Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.

BACKGROUND: The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). PATIENTS AND METHODS: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. RESULTS: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. CONCLUSIONS: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths. CLINICAL TRIAL IDENTIFICATION: NCT00112918.

SEOM/SERAM consensus statement on radiological diagnosis, response assessment and follow-up in colorectal cancer

Colorectal cancer (CRC) is one of the world’s most common cancers, and has one of the highest mortality rates. The last few decades have seen great progress in preventing, diagnosing and treating this disease, providing undeniable impact on patients’ prognosis and quality of life. At all these stages of CRC management, imaging techniques play an essential role. This article reviews some important issues concerning the use of various radiological techniques in the screening, diagnosis, staging, assessment of treatment response, and follow-up of patients with CRC. It also includes a number of practical recommendations on indications for use, technical requirements, minimum information required in the radiology report, evaluation criteria for the response to various drugs, and the recommended frequency at which different examinations should be performed. This consensus statement is the result of cooperation between the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Radiology (SERAM) (AU)

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Adjuvant treatment with infusional 5-fluorouracil in high risk adenocarcinoma of the stomach or gastroesophageal junction

Purpose. In high risk gastric and gastroesophageal adenocarcinoma, adjuvant radiochemotherapy with 5-fluorouracil bolus became a standard adjuvant treatment, showing significant improvement in overall survival after surgery, although with substantial toxicity. We explored the efficacy and toxicity of a modified 5-fluorouracil continuous infusion scheme. Methods. We conducted an observational retrospective study in our centre. Gastric/gastroesophageal junction adenocarcinoma patients were treated with a schedule consisting in four infusions of bolus 5-fluorouracil 400 mg/m2 iv with leucovorin 200 mg/m2 iv and 1200 mg/m2 in 46-hour infusion of 5-fluorouracil (D’Gramont scheme), followed by concomitant radiochemotherapy (45 Gy in 25 fractions of 1.8 Gy) with 5-fluorouracil continuously infusion 225 mg/m2/day and four additional infusions of chemotherapy one month after complete radiochemotherapy. Results. Between January 2007 and December 2013, 55 patients received a mean of 3.16 bi-weekly adjuvant infusions followed by 4.6 weeks of continuous treatment concurrent with radiotherapy and 3.72 bi-weekly infusions after radiotherapy treatment. During adjuvant treatment, grade III toxicity was mostly haematologic, while gastrointestinal and cutaneous toxicity was predominant during concurrent treatment. There were no grade IV- or treatment-related deaths during this study. Disease-free survival (DFS) was 79.2 months (56.3–102.1 months), and the 3-year survival rates were 52.7 %. Conclusions. This 5-fluorouracil infusional scheme has an excellent tolerability profile and favourable efficacy results (AU)

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Adjuvant treatment with infusional 5-fluorouracil in high risk adenocarcinoma of the stomach or gastroesophageal junction.

PURPOSE: In high risk gastric and gastroesophageal adenocarcinoma, adjuvant radiochemotherapy with 5-fluorouracil bolus became a standard adjuvant treatment, showing significant improvement in overall survival after surgery, although with substantial toxicity. We explored the efficacy and toxicity of a modified 5-fluorouracil continuous infusion scheme. METHODS: We conducted an observational retrospective study in our centre. Gastric/gastroesophageal junction adenocarcinoma patients were treated with a schedule consisting in four infusions of bolus 5-fluorouracil 400 mg/m(2) iv with leucovorin 200 mg/m(2) iv and 1200 mg/m(2) in 46-hour infusion of 5-fluorouracil (D'Gramont scheme), followed by concomitant radiochemotherapy (45 Gy in 25 fractions of 1.8 Gy) with 5-fluorouracil continuously infusion 225 mg/m(2)/day and four additional infusions of chemotherapy one month after complete radiochemotherapy. RESULTS: Between January 2007 and December 2013, 55 patients received a mean of 3.16 bi-weekly adjuvant infusions followed by 4.6 weeks of continuous treatment concurrent with radiotherapy and 3.72 bi-weekly infusions after radiotherapy treatment. During adjuvant treatment, grade III toxicity was mostly haematologic, while gastrointestinal and cutaneous toxicity was predominant during concurrent treatment. There were no grade IV- or treatment-related deaths during this study. Disease-free survival (DFS) was 79.2 months (56.3-102.1 months), and the 3-year survival rates were 52.7 %. CONCLUSIONS: This 5-fluorouracil infusional scheme has an excellent tolerability profile and favourable efficacy results.

A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer.

BACKGROUND: Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting. PATIENTS AND METHODS: LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m2 infused over 2 h, followed by 5-FU as a 400 mg/m2 i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m2 over 46 h (LV5FUs) with or without irinotecan: 180 mg/m2 infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety. RESULTS: Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%). CONCLUSION: FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.

Enemas en paciente con insuficiencia renal: una causa de hiperfosforemia severa / No disponible

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[CA-P control in haemodialysis and K/DOQI guidelines]. / Control del metabolismo calcio-fósforo en hemodiálisis y su adecuación a las guías K/DOQI 2003.

BACKGROUND: The publication in 2003 of the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommended targets levels for serum iPTH, Ca, P, and CaxP product. However, many patients do not achieved these target ranges. It is necessary to known the percentage of patients out of range in order to prevent the development of bone disease and to reduce mortality and morbidity. OBJECTIVES: To know the degree of control of Ca-P metabolism in haemodialysis patients in our haemodilalysis facilities and the achievement of target levels recommended by K/DOQI Guidelines. PATIENTS AND METHODS: We have retrospectively investigated in 190 prevalent haemodialysis patients (males 58.2%, ratio M/F 1.4, mean age 70 years, range 17-87 years, at least 3 months in haemodialysis) the serum levels of Ca, albumin-corrected serum Ca, P, CaxP product and iPTH in all analitycal determinations performed in 2004. In each patient we have obtained the average (and median) of these serum markers. Cut-off levels were carried out following the recommendations of the K/DOQI Guidelines. RESULTS: The average of serum Ca and albumin-corrected serum Ca is normal (means +/- SD = 8.9 +/- 0.6 mg/dL and 9.2 +/- 0.7 mg/dL, respectively); however, 53.7% has normal values, 9.1% hypocalcemia and 37.1% hypercalcemia. The average of serum P is also normal (mean +/- SD = 5.0 +/- 1.3 mg/dL); however, only 57.2% has normal values, and 11.7% has hypophosphoremia and the remaining 31, 1% hyperphosphoremia. The CaxP product is normal (mean +/- SD = 46.3 +/- 13.3 mg2/mL2), 4.9% with low values and 23.4% with high values. The median of serum iPTH is 253 pg/mL, but only 31.1% of them have normal values, 25.1% low range values and 43.7% has hyperparathyroidism; 9.3% with iPTH higher than 800 pg/mL. The percentage of patients with hyperphosphoremia is higher in the group with iPTH higher than 300 pg/mL (23.3% vs. 40%, chi2, p= 0.006). In patients with PTHi in normal range, 3.6% have low CaxP product and the remaining 17.8% high CaxP product. Overall, only 25% of patients falls within recommended ranges for all indicators of mineral metabolism and 17% has all serum markers outside these recommendations. CONCLUSIONS: The degree of control of mineral metabolism in haemodyalisis patients if clearly insufficient and a large percentage of them do not achieved the recommended serum targets recommended by K/DOQI Guidelines. This groups of patients are exposed to a increased risk for oseous and cardiovascular morbimortality. The analysis of adequacy must be performed with percentage of patients out of range in order to apply new therapeutical strategies.

Control del metabolismo calcio-fósforo en hemodiálisis y su adecuación a las guías K/DOQI 2003 / CA-P control in haemodialysis and k/doqi guidelines

Introducción: Desde la publicación de las Guías K/DOQI en 2003 sobre metabolismomineral en la enfermedad renal crónica se ha observado que algunospacientes no alcanzan en la práctica clínica un adecuado control y es necesarioconocer el porcentaje de ellos que están fuera de rango normal, para evitar complicacionesmetabólicas y cardiovasculares.Objetivos: Conocer el grado de control del metabolismo Ca-P en pacientes tratadoscon hemodiálisis en nuestra provincia, estudiando los valores de tendenciacentral y el porcentaje de casos que se encuentran dentro y fuera de rango.Pacientes y métodos: Estudio retrospectivo realizado en 190 pacientes (58,2%varones, V/H 1,4, mediana de edad 70 años, rango de edad 17-87 años) incluidosen hemodiálisis durante al menos 3 meses, durante todo el año 2004. Decada paciente se obtiene la media (y mediana) de los valores de Ca, Ca corregidocon albúmina, P, producto CaxP y PTHi. Los niveles de corte se establecensegún las recomendaciones de las Guías K/DOQI de 2003.Resultados: Las medias de Ca total y corregido con albúmina están en rangonormal (medias ± DE = 8,9 ± 0,6 mg/dL y 9,2 ± 0,7 mg/dL, respectivamente);no obstante el 53,7% de ellos tienen valores de normocalcemia, mientras que el9,1% tiene hipocalcemia y el 37,1% hipercalcemia. La media de P también seencuentra en rango normal (media ± DE = 5,0 ± 1,3 mg/dL); no obstante sóloel 57,1% de ellos tienen valores en rango normal, mientras que el 11,7% tienehipofosforemia y el 31,1% hiperfosforemia. El producto CaxP se encuentra enrango normal (media ± DE = 46,3 ± 13,3 mg2/mL2, pero un 4,9% tiene valoresdisminuidos y un 23,4% valores elevados. La mediana de PTHi es 253 pg/mL,pero sólo el 31,1% se encuentra en el rango normal mientras que el 25,1% tienevalores disminuidos y un 43,7% en rango de hiperparatiroidismo, entre ellos un9,3% con niveles por encima de 800 pg/mL. El porcentaje de casos con hiperfosforemiaes superior en el grupo de pacientes con niveles de PTHi superiores a300 pg/mL (23,3% vs 40%, chi2, p = 0,006). Entre los pacientes con valores dePTHi en rango normal, un 78,6% tienen un producto CaxP normal, un 3,6% disminuidoy el 17,8% restante elevado. Al analizar los resultados globales, sólo lacuarta parte de los pacientes presenta un perfil completo en rango normal y un17% tiene todos los parámetros fuera de rango. Conclusiones: El control del metabolismo Ca-P es insuficiente y muchos pacientesno se encuentran en los rangos recomendados por las Guías K/DOQI de2003, por lo que están expuestos un mayor riesgo de complicaciones óseas y cardiovasculares.El análisis de la adecuación de los parámetros del metabolismo Calcio-Fósforo debe realizarse mediante porcentajes para conocer el grupo de pacientesque requieren nuevas estrategias terapéuticas

Backgroung: The publication in 2003 of the K/DOQI Clinical Practice Guidelinesfor Bone Metabolism and Disease in Chronic Kidney Disease recommendedtargets levels for serum iPTH, Ca, P, and CaxP product. However, many patientsdo not achieved these target ranges. It is necessary to known the percentage ofpatients out of range in order to prevent the development of bone disease and toreduce mortality and morbidity.Objectives: To know the degree of control of Ca-P metabolism in haemodialysispatients in our haemodilalysis facilities and the achievement of target levels recommendedby K/DOQI Guidelines.Patients and methods: We have retrospectively investigated in 190 prevalenthaemodialysis patients (males 58,2%, ratio M/F 1,4, mean age 70 years, range 17-87 years, at least 3 months in haemodialysis) the serum levels of Ca, albumin-correctedserum Ca, P, CaxP product and iPTH in all analitycal determinations performedin 2004. In each patient we have obtained the average (and median) ofthese serum markers. Cut-off levels were carried out following the recommendationsof the K/DOQI Guidelines.Results: The average of serum Ca and albumin-corrected serum Ca is normal(means ± SD = 8,9 ± 0,6 mg/dL and 9,2 ± 0,7 mg/dL, respectively); however,53,7% has normal values, 9,1% hypocalcemia and 37,1% hypercalcemia. Theaverage of serum P is also normal (mean ± SD = 5,0 ± 1,3 mg/dL); however, only57,2% has normal values, and 11,7% has hypophosphoremia and the remaining31,1% hyperphosphoremia. The CaxP product is normal (mean ± SD = 46,3 ±13,3 mg2/mL2) , 4,9% with low values and 23,4% with high values. The medianof serum iPTH is 253 pg/mL, but only 31,1% of them have normal values, 25,1%low range values and 43,7% has hyperparathyroidism; 9,3% with iPTH higherthan 800 pg/mL. The percentage of patients with hyperphosphoremia is higher inthe group with iPTH higher than 300 pg/mL (23,3% vs 40%, chi2, p= 0,006). Inpatients with PTHi in normal range, 3,6% have low CaxP product and the remaining17,8% high CaxP product. Overall, only 25% of patients falls within recommendedranges for all indicators of mineral metabolism and 17% has all serummarkers outside these recommendations.Conclusions: The degree of control of mineral metabolism in haemodyalisis patientsif clearly insufficient and a large percentage of them do not achieved therecommended serum targets recommended by K/DOQI Guidelines. This groupsof patients are exposed to a increased risk for oseous and cardiovascular morbimortality.The analysis of adequacy must be performed with percentage of patientsout of range in order to apply new therapeutical strategies

Toxicological studies of the aqueous extract from Achyrocline satureioides (Lam.) DC (Marcela).

Achyrocline satureioides (Lam.) DC (Marcela) is known to possess a broad spectrum of pharmacological, medicinal and therapeutic properties. Previous studies have demonstrated various protective abilities of the marcela extracts against various pathological conditions. However, no extensive safety studies have been conducted on these extracts to date. In this paper, we evaluated the acute toxicity (dose levels of 30-300 mg/kg) of an aqueous extract of marcela, administered intraperitoneally and orally in mice and rats. The acute oral maximun tolerable dose in repeated administration during 4 h (1, 3 until 5 g/kg) was also studied in rats. The extract had low acute toxicity when administered intraperitoneally and no toxicity upon oral administration. The LD(50) of aqueous extracts of marcela was found to be greater than 5 g/kg when administered once via gastric intubation to rats. Weight gain, toxicity signs, enzymatic studies (transaminases and phosphatases) and histological evaluation of several organs indicated that the extract was devoid of acute toxicity. These acute studies demonstrated that an aqueous extract of marcela obtained after a 2% infusion is safe and did not cause any detrimental effects in vivo under the conditions investigated in this study.

In vivo transfection microsystems.

Transfection is currently used to insert molecules into cells. In vivo transfection is mainly performed via viral or chemical transfection. However, electrical transfection is known to be a more efficient way to insert drugs into cells without side effects. In spite of this advantage, not too many devices allow to perform electrotransfection in vivo because of their invasiveness. Here we present a new microfluidic microdevice which is small enough to be inserted into deep region with a minimum of drawbacks. Therapeutic molecules, genes or drugs can be injected into targeted tissues. High voltage electric impulsions can be applied. This device offers the advantage to be a stand alone device with a 500 mum square section. This generic tool can be used for drug delivery, electrotransfection as well as electrostimulation.

Tratamiento de lesiones vasculares binignas cutaneas toracocervicofaciales por luz pulsada / Treating benign vascular lession cutaneous thoraxccervicofacial for intence pulsed light

Durante el siglo pasado numerosos procedimientos fueron descriptos para resolver aquella afecciones cutáneas benignas con componente vascular. Estps procedimientos solían dejar coimo secuelas del tratamiento cicatrices, hipopigmentación, hiperpigmentación o eran ineficaces para la resolución de la patología. Desde 1962 se agregó el uso de láseres vasculares. Estos presentaban todavía la posibilidad de efectos indeseados como así tambien la dificultad para la resolución de la amplia gama de las lesiones vasculares benignas. Se presentan los resultados obtenidos sobre 27 lesiones vasculares benignas cutáneas (angiomas y malformaciones vasculares) y dermopatías con compònente vascular localizadas en tórax, cuello y/o rostro de 25 pacientes, tratados entre junio de 1999 y marzo de 2001, mediante el uso de tecnología luz pulsada. Los autores hacen referencia a diferencias y similitudes entre laser y la luz pulsada, y presentan otras dermatopatías con componente vascular plausibles de ser tratadas mediante esta tecnología. (AU)

Tratamiento de lesiones vasculares binignas cutaneas toracocervicofaciales por luz pulsada / Treating benign vascular lession cutaneous thoraxccervicofacial for intence pulsed light

Durante el siglo pasado numerosos procedimientos fueron descriptos para resolver aquella afecciones cutáneas benignas con componente vascular. Estps procedimientos solían dejar coimo secuelas del tratamiento cicatrices, hipopigmentación, hiperpigmentación o eran ineficaces para la resolución de la patología. Desde 1962 se agregó el uso de láseres vasculares. Estos presentaban todavía la posibilidad de efectos indeseados como así tambien la dificultad para la resolución de la amplia gama de las lesiones vasculares benignas. Se presentan los resultados obtenidos sobre 27 lesiones vasculares benignas cutáneas (angiomas y malformaciones vasculares) y dermopatías con compònente vascular localizadas en tórax, cuello y/o rostro de 25 pacientes, tratados entre junio de 1999 y marzo de 2001, mediante el uso de tecnología luz pulsada. Los autores hacen referencia a diferencias y similitudes entre laser y la luz pulsada, y presentan otras dermatopatías con componente vascular plausibles de ser tratadas mediante esta tecnología.

Effect of zinc supplementation on development and growth of Chilean infants.

OBJECTIVE: To evaluate the effect of zinc supplementation on growth and development during infancy. DESIGN: We randomized 150 term neonates of low socioeconomic status to receive supplemental zinc 5 mg/d (SG) or a lactose placebo (PG); 112 completed a 1-year follow-up. All were breast-fed and given cow milk formula after weaning; solid foods and iron were added at 5 months. Anthropometry measured monthly, psychomotor development (PDI), mental development (MDI), and behavior including motor quality factor were assessed by Bayley Scales at 6 and 12 months. The groups were comparable in maternal characteristics, birth weight, home environment, and mother-infant interaction. RESULTS: No effects of zinc on weight, length, and weight for length at 12 months were found controlling for sex and breast-feeding. The mean PDI (SG: 84.5 +/- 11.5 vs PG: 87.6 +/- 9.9) and MDI (90.9 +/- 10.5 vs 88.9 +/- 9.1) were similar; however, 46 of 52 infants in the PG scored <100 in MDI vs 42 of 57 in the SG (P <.05). A smaller proportion of the SG, 2 of 57, scored low in motor quality factor at 6 months compared with the PG, 8 of 52 (P =.02). The mean at 12 months for the SG was 31.9 +/- 2.8 and for the PG 30.8 +/- 2.9 (P <.05); zinc supplementation entered the multiple regression at 12 months (P =.037). CONCLUSIONS: Zinc supplementation may have a beneficial effect on mental development and motor quality behavior of healthy term infants.

Comparison of two aquaretic drugs (niravoline and OPC-31260) in cirrhotic rats with ascites and water retention.

kappa-Opioid receptor agonists (niravoline) or nonpeptide antidiuretic hormone (ADH) V2 receptor antagonists (OPC-31260) possess aquaretic activity in cirrhosis; however, there is no information concerning the effects induced by the chronic administration of these drugs under this condition. To compare the renal and hormonal effects induced by the long-term oral administration of niravoline, OPC-31260, or vehicle, urine volume, urinary osmolality, sodium excretion, and urinary excretion of aldosterone (ALD) and ADH were measured in basal conditions and for 10 days after the daily oral administration of niravoline, OPC-31260, or vehicle to cirrhotic rats with ascites and water retention. Creatinine clearance, serum osmolality, ADH mRNA expression, and systemic hemodynamics were also measured at the end of the study. Niravoline increased water excretion, peripheral resistance, serum osmolality, and sodium excretion and reduced creatinine clearance, ALD and ADH excretion, and mRNA expression of ADH. OPC-31260 also increased water metabolism and sodium excretion and reduced urinary ALD, although the aquaretic effect was only evident during the first 2 days, and no effects on serum osmolality, renal filtration, and systemic hemodynamics were observed. Therefore, both agents have aquaretic efficacy, but the beneficial therapeutic effects of the long-term oral administration of niravoline are more consistent than those of OPC-31260 in cirrhotic rats with ascites and water retention.

Increased renal expression of nitric oxide synthase type III in cirrhotic rats with ascites.

This article assesses the circulating levels of L-arginine, the renal response to L-arginine infusion, and the renal expression of inducible and constitutive nitric oxide synthase (NOS II and NOS III, respectively) in cirrhotic rats with ascites. Systemic and renal hemodynamics and renal function were measured in basal conditions and following two doses of L-arginine (5 and 10 mg x kg(-1) x min for 40 minutes). Renal NOS II and III messenger RNA (mRNA) expression was evaluated in basal conditions by polymerase chain reaction and Northern blot, respectively. Renal NOS II and III protein expression was assessed by Western blot and immunohistochemistry. Plasma concentration of L-arginine was significantly lower in cirrhotic rats than in control rats (48+/-11 vs. 86+/-9 micromol/L, P < .025). In both groups L-arginine infusion had no effect on systemic hemodynamics, but markedly increased renal perfusion. This effect was significantly more intense in cirrhotic rats. A very weak signal of similar intensity was found for NOS II mRNA in both groups of animals. However, no NOS II protein expression was detected. In contrast, higher NOS III mRNA abundance and protein expression, which was mainly located in the endothelial lining of the renal arterioles, were found in the kidney of cirrhotic animals. These results indicated increased renal expression of NOS III mRNA and protein, deficient circulating levels of L-arginine, and increased renal hemodynamic response to this amino acid in cirrhotic rats with ascites. Our results suggest that L-arginine supplementation at doses not affecting arterial pressure could have beneficial effects on renal perfusion in cirrhosis.

Effect of transamniotic administration of epidermal growth factor on fetal rabbit small intestinal nutrient transport and disaccharidase development.

As fetal swallowing is documented in utero, supplementation of the ingested amniotic fluid with nutrients or hormones has been postulated as a potential prenatal treatment for intrauterine growth retardation (IUGR). To study the effect of epidermal growth factor (EGF) on the developing fetal small intestine, 12 pregnant rabbits underwent operation on day 24 of a normal 31-day gestation. Bilateral ovarian end fetuses underwent catheterization of their respective amniotic cavities with attachment to a miniosmotic pump. Study fetuses received recombinant human EGF at approximately 300 micrograms/kg/d for 1 week; controls received carrier solution only at an equivalent rate. On gestational day 31, fetuses were delivered by cesarean section and somatic measurements were recorded. The small intestine was harvested and proximal, middle, and distal regions were analyzed for lactase and maltase enzyme activity. Additionally, the uptake of radiolabeled glucose and proline was measured by a standard everted mucosal sleeve technique for each segment. Results were analyzed by Student's paired t test and reported as mean +/- SEM. Nine fetal pairs survived (75%). Small intestinal (SI) length was increased in EGF fetuses (54.8 +/- 1.9 cm) versus control (50.4 +/- 2.7 cm) (P = .02). Lactase activity, reported as UE/g protein, was significantly increased in the proximal segments in the EGF-infused fetuses; maltase was significantly increased in both the proximal and middle segments (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of spironolactone on the renin-aldosterone system in rats.

PRA, PRC and the plasma concentration of aldosterone (Aldo) were measured in rats (Sp-rats) receiving a daily sc injection of Spironolactone, (Sp, 20 mg in olive oil) and in control rats (C-rats) receiving olive oil only. Animals were studied one day after starting treatment, 5 days on treatment or after 5 weeks on the study. PRA, PRC and Aldo were significantly increased in Sp-rats as compared to C-rats throughout all the study. In additional Sp-rats and C-rats, the urine volume, serum Na+ and K+ concentration, Na+ and K+ intake and the urinary excretion of Na+, K+ and aldosterone-18-glucuronide (UAldV) were serially measured during 5 weeks. The total radioactivity plasma clearance after an i.v. bolus injection of 3H-aldosterone was subsequently measured in (5 Sp-rats and 5 C-rats). No significant differences in serum Na+ and K+ concentration and in Na+ and K+ balance were observed between Sp-rats and C-rats. UAldV was significantly higher in Sp-rats than in C-rats during all the study. After 5 weeks on treatment the total radioactivity plasma clearance was significantly higher in Sp-rats than in C-rats. These results indicate that Sp, at high dosage, stimulates renin release and aldosterone secretion by a mechanism unrelated to alterations in Na+ and K+ balance.