Atrial natriuretic peptide inhibits mineralocorticoid receptor function in rat colonic surface cells.

Atrial natriuretic peptide (ANP) inhibits and aldosterone (ALDO) stimulates Na conductive transport. Therefore, the effects of ANP and its second messenger cGMP on mineralocorticoid receptor (MR) function in rat colon surface and crypt cells were examined. 100 nM 8-Br-cGMP decreased surface [3H]ALDO binding by 42 +/- 4% but increased crypt [3HvALDO binding by 52+/-16%. ANP decreased surface [3H]ALDO binding by approximately 50% after a 2.5-h lag period but had no effect on crypt ALDO binding. ANP and cGMP rapidly (< 15 min) inhibited surface cell ALDO-induced MR nuclear translocation but did not affect crypt MR nuclear translocation. Inhibition of cGMP-dependent protein kinase with KT5823 blocked the inhibitory effects of ANP and 8-Br-cGMP on surface cell ALDO binding and MR nuclear translocation. In crypt, KT5823 increased baseline [3H]ALDO binding but did not inhibit the stimulatory effect of exogenous cGMP. DEAE-cellulose chromatography and gel mobility shift assay showed that ANP did not inhibit surface MR activation. ANP inhibited ALDO stimulated short circuit current in distal colon. These data demonstrate cell-specific regulation of MR function. In surface cells, ANP rapidly inhibits MR nuclear translocation and ALDO-induced short circuit current. ANP inhibition of MR function may be an additional mechanism of ANP antagonism of Na reabsorption.

Competitive binding studies of compounds that interact with DNA utilizing fluorescence polarization.

The increase in the fluorescence polarization of acridine orange upon binding to DNA molecules is used as the basis of a competitive method to study the interaction of a variety of fluorescent and non-fluorescent compounds with DNA. Test compounds that interact with DNA inhibit both the binding of acridine orange to DNA and the accompanying increase in fluorescence polarization. Actinomycin D exhibits a dose-dependent inhibition of acridine orange-DNA binding with Micrococcus luteus DNA, calf thymus DNA, and poly(dG-dC); no detectable inhibition of acridine orange intercalation into poly(dA-dT) is observed. In contrast, proflavine shows similar acridine orange inhibition for poly(dA-dT), calf thymus DNA and M. luteus DNA.

Demonstration of nuclear translocation of the mineralocorticoid receptor (MR) using an anti-MR antibody and confocal laser scanning microscopy.

Using a synthetic peptide that corresponds to a unique region of the N-terminal domain of the human mineralocorticoid receptor (MR), amino acids 87-96, we have generated a polyclonal antibody, human (h) MRsN. This sequence shares no homology with the corresponding sequences of the glucocorticoid receptor or other steroid/thyroid hormone receptor superfamily members. Antibody hMRsN cross-reacts with MR from human, rat, and mouse cells and recognizes denatured MR from either crude preparations or partially purified rat kidney cytosol, rat colon, or recombinant hMR overexpressed in baculovirus-infected Sf9 cells. Immunoprecipitation of the native MR from either partially purified or crude preparations of rat kidney cytosol with hMRsN, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver stain, demonstrated a major protein band with a mol wt of 116 kilodaltons. In addition, using confocal laser scanning microscopy and digital image analysis, the immunocytochemical localization of the recombinant hMR over-expressed in Sf9 cells 24 h post-transfection was determined. In the absence of ligand, the MR was detected solely in the cytoplasm, after a 30-min exposure to 100 nM aldosterone the MR was perinuclear, and after 60 min, the MR was predominantly nuclear. To ascertain that this phenomenon was not unique to insect cells, aldosterone induced MR nuclear translocation in mouse macrophage cells was also demonstrated immunocytochemically, clearly indicating a role for nuclear translocation in MR function.

Effects of celecoxib and naproxen on renal function in the elderly.

OBJECTIVE: To compare the effects of celecoxib, a cyclooxygenase 2-specific inhibitor, with the nonspecific cyclooxygenase 1 and 2 inhibitor naproxen on renal function in 29 healthy elderly subjects in a single-blind, randomized, crossover study. METHODS: Subjects received either celecoxib, 200 mg twice daily, for 5 days followed by celecoxib, 400 mg twice daily, for the next 5 days, or they received naproxen, 500 mg twice daily, for 10 days. After a 7-day washout, subjects were crossed over to receive the other regimen. RESULTS: After the first dose, the trend was for a greater decrease in glomerular filtration rate with naproxen (-5.31 mL/min per 1.73 m2) compared with celecoxib (-0.86 mL/min per 1.73 m2). The treatment difference became statistically significant on day 6 (-7.53 vs -1.11 mL/min per 1.73 m2 for naproxen and celecoxib, respectively; P=.004). Urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion was significantly reduced from baseline across the treatment interval with both celecoxib and naproxen (P< or =.04). There were no significant differences in prostaglandin excretion between these 2 agents (P> or =.07). Small, transient decreases (P<.05) in urinary sodium excretion were observed after the initiation of both celecoxib and naproxen treatment. Sodium excretion values returned to baseline by the end of the study. CONCLUSIONS: The results indicate that cyclooxygenase 2-specific inhibition in healthy elderly subjects may spare renal hemodynamic function, although the effects on sodium excretion, as well as urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion, appear to be similar to those of nonspecific cyclooxygenase inhibitors such as naproxen.

Vancomycin prescribing practices in hospitalized chronic hemodialysis patients.

To determine the prevalence of and indications for vancomycin administration among hospitalized chronic hemodialysis patients, we performed a 3-month prospective cohort study at a tertiary care center. Modified guidelines for vancomycin use from the Hospital Infections Control Practices Advisory Committee of the Centers for Disease Control and Prevention were used. Vancomycin was administered during 56 of 144 admissions (39%) requiring chronic hemodialysis compared with 336 of 7,212 admissions (5%) not requiring hemodialysis (relative risk, 11; 95% confidence interval, 8 to 15; P < 0.001). Among chronic hemodialysis patients, vancomycin use was judged appropriate for 131 of the 164 vancomycin doses (80%). The most common appropriate indication was empiric therapy in a febrile patient before culture or susceptibility results. Of 32 infections identified in patients who received empiric vancomycin, 15 infections (47%) were caused by beta-lactam-resistant pathogens. Among the 33 doses (20%) judged inappropriate, continued therapy for a presumed infection despite failure to identify a beta-lactam-resistant pathogen was the most common indication. Although vancomycin administration was frequent among hospitalized chronic hemodialysis patients, its use was justified in the majority of cases. Efforts should focus on limiting vancomycin administration for treating infections caused by beta-lactam-sensitive pathogens.

Prescribed versus delivered dialysis in acute renal failure patients.

The current study was designed first to determine separately the prescribed and delivered dose of dialysis and, second, to determine what factors lead to failure to deliver the prescribed dose of dialysis in patients with acute renal failure (ARF). Forty patients, who collectively underwent 136 dialysis treatments, were studied prospectively at two institutions. The results showed that almost half the prescriptions (49%) were for a Kt/V less than 1.2 and, more importantly, nearly 70% of the treatments delivered a Kt/V less than 1.2, the minimally acceptable dose defined in the Dialysis Outcomes Quality Initiative (DOQI) guidelines for chronic hemodialysis (CHD) patients. Patient predialysis weight was the most important variable associated with a low prescribed and delivered dose of dialysis, as well as lack of delivery of the prescribed dose of dialysis. From the statistical model, it is estimated that for every 10-kg increase in predialysis weight, the chance of prescribing or delivering a Kt/V less than 1.2 increased 4.6- and 1.95-fold, respectively. The lower than prescribed blood flow achieved by the temporary catheters and patients not receiving anticoagulation were variables also associated with not receiving the prescribed Kt/V. It is concluded that patients with ARF are prescribed and receive a dose of dialysis that would be considered inadequate for CHD patients. Until the association between dose of dialysis and outcome is better defined, it would be prudent that both the dialysis prescription and the delivery of dialysis to patients with ARF should be performed with the same care and goals as that currently received by patients with end-stage renal disease (ESRD).

Respiratory illness and hypophosphatemia.

We retrospectively reviewed the charts of 308 admissions to a pulmonary disease ward and 100 admissions to the general medical service over one year to find the prevalence, sequelae, and etiology of hypophosphatemia. The overall prevalence of low serum phosphate levels (less than 2.4 mg/dl) occurring at least once during hospitalization in chest patients was 17 percent, but was higher in patients with respiratory infections (28 percent). Moreover, the prevalence of hypophosphatemia on admission (before institution of intravenous fluid or drug therapy) was ten times higher in patients with respiratory infections than in patients with noninfectious respiratory illness or general medical patients (21 vs 2 percent, p less than 0.001). Serum phosphate less than 2.0 mg/dl occurred in 4 percent of patients. Twenty-seven percent of the patients (including two with ventilatory failure) with abnormally low serum phosphate levels had symptoms or signs of uncertain etiology later explicable by the presence of hypophosphatemia. The most common additional laboratory finding associated with hypophosphatemia was elevation of muscle enzymes. Although mortality was no higher in hypophosphatemic patients, hospital stay was twice as long as that of patients with normal levels of serum phosphate. No correlation was found between simultaneous arterial blood gases and serum phosphate levels. Two patients given antacids had severe hypophosphatemia and worsened ventilatory function; phosphate-binding antacids should be used judiciously in patients with severe respiratory disease, since they may lead to the development or worsening of hypophosphatemia and diminished ventilatory function.

Mechanism of the renal response to contrast medium in dogs. Decrease in renal function due to hypertonicity.

Radiographic contrast media (CM) (meglumine/sodium diatrizoate-76%; 1650 mOsm/kg) and other hypertonic solutions induce renal vasoconstriction by an unknown mechanism. In anesthetized dogs, renal blood flow (RBF) was measured with an electromagnetic flowmeter and filtration fraction (FF) and glomerular filtration rate (GFR) by the renal extraction of technetium-99m tin chelate. Ureteral pressure (UP) and wedged renal venous pressure (VP) were measured as indices of intrarenal pressure. Measurements of renal length (L), along with pressures, made it possible to examine the compliance of the system. A 4-cc intrarenal bolus of CM caused a 59% reduction in GFR (control: 0.63 +/- 0.04 to 0.26 +/- 0.04 ml/min X g, mean +/- SEM), in association with a 23% reduction in RBF (control: 3.10 +/- 0.11 to 2.39 +/- 0.26 ml/min X g) and a 44% decrease in FF (control: 0.32 +/- 0.01 to 0.18 +/- 0.03). These responses were compared with a 3-microgram intrarenal bolus of norepinephrine (NOREPI) which resulted in a 79.0 +/- 7.5% reduction in RBF, 68.3 +/- 7.3% reduction in GFR and 42.6 +/- 15.6% increase in FF. The NOREPI-induced vasoconstriction caused transient decreases in renal L, UP, and VP, whereas the CM-induced decrease in renal blood flow was associated with increases in these parameters. In studies employing ureteral occlusion to elevate intrarenal pressure, the magnitude (area, cm2) of the CM-induced decrease in renal perfusion was accentuated with increased UP (r = 0.79, n = 24, P less than 0.001). The CM-induced increase in renal L, UP, and VP must reflect osmotic forces and an increase in intrarenal pressure. The decreases in FF and GFR probably reflect Starling forces in the glomerular capillaries, with osmotic transients dominating. The results suggest a mechanical mechanism for the CM-induced decrease in RBF.

Comparison of the response of the renal blood supply to acetylcholine and to a calcium channel blocking agent, diltiazem, in the dog.

Several vasodilators, including acetylcholine, are capable of inducing maximal renal vasodilatation when infused into the renal artery. Despite substantial interest in the renal vascular response to calcium channel blocking agents, there has been no systematic comparison of any of these agents to an index vasodilator, such as acetylcholine. We compared the renal vascular angiographic response to acetylcholine and diltiazem, infused into the renal artery in graded dosage, in 14 dogs. In eight of the dogs renal blood flow was measured with an electromagnetic flowmeter. At peak, the acetylcholine-induced increase in renal blood flow (155 +/- 25 to 309 +/- 55 ml/min) slightly exceeded that induced by diltiazem (143 +/- 13 to 257 +/- 58 ml/min). A close correlation was found between the maximal blood flow increase induced by acetylcholine and by diltiazem (R = .95). Dilatation of the intrarenal arterial tree evident on the renal arteriogram was substantially less striking with diltiazem than with acetylcholine in these eight dogs. To ascertain the possible contributing role of the surgery required for blood flow measurement, the two agents were assessed in six additional dogs without blood flow measurement. In these six dogs diltiazem and acetylcholine induced essentially identical degrees of renal arterial vasodilatation. It is concluded that diltiazem, the calcium channel blocking agent, produces near maximal renal vasodilatation at the arteriolar level and that responses of more proximal elements of the renal arterial tree, visible during renal arteriography, are sensitive to the conditions of the experiment.

A review of the concept of biocompatibility.

The consequences of blood-membrane interactions are numerous. The perturbations created in the cellular components and humoral pathways are being actively pursued. These changes interact with and may be modified by other aspects of the hemodialysis treatment. They are capable of producing adverse events in the hemodialysis patient. Events range from acute life-threatening reactions, through chronic changes which may interfere with the immune response, impact upon the patients' nutritional status and cause residual renal function to deteriorate.

Adequacy of dialysis.

Despite improvements in the delivery of dialysis, morbidity and mortality remain excessively high in end-stage renal disease patients. Multiple lines of evidence suggest that inadequate dialysis is responsible these trends. The limits of our understanding of the influence of dialysis dose on mortality and morbidity are discussed. In that context, the relationship between dialysis dose and nutritional status of dialysis patients is also reviewed. The best marker for adequacy of dialysis is yet to be determined. However, urea as a surrogate for small molecular weight solute clearance, has been demonstrated by many studies to be a parameter of adequacy, both in hemodialysis and peritoneal dialysis populations. The application of kinetic modeling of urea is discussed for hemodialysis. The new insights that will be forthcoming at the conclusion of the National Institute of Health HEMO study should help to define an optimal dose of dialysis.

Nitrogen balance in hospitalized chronic hemodialysis patients.

Malnutrition is an important factor in the increased morbidity and mortality of chronic hemodialysis (CHD) patients. Dietary protein intake necessary to maintain neutral nitrogen balance appears to be higher in CHD patients due to various catabolic effects of the hemodialysis procedure, including nutrient losses and increased energy expenditure. Dietary intake may be further decreased in hospitalized CHD patients. We examined this issue in 18 CHD patients (9 male, 9 female) who were admitted to a regular ward. Daily protein intake (DPI) and daily caloric intake were measured for each patient. In addition, protein catabolic rate (PCR) calculated from interdialytic changes in BUN were calculated. Our results showed that mean (+/- SD) DPI was 0.79 +/- 0.41 g/kg/day, while PCR was 0.93 +/- 0.38 g/kg/day. Dietary protein and energy intake were 66% and 50% of suggested values, respectively, and DPI accounted for only 85% of PCR. Mean nitrogen balance was negative by -2.11 +/- 2.77 g of nitrogen/day (range -9.91 g of nitrogen/day to +3.89 g of nitrogen/day). Biochemical nutritional parameters such as serum albumin, cholesterol, prealbumin and transferrin obtained one week following admission were also indicative of undernutrition (3.16 +/- 0.39 g/dl, 132 +/- 30 mg/dl, 20 +/- 7.4 mg/dl, 154 +/- 49 mg/dl, respectively). We conclude that hospitalized CHD patients have inadequate protein and energy intake and this is evidenced by a significant deterioration in nutritional parameters during hospitalization. More aggressive nutritional interventions may be needed for this group of patients to prevent the adverse effects of hospitalization on nutritional status.

Contrast medium-induced renal vasoconstriction and endogenous vasoconstrictor hormones.

Hypertonic solutions, such as contrast media (meglumine/sodium diatrizoate-76%; Renografin-76), induce vasoconstriction in the renal vascular bed via an unknown mechanism. We assessed a possible role of two vasoconstrictor hormones known to be released by the kidney, angiotensin II (AII) and the prostaglandin, thromboxane. Specific inhibition of AII at the smooth muscle receptor level by saralasin (0.33-0.75 microgram/kg/min, IA) did not attenuate the response. Inhibition of prostaglandin formation by indomethacin (4 mg/kg, IV), likewise, did not prevent the decrease in renal perfusion. We conclude that neither AII nor the prostaglandin system mediate the contrast medium-induced renal vasoconstriction.

Psyche and skin.

In this short communication, I intend to present a specific psycho-dynamic theory which explains some of the psychodynamics associated with eczemas and perhaps to some other skin lesions. It provides a framework for understanding and treating such lesions with pure psychodynamic methods, i.e., by psychoanalysis or analytic psychotherapy. These ideas were first presented in 1968 by Ester Bick, a Polish psychoanalyst living in London. Her theory of the role of the primal object for the baby, as the provider of necessary psychological containment, a kind of psychological skin, has proven to be of great value for psychoanalysts and psychotherapists treating adults and children with skin problems. When this "skin function" of the caretaking object fails, real skin lesions may follow. When the person finds in treatment an object who has this containing function, his/her skin heals.

Siblings revisited: old conflicts and new opportunities in later life.

This article discusses and gives clinical examples of crises that occur among and affect adult siblings in later life. They may be related to normative changes or they may be conflicts that have an impact on the well-being of the current family. Both are viewed as unique opportunities for resolution and reconciliation that can lead to a more realistic view of the past, and they may break an unfortunate cycle affecting future generations. Therapists are urged to be aware of and utilize these forces so that healing can take place.