Initial experience with oral valganciclovir for pre-emptive cytomegalovirus therapy after lung transplantation

BACKGROUND: The most common opportunistic viral pathogen after lung transplantation is cytomegalovirus (CMV). Oral valganciclovir, a prodrug of ganciclovir, has been introduced as a potential drug for prophylaxis and treatment of CMV infection and disease in lung transplantation. The goal of this study was to describe our initial experience with oral valganciclovir for pre-emptive treatment of CMV infections after lung transplantation. METHODS AND PATIENTS: We summarize our experience with 19 patients who underwent lung transplantation and received pre-emptive oral valganciclovir therapy in the situation of positive CMV polymerase chain reaction (PCR) in either plasma or bronchoalveolar lavage. None of the patients presented with manifest CMV disease. Treatment dosage of valganciclovir was 450 mg to 1800 mg daily, depending on renal function and white blood count. Treatment was continued until the CMV PCR became negative, in any case for a period of at least 14 days. RESULTS: Three patients received two courses of pre-emptive oral valganciclovir; 16 patients were treated once. Eleven patients (57.9%) were treated because of a positive plasma CMV PCR; in eight patients (42.1%) the PCR was positive only in bronchoalveolar lavage. Therapy was initiated 896 +/- 1186 days (range, 108-3911) after transplantation with a mean CMV PCR of 45,536 +/- 149,294 copies (range, 426-706,000). In all cases the PCR fell below detectability (<400 copies) after a period of 22 +/- 10 days of treatment (range, 7-50 days). Mild to moderate leucopenia was observed in seven patients (36.8%) during treatment. None of the patients developed new onset of other potentially drug-related disorders such as neutropenia, anemia, deterioration of renal function or gastrointestinal disorder. CONCLUSIONS: Pre-emptive therapy with oral valganciclovir for CMV infections detected by PCR in either plasma or bronchoalveolar lavage after lung transplantation seems to be efficacious and safe. However, regular blood counts should be performed to detect developing leucopenia.     

Feasibility and reliability of four pain self-assessment scales and correlation with an observational rating scale in hospitalized elderly demented patients

BACKGROUND: Acute and chronic pain is common in hospitalized demented elderly people, yet there are limited data about the performance of pain assessment tools in this population. The aim of this study was to evaluate the feasibility and reliability of four pain self-assessment scales in this population and compare their performance to an observational pain rating scale. METHODS: Our prospective clinical study was conducted in an acute-care and intermediate-care geriatric hospital on 160 consecutive inpatient referrals to the dementia consultation who met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for dementia. Exclusion criteria were delirium, terminal care, and severe sensory impairment. Four unidimensional self-assessment tools--the verbal, horizontal visual, vertical visual, and faces pain scales--were administered in randomized order to mild, moderate, and severely demented patients. An observational pain rating scale was independently completed by the nursing team. RESULTS: Only 12% of the 160 patients (mean age 85 years, 71% women) understood no scale. Respectively, 97%, 90%, and 40% of patients with mild, moderate, and severe dementia understood at least one scale (p <.05). There was a nonsignificant trend toward poorer comprehension of the faces scale. Test-retest reliability was high for all four self-assessment scales, and the correlation between these scales was very strong (Spearman's r(s) = 0.81-0.95; p <.001). Observational rating correlated moderately with self-assessment and tended to underestimate pain intensity (r(s) = 0.31-0.40; p <.05). CONCLUSIONS: Self-assessment pain scales can be used reliably in the vast majority of older hospitalized patients with mild to moderate dementia and in nearly half of those with severe dementia. Observational pain rating scales correlate only moderately with self-assessment and should be reserved for those few patients who have demonstrated that they cannot complete a self-assessment.     

Early event-related potential changes during working memory activation predict rapid decline in mild cognitive impairment

BACKGROUND: The conversion of mild cognitive impairment (MCI) to Alzheimer's disease is associated with substantial compromise of neocortical circuits subserving rapid cognitive functions such as working memory. Event-related potential (ERP) analysis is a powerful tool to identify early impairment of these circuits, yet research for an electrophysiological marker of cognitive deterioration in MCI is scarce. Using a "2-back" activation paradigm, we recently described an electrophysiological correlate of working memory activation (positive-negative working memory [PN(wm)] component) over parietal electrodes. METHODS: Ours was a longitudinal study of 24 MCI patients with ERP analysis at inclusion and neuropsychological follow-up after 1 year. We used ERP waveform subtraction analysis between the n-back and control tasks. Analysis of variance (ANOVA) was used to compare electroencephalograph latencies between progressive MCI (PMCI) and stable MCI (SMCI), and univariate regression was used to assess the relationship between neuropsychological measures at baseline and clinical outcome. RESULTS: Thirteen (54%) MCI patients showed PMCI, and 11 (46%) remained stable (SMCI). In SMCI, a PN(wm) component with significantly larger density compared to baseline was identified when subtracting the detection task for both the 1- and 2-back tasks. In contrast, in PMCI, the PN(wm) component was absent in both 1-back and 2-back conditions. Neuropsychological variables and n-back test performance at inclusion did not predict cognitive deterioration 1 year later. CONCLUSIONS: In conjunction with recent functional imaging data, the present results support the notion of an early dysfunction of neural generators within the parietal cortex in MCI. They also reveal that the absence of the PN(wm) component may provide an easily applicable qualitative predictive marker of rapid cognitive deterioration in MCI.     

Multiple forms of anti-acetylcholine receptor antibody in myasthenia gravis

Sera of patients with myasthenia gravis (MG) contain anti-acetylcholine receptor (AChR) lgG antibodies (Ab) which have different antigenic specificities. Three Ab types were detected: (1) MG-I, which forms immune complexes with AChR; (2) MG-C, which decreases binding of AChR to concanavalin A; and MG-B, which blocks α-bungarotoxin binding to AChR. Sera from 152 MG patients were screened for the Ab types. Sixty-one percent contained MG-I, 26% contained MG-C, 10% contained MG-B, and 5% contained both MG-C and MG-B. The latter Ab types were associated with more severe forms of MG but showed no other clinical correlations. IgG antibodies of defined type were purified, and their interaction with unlabeled and toxin-prelabeled AChR from denervated rat muscle was studied in detail. Receptors are homogeneous with respect to determinants recognized by MG-I, but heterogeneous with respect to determinants recognized by MG-C (3 subpopulations, 22%, 28%, and 50% of AChR) and by MG-B (2 subpopulations, 30% and 70% of AChR). The stoichiometry of AChR interaction with the antibodies indicates that for each toxin-binding site, the receptor is divalent as an antigen for MG-I and MG-C but is tetravalent for MG-B. Denervated muscle AChR appears to be a mixture of at least 3 molecular forms of AChR, each of which has distinct immunological features as well as components common to all the receptor subpopulations.     

Evaluation of diuretic therapy by impedance cardiography in acute myocardial infarction

Changes in transthoracic electrical impedance (TEI) were recorded in 20 patients with acute myocardial infarction before, during, and 60 min after intravenous administration of furosemide (Impugan®). The major change was an increase in TEI (Z₀) (6.2%, p<0.001). The mean impedance stroke volume (n = 10) decreased by 7.8% (p<0.05) while the mean impedance cardiac output (n = 10) decreased by 6.3% (p>0.05). Heart rate and blood pressure remained unchanged. It was possible to differentiate between two types of TEI changes after furosemide. In 10 patients there was an early and rapid increase in Z₀ (type A), while the rest of the patients showed a decreased or unchanged Z₀ followed by a slow increase (type B). The line describing the mean Z₀ change in type A was significantly higher than that of type B and fell outside ±2 SEM of the line describing the mean Z₀ change found in five normal subjects (type C). The Z₀ change in type B was similar to that in type C. It is assumed that Z₀ change in type A may represent patients with an increased amount of extravascular fluid (heart failure), while the change in type B represents patients without heart failure. This assumption is based on the difference in dependency of TEI on extravascular volume versus intravascular volume changes. It is suggested that the impedance method may be used as a simple noninvasive method to assess the effect of diuretic therapy and may have the value of detecting extravascular thoracic fluids in acute myocardial infarction.     

The effect of α-naphthylisothiocyanate on bile secretion prior to and during the onset of cholestasis in the rat

The effect of α-naphthylisothiocyanate (ANIT) on bile flow, erythritol clearance, bile acid excretion and bilirubin excretion was studied in rats. The median time-to-effect (Et50) for the appearance of cholestasis was about 15 h. ANIT failed to exert a gradual effect on bile flow or erythritol clearance before the onset of cholestasis. However, 3 h before complete cessation of bile flow, a rapid decline in bile flow and bile acid excretion was observed. Bile acid-independent flow was markedly reduced. However, the bile acid-dependent component was also affected.     

Pharmacokinetics of metronidazole in patients with varying degrees of renal failure.

Twenty-nine patients with varying degrees of renal insufficiency were given a single intravenous dose of metronidazole (500 mg). Plasma and urinary concentrations of metronidazole and two major metabolites were determined using a specific high performance liquid chromatographic assay. The pharmacokinetic parameters of metronidazole elimination half-life, area under the metronidazole concentration against time curve, apparent volume of distribution, metronidazole clearance and predicted degree of accumulation of metronidazole on repeated dosing were not statistically significantly affected by renal inadequacy of any degree. The urinary excretion of metronidazole in patients with moderate or severe renal insufficiency was approximately half the value in healthy volunteers. The renal clearance of metronidazole was significantly greater in healthy volunteers compared to renally insufficient patients, but accounted for less than 10% of the total metronidazole clearance in all groups. The elimination half-life and predicted accumulation (on three times daily dosing) of metabolite I [1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole] were significantly increased with decreasing renal function from 9.2 h and 2.3, respectively, in healthy volunteers to 34 h and 6.7, respectively, in patients with total renal failure. The degree of accumulation of this metabolite on repeated dosing is probably of limited clinical significance in all patients except those with severe or total renal failure for reasons detailed in the text. The elimination half-life and predicted accumulation on three times daily dosing of metabolite II, [2-methyl-5-nitroimidazole-1-acetic acid] increased rapidly with decreasing renal function.(ABSTRACT TRUNCATED AT 250 WORDS)     

The major grass pollen group 5 allergen from Dactylis glomerata and its C-terminal split product both behave as dimers: implications for allergen standardization

BACKGROUND: On SDS-PAGE grass pollen group-5 allergens migrate as a doublet with an apparent molecular mass (M(r)) of 25 kDa. Immunoblot analysis revealed additional group 5 reactivity at double and half this M(r). The aim of this study was to investigate these group 5 molecular entities and to compare their allergenicity and behavior in quantitative immunoassays. METHODS: Group-5-specific monoclonal antibodies were produced and used for the development of a group-5-specific sandwich ELISA. Affinity-purified Dac g 5 was separated by SDS-PAGE/Western blotting; individual bands were analyzed by N-terminal sequencing. Size exclusion chromatography (SEC) in conjunction with group-5-specific ELISA, competitive RIA and RAST inhibition were used to analyze the size distribution of Dac g 5. Basophil histamine release assays were used to assess biological activity. RESULTS: The lower band of the typical group 5 doublet was identified as a truncated form lacking the typical group 5 N-terminus AD(L)/(A)GY, observed in the upper band. The 12-kDa peptide was shown to be the C-terminal half of Dac g 5 (amino acid 127 onwards). SEC in conjunction with competitive RIA revealed that around 45% of Dac g 5 is represented by the 12-kDa peptide. Both the C-terminal half and the whole allergen dimerize under nondenaturing conditions. In competitive RIA and RAST inhibition both forms are equally well detected. In contrast, the half molecule is poorly recognized in sandwich ELISA and displays negligible biological activity in basophil histamine release tests with purified IgE. CONCLUSIONS: These observations stress the need to evaluate the performance of allergen standardization protocols in detail, with special attention to allergen size distribution.