Hernia repair and simultaneous continuous ambulatory peritoneal dialysis (CAPD) catheter implantation: feasibility and outcome.

BACKGROUND: Occurrence of abdominal wall hernias during and before peritoneal dialysis constitutes a pivotal role in treatment discontinuation, failure, and exclusion from this dialysis method. We herein present a single-center experience regarding a one-stage surgical strategy, including hernia repair and simultaneous peritoneal dialysis catheter implantation. PATIENTS AND METHODS: Over a 4-year period, 123 patients underwent peritoneal dialysis catheter implantation and 23 patients (19%) had concomitant abdominal wall hernias and were enrolled in this monocentric prospective study. Data collection included recurrent and new-onset hernias, surgical site infection, 1-year and 2-year catheter survival. RESULTS: In 23 patients, 27 hernia repairs combined with peritoneal dialysis catheter implantation were performed. Median age was 52 years (range, 30-85 years) and 18/23 (78%) patients were male. There were no recurrent hernias and no early surgical site infections. Daily flushing was regularly started on the 1st to 3rd postoperative day. Five patients (22%) developed hernias on other anatomical sites, which required hernia repair and perioperative discontinuation of peritoneal dialysis. After a median follow-up of 37 months (range, 28-87 months), 96% of all implanted catheters were still working. CONCLUSION: Hernia repair and simultaneous peritoneal dialysis catheter implantation are associated with no recurrent hernias, an early start of peritoneal dialysis, a very low postoperative morbidity and very high 1-year and 2-year catheter survival.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy combined with liver resection for concurrent peritoneal and hepatic metastases of gastrointestinal and gynecological primary tumors.

AIM OF THE STUDY: Cytoreductive surgery including liver resection and hyperthermic intraperitoneal chemotherapy provide survival benefit to selected patients but is associated with relevant morbidity and mortality rates. We aimed to report morbidity and mortality rates and parameters linked to increased morbidity. PATIENTS AND METHODS: Retrospective analysis of 37 patients who underwent liver resection and cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy between 2006 and 2016. From a prospectively collected database the morbidity and mortality rates and survival data were analyzed. RESULTS: The mortality rate was 0% and grade III-IV morbidity was 42%. Re-operation rate was 27%. Patients with complications tended to have a higher peritoneal cancer index (16 vs. 13; P=0.23). The performance of rectal resections was statistically significantly associated with morbidity (P=0.02). Neither performance of other type of resections nor the hyperthermic intraperitoneal chemotherapy compound nor the completeness of cytoreduction score was associated with elevated morbidity. No complications related to liver resections were observed. Furthermore, origin of peritoneal metastases did not impact on occurrence of complications. Median overall survival for colorectal primaries was 22 months (range, 9-60 months) and 30 months (range, 12-58 months) for ovarian cancer. CONCLUSION: Simultaneous resection of hepatic and peritoneal metastases seems to provide a survival benefit for selected patients and is associated with acceptable morbidity and mortality rates. Knowledge of patients and operative factors linked to morbidity will help to provide a strict selection process and a safer surgical procedure.

[Multivisceral resection with and without HIPEC in cancer surgery]. / Multiviszerale Resektionen mit und ohne HIPEC in der Karzinomchirurgie.

BACKGROUND: Multivisceral resections seem to be naturally associated with an elevated morbidity rate. Data regarding the impact of multivisceral resections on progression-free and overall survival are only available in insufficient quantities. OBJECTIVE: Data on multivisceral resections in cancer surgery are presented exemplified by gastric cancer, colorectal cancer and peritoneal metastases, focusing on overall and progression-free survival as well as morbidity and mortality. MATERIAL AND METHODS: A PubMed search was carried out including the following terms: multivisceral resection, peritoneal metastases, cytoreduction, morbidity, HIPEC (hyperthermic intraperitoneal chemotherapy) RESULTS: Multivisceral resections should only be performed if an R0 status can be achieved for all tumor entities. Preoperative performance of an FDG-PET-CT scan (fluorodeoxyglucose positron emission tomography computed tomography scan) can help in the selection of appropriate patients. In gastric cancer, extensive lymphatic metastases are associated with a poor overall survival despite multivisceral resection. Recurrent rectal cancer shows elevated morbidity rates and also decreased overall survival rates. Maximum cytoreductive surgery can be conducted for peritoneal metastasized appendiceal neoplasms and colorectal cancer with acceptable morbidity and without an increased risk for reduced overall survival. CONCLUSION: After adequate patient selection and exclusion of stage IV distant metastatic disease, multivisceral resections can be offered to patients with the goal of an R0 resection.

[Surgical treatment of peritoneal metastases from gynecological primary tumors]. / Chirurgische Therapie bei peritonealen Metastasen gynäkologischer Primärtumoren.

BACKGROUND: The principle of surgical treatment of peritoneal metastases of ovarian cancer in the primary as well as in the recurrent disease setting includes macroscopic complete cytoreductive surgery. The addition of intraperitoneal chemotherapy after cytoreduction is currently not part of the standard treatment. OBJECTIVE: Data on intraperitoneal chemotherapy for treatment of peritoneal metastases of ovarian cancer are presented focusing on overall and progression-free survival and on morbidity and mortality rates. METHOD: PubMed search including the following terms: ovarian cancer, peritoneal metastases, cytoreduction and HIPEC. RESULTS: Randomized-controlled and non-randomized controlled trials showed that intraperitoneal chemotherapy after maximum cytoreductive surgery results in a survival benefit regarding overall and progression-free survival for primary as well as recurrent disease. Addition of HIPEC does not impact on the initiation of postoperative systemic chemotherapy. CONCLUSION: Macroscopic complete cytoreduction is the most important prognostic factor. The addition of intraperitoneal chemotherapy for the treatment of peritoneal metastases of ovarian cancer showed promising results but so far it is not accepted as a part of a multimodal treatment concept.

The contribution of skin glycosaminoglycans to the regulation of sodium homeostasis in rats.

The glycosaminoglycan (GAG) molecules are a group of high molecular weight, negatively charged polysaccharides present abundantly in the mammalian organism. By their virtue of ion and water binding capacity, they may affect the redistribution of body fluids and ultimately the blood pressure. Data from the literature suggests that the mitogens Vascular Endothelial Growth Factor (VEGF)-A and VEGF-C are able to regulate the amount and charge density of GAGs and their detachment from the cell surface. Based on these findings we investigated the relationship between the level of dietary sodium intake, the expression levels of VEGF-A and VEGF-C, and the amount of the skin GAGs hyaluronic acid and chondroitin sulfate in an in vivo rat model. Significant correlation between dietary sodium intake, skin sodium levels and GAG content was found. We confirmed the GAG synthesizing role of VEGF-C but failed to prove that GAGs are degraded by VEGF-A. No significant difference in blood pressure was registered between the different dietary groups. A quotient calculated form the ion and water content of the skin tissue samples suggests that - in contrast to previous findings - the osmotically inactive ions and bound water fractions are proportional.

Utilidad diagnóstica de la ecografía tiroidea en la evaluación de nódulos tiroideos en niños y adolescentes / Diagnostic utility of thyroid ultrasound ecografy in thyroid nodules evaluation in children and adolescents

AIM: To evaluate the diagnostic utility of ultrasonography and other antecedents and exams usually availables, in the study of patients with thyroid nodules aged 0-20 years. SUBJECTS AND METHODOLOGY: Cross-sectional analytical observational study. We reviewed the data of patients undergoing FNAP (thyroid puncture with a fine needle) and / or thyroidectomy between January 2007 and December 2013. The ultrasound evaluation was performed by 3 specialists. The surgical biopsy was considered an indicator of benignity or malignancy and, in its absence the FNAP (excluding the Bethesda diagnoses 3 and 4). The association between cancer and the different variables was evaluated through binary logistic regression, with measure of association of odds ratio (OR). With the initially significant variables, a multivariate analysis was carried out and a cut-off score was subsequently defined to allow the diagnosis to be discriminated. RESULTS: 104 nodules are included in the analysis (100 patients), 89♀ / 11♂; age x16 ± 2.8; TSH 2.8 uIU / ml ± 5; lymphocytic thyroiditis 30%; pathological anatomy: benign 46 (44%) cancer 58 (56%). Sonographic findings predictive of malignancy were: hypoechogenicity (OR 2.95 p = 0.008) irregular shape (100% CA) non-smooth edges (OR 8.5 p = 0.000) microcalcifications (OR 39 p = 0.000) thick calcifications (OR 18 p = 0.001) and presence of suspicious adenopathy (100% CA). In the TIRADS classification, cases classified as 4 and 5 corresponded to cancer in 50 and 92%. The presence of thyroiditis did not show an insignificant association with malignancy. From the joint analysis of the significant variables, a score with adequate sensitivity and specificity is obtained. CONCLUSIONS: The usefulness of ultrasound as a fundamental examination in the evaluation of the pediatric patient who consults by thyroid nodule is corroborated. Accurately describing their sonographic characteristics and, above all, analyzing them together, allows us to determine an approximate risk of malignancy and define with greater certainty the indication of performing FNAP

Abdominal Wall Morbidity Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Incisional hernia formation has been reported as high as 20% within 1 year following midline laparotomy. Since hyperthermic intraperitoneal chemotherapy is likely to impair wound healing, we sought to investigate the incidence of incisional hernia formation and abdominal wall rupture following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. METHODS: Consecutive patients with radiographic evidence of peritoneal metastases were scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at the Comprehensive Cancer Center, University Hospital Tuebingen, Germany. Clinical data were retrospectively analyzed. RESULTS: Between May 2005 and May 2014, 271 patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Within follow-up, 19 (7%) incisional hernias and 11 (4%) abdominal wall ruptures were observed. Age ⩾70 years, cardio-pulmonary comorbidity, the presence of pseudomyxoma peritonei or mesothelioma, and postoperative abdominal wall rupture were detected as risk factors for hernia formation. However, Cox multivariate analysis only confirmed the presence of pseudomyxoma peritonei or mesothelioma and postoperative abdominal wall rupture as independent risk factors. CONCLUSION: Our data do not suggest that cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is necessarily associated with a higher incidence of incisional hernia formation. However, patients suffering from pseudomyxoma peritonei or mesothelioma and patients with postoperative abdominal wall rupture seem to be at risk for developing incisional herniation.

Kidney Graft Salvage Strategies for Vascular Complications During Kidney Transplantation: A Single-center Experience.

BACKGROUND: Kidney-related unknown vascular injuries are rare and usually diagnosed only after reperfusion. Hemorrhage that makes in situ reconstruction impossible can lead to graft loss. In an era of organ shortage and an increasing number of patients on the waiting list for transplantation, a kidney graft salvage procedure consisting of graft nephrectomy, reperfusion, reconstruction, and reimplantation should be undertaken whenever possible as a contribution to extending the organs available for transplantation. METHODS AND PATIENTS: From January 2010 to December 2015, in total five patients suffered from intraoperative or immediate postoperative vascular complication and were included for this retrospective analysis. Age, sex, etiology of kidney failure, delayed graft function, kind of vascular complications and therapy, presence of aortoiliac calcification, cold and warm ischemia time, and length of hospital stay were analyzed. RESULTS: By applying this "one-step-back" procedure in three consecutive patients and a structured in situ repair in two patients, all grafts were saved. Two of five patients developed delayed graft function requiring hemodialysis. At discharge, graft function was excellent in all five patients. Reconstructed vasculature showed 100% patency. CONCLUSION: These graft salvage strategies are safe with excellent outcome and should be considered in the event of an acute vascular complication during kidney transplantation.

Comparison of clinical outcome of laparoscopic versus open appendectomy for complicated appendicitis.

BACKGROUND: Laparoscopic appendectomy is now the treatment of choice in uncomplicated appendicitis. To date its importance in the treatment of complicated appendicitis is not clearly defined. METHODS: From January 2005 to June 2013 a total of 1762 patients underwent appendectomy for the suspected diagnosis of appendicitis at our institution. Of these patients 1516 suffered from complicated appendicitis and were enrolled. In total 926 (61 %) underwent open appendectomy (OA) and 590 (39 %) underwent laparoscopic appendectomy (LA). The following parameters were retrospectively analyzed: age, sex, operative times, histology, length of hospital stay, 30-day morbidity focusing on occurrence of surgical site infections, intraabdominal abscess formation, postoperative ileus and appendiceal stump insufficiency, conversion rate, use of endoloops and endostapler. RESULTS: A statistically significant difference in operative time was observed between the laparoscopic and the open group (64.5 vs. 60 min; p = 0.002). Median length of hospitalization was significantly shorter in the laparoscopic group (p < 0.000). Surgical site infections occurred exclusively after OA (38 vs. 0 patients). Intraabdominal abscess formation occurred statistically significantly more often after LA (2 vs. 10 patients; p = 0.002). There were no statistical significances concerning the occurrence of postoperative ileus (p = 0.261) or appendiceal stump insufficiencies (p = 0.076). CONCLUSIONS: The laparoscopic approach for complicated appendicitis is a safe and feasible procedure. Surgeons should be aware of a potentially higher incidence of intraabdominal abscess formation following LA. Use of endobags , inversion of the appendiceal stump and carefully conducted local irrigation of the abdomen in a supine position may reduce the incidence of abscess formation.

Pancreas-preserving surgical management of grade-C pancreatic fistulas after pancreatic head resection by external wirsungostomy.

PURPOSE: Completion pancreatectomy for grade-C pancreatic fistula is associated with unacceptably high mortality and therefore this strategy should be reassessed. This study presents an update of our experience with a pancreas-preserving technique in the course of salvage re-laparotomy in terms of closure of the open jejunum via segmental resection and external drainage of the pancreas. METHODS: Between April 2004 and January 2015, 292 pancreaticoduodenectomies (PD) with pancreaticojejunostomy (PJ) were performed. Thirteen patients (5 %) underwent salvage re-laparotomy for symptomatic grade-C fistulas, and clinical data were retrospectively analyzed. RESULTS: In all patients, the preservation of the pancreas remnant and external drainage of the pancreatic juice was feasible. Median hospital stay was 58 days (range, 21-142 days). In 4/13 patients (31 %), further reoperations were necessary. In-hospital mortality was 15 % (2/13). 3/13 patients (23 %) were readmitted and two received inpatient non-surgical treatment. To date re-pancreaticojejunostomy was performed in seven of the remaining 11 patients (63 %) after 168 days in median. In 1/7 patients (14 %), a re-operation after re-PJ was necessary. In one patient, externalization of the pancreas juice was chosen as a definite option. In another patient, secretion ceased spontaneously without stasis and normal endocrine function. Neither before nor after re-anastomosis impairment of endocrine function was observed. CONCLUSIONS: Closure of the intestinum and preservation of the pancreas remnant in grade-C pancreatic fistula is easy to perform and can be categorized as a life-saving procedure. Prevention of total pancreatectomy associated with high morbidity and mortality was achieved in all cases.

Vitamin D-neutralizing CYP24A1 expression, oncogenic mutation states and histological findings of human papillary thyroid cancer.

OBJECTIVE: The aims of the present study were to examine gene and protein expression of the vitamin D-inactivating 24-hyroxylase (CYP24A1) and the activating 1-alpha-hydroxylase (CYP27B1) enzyme in human papillary thyroid cancer (PTC), furthermore, to investigate the association between CYP24A1 expression and numerous clinical, histological parameters and somatic oncogene mutation status of thyroid tumor tissues. MATERIALS AND METHODS: Gene expression analysis was carried out in 100 Hungarian thyroid samples, both normal and papillary tumor tissue sections of the same patient. The specific mRNA to the selected genes was analyzed by TaqMan probe-based quantitative real-time RT-PCR. The somatic oncogene mutation states of BRAF, NRAS, HRAS and KRAS were also tested. RESULTS: CYP24A1 mRNA expression was markedly increased in 52 cases (52%) of the examined papillary cancers compared with that of normal thyroid tissue. There was a tendency toward difference in the distribution of high-level CYP24A1 in the PTC accompanied with somatic oncogene mutation. Positive correlation was seen between increased CYP24A1 expression rate and a group of variables reflecting tumor malignity (mainly vascular invasion, lymph node metastasis, tumor size, hypothyreosis) by principal components analysis. No significant alteration was seen in CYP27B1 gene expression between neoplastic and normal tissues. CONCLUSIONS: A definite alteration was seen in vitamin D3-inactivating CYP24A1 gene activity in PTC compared to their normal tissues on a relatively large patient population. Our findings raise the possibility that CYP24A1 may also directly be involved in thyroid carcinogenesis.

Direct effects of chemoradiotherapy following esophagectomy.

BACKGROUND: Esophageal cancer is a major cause of morbidity and mortality, but despite continuing research, few effective therapies have been identified. In recent years, surgical resection following chemoradiotherapy has been associated with improved survival in several clinical models. AIM: In a prospective, observational study, we evaluated the direct effects of chemoradiotherapy on postoperative mortality, morbidity, and inflammatory response in patients following esophagectomy. METHODS: The study cohort was divided into two groups: the first group received preoperative chemoradiotherapy, while the second group had surgical intervention without prior treatment. Nutritional status was evaluated for the members of both patient groups at various time points. RESULTS: Preoperative chemoradiotherapy did not influence morbidity or organ function, and the postoperative inflammatory response did not show immunosuppressive side effects directly after surgery. CONCLUSION: Preoperative chemoradiotherapy does not improve postoperative organ function, inflammatory response or nutritional status in the patients. These findings may help to improve outcome in patients with esophageal cancer in the future.

Involvement of toll-like receptor 4 in alveolar bone loss and glucose homeostasis in experimental periodontitis.

BACKGROUND AND OBJECTIVE: There is general agreement that certain fatty acids and lipopolysaccharides (LPS) promote inflammation through toll-like receptor 4 (TLR4), and that inflammation promotes insulin resistance. We therefore hypothesized that mice with periodontitis and a TLR4 loss-of-function (LOF) mutation fed a high-fat (HF) diet would develop improved glucose homeostasis compared with wild-type (WT) animals with periodontitis fed a HF diet. MATERIAL AND METHODS: Wild-type and TLR4 mutant mice fed a HF diet were divided into four groups (n = 6/group): WT; WT with periodontitis (WT/P); mutant (Mut); and mutant with periodontitis (Mut/P). Periodontitis was induced by placing LPS soaked ligatures around maxillary second molars. Fasting insulin and glucose levels were measured weekly for 10 wk. Glucose tolerance was evaluated at baseline (week 1) and at 9 wk. Insulin signaling (phosphorylation of Akt) and tumor necrosis factor-α (TNF-α) mRNA levels in liver were determined when the mice were killed at week 10. RESULTS: Mut/P mice developed less alveolar bone loss compared with WT/P mice (p < 0.05). Fasting glucose levels were improved after 8 wk of feeding a HF diet (weeks 9 and 10) in Mut/P mice compared with Mut, WT and WT/P mice (p < 0.05). Glucose tolerance was impaired in all groups compared with baseline (p < 0.05), except for the Mut/P group. Insulin signaling was improved (p < 0.05), and expression of TNF-α was decreased (p < 0.05) in the liver of Mut/P mice compared with the liver of WT/P mice. CONCLUSION: The TLR4 LOF mutation partially protects against alveolar bone loss and improves glucose homeostasis in mice with periodontitis fed a HF diet.

Effect of glutamine in patients with esophagus resection.

UNLABELLED: Glutamine is the most abundant amino-acid in the extra- and intracellular compartments of the human body, which accounts for over 50% of its free amino-acid content. Utilization of glutamine peptides is explicitly useful, resulting in a decrease in the number of postoperative infectious complications, period of hospitalization, and therapeutic costs. This article aims to study the effects of glutamine on systemic inflammatory response, morbidity, and mortality after esophagectomy. A prospective, randomized, double-blind, and controlled trial was used. Following sealed-envelope block randomization, the patients were divided into two groups. Members of the glutamine group (group G) received glutamine (Dipeptiven, Fresenius) as continuous infusion for 6 hours at 0.5 g/kg for 3 days prior to, and 7 days following surgery; while patients of the control group were given placebo. We examined 30 patients in group G, and 25 patients as controls. In both patient groups, the levels of total protein, albumin, pre-albumin, retinol binding protein, transferrin, transferring-saturation, C-reactive protein, procalcitonin, lymphocte, Interleukin-6, Interleukin-8, tumor necrosis factor alpha, and serum lactate were determined prior to surgery (t(0)), directly after surgery (t(u)), following surgery on day 1 (t(1)), day 2 (t(2)), and day 7 (t(7)). For statistical analysis Mann-Whitney U test and chi-square test were used. There was no significant difference between the two groups regarding age, male/female ratio, and SAPS II scores. Intensive care unit morbidity and mortality was similar in both groups (group G: 24 survivors/6 nonsurvivors; CONTROL: 17 survivors/8 nonsurvivors; P= 0.607). Daily Multiple Organ Dysfunction Score did not differ significantly between the two groups. The observed inflammatory markers followed the pattern we described without significant difference. Based on our study, the glutamine supplementation that we used had no influence on morbidity, mortality, or postoperative inflammatory response after esophagectomy.

Does transthoracic compared to transhiatal resection alter the early postoperative course of oesophagectomy?

SUMMARY: Several techniques for esophageal resections have been reported. However, clear clinical evidence is still lacking whether any of the procedures is superior to the others regarding morbidity and mortality in the early postoperative period. Two operative approaches for esophageal carcinoma, transhiatal and transthoracic, were compared with respect to operative morbidity, mortality and systemic inflammatory response. In our prospective study between 2000 and 2002 83 patients were investigated. In a retrospective post hoc analysis patients were divided into two groups due to the performed operational procedure, transhiatal (TH) or transthoracic (TT). Multiple Organ Dysfunction Score (MODS) was monitored daily (t1,t2,t3). Serum procalcitonin (PCT) levels were determined on admission to the ICU (t0), then 24 hourly (t24,t48,t72). Microalbuminuria (M:Cr) was measured before (tp), and after surgery (t0,t6,t24,t48,t72). For statistical analysis Wilcoxon rank sum test, Mann-Whitney U-test and chi-square test were used as appropriate. We examined 52 patients in the TH group, and 31 patients in the TT group. There was no significant difference between the two groups regarding age, male/female ratio, and SAPS II scores. Operations lasted significantly longer in the TT group: 375 (300-480) min compared to the TH group 240 375 (180-319) min, P < 0.001. ICU mortality was similar in both groups (TH: 46 survivors/6 non-survivors; TT: 27 survivors/4 non-survivors; P = 0.607, respectively). Daily MODS did not differ significantly between the two groups. The observed inflammatory markers (PCT and M:Cr) followed the pattern we described earlier, without significant difference. In this study there was no difference in the clinical and biochemical variables of the patients between the transthoracic and transhiatal groups. The observed early postoperative morbidity and mortality may indicate, that both procedures can be considered as procedures with similar postoperative risk.

Resonancia Magnetica Mamaria: Indicaciones Poco Habituales / Breast MR imaging: unusual indications

The indications of breast MRI are now clearly established and internationally accepted. They are also applied in Chile as was agreed in the last the National Consensus on the management of breast cancer. In our study the indications not mentioned in the consensus were classified as infrequent. We determined that a 9.2 percent of breast MRI performed in our study centers were due to infrequent indications, leading to a change in medical management in 71,4 percent of these patients, although this change sometimes had no scientific evidence availing it. These results suggest that MRI could be useful in specific situation and reveal a need for multicentric high quality studies in order to gather enough evidence to justify its use in indications other than the ones already established. In other situations MRI would not be recommended. In exceptional cases, where it seems useful to perform this type of exam it is suggested to make the advisable to make the decision after discussion in a interdisciplinary committee.

Las indicaciones de resonancia magnética mamaria están bien definidas e internacionalmente aceptadas. Se aplican también en Chile según lo establecido en el último Consenso Nacional sobre cáncer mamario, sin embargo observamos que un porcentaje no despreciable (9.2 por ciento) de las resonancias mamarias realizadas en nuestros centros de atención son por indicaciones distintas a las establecidas. En un 71.4 por ciento de estos casos generó un cambio en la conducta médica, situación que en algunos casos no contó con respaldo científico establecido. Estos resultados orientan a pensar que la resonancia sería de utilidad en casos específicos y demuestran la necesidad de estudios sistematizados, multicéntricos que lleven a reunir la evidencia suficiente para justificar su uso en indicaciones distintas a las ya aceptadas. En los casos en que parezca conveniente realizar este tipo de estudio, sería recomendable discutir su eventual utilidad e influencia en la conducta clínica, en el seno de equipos de especialistas multidisciplinarios.

Impairment by lovastatin of neural relaxation of the rabbit sphincter of Oddi.

We sought whether inhibition of cholesterol biosynthesis by lovastatin influenced the nitrergic relaxation response of the sphincter of Oddi. Rabbit sphincters of Oddi rings were tested for changes in isometric tension in response to field stimulation in the presence of 4 microM guanethidine and 1 microM atropine. Tissue samples were then analyzed for cAMP and cGMP content by radioimmunoassay for nitric oxide concentration by electron spin resonance and for vasoactive intestinal peptide and calcitonin gene-related peptide (CGRP) release by radioimmunoassay. Membrane G(salpha) protein was determined by Western blot analysis. Field stimulation relaxed the preparations with an increase in nitric oxide, cAMP and cGMP concentrations at increased calcitonin gene-related peptide and vasoactive intestinal polypeptide (VIP) release. Preparations from rabbits pre-treated with lovastatin (5 mg/kg/day intragastrically, over 5 days) contracted under the same conditions with an attenuated cGMP-increase at preserved increase in NO content and neuropeptide release. The relaxation was recaptured combining lovastatin with farnesol (1 mg/kg intravenously, twice a day for 5 days). The field stimulation-induced increase in cyclic nucleotides was also restored. Lovastatin decreased membrane G(salpha) protein content, which was re-normalized by farnesol. Farnesol treatment reinstates neurogenic relaxation of the sphincter of Oddi deteriorated by lovastatin possibly by normalizing G-protein coupling.

A 27-bp region of the inducible nitric oxide synthase promoter regulates expression in glial cells.

The expression of inducible nitric oxide synthase (NOS2) in glial cells is inhibited by neurotransmitters such as norepinephrine (NE) which elevate cAMP levels. We examined the molecular basis for this effect using a 2.2-kb fragment of the rat NOS2 promoter transfected into rat C6 glioma cells. Promoter activation (up to six-fold) by lipopolysaccharide (LPS) and interferon-gamma (IFNgamma) was reduced by NE, which alone had no effect. However, a promoter construct extending to bp -130 and containing the proximal nuclear factor-kappa B (NF-kappaB) binding site was minimally activated by LPS and cytokines, but activated up to three-fold by NE. Deletion analysis identified a 27-bp region (bp -187 to -160) as critical for mediating this suppressive effect. This region also enhanced promoter activation by LPS and cytokines, and prevented activation by NE alone. Gel shift analysis revealed constitutive binding to this region, and induction by NE of additional complexes which could be blocked by an antibody against CREB. NE also increased levels of the IkappaBalpha protein which could contribute to its suppressive effects. These results identify a critical role for this 27-bp region in regulation of NOS2 promoter activation and suppression by cAMP.

Impaired bronchomotor responses to field stimulation in guinea-pigs with cisplatin-induced neuropathy.

Pre-treatment with cisplatin (3 mg/kg) i.p. once a day over 6 days induced sensory neuropathy as confirmed by femoral nerve conduction velocity test and significantly decreased contractions induced by electrical field stimulation (100 stimuli, 20 V, 0.1 ms, 20 Hz) in isolated main bronchial rings from guinea-pigs. The field stimulation-induced non-adrenergic, non-cholinergic (NANC) relaxations, however, were amplified in rings from animals with cisplatin neuropathy. The NANC relaxation response was completely blocked by 30 microM N(G)-nitro-L-arginine methyl ester in preparations from both control and cisplatin-treated animals. Superoxide dismutase (40 units/ml) was without effect on NANC relaxation in control rings, however, it substantially decreased NANC relaxation in preparations from animals with cisplatin neuropathy. These results show that cisplatin-induced sensory neuropathy is accompanied by attenuation of neural bronchoconstriction and an enhanced NANC relaxation. The latter is in part attained by an increased peripheral superoxide production.