Sodium reabsorption by the Henle loop in humans

In a previous study, we described a new method [3] to measure Na reabsorption by each segment of the human nephron independently. Reabsorption was expressed as equivalent volumes of solute-free water (CH2O) generated by the loop of Henle (CH2O-HL) and by the distal tubule (CH2O-DT), and dissipated by back diffusion (BD) across collecting ducts (CH2O-BD). These data were obtained during maximal water diuresis (MWD). The present study was undertaken to calculate CH2O-HL by experiments performed during maximal antidiuresis (MA). For this purpose, a new theoretical approach was devised, described by algebraic equations which allowed calculations of segmental transport during MA alone, where only CH2O-HL could be calculated independently. The study was performed on 14 normal volunteers who were studied twice by clearance measurements, firstly during MWD and again during MA. In each experiment, clearance periods were performed during baseline conditions and during the administration of furosemide (0.7 mg/kg bolus injection followed by 0.06 mg/kg/min maintenance infusion). From the values measured during either condition, segmental reabsorption was calculated. During MWD, CH2O-HL averaged 19.4 + 10.4, during MA 20.4 + 8.0 ml/min/GFR X 100; p greater than 0.05. The paired measurements were significantly correlated (r = 0.80; p less than 0.01). These data demonstrate that CH2O-HL obtained with the original theory is a reproducible result that can be confirmed with independent measurements obtained during different experimental conditions. Thus, measurements of segmental Na transport in the human nephron are feasible and can contribute important informations on disease states.     

A new shape for an old function: lasting effect of a physiologic surgical restoration of the left ventricle

Background  

Long-term morphofunctional outcome may vary widely in surgical anterior left ventricular wall restoration, suggesting variability in post-surgical remodeling similar to that observed following acute myocardial infarction. The aim of this pilot study was to demonstrate that surgical restoration obtained with a particular shape of endoventricular patch leads to steady morphofunctional ventricular improvement when geometry, volume and residual akinesia can be restored as normal as possible.     

Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study

The pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30-35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, less than or equal to 60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2-12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was less than 60 ml/min [group N, 122.8 +/- 44.0 l/h; group L, 104.4 +/- 27.7 l/h (P = 0.58) vs group R, 83.4 +/- 18.3 l/h (P = 0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6 +/- 10.8 h; group L, 69.9 +/- 10.2 h (P = 0.27) vs group R, 83.2 +/- 10.9 h (P = 0.025) and t1/2 gamma: group N, 41.3 +/- 10.1 h; group L, 47.0 +/- 7.4 h (P = 0.31) vs group R, 55.8 +/- 8.2 h (P = 0.025)]. After oral treatment, drug absorption occurred during in the first 2-4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4-18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1-21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Block of the endplate acetylcholine receptor channel by the sympathomimetic agents ephedrine, pseudoephedrine, and albuterol

Recent observations suggest that some patients with congenital myasthenic syndromes respond favorably to ephedrine, pseudoephedrine, or albuterol. Conventional microelectrode studies, however, provide no clear explanation for a beneficial effect of ephedrine in endplate diseases. To gain further insight into how these drugs affect neuromuscular transmission, we investigated their effects on the kinetic properties of the acetylcholine (ACh) receptor. Single channel currents were recorded from rat lumbrical muscles endplates using low concentrations of ACh and 2.5–100 μM of drugs. Between 10–100 μM, each drug progressively increased the rate of channel closure in a concentration dependent manner, consistent with an open-channel block. Albuterol acted as a sequential fast-acting channel blocker, increasing the mean burst duration in a concentration dependent manner without altering the total open time per burst or the duration of intraburst blockages. Increasing concentrations of ephedrine and pseudoephedrine also increased the number of intraburst closures but decreased the total open time per burst. None of the drugs altered single channel conductance. The channel blocking effects of ephedrine and pseudoephedrine might reduce the synaptic overactivity that occurs in the slow-channel myasthenic syndromes or in endplate ACh esterase deficiency, but these effects occur at concentrations not attainable in clinical practice.     

Development of a molecular-beacon assay to detect the G1896A precore mutation in hepatitis B virus-infected individuals

The 1896 precore (PC) mutation is the most frequent cause of hepatitis B virus e-antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection. Detection of the 1896 PC mutation has application in studies monitoring antiviral therapy and the natural history of the disease. Identification of this mutation is usually performed by direct sequencing, which is both costly and laborious. The aim of this study was to develop a rapid, high-throughput assay to detect the 1896 PC mutation using real-time PCR and molecular-beacon technology. The assay was initially standardized on oligonucleotide targets and plasmids containing the wild-type (WT) and PC mutation and then tested on plasma samples from children with HBV DNA of >10(6) copies/ml. Nine individuals were HBeAg negative and suspected to harbor HBeAg mutations, while 12 children were HBeAg positive and selected as controls. Ninety percent (19 of 21) of plasma samples tested with molecular beacons were in complete agreement with sequencing results. The remaining 10% (2 of 21) of samples were identified as heterogeneous mixtures of WT and mutant virus by molecular beacons, though sequencing found only a homogeneous mutant in both cases. Overall, the 1896 PC mutation was detected by this assay in 55.5% of the children with HBeAg-negative infection. In summary, this assay is a rapid, sensitive, and specific technique that effectively discriminates WT from 1896 PC mutant HBV and may be useful in clinical and epidemiological studies.