Potassium-selective channels in the basolateral membrane of single proximal tubule cells of frog kidney

The membrane potential of proximal tubule cells is dominated by the potassium conductance of the basolateral membrane. In the present paper the nature of this conductance is investigated by the patch-clamp technique. Only one type of K channel was found in the basolateral membranes of freshly isolated proximal cells. In cell-attached patches, the current/voltage relationship is markedly non-linear with much larger inward (30 pS) than outward ( 6 pS) conductances, even in the presence of roughly symmetrical K concentrations. Thus the channels show inward rectification. The determination of the conductance for outward current flow is complicated since the current/voltage curves show an area of negative conductance. Nevertheless, taking the conductance for outward current flow and the density of the channels it is possible to account for all of the previously reported potassium conductance of amphibian proximal tubule cells. The open probability of the channels was found not to depend upon the membrane potential. However, the non-linearity of the current/voltage relationships will confer upon the channel the same voltage dependence as that seen in intact proximal tubules, i.e. the conductance decreases with depolarisation. Incubation of cells in Ringer with no substrates or in the presence of alanine and/or glucose showed no change in the activity of the channels. These findings suggest that, although these channels may represent the basolateral conductance of frog proximal tubule cells, they are not involved in the well-established coupling between transport rate and potassium conductance.This work was supported by the Wellcome Trust     

Genetic and clinical heterogeneity of Stickler syndrome.

We have studied 6 multigeneration Stickler syndrome families. Manifestations of the syndrome in the families included myopia, deafness, arthritis, characteristic facial changes with "flat" midface and cleft palate, although not all these were present in all families. COL2A1 has been implicated as a gene which can give rise to Stickler syndrome based on evidence from 2 large families which each showed significant linkage between the disease locus and restriction fragment length polymorphisms for the gene (Francomano CA, Lieberfarb RM, Hirose T, Maumenee IH, Streeten EA, Meyers DA, Pyeritz RE (1987): Genomics 1:293-296; Knowlton RG, Weaver EJ, Struyk AF, Knobloch WH, King RA, Norris K, Shamban A, Uitoo J, Jimenez SA, Prockop DJ (1989): Am J Hum Genet 45:681-688). We have found crossovers between the disease locus and COL2A1 in 2 families with Stickler syndrome. This could be explained by either genetic heterogeneity or the actual mutation being in a closely linked, currently unrecognized gene. We found a weakly positive overall lod score (z = 0.96 at theta = 0.10) suggesting that genetic heterogeneity is a more likely explanation. In one family, with typical findings, a translocation t5;17 (q15:q23) was found to segregate with the disease in 4 affected relatives. In view of the possible heterogeneity, although no crossovers with COL2A1 were seen in this family, either of these breakpoints could be the position of a further disease causing gene.     

Experimental measurement of impulse response and noise for an emission computed tomography system

Experimental studies have been made of the impulse response and noise characteristics of a tomographic system using a gamma camera. Fourier transform, deconvolution and iterative methods have been used with a CDC 6600 computer to reconstruct images from data obtained for various experimental arrangements of sources in a cylindrical phantom. It is shown that with an appropriate attenuation correction the impulse response in the reconstruction is substantially constant, independent of the position of the source in the phantom and that the reconstruction technique used is of secondary importance.The resolution obtained for the impulse response and the relative noise level throughout the non image part of the reconstructions is shown for different experimental situations.The measured variance in the reconstruction of an extended uniform activity source was found to be somewhat below the theoretical value except at high count densities (above 1,000 counts per image element) where the limit of accuracy of the reconstruction is shown to be imposed by the variation in the camera sensitivity over the field of view.     

Cerebrospinal fluid cyclic AMP and acid monoamine metabolites following probenecid: Studies in psychiatric patients

At probenecid levels greater than 10 g/ml, CSF cAMP was independent of CSF probenecid concentration. At these levels of probenecid, cAMP transport out of CSF is probably maximally blocked and cAMP levels reflect cAMP release into CSF. CSF cAMP was significantly higher in RDC-diagnosed schizophrenics than in other psychotics or depressives. A significant decrease in CSF cAMP was found in psychotic patients treated with chlorpromazine. No changes in CSF cAMP were observed in patients treated with tricyclic antidepressants or lithium.     

Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel tube” model using lidocaine in the perfused rat liverin situ preparation

Theoretical analysis of two models of hepatic drug clearance revealed that one powerful discriminator between them is the effect of changes of hepatic blood flow on either the emergent drug concentration or the availability of a highly extracted compound when operating under linear conditions. Lidocaine (extraction ratio 0.997) was employed in the discriminatory studies. The behavior of this drug under linear conditions (input lidocaine concentrations < 5 mg/ liter) to changes in hepatic blood flow rate (10–16 ml/min per liver) was examined in the perfused rat liver in situpreparation. The steady-state output lidocaine concentration in the blood leaving the liver was predicted better by a well-stirred model than by a parallel tube model. As anticipated, the clearance of a poorly extracted compound, antipyrine (extraction ratio 0.08),was unaltered by changes in hepatic blood flow. These experimental findings, and the data from the literature, point to the acceptance of the well-stirred model, which describes the liver as a well-stirred compartment with the drug in the hepatic venous blood being in equilibrium with that in the liver.Supported in part by National Institutes of Health Grant GM 16496 and the Patent Fund, Graduate Division, University of California, San Francisco.Abstracted in part from a dissertation submitted by K. Sandy Pang to the Graduate Division, University of California, San Francisco, California, in partial fulfillment of the Doctor of Philosophy degree requirements.     

Short Bowel Syndrome

Abstract The short bowel syndrome is a symptom complex that occurs in adults who have less than 200 cm of jejunum-ileum remaining after intestinal resection. Similar symptoms are observed in infants and children following massive bowel resection or congenital anomalies and in individuals with longer segments of intestine with severe mucosal disease. Initial care should focus on a thorough excision of nonviable bowel, an exact measurement of the remaining viable bowel, placing all intestine in continuity at the initial or subsequent operation, and controlling initial food intake. With time, adaptation of the remnant intestine occurs, and absorptive function may be maximized by enhancing the enteral diet and minimizing parenteral nutrition. Growth factors and specialized nutrients may also enhance this process. Intestinal transplantation should be considered in selected individuals with the short bowel syndrome who fail intestinal rehabilitation protocols. E-pub: 31 October 2000     

Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies.

PURPOSE: To discuss the absolute benefits from adjuvant systemic therapy knowledge of long-term outcomes and baseline risks of relapse and disease-specific survival are required. We assessed the 10-year outcomes in a population-based cohort of node-negative (N-) lymphovascular negative (LV-) early breast cancers diagnosed from 1989 to 1991 who did not receive adjuvant systemic therapy. METHODS: One thousand one hundred eighty-seven cases of pT(1-2)N(0) LV- breast cancers with a median follow-up of 10.4 years were reviewed. Kaplan-Meier survival curves for relapse free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS) were compared with log-rank tests with cohorts stratified for tumor size and grade. RESULTS: The median age of this series was 62 years. Four hundred thirty tumors were < or = 1 cm in diameter (cohort 1), 507 were 1.1-2 cm (cohort 2), and 250 were 2.1 to 5 cm in diameter (cohort 3). The 10-year outcomes for cohorts 1, 2, and 3, respectively, were significantly different: RFS, 82%, 75%, and 66%; BCSS, 92%, 90%, and 77%; and OS, 79%, 78%, and 66%. Tumor grade significantly altered outcome within size cohorts, particularly in pT(1)N(0) breast cancers. CONCLUSION: This study provides detailed information on the continued relapse and breast cancer death rate to 10 years of follow-up. Specifically, without adjuvant systemic therapy, patients with LV-, N - breast cancer had a > or = 25% 10-year risk of relapse and a corresponding 10-year breast cancer death rate of > or = 10% if they had either a grade 3 tumor < or = 1 cm, a grade 2 to 3 tumor from 1.1 to 2 cm, or any grade tumor greater than 2 cm.     

Increased placental apoptosis in intrauterine growth restriction

OBJECTIVES: Our purpose was to investigate a possible role for apoptosis in the pathophysiologic mechanisms of intrauterine growth restriction. STUDY DESIGN: Placental samples were obtained from 43 uncomplicated third-trimester pregnancies and from 26 pregnancies complicated by intrauterine growth restriction. The definition used to identify cases of intrauterine growth restriction depended on three criteria: clinical evidence of suboptimal growth, ultrasonographic evidence of deviation from an appropriate growth percentile, and individualized birth weight ratios <10th percentile. Light microscopy was used to quantify the incidence of apoptosis. Electron microscopy and TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling) staining were used to confirm the occurrence of apoptosis. RESULTS: Quantification of apoptosis (medians and interquartile ranges) resulted in the following values: normal third trimester (n = 43) 0.14% of cells (0.08% to 0.20%) and intrauterine growth restriction third trimester (n  = 26) 0.24% of cells (0.16% to 0.29%). The incidence of apoptosis was significantly higher in placentas from pregnancies with intrauterine growth restriction compared with normal third-trimester placentas (p < 0.01, Mann Whitney U test). CONCLUSIONS: These results suggest that apoptosis may play a role in the pathophysiologic mechanisms of intrauterine growth restriction.(Am J Obstet Gynecol 1997;177:401)