This article discusses the key decisions and steps that have partially formalized instruction in the responsible conduct of research (RCR) in U.S. research institutions, the different purposes for offering and/or requiring such instruction, and suggestions for what needs to be done to enhance the professional development of researchers in the future. RCR education has developed during three distinct eras: the 1980s, when policy makers were most concerned with defining and investigating research misconduct; the 1990s, when there was significant but highly decentralized growth in RCR instruction; and the years since 2000, when there have been a series of reforms and educational developments. There is still a need for scientists, universities, and professional societies to develop consensus on best ethical practices in many areas of scientific research. More also needs to be learned about assessing the quality of RCR instruction and the effects of training on researchers' behavior. To help set the course for RCR instruction in the future, more effort and funding need to be directed to studying actual research behavior and the factors that influence it; RCR educators and administrators must develop a common vocabulary and framework for developing and evaluating the impact of RCR instruction; and research institutions and funding agencies alike need to take a more active role in promoting and supporting RCR instruction.

Carbonic anhydrase is a zinc metalloenzyme widely distributed throughout the tissues of the body. This enzyme exists in a number of isozymic forms in most mammalian species. Significant advances over the past decade have been made in characterizing the nature of renal carbonic anhydrase. In the kidney, this enzyme is thought to play a pivotal role in urinary acidification and bicarbonate reabsorption. Two distinct isozymes of carbonic anhydrase have now been identified in the mammalian kidney. A soluble cytoplasmic form, similar if not identical to human erythrocyte carbonic anhydrase C, accounts for the bulk of the renal carbonic anhydrase activity. In addition, a membrane-bound form constituting only about 2--5% of the renal activity has been found in the brush border and basolateral fractions of kidney homogenates. The histochemical and immunocytochemical localization of these isozymes along the nephron and collecting duct system of various mammalian species suggests that marked heterogeneity exists. The Editorial Review examines the biochemical and morphological approaches that have been used to elucidate the nature of renal carbonic anhydrase and to assess its distribution along the urinary tubule. Possible physiological roles for the renal carbonic anhydrases are considered for the different segments of the nephron and collecting duct system.

The presence of carbonic anhydrase activity in rabbit and mouse kidneys was examined using a histochemical procedure with plastic embedded sections stained by the modified version of the cobalt-phosphate method (Hansson, 1967, 1968; Ridderstrale, 1976). Proximal convoluted tubules (S1 and S2 segments) in both species were strongly positive for carbonic anhydrase activity on the membranes of the luminal, lateral, and basal surfaces. The apical cytoplasm beneath the brush border and the nuclei also stained positively for carbonic anhydrase. The S3 segment (pars recta) of the proximal tubule in the rabbit was positive on the luminal membrane, with somewhat less intensity seen on the lateral and basal surfaces. This segment in the mouse was completely negative. The first part of the thin limbs of long-looped nephrons exhibited strong staining in the mouse. Faint luminal staining was present on descending thin limbs of short-looped nephrons in the mouse. In the rabbit, both the medullary and cortical ascending thick segments of the limb of Henle were completely negative. In contrast, the medullary and cortical ascending thick limbs in the mouse kidney showed staining on all plasma membranes. The intercalated cells in the cortical and medullary portion of the collecting tubules stained positively for carbonic anhydrase in both species. The principal cells of the collecting duct in the cortex were negative in the rabbit and faintly positive in the mouse. The principal cells in the upper medullary collecting tubules in both species stained intensely along the luminal, lateral, and basal cell membranes. The papillary collecting ducts were largely negative in both the rabbit and the mouse. Some interstitial cells in the rabbit in the region of the papillary tip were strongly positive. We conclude that there is a marked difference in carbonic anhydrase activity within and between the renal tubular segments of the rabbit and the mouse. In addition, these distinct differences that exist between the two species correlated with known physiological roles in ion transport.

Abstract. The present study examined whether a pre-or postischemic infusion of verapamil (V) or a postischemic infusion of nifedipine (N), drugs which block calcium (Ca"+) influx across plasma membranes, provides protection against ischemic acute renal failure (ARF) in dogs. Renal hemodynamics and excretory function were examined 1 h (initiation phase) and 24 h (maintenance phase) after a 40-min intrarenal infusion of norepinephrine (NE). In each case, the uninfused contralateral kidney served as control. Four groups were studied: (a) at 24 h (P < 0.05 as compared with GFRs in the NE kidneys). In addition, function of cortical mitochondria (Mito) was examined at the end of the 40-min NE infusion and after 1 and 24 h of reperfusion in the NE alone and NE + V groups. Mito respiration, assessed by acceptor control ratios, was reduced at each period in the NE alone kidneys. After 24 h, these Mito had accumulated Ca++ and exhibited reduced Ca++ uptake and increased Ca++ release rates. Mito from NE + V kidneys respired normally, did not accumulate Ca++, and exhibited no alterations in Ca++ uptake or release. Light and electron microscopy also demonstrated morphological protection of V against tubular necrosis and cell injury. Mito

New graduate biomedical sciences students have inadequate and inconsistent knowledge of RCR, irrespective of their prior education or experience. Incoming trainees with previous graduate RCR education may also have gaps in core knowledge.

The present study investigated the protective effect of acute volume expansion (25%) with isotonic saline, isotonic mannitol, and hypertonic mannitol in a model of unilateral norepinephrine-induced acute renal failure (ARF). Three hours following a 40-min intrarenal infusion of norepinephrine (NE) (0.75 microgram/kg/min), inulin clearance had fallen from a control value of 54.1 +/- 6.5 to 1.3 +/- 1.3 ml/min in untreated dogs and fell similarly (P = NS) to 3.3 +/- 1.5 ml/min in animals preexpanded with 0.9% saline (0.75 ml/kg/min). In contrast, as compared to the untreated animals, inulin clearance 3 hr post NE infusion was significantly greater in dogs preexpanded with 5% mannitol (9.2 +/- 2.5 ml/min, P less than 0.01), or 20% mannitol (16.6 +/- 3.9 ml/min, P less than 0.01). The protective effects of 5% and 20% mannitol were not statistically different from each other. Recovery of renal excretory function in all groups, expressed as 3-hr post NE inulin clearance, correlated with the magnitude of pre NE solute excretion rate (r = 0.612, P less than 0.001) and osmolar clearance rate (r=0.593, P less than 0.001), but not with pre insult inulin clearance (r = 0.233, P = NS) or renal blood flow (r = 0.249, P = NS). In the presence of a profound fall in inulin clearance, proximal tubular (PT) pressures in untreated dogs 3 hr post NE infusion achieved a value equal to control (26 +/- 11 vs. 25 +/- 2 mm Hg). In contrast, pretreatment with isotonic mannitol produced a rise in PT pressure both before (45 +/- 4 mm Hg, P less than 0.05) and 3 hr post NE infusion (38 +/- 5 mm Hg, P less than 0.05). In all groups of animals, at both 3 and 24 hr post NE, tubular injury was observed but glomerular architecture remained normal by light and electron microscopy. Conclusion. the protective effect of mannitol in this reversible model of ARF did not correlate with inulin clearance, renal blood flow, extracellular fluid (ECF) volume, ECF hypertonicity, or renal histologic changes but did correlate with the solute excretion rate. The increased PT pressures with mannitol both before and after the NE insult could contribute to the protective effect of attenuating any relative intratubular obstruction.

The electrolyte and water content of cellular and interstitial compartments in the renal papilla of the rat was determined by x-ray microanalysis of frozen-hydrated tissue sections . Papillae from rats on ad libitum water were rapidly frozen in a slush of Freon 12, and sectioned in a cryomicrotome at -30 to -40°C . Frozen 0.5-,um sections were mounted on carbon-coated nylon film over a Be grid, transferred cold to the scanning microscope, and maintained at -175°C during analysis . The scanning transmission mode was used for imaging. Structural preservation was of good quality and allowed identification of tissue compartments . Tissue mass (solutes + water) was determined by continuum radiation from regions of interest . After drying in the SEM, elemental composition of morphologically defined compartments (solutes) was determined by analysis of specific x-rays, and total dry mass by continuum. Na, K, CI, and H2O contents in collecting-duct cells (CDC), papillary epithelial cells (PEC), and interstitial cells (IC) and space were measured . Cells had lower water content (mean 58 .7%) than interstitium (77.5%) . Intracellular K concentrations (millimoles per kilogram wet weight) were unremarkable (79-156 mm/kg wet weight) ; P was markedly higher in cells than in interstitium . S was the same in all compartments . Intracellular Na levels were extremely high (CDC, 344 ± 127 SD mm/kg wet weight ; PEC, 287 ± 105; IC, 898 ± 194) . Mean interstitial Na was 590 ± 119 mm/Kg wet weight . CI values paralleled those for Na . If this Na is unbound, then these data suggest that renal papillary interstitial cells adapt to their hyperosmotic environment by a Na-uptake process.Cells of the rat renal papilla are exposed to wide changes in the ionic and osmotic composition of their environment . The papillary epithelium of the rat is exposed to urine whose osmolality ranges from <100 to >3,000 mosmol/kg H2O. Tubular and interstitial cells within the papilla live in the hypertonic environment associated with the urine-concentrating mechanism. Because few mammalian cell types are exposed to such environmental conditions, the mechanism by which these cells adapt to the high salt and urea content of their environment is of great interest to cell biologists. and Morgan (20), using in vitro centrifugation or incubation techniques, have reported that the Na content of papillary cells increases with increasing osmolality and reaches more than 400 mM. However, until recently no method existed for the 274 definition of chemical composition of defined cell types within the papilla. The development of techniques for direct x-ray microanalysis of frozen-hydrated tissue sections (19,22,23) now makes such analysis possible. MATERIALS AND METHODSSix male Long-Evans rats (bred in our colony), weighing 125-200 g, were housed individually in metabolic cages for 2 dor more before the experiment . They were given Purina Rat Chow (0.29% Na, 0.46% K; Ralston Purina Co., St. Louis, Mo.) and water ad libitum. An overnight urine sample was collecte...

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