by HPLC-ECD of the dopamine formed. Lower limit of detection was 0.5 nmol/l. No differences in plasma DOPA levels were found between normal children (0-15 yr, n = 60), normal adults (n = 39) and patients with essential hypertension (n = 40) or Parkinson's disease (no DOPA therapy, n = 30). In normal individuals and in patients with essential hypertension venous plasma levels were higher than arterial levels (10.2 vs 9.3 nmol/l, p less than 0.001, V/A ratio 1.11 (SD 0.08), n = 15). Sympathetic stimuli (standing, tilting, bicycle exercise, tyramine) did not influence DOPA levels. In untreated depressed patients (n = 10) and in non-parkinsonian neurological patients (n = 12) cerebrospinal fluid levels of DOPA were 4.5 (SD 2.4) and 5.2 (SD 1.3) nmol/l respectively. A direct method for the measurement of DOPA by HPLC-ECD after deproteinization of plasma is also described and compared with the conversion method. Good agreement was found when plasma DOPA levels exceeded 0.25 mumol/l (y(conversion method) = 0.943x (direct method) + 0.118; n = 60; r = 0.985). The direct method, because of greater simplicity and the possibility of simultaneous measurement of the DOPA metabolite 3-O-methyldopa, is the method of choice with plasma samples from DOPA-treated patients. In non-DOPA treated individuals the conversion method is superior and has proved to be an accurate and sensitive method for the determination of DOPA levels in plasma and cerebrospinal fluid.     

Is additional epidural sympathetic block in microvascular surgery contraindicated? A preliminary report

The use of additional epidural sympathetic block during and after microvascular surgery in the lower extremities to prevent vasospasm is generally agreed on. However, a significant fall in the perfusion rate of the transplants was seen after application of bupivacaine (Marcain) via the epidural catheter. This effect has, to our knowledge, not been described before and is probably caused by the sympathectomy effect of this type of analgesia.     

Therapeutic Consequences of Variation in Intraarterial Pressure Measurements After Iliac Angioplasty

Purpose: To assess the accuracy of intraarterial measurement of transstenotic pressure gradients for the detection of hemodynamically suboptimal iliac angioplasty. Methods: In 14 patients, referred for diagnostic angiography, mean pressure gradients in the aorta and iliac artery were obtained twice, using a double-sensor pressure catheter. Additional iliac measurements were performed during pharmacologically induced flow augmentation. Repeatability was assessed by calculation of the mean difference plus standard deviation (MD ± SD) and repeatability coefficient (2 × SD). These results were extrapolated to 137 iliac angioplasty procedures with secondary stenting where there was a residual pressure gradient > 10 mmHg. Results: MD ± SD for repeated measurements at rest and during flow augmentation were 0 ± 2 mmHg and 1 ± 3 mmHg, respectively. Repeatability coefficients were 3 and 6 mmHg. Mean pressure gradients after hemodynamically insufficient angioplasty were 8 ± 7 mmHg at rest and 17 ± 5 mmHg following vasodilatation. Inaccurate pressure recordings may have led to inappropriate stent placement in less than 2.5%, and inappropriate denial of stent placement in less than 5% of the lesions. Conclusion: Variability of intraarterial pressure measurements has little consequence in the detection of hemodynamically significant stenosis after angioplasty. Received: 0/00/00/Accepted: 0/00/00     

Estimating Potency for the E max-Model Without Attaining Maximal Effects

The most widely applied model relating drug concentrations to effects is the E_max model. In practice, concentration–effect relationships often deviate from a simple linear relationship but without reaching a clear maximum because a further increase in concentration might be associated with unacceptable or distorting side effects. The parameters for the E_max model can only be estimated with reasonable precision if the curve shows sign of reaching a maximum, otherwise both EC₅₀ and E_max estimates may be extremely imprecise. This paper provides a solution by introducing a new parameter (S₀ ) equal to E_max/EC₅₀ that can be used to characterize potency adequately even if there are no signs of a clear maximum. Simulations are presented to investigate the nature of the new parameter and published examples are used as illustration.     

Mitotic and meiotic detection of radiation-induced translocations in mouse stem cell spermatogonia using fluorescencein situ hybridization

The efficiency of two methods of detection of translocations induced in mouse stem cell spermatogonia by X-ray doses of 2, 5 and 7 Gy was compared: classical multivalent analysis at diakinesis-metaphase I of meiosis and observation via fluorescencein situ hybridization analysis of mitotic or meiotic stages. Specific DNA libraries for chromosomes 1, 11 and 13 were used. The results obtained indicate that (a) chromosomes 1, 11 and 13 are more involved in multivalent formation than expected on the basis of DNA content and (b) if the mitotic FISH analysis data are corrected for the observed over-representation, the frequencies of induced translocations are similar to those recorded in the classical multivalent studies, suggesting equal scoring efficiencies in both systems.