Acid-base transport in Henle's loop: the effects of reduced renal mass and diabetes.

The loop of Henle (LOH) is an important site of renal acidification. Using the in vivo microperfusion technique of LOH combined with quantitative polymerase chain reaction (PCR) performed on isolated thick ascending limbs (TAL), we demonstrated that the Na + -H + exchanger is the main transport mechanism involved, although a small, but significant contribution from the H+-ATPase also occurs. Among the various Na+-H+ exchanger isoforms we have evidenced that NHE3 is expressed and functionally active along the TAL. Since the LOH is exposed to osmotic stress, bicarbonate transport was also measured under medullary hypotonicity conditions, which led to the stimulation of bicarbonate reabsorption. We demonstrated that the LOH can participate in the tubular adaptation to an increased filtered bicarbonate load by increasing net LOH bicarbonate transport. In this setting, at the molecular level, mRNA and protein abundance of NHE3 were also stimulated, and coincided with an increase in NHE3 activity. Finally, NHE3 expression and abundance was highly stimulated in the early phase of diabetes, which is characterized by increased glomerular filtration rate (GFR).

Use of transgenic mice in acid-base balance studies.

The kidney is essential in maintaining body acid-base status. Recently, the use of transgenic mice has largely contributed to the understanding of the mechanisms involved. Important issues have been addressed in terms of the function of proteins or their regulation. In the proximal tubule, the role of Na+/HCO3-cotransport has been established, although further studies are needed to understand how its mutations lead to renal disease. Na+/H+ exchange has also been extensively studied, and its role in diuretic and natriuretic responses following an increase in blood pressure has been elucidated. The interaction of other transport proteins, such as the Na+/phosphate cotransporter NaPi II-a, with the Na+/H+ exchanger has also been investigated. In the medullary thick ascending limb of Henle's loop (MTAL), a role for NHE1 in transepithelial HCO3- absorption has been demonstrated: basolateral NHE1 controls the function of apical NHE3. As for the distal nephron, the majority of observations suggest that the regulation of H+-ATPase activity in response to acid-base status is mediated by the trafficking of pumps or pump sub-units, especially for the a4 subunit, rather than changes in subunit expression levels. Furthermore, the function of pendrin, a chloride/anion exchanger, has been assessed in response to changes in acid-base status. Important results have been obtained regarding the regulation of proximal tubule transport by several mechanisms, such as microvilli changes and the inducible and endothelial isoform of nitric oxide synthase (NOS). Finally, the interaction of chloride channels and potassium-chloride cotransporter with proton secretion has been evaluated. These findings highlight the importance of knockout animal models in studying kidney regulation of acid-base balance.

Maxi-K channels contribute to urinary potassium excretion in the ROMK-deficient mouse model of Type II Bartter's syndrome and in adaptation to a high-K diet.

Type II Bartter's syndrome is a hereditary hypokalemic renal salt-wasting disorder caused by mutations in the ROMK channel (Kir1.1; Kcnj1), mediating potassium recycling in the thick ascending limb of Henle's loop (TAL) and potassium secretion in the distal tubule and cortical collecting duct (CCT). Newborns with Type II Bartter are transiently hyperkalemic, consistent with loss of ROMK channel function in potassium secretion in distal convoluted tubule and CCT. Yet, these infants rapidly develop persistent hypokalemia owing to increased renal potassium excretion mediated by unknown mechanisms. Here, we used free-flow micropuncture and stationary microperfusion of the late distal tubule to explore the mechanism of renal potassium wasting in the Romk-deficient, Type II Bartter's mouse. We show that potassium absorption in the loop of Henle is reduced in Romk-deficient mice and can account for a significant fraction of renal potassium loss. In addition, we show that iberiotoxin (IBTX)-sensitive, flow-stimulated maxi-K channels account for sustained potassium secretion in the late distal tubule, despite loss of ROMK function. IBTX-sensitive potassium secretion is also increased in high-potassium-adapted wild-type mice. Thus, renal potassium wasting in Type II Bartter is due to both reduced reabsorption in the TAL and K secretion by max-K channels in the late distal tubule.

[Glomerulo-tubular balance in diabetes mellitus: molecular evidence and clinical consequences]. / Bilancio glomerulo-tubulare nel diabete mellito: evidenze molecolari e conseguenze cliniche.

Diabetes mellitus is fast becoming a world epidemic. About one-third of individuals with diabetes, after 10 yrs, develop diabetic nephropathy, the first cause of end-stage kidney disease. The evolution of diabetic nephropathy can be considered in three stages: glomerular hyperfiltration, microalbuminuria (30-300 mg/24 hr) and proteinuria (>300 mg/24 hr). This study was designed to investigate the tubular basis of glomerular hyperfiltration in early diabetes mellitus. Diabetes was inducted in rats with i.p. streptozotocin (65 mg/kg bw) for 6 days. At the end of the treatment, the glomerular filtration rate (GFR), measured by inulin clearance, had substantially increased in diabetic rats compared with controls. Quantitative polymerase chain reaction (PCR) and Western blot analysis reveal that in diabetic rats compared with controls, mRNA and protein abundance was higher for type 3 sodium/hydrogen exchanger (NHE3) in proximal tubule and ascending limbs of Henle's loop, and higher for bumetanide-sensitive sodium-potassium-2 chloride cotransporter (NKCC2) in ascending limbs of Henle's loop. Western blot analysis confirmed the PCR results. Finally, the abundance of á -ENaC protein was unchanged in diabetic rats compared to controls. These results show that the primary sodium reabsorption increase in proximal tubule reduces salt concentrations at the macula densa. This elicits a tubuloglomerular feedback-dependent increase in single nephron GFR.

[Spontaneous (idiopathic) pneumopericardium. A case report and review of the literature]. / Pneumopericardio spontaneo (idiopatico). Descrizione di un caso e revisione della letteratura.

Pneumopericardium is a rare entity, but it can occur in a wide variety of clinical situations. The spontaneous cases are very rare and generally can be associated with some predisposing or precipitating conditions. We report a case in which the pathogenesis of pneumopericardium undefined after conventional diagnostic clinical investigation. A concise review of the recent literature is presented, and some practical clinical remarks are made.

Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer.

BACKGROUND: Patients with TNM stage IV non-small-cell lung cancer have short survival times. Previous controlled studies comparing chemotherapy and supportive care for the treatment of this type of cancer have not given consistent results, have included patients with different disease stages, and have rarely reported drug dose intensity. PURPOSE: The present trial was designed to assess the safety and the effect on survival of supportive care alone versus chemotherapy with cisplatin, cyclophosphamide, and mitomycin combined with appropriate supportive care in patients with stage IV non-small-cell lung cancer. METHODS: Patients (n = 102) with stage IV non-small-cell lung cancer were randomly assigned to one of two treatment regimens. The combined modality group (52 patients) received supportive care along with cisplatin (75 mg/m2), cyclophosphamide (400 mg/m2), and mitomycin (10 mg/m2) given intravenously at 3-week intervals. The supportive care group (50 patients) received supportive care alone. Randomization was stratified on the basis of histology (squamous versus nonsquamous cell carcinoma), performance status (Karnofsky), and weight loss (during the 6 months preceding randomization). The two groups were well matched for age and sex. Survival analysis was performed after the last patient died. RESULTS: The median number of chemotherapy cycles was 3.5 per patient. Mean weekly delivered doses of drugs were as follows: cisplatin, 22.1 mg/m2; cyclophosphamide, 118 mg/m2; and mitomycin, 2.9 mg/m2. Toxic effects due to chemotherapy were generally mild, but peripheral neuropathy and hematologic and renal toxic effects were observed. In the supportive care group, mean survival was 6.1 months (median, 4.0 months); six patients lived at least 12 months and two lived at least 18 months. In the combined modality group, mean survival was 11.3 months (median, 8.5 months); 20 patients lived at least 12 months, 13 lived at least 18 months, and five lived at least 24 months. Difference in survival was statistically significant (P < .0001). Survival was directly related to initial performance status in both groups (P < .01) and was significantly (P < .01) longer for patients with squamous cell carcinoma than for those with nonsquamous cell carcinoma. CONCLUSIONS: The combination of supportive care and cisplatin-cyclophosphamide-mitomycin therapy offers a survival advantage over supportive care alone in patients with advanced non-small-cell lung cancer. IMPLICATIONS: Metastatic non-small-cell lung cancer, generally considered to be unresponsive or marginally responsive to chemotherapy, can be treated with chemotherapy, with an expectation of prolonging patient survival. Although the results of the present study are encouraging, clinical research should continue to be directed toward developing more effective treatments for this disease.

[Cyclophosphamide, adriamycin and platinum (CAP) in the preoperative neoadjuvant phase and the therapy phase]. / Ciclofosfamide, adriamicina e platino (CAP) in fase neoadiuvante preoperatoria e in fase curativa.

Forty-two patients with metastasized, and 7 patients with locally advanced forms of carcinoma of the breast were treated with a combination of three drugs: CTX 200-400 mg/sq.m. on days 1, 3 and 5, ADM 40 mg/sq.m. on day 1, and DDP 30 mg/sq.m. on days 1, 3 and 5 (CAP), every 21 days. The 42 patients with metastasized carcinoma had already received substantial pre-treatment by surgery and with adjuvant polychemotherapy +/- chemotherapy on recurrence +/- hormonotherapy +/- radiotherapy. The disease sites were: bone (30%), skin (19%), lymph nodes (13.5%), pleura (12.5%), lung (12%) and liver (11%). The 7 patients with locally advanced carcinoma had not been pre-treated; they received the same chemotherapy in the pre-operative neo-adjuvant phase. Positive responses to CAP in the cases with metastasized carcinoma according to individual disease sites (37 pre-treated patients assessable after at least two courses of therapy) were as follows in percentage terms: 24% bone lesions, 56% skin lesions, 77% lymph node lesions, 30% liver lesions, 56% lung lesions, 22% pleural lesions. 3/37 patients (8%) showed complete remission in all disease sites, while 6/37 showed partial remission. This percentage (8 + 16 = 24%) is encouraging, as CAP, in these patients, represents on average the 3rd to 4th line of therapy. Responses to neo-adjuvant CAP therapy (7 patients assessable after at least two courses of therapy) were as follows: 5 patients showed partial remission after 3-6 courses, 1 complete remission, and 1 objective improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

[Variation in weight and food intake of rats exposed to a high-intensity electrical field at 50 Hz]. / Variazioni ponderali ed assunzione di alimenti nel ratto esposto a campi elettrici di intensità elevata a 50 Hz.

The effects of exposure to electric fields at 50 Hz of various intensities (100, 25, 10 kV/m) on the food intake and body growth were determined in the rat at various stages of development. The different field intensities were induced between 1.5 by 2 m steel plates. At 100 kV/m, 25 rats were exposed 8 h/d for 48 days. In respect to controls, after 2 weeks of exposure a marked decrease of the growth rate was observed in exposed animals, but not of the food intake. At 25 kV/m 11 animals, 28 days old, were exposed 8 h/d for 35 days. A slight decrease in growth rate, statistically significant only at the 23rd and the 26th day of exposure, was found. No effect was observed on food intake and full recovery of body weight of exposed animals was achieved in 4 weeks after the end of the exposure. At 10 kV/m, in addition to 5 rats 28 days old, exposed 8 h/d for 35 days and to the corresponding controls, 15 "sham exposed" animals were studied. No significant difference in growth rate was found between the exposed animals and the two other groups. Food intake of exposed was for two weeks of treatment the same of control animals. Thereafter, there was tendency toward a higher food intake in the exposed animals being significant during recovery.

Effect of maternal diet on ganglioside distribution in fetal rat brain.

Female rats were fed a diet with low protein content or with low and high amount of essential fatty acids (EFA). Ganglioside content and distribution were analyzed in the brain of animals at two different periods of fetal life (15th or 20th day). In the fetuses from mothers fed the diet with low amount of EFA the content of ganglioside is significantly lower than in the control group. The three diets resulted in the modification of ganglioside pattern, mainly for the animals on the 15th day of gestation.

Na+ dependence of phenacetin absorption.

Phenacetin in solution at different concentrations of Na+ was orally administered to dogs. Phenacetin absorption is increased by the Na+: a positive correlation was noted between the Na+ concentration in the medium and the plasma levels of phenacetin. Ouabain antagonizes the effect of Na+ on phenacetin absorption.