One-dimensional transport of bosons between weakly linked reservoirs.

We study a flow of ultracold bosonic atoms through a one-dimensional channel that connects two macroscopic three-dimensional reservoirs of Bose-condensed atoms via weak links implemented as potential barriers between each of the reservoirs and the channel. We consider reservoirs at equal chemical potentials so that a superflow of the quasicondensate through the channel is driven purely by a phase difference 2Φ imprinted between the reservoirs. We find that the superflow never has the standard Josephson form ∼sin2Φ. Instead, the superflow discontinuously flips direction at 2Φ=±π and has metastable branches. We show that these features are robust and not smeared by fluctuations or phase slips. We describe a possible experimental setup for observing these phenomena.

Prolonged (12 hours) intravenous anesthesia in the rat.

A method is described for prolonging anesthesia in the rat for periods of up to 12 h, with subsequent recovery. Ketamine and xylazine in a ratio of 30 to 1 were infused intravenously by use of an adjustable syringe pump at rates of 40 to 50 microliters/min (1,000 to 1,250 micrograms/kg of body weight/min for ketamine and 32 to 40 micrograms/ kg/min for xylazine), and the rate of infusion was adjusted to maintain a stable depth of anesthesia. Primary assessment of the depth of anesthesia was provided by observation of the respiratory rate, which was maintained between 80 and 100 breaths/min. Rectal temperature was maintained between 35 and 36 degrees C. Blood pressure, pulse, and blood pH and bicarbonate concentration were stable during the 12-h period. The PCO2 increased slightly to 53 mm Hg; PO2 decreased gradually to 59 mm Hg at the last measurement. Plasma glucose concentration decreased progressively; supplemental glucose was given to maintain plasma concentration > 5 mM. After anesthetic administration was discontinued, the animals recovered promptly.

Substrate responses to acid-base alterations in dog renal proximal tubules.

Proximal tubules from dog kidney were incubated for 2-6 min with low concentrations of pyruvate, glutamine, and malate. When initial medium citrate was between 0 and 0.5 mM and alpha-ketoglutarate was between 0 and 0.1 mM, concentrations of these two substrates in tubules and media after incubation were lower with 10 than with 40 mM HCO3-. Malate levels in tubules and media changed in the opposite direction. CO2 formation from labeled citrate or alpha-ketoglutarate was greater at low than at high HCO3-. In tubules treated with digitonin to disrupt the cell membrane, differences in citrate and alpha-ketoglutarate concentrations in tubules at high and low HCO3- were eliminated. The effects of acid-base changes seen in intact tubules on malate levels and on the rate of oxidation of labeled citrate persisted after digitonin pretreatment. These results show that acute effects of acid-base changes on citrate, alpha-ketoglutarate, and malate levels observed in intact renal cortex can be reproduced in isolated tubules. They suggest that these changes are related to changes in levels of citrate and alpha-ketoglutarate in cytoplasm without corresponding changes within mitochondria.

Hyperplasia precedes increased glomerular filtration rate in rat remnant kidney.

Using 3H-thymidine (3H-T), we examined DNA synthesis in rats subjected to either uninephrectomy (UNI), five-sixths nephrectomy (R) or sham (S) surgery. Twenty-four, 48, or 72 hours later, animals were infused with 14C-inulin, PAH and 3H-T and clearances obtained. Prior to sacrifice, India ink was injected for glomerular counting. By 24 hours, glomerular filtration rate per nephron was significantly increased in UNI. However, in R, glomerular filtration rate per nephron was significantly lower than S until 72 hours. Total micrograms DNA per nephron was unchanged in UNI but significantly increased in R compared to S at all times. 3H-T incorporation into DNA was twice as great in UNI as in S was over five-fold greater at 24 hours in R than in S; this marked increase persisted in R at 48 and 72 hours. Autoradiographs confirmed that DNA was synthesized predominantly by renal tubular cells and not infiltrating cells. These results indicate that hyperplasia in compensatory renal growth is related to the quantity of tissue removed and that, in the remnant kidney, DNA synthesis precedes the compensatory increase in glomerular filtration rate per nephron.

Dissociation of acid-base effects on substrate accumulation and on delta pH in dog mitochondria.

The relationship between the pH gradient (delta pH) and substrate accumulation was examined in mitochondria from dog renal cortex. Mitochondria were incubated in media containing bicarbonate or nonbicarbonate buffers. Mitochondrial delta pH was at equilibrium after 2 min incubation but citrate accumulation in the matrix space was still increasing. With nonbicarbonate buffer in rotenone-inhibited mitochondria, citrate and alpha-ketoglutarate concentrations in the matrix did not vary between pH 7.5 and 7.1; delta pH decreased from 0.62 to 0.52 as medium pH fell. With decreasing bicarbonate concentration (from 40 to 10 mM) and constant CO2 tension, concentrations of citrate, alpha-ketoglutarate, malate, glutamate, glutamine, and formate increased; pyruvate accumulation was lower at 10 than at 25 mM bicarbonate; delta pH remained constant. When respiratory changes were produced, concentrations of citrate, alpha-ketoglutarate, malate, and glutamate increased as medium pH fell and CO2 tension increased; accumulation of pyruvate, glutamine, and formate was unaffected. delta pH fell from 0.48 to 0.39 as CO2 tension rose from 3 to 12%. In uninhibited mitochondria, 14CO2 formation from labeled citrate was greater with 10 than with 40 mM bicarbonate; this difference as well as the accumulation of citrate in the matrix was blocked by inhibition of the tricarboxylate carrier with 1,2,3-benzenetricarboxylate. These results dissociate effects of acid-base change on mitochondrial substrate accumulation from changes in delta pH. They suggest a direct, bicarbonate-dependent influence of pH on multiple mitochondrial substrate carriers. This phenomenon may play an important role in metabolic regulation in renal cortex.

Specific gene expression during compensatory renal hypertrophy in the rat.

The compensatory growth of the kidney which is induced by unilateral nephrectomy is a highly regulated process resulting principally in hypertrophy of the remaining kidney. The events which regulate this process are unknown. We have examined the levels of transcripts for the proto-oncogenes, myc, H-ras, K-ras, and fos, and the cellular genes, H4 histone, ornithine aminotransferase, and gamma-glutamyl transpeptidase, following unilateral nephrectomy in the rat. The pattern of expression of c-myc, c-H-ras, and c-K-ras during compensatory growth of the kidney differs from the pattern of expression of these proto-oncogenes during liver regeneration, in which, unlike the kidney, hyperplasia rather than hypertrophy predominates. The lack of change in the abundance of these proto-oncogene transcripts following unilateral nephrectomy suggests a primary relationship between the expression of these proto-oncogenes and DNA synthesis and indicates there may be separate signals for cell growth, one to double cell size and one to replicate DNA. Increased mRNA transcripts for the enzymes ornithine aminotransferase and gamma-glutamyl transpeptidase were induced in the contralateral kidney after nephrectomy. The time course of expression for these two enzymes differs. The early expression of the gamma-glutamyl transpeptidase gene may indicate an involvement of this glutathione-metabolizing enzyme during renal compensatory growth, while the function of the delayed increase in ornithine aminotransferase transcripts in the remaining kidney is not apparent.

Bicarbonate-carbon dioxide buffer system: a determinant of the mitochondrial pH gradient.

The influence of the bicarbonate-carbon dioxide buffer system on the pH gradient (delta pH) across the inner membrane of mitochondria from rabbit renal cortex was studied with and without phosphate in the medium. delta pH with bicarbonate buffer or phosphate in the medium was greater at low than at high medium pH so that the difference (delta delta pH) between delta pH at pH 7.1 and at 7.6 was positive. Varying the concentration of phosphate from 0 to 10 mM had little effect on delta delta pH produced by bicarbonate buffer. Inhibition of the phosphate-hydroxyl carrier with N-ethylmaleimide abolished delta delta pH when phosphate was present in non-bicarbonate-containing media. With bicarbonate buffer present, N-ethylmaleimide increased delta delta pH. Similar effects were observed in mitochondria from liver and heart as well as from kidney. The effects of the bicarbonate buffer system on delta pH may result either from an inner membrane permeable to carbon dioxide but not to bicarbonate ion or from an active carrier for bicarbonate ion in the inner membrane. In intact kidney cells, the influence of the bicarbonate buffer system on delta pH may provide a mechanism for regulating substrate metabolism in response to acid-base changes. It may also serve in many organs to reduce fluctuations in matrix pH when alterations in cytoplasmic pH occur.

Idiopathic acute interstitial nephritis: characterization of the infiltrating cells in the renal interstitium as T helper lymphocytes.

A previously healthy 39-year-old man presented with acute renal failure. There was no history of exposure to drugs nor was there any infection. Renal biopsy revealed interstitial nephritis with extensive acute degenerative changes in the tubules and extensive interstitial infiltration with mononuclear cells and no eosinophils. Monoclonal antibody staining studies identified the cells in the renal interstitium to be a helper/inducer subset of T lymphocytes. We suggest that a delayed hypersensitivity mechanism played a pathogenetic role in this patient's idiopathic acute interstitial nephritis.

The effects of chronic metabolic acidosis on patterns of protein synthesis in rat renal cortex.

In the rat chronic metabolic acidosis increases the net synthesis of 17 renal cortex proteins by amounts ranging from 1.5 to 4.5-fold. These proteins have molecular weights between 13,000 and 42,000 and isoelectric points between approximately 5.5 and 7.0. No new proteins not also present in normal animals are detected in renal cortex samples from acidotic animals. Three proteins undergo substantial reductions in their net synthetic rates in chronic metabolic acidosis. On the basis of their physical properties and similar alterations in net synthetic rate in acidosis some of these proteins appear to be closely related and may be coordinately expressed in the rat kidney.

Citrate excretion: a window on renal metabolism.

The rate of intracellular metabolism of citrate plays a major role in determining the amount of citrate excreted in the urine. Fractional excretion of citrate can be increased either by increasing intracellular citrate synthesis from precursors or by inhibiting mitochondrial citrate metabolism. Increased excretion secondary to increased synthesis of citrate occurs when citric acid cycle precursors such as malate or succinate are infused. Increased excretion resulting from inhibition of citrate metabolism occurs when malonate, maleate, or fluorocitrate is administered. Systemic acid-base changes cause striking changes in citrate clearance and metabolism. Recent evidence suggests that the effects of acid-base changes are mediated by alteration in the pH gradient across the inner mitochondrial membrane. Metabolic alkalosis causes cytoplasmic pH and bicarbonate to increase, resulting in a decrease in the mitochondrial pH gradient. This change inhibits the tricarboxylate carrier, slowing entry of citrate into the mitochondrial matrix compartment. The level of citrate in the cytoplasm increases, tubular and peritubular citrate uptake are reduced, and citrate clearance increases. Opposite changes occur in acidosis. Change in the mitochondrial pH gradient provides a sensitive mechanism for regulating renal substrate metabolism.

Intracellular pH in intact rat renal cortex estimated with [14C]-5,5-dimethyl-2,4-oxazolidinedione.

The distribution of [14C]-5,5-dimethyl-2,4-oxazolidinedione ([14C]-DMO) was measured in intact rat renal cortex using 22Na+ to estimate extracellular fluid volume. Results of two different methods to obtain tissue were compared, a cortical slice technique and a whole kidney frozen technique. In normal animals with a mean blood pH of 7.41 +/- 0.006 (SEM) the cortical slice method measured an intracellular pH of 6.97 +/- 0.03 (SEM). Corrections are described which can be used to compensate for varying volumes of tubular fluid in the slice and for differing concentrations of intracellular sodium. Using reasonable estimates for tubular fluid volume and intracellular sodium these corrections increase the value of intracellular pH to about 7.20. The results of the study indicate that the cortical slice [14C]-DMO method provides a satisfactory technique to obtain baseline values for intracellular pH in intact renal cortex, which can be used to detect changes in intracellular pH produced by experimental manipulations.

Influence of alterations in acid-base conditions on intracellular pH of intact renal cortex.

Intracellular pH (pHI) of intact rat renal cortex was estimated using [14C]-5,5-dimethyl-2,4-oxazolidinedione and 22Na+ under conditions of metabolic acidosis and alkalosis, potassium depletion and carbonic anhydrase inhibition. In metabolic acidosis and alkalosis, pHI and bicarbonate concentration changed in the same direction as occurred in plasma. In potassium depletion, systemic acid-base balance was unaltered but a marked intracellular acidosis developed. Carbonic anhydrase inhibition with acetazolamide was associated with an extracellular respiratory acidosis and a rise in intracellular bicarbonate concentration. Another carbonic anhydrase inhibitor, benzolamide, caused no change in systemic acid-base state but produced a decrease in intracellular bicarbonate concentration. When appropriate corrections were made for predicted change in tubular fluid bicarbonate and for intracellular sodium, modification in the absolute values of the above changes occurred but the directions of the changes in pHI and bicarbonate concentration were unaltered.

Continuous ambulatory peritoneal dialysis in diabetes mellitus. The risks and benefits of intraperitoneal insulin.

14 insulin-dependent diabetic patients completed 122 patient months on continuous ambulatory peritoneal dialysis (CAPD), using only intraperitoneal insulin for glucose control. Survival was 70% at 1 year, in this relatively high-risk group, several members of which had been refused other modalities of treatment. Blood glucose control, using approximately 111 units of regular insulin per day intraperitoneally, was improved over pre-CAPD control, as assessed by monthly blood glucose determinations and Hgb A1c measurements. Pre-CAPD random blood glucose values fell in 13 of 14 from a mean of 367 +/- 42 to 207 +/- 15 mg/dl during CAPD. Mean pre-CAPD Hgb A1c levels were 14.2% with a fall to 10.5-11.4% during CAPD. The intraperitoneal insulin dose represented approximately 3.5 times the pre-CAPD total daily subcutaneous dose of insulin, and no patient required less than approximately twice the pre-CAPD insulin dose. Peritonitis rates were no different when compared to the general nondiabetic population on CAPD (269 patient months), and complicated episodes tended to be less frequent in diabetic patients. Intraperitoneal insulin administration is an effective means of controlling blood sugar in diabetics on CAPD, and does not increase the risk of infection.

Longitudinal comparison of intermittent versus continuous ambulatory peritoneal dialysis, in the same patients.

Twelve patients who had been on intermittent peritoneal dialysis (IPD) for an average of 18.3 months each, were switched to continuous ambulatory peritoneal dialysis (CAPD). CAPD experience is now 118 patient months (average 9.8 months per patient), and ten patients remain on CAPD. Serum chemistries reflected the change to continuous dialysis with a fall in serum creatinine, potassium, uric acid, phosphate, and BUN. The total CO2 rose markedly, indicating prevention of the recurrent metabolic acidosis experienced in IPD. Serum phosphate fell significantly into the normal range. Serum calcium rose slightly in six patients and significantly in three others. Serum alkaline phosphatase activity rose in seven patients, without development of clinical evidence of bone disease. Mean hematocrit values were higher in most patients of CAPD, but fell again after one year. The transient nature of the rise in hematocrit suggests that improved volume control, as reflected in blood pressure changes, may play a role in the frequently reported increase in hematocrit on CAPD. Despite an increase in peritonitis rate (one infection per 5.9 patient months on CAPD, versus one per 12.2 patient months on IPD), CAPD offers several distinct advantages over IPD, especially in control of uremic acidosis, phosphate retention, blood pressure and fluid management, as well as an overall improvement in physical and psychosocial well-being.

Long-term therapy of uremic osteodystrophy in adults with calcitriol.

Patients with end-stage renal failure develop osteodystrophy in part due to defective production of 1,25-dihydroxycholecalciferol by the kidney. We treated eight adults with chronic renal failure and osteodystrophy with 1,25-dihydroxycholecalciferol (calcitriol) for 30-44 months. Seven of these patients were also symptomatic with bone pain and/or muscle weakness. Striking amelioration of muscle weakness occurred, and bone pain was considered to be significantly improved in four of seven patients. Hypercalcemia was noted in all the patients, necessitating a reduction in the daily dose of calcitriol to a range of 0.125 to 0.5 microgram/day. While serum alkaline phosphatase fell during therapy, serum iPTH did not show any significant change. Bone mineral content improved in four patients, though it still remained below normal. Radiographic changes of osteodystrophy showed definite improvement in only three.

Lactic acidosis associated with metastatic breast carcinoma.

Occurrence of lactic acidosis with adequate tissue oxygenation (type B lactic acidosis) has been described in association with leukemia, lymphoma and a single case of Hodgkin's disease. No cases of this type have been reported in association with solid tumors. A case of type B lactic acidosis in a woman with rapidly progressing metastatic breast carcinoma is described.