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Biomedical subjects

M L Graber

Publications and source records attributed to M L Graber.

At least 19 recordsLinked to original sources
PubMed1999

Physician participation in quality management. Expanding the goals of peer review to detect both practitioner and system error.

BACKGROUND: The goals of peer review are to improve the quality of medical care and to provide fair review of individual practitioner actions, judged against the local standard of medical care. A new system for conducting peer review was evaluated which included in every case a root cause analysis to identify latent system flaws and a consideration of performance improvement projects to remedy these flaws. METHODS: The peer review committee of the medical service in a tertiary care, affiliated Department of Veterans Affairs Medical Center, which conducted the evaluation, was familiar with the local standards of care and the systems issues relevant to each case. Four questions were answered for each case: Was the quality of care less than ideal? If so, was the practitioner negligent? What system flaws contributed to the error or to the severity of injury? How could the system flaws be eliminated? RESULTS: Compared with the prior method of peer review, expanding the scope of review identified four times as many system problems (in 46% of cases versus 11%) without changing the incidence of finding provider negligence (21% preintervention versus 25% postintervention). Performance improvement projects were generated in 36 of 89 of these cases during the three-year period. DISCUSSION: Expanding the scope of peer review to include both root cause analysis and performance improvement thinking increased the detection of latent system flaws and the number of performance improvement projects without compromising the peer review committee's ability to identify negligence.

Hospitals, Veterans↗
PubMed1995

Unreliability of the abdominal fat pad biopsy in the evaluation of nephrosis: report of 3 consecutive cases.

In the workup of unexplained nephrotic syndrome in the elderly patient, renal biopsy has shown amyloidosis to be the cause in 15-30% of the cases. Most of the cases of amyloidosis are primary and are, therefore, treatable with alkylating agents, albeit at a high level of toxicity. Abdominal fad pad biopsy has been suggested as a minimally invasive, low-cost method for diagnosing amyloidosis that is 100% specific. We report our experience with 3 consecutive cases of fat pad biopsy in the workup of unexplained nephrosis in the elderly patient: including the first false positive reported with respect to nephrotic renal disease, a false negative, and a true positive. We feel that in an elderly patient with unexplained nephrosis though the abdominal fat pad biopsy may be helpful, the patient should not be committed to a regimen with potentially very high toxicity on the basis of a positive fat pad biopsy alone. We recommend that the more invasive renal biopsy be performed should therapy with alkylating agents be contemplated.

Abdomen↗
PubMed1995

Endocrine effects of erythropoietin.

Uremic men may manifest a variety of hormonal abnormalities, including decreased serum concentrations of testosterone and thyroid hormones and increased serum levels of growth hormone and prolactin. Some previous investigations have reported that erythropoietin therapy may reverse these hormonal changes. To investigate this possibility further, we measured serum prolactin, testosterone, LH, FSH, TSH, free thyroxine, triiodothyronine, growth hormone and IGF-I in 21 generally elderly male hemodialysis patients before and during erythropoietin therapy; many of the patients also received an anabolic steroid or metoclopramide treatment. Despite a significant erythropoietic response in a majority of the subjects, no significant changes were seen in any of the hormonal parameters other than a small decrease in serum growth hormone concentrations. Advanced age and chronic illness in our patients may have played a role in limiting the hormonal response reported by others.

Adult↗
PubMed1993

Perturbation of cell pH regulation by H2O2 in renal epithelial cells.

The purpose of these studies was to define the effect of oxidant stress on intracellular pH in renal tubular epithelial cells. Cell pH was therefore quantitated from the fluorescence ratio of 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein in the BSC-1 and opossum kidney (OK) established cell lines, both of which are known to be susceptible to oxidant injury. Exposure to 1 mM H2O2 acidified cytosolic pH in both cell types, and this acidification reversed on withdrawal of the H2O2. Half-maximal acidification was seen at 10 microM H2O2. Effects on Na/H antiport were first measured as the recovery from an NH4Cl-pulse acid load: 1 mM H2O2 inhibited Na/H antiport-mediated pH recovery by approximately 40% in both cell types. H2O2 substantially increased the rate of passive Na-independent H+ flux in the OK cell but under the conditions used did not effect this flux in the BSC-1 cell. When both the Na/H antiport and Na-independent transport systems were blocked by perfusion with a 0-Na depolarizing buffer, the H2O2-induced acidification was totally abolished. Measured from the rate of H+ appearance in the medium, H2O2 decreased the rates of endogenous H+ production in both cell types. As measured from the fluorescence of endocytosed fluorescein isothiocyanate-dextran, H2O2 alkalinized lysosomes/late-endosomes, but at a rate much slower than the rate of cytosolic acidification. The results indicate that H2O2 acidifies cell pH in these cell lines by inhibiting Na/H antiport, by accelerating the passive influx of H+, and to some extent by releasing H+ from subcellular compartments. The acidification may have important effects in modulating the toxicity of H2O2.

Acid-Base Equilibrium↗
PubMed1992

Parathyroid hormone decreases HCO3 reabsorption in the rat proximal tubule by stimulating phosphatidylinositol metabolism and inhibiting base exit.

The mechanism of inhibition of HCO3 transport by parathyroid hormone (PTH) in the proximal tubule is not clearly defined. Previous studies in vitro have suggested that this effect is mediated via cAMP generation, which acts to inhibit Na/H exchange, resulting in cell acidification. To examine this question in vivo, intracellular pH (pHi) was measured in the superficial proximal tubule of the rat using the pH-sensitive fluoroprobes 4-methylumbelliferone (4MU) and 2',7'-bis(carboxyethyl)-(5, and 6)-carboxyfluorescein (BCECF). PTH was found to alkalinize the cell. This alkalinization suggested inhibition of basolateral base exit, which was confirmed by in situ microperfusion studies: lowering HCO3 in peritubular capillaries acidified the cell, an effect blunted by PTH. Removal of luminal Na promoted basolateral base entry, alkalinizing the cell. This response was also blunted by PTH. Readdition of luminal Na stimulated the luminal Na/H exchanger, causing an alkalinization overshoot that was partially inhibited by PTH. cAMP inhibited luminal H secretion but did not alkalinize the cell. Stimulation of phosphatidylinositol-bis-phosphate turnover by PTH was suggested by the effect to the hormone to increase cell Ca. Blocking the PTH-induced rise in cell Ca blunted the effect of the hormone to alkalinize the cell, as did inhibition of phosphatidylinositol breakdown. Furthermore, stimulation of protein kinase C by a phorbol ester and a diacylglycerol applied basolaterally alkalinized the cell and inhibited luminal H secretion. The findings indicate that both arms of the phosphatidylinositol-bis-phosphate cascade play a role in mediating the effect of PTH on the cell pH. The results are consistent with the view that PTH inhibits base exit in the proximal tubule by activation of the phosphatidylinositol cascade. The resulting alkalinization may contribute, with cAMP, to inhibit apical Na/H exchange and the PTH-induced depression of proximal HCO3 reabsorption.

Animals↗
PubMed1987

Axial heterogeneity of intracellular pH in rat proximal convoluted tubule.

In the proximal convoluted tubule (PT), the HCO3- reabsorptive rate is higher in early (EPS) compared with late proximal segments (LPS). To examine the mechanism of this HCO3- reabsorption profile, intracellular pH (pHi) was measured along the superficial PT of the rat under free-flow and stationary microperfusion using the pH-sensitive fluorescence of 4-methylumbelliferone (4MU). With 4MU superfusion, pHi was found to decline along the PT. Observation with 365-nm excitation revealed that EPS were brightly fluorescent and always emerged away from their star vessel. Midproximal segments were darker and closer to the star vessel which was surrounded by the darkest LPS. Decreasing luminal HCO3- from 15 to 0 mM lowered pHi in both EPS and LPS, but pHi remained more alkaline in EPS with both perfusates. Thus the axial decline in pHi along the PT is due to both luminal factors and intrinsic differences in luminal H+ extrusion in PT cells.

Absorption↗
PubMed1987

Renal wasting of magnesium and phosphate.

We report an asymptomatic man found to have simultaneous renal transport defects for magnesium and phosphate. Associated findings include gout, high frequency hearing loss, chronic elevations of SGOT and SGPT, metabolic bone disease, and hyperparathyroidism. The clinical expression of hyperparathyroidism was masked for 5 years by hypomagnesemia, and the patient became hypercalcemic only when magnesium levels were normalized by intravenous infusion. Both the phosphate and magnesium transport abnormalities persisted after parathyroidectomy. The many unique features of this case distinguish it from previously described disorders of magnesium or phosphate wasting.

Adult↗
PubMed1986

Characteristics of fluoroprobes for measuring intracellular pH.

We evaluated four different fluoroprobes to determine their capabilities and limitations in measuring intracellular pH by the fluorescent indicator technique. In vitro, carboxyfluorescein, dimethylcarboxyfluorescein, biscarboxyethyl carboxyfluorescein, and 4-methylumbelliferone (4MU) all showed comparably intense fluorescence and excellent pH sensitivity near their respective pKa values. Major differences were found between 4MU and the fluoresceins in terms of protein binding, concentration effects, bleach rates, and the retention time within cells. Both fluorescence and a fluorescence ratio at pH-sensitive/pH-insensitive excitation wavelengths increased with pH for all compounds, and the ratio completely corrected for large changes in the excitation light intensity. In contrast, the ratio showed large artifactual changes as dye concentration increased because of self-quenching effects and spectral shifts. Protein interactions likewise caused spectral shift and ratio aberrancies, but calcium, magnesium, and oxygen had no effect on the fluorescence ratios. We conclude that measurements of cell pH by fluorescence techniques are subject to artifacts induced by self-quenching and protein binding. Use of the fluorescence ratio technique does not necessarily correct for these artifacts, and in particular the ratio technique does not correct for changes in fluoroprobe concentration. Because the major artifacts cause the ratios for 4MU and for the fluoresceins to move in opposite directions, an experimental maneuver can be shown to cause a true change in pH if the fluorescence and ratios change in the same direction for these two classes of fluoroprobes.

Cations↗
PubMed1986

Fluorescence identifies an alkaline cell in turtle urinary bladder.

Intracellular pH (pHi) of turtle bladder mucosal cells was studied by the trapped fluorescent indicator technique. Bladders efficiently accumulated and converted 4-methylumbelliferyl acetate to its pH-sensitive derivative 4-methylumbelliferone (4MU). Excited at the pH-indifferent wavelength 334 nm, bladders fluoresced a uniform blue. Using pH-sensitive 365-nm excitation, 10-20% of the mucosal cells fluoresced distinctly brighter, suggesting a more alkaline pHi. Using the 365/334 ratio to quantitate pHi, this difference averaged 0.1 pH units. Bright cells were more distinct after SITS or acetazolamide but disappeared after digitonin permeabilization, dinitrophenol, or treatment with propionate, DMO, and NH4Cl. Essentially the same population of bright cells was identified by carboxyfluorescein diacetate. The brighter cell corresponded exactly to a population of cells with distinctive acridine orange staining and bright costaining with the potential-sensing probes Di-O-C5, Di-S-C3, and 4-Di-5-Asp. Two extremes of bright cell shape were seen: an elongate cell, prevalent under conditions stimulating H+ secretion, and a more compact cell, when acidification was inhibited. These observations support the hypothesis that acidification represents H+ secretion via the luminal membrane and that a primary role of carbonic anhydrase in this process is to support the exit of base from the cell. The more alkaline cells appear to be the carbonic anhydrase-rich cells. These cells are chemically isolated from the surrounding granular cells and change their morphology in response to changes in acidification. These special properties indicate a unique role for the carbonic anhydrase cell in H+ secretion.

Acridine Orange↗
PubMed1983

Effect of respiratory acidosis on acidification by the medullary collecting duct.

The effect of acute respiratory acidosis (ARA) on inner medullary collecting duct (IMCD) acidification was studied and the results were compared with previously obtained data by our laboratory in rats with acute metabolic acidosis (AMA). We employed the microcatheterization technique to directly measure pH and PCO2 with glass-membrane electrodes, and fluid samples were obtained for measurement of bicarbonate, phosphate, and ammonium. Arterial pH was 7.18 +/- 0.01 and PCO2 was 88 +/- 2 mmHg. The IMCD data were analyzed as a function of IMCD length (approximately 6 mm). pH decreased from 5.78 +/- 0.07 to 5.27 +/- 0.03 and PCO2 increased from 55 +/- 4 to 75 +/- 2 mmHg between origin and tip. Bicarbonate delivery decreased from 154 +/- 34 to 25 +/- 3 nmol/min but no change was noted in acid phosphate, ammonium, or net acid addition along the IMCD. However, net acid excretion was not different from that found previously in AMA. We conclude that during ARA acidification is augmented prior to, but not along, the IMCD. In contrast, during AMA we previously found that IMCD plays a major regulatory role in urinary acidification, accounting for about 50% of the excreted hydrogen ion.

Acidosis↗
PubMed1983

Spurious hyperchloremia and decreased anion gap in hyperlipidemia.

A patient with overt lipemia presented with hyponatremia, hyperchloremia, and a negative anion gap. The hyperchloremia and negative gap resulted from overestimation of chloride levels due to a light-scattering effect in the colorimetric assay, an effect that was reproducible in vitro. In a prospective study, this effect produced substantial overestimations at even modest degrees of hyperlipemia. This effect expands the differential diagnosis of a decreased gap, adds to the list of technique-dependent artifacts in lipemia, and, if present, must be recognized for a patient's fluid and electrolyte status to be accurately defined.

Adult↗
PubMed1982

Elevated urinary PCO2 in the rat: an intrarenal event.

During a bicarbonate diuresis, final urine Pco2 considerably exceeds systemic Pco2, an effect thought to reflect the postpapillary delayed dehydration of carbonic acid. To test this explanation, Pco2 tensions along the inner medullary collecting duct (IMCD) of bicarbonate-loaded rats were measured directly using Pco2 microelectrodes. With systemic Pco2 held at 40 mm Hg, IMCD Pco2 exceeded systemic Pco2 in every measurement by an average of 20 to 30 mm Hg. A significant increment in Pco2 was seen between 50% IMCD length and the papilla tip. During the infusion of carbonic anhydrase, IMCD Pco2 was reduced but not to systemic levels. Finding elevated Pco2 along the terminal IMCD deemphasizes the importance of postpapillary delayed dehydration and suggests the possibility that bicarbonaturia is associated with papillary accumulation of carbon dioxide.

Animals↗
PubMed1981

pH and PCO2 profiles of the rat inner medullary collecting duct.

To directly characterize acidification by the collecting duct, we developed pH and PCO2 microelectrodes suitable for microcatheterization of the inner medullary collecting duct (IMCD). In saline-infused control rats apparent in situ pH fell significantly along the IMCD, from 5.95 at 60% length to 5.49 at the papilla tip. Luminal PCO2 averaged 34 +/- 1 mmHg and PD averaged +3 mV. In rats acutely infused with 0.1 N HCl, apparent in situ pH also decreased significantly from 5.56 to 5.28, PD averaged +2 mV, and luminal PCO2 31 +/- 1 mmHg. The luminal PCO2 of HCl-infused rats was significantly less than controls and both levels were significantly below arterial PCO2. Corroborating the in situ pH profiles, equilibrium pH measured on collected IMCD samples also decreased significantly with percent length. In samples measured in situ and at equilibrium, a small but significant acid disequilibrium pH ws seen in both groups. We interpret these results to indicate that the IMCD actively participates in distal acidification. It is proposed that acidification by the IMCD is predominantly mediated by hydrogen ion secretion which simultaneously acidifies luminal fluid and generates a cellular sink for CO2, thereby inducing an acid disequilibrium pH by two mechanisms.

Acidosis↗
PubMed1981

Acute metabolic acidosis augments collecting duct acidification rate in the rat.

It is generally assumed that at least part of distal acidification occurs along the collecting duct. Complete and direct evaluation of acidification along this nephron segment is unavailable, however. The purpose of these experiments was to quantify the net acidification rate along the inner medullary collecting duct (IMCD) and to measure the effect of acute HCl acidosis. In 13 control rats (arterial pH, 7.39 +/- 0.01; PCO2, 39 +/- 1 mmHg) and 11 HCl-infused rats (arterial pH 7.18 +/- 0.01; PCO2, 40 +/- 1 mmHg) we obtained four to eight IMCD samples by a modified microcatheterization technique that also permitted measurement of in situ and in vitro pH. Tubular fluid pH decreased along the IMCD in both groups and was more acidic by 0.2-0.4 pH units in the acid-infused rats. Bicarbonate reabsorption was noted in both groups as delivery along the IMCD decreased from 205 +/- 127 to 26 +/- 6 nmol/min in control rats and from 219 +/- 118 to 17 +/- 4 nmol/min in the acidotic group. Ammonia delivery to and addition along the IMCD was significantly greater in the acidotic rats--from 193 +/- 59 to 462 +/- 53 nmol/min in control and from 887 +/- 126 to 1,396 +/- 90 nmol/min in acidotic rats. No significant change in total or titrated phosphate was seen. Net acid addition along the IMCD was over twice as great in acidotic rats, 450 vs. 970 nmol/min. Our results indicate that significant net acid addition occurs along the IMCD and that during acidosis this acidification rate increases.

Acid-Base Equilibrium↗
PubMed1977

Chronic active hepatitis and membraneous glomerulonephritis.

A 26-year old man with documented HBs antigenemia of five years' duration developed the nephrotic syndrome. Histologic patterns of chronic active hepatitis and membraneous glomerulonephritis were found. The glomeruli stained positively for Ig-G, complement and HBs Ag. The relationship of HBs Ag-positive chronic active hepatitis and membraneous glomerulonephritis is discussed.

Adult↗