Diagnostic approach to subcutaneous nodules in patients with neuroendocrine tumours treated with depot somatostatin analogs: a cross-sectional study.

BACKGROUND: The presence of cutaneous nodules in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) receiving depot somatostatin analogs (SSAs) is a diagnostic challenge as differential diagnosis between injection site reactions and metastases is essential. OBJECTIVE: To characterize the clinical, radiological, cytological and histopathological features of subcutaneous nodules in patients with GEP-NETs treated with SSAs. MATERIALS AND METHODS: Retrospective, cross-sectional study of patients with GEP-NETs treated with SSAs in whom subcutaneous nodules were detected on routine abdominal computed tomography (CT) scans. High resolution and colour Doppler ultrasonography was performed. Those patients with inconclusive radiological studies went through fine-needle aspiration cytology (FNAC) and/or biopsy. RESULTS: Twelve patients (five males, seven females) were included (six midgut carcinoid NETs, six pancreatic NETs). Three patients received intramuscular depot octreotide, seven subcutaneous lanreotide, and two both treatments. CT scan findings were nonspecific. Sonography revealed a hyperechoic pattern in recent injections, and a hypoechoic pattern with a characteristic hyperechoic peripheral rim in long-term injections (more than 3 months after injection). On colour Doppler sonography, nodules showed no signs of intralesional vascularity. Fine-needle aspiration cytology (FNAC) was performed in five patients, revealing a characteristic acellular proteinaceous material. Biopsy in four patients showed different reactional infiltrates around the acellular material. CONCLUSIONS: High resolution and colour Doppler ultrasonography may be very useful for the differential diagnosis of subcutaneous nodules in patients with GEP-NETs treated with SSAs. FNAC and a biopsy are useful tests for confirmation of the diagnosis in patients with inconclusive findings. We propose a management algorithm.

TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP.

TRPM8 is the molecular sensor for cold; however, the physiological role of TRPM8+ neurons at mucosal surfaces is unclear. Here we evaluated the distribution and peptidergic properties of TRPM8+ fibers in naive and inflamed colons, as well as their role in mucosal inflammation. We found that Trpm8(-/-) mice were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis, and that Trpm8(-/-) CD11c+ DCs (dendritic cells) showed hyperinflammatory responses to toll-like receptor (TLR) stimulation. This was phenocopied in calcitonin gene-related peptide (CGRP) receptor-deficient mice, but not in substance P receptor-deficient mice, suggesting a functional link between TRPM8 and CGRP. The DSS phenotype of CGRP receptor-deficient mice could be adoptively transferred to wild-type (WT) mice, suggesting that CGRP suppresses the colitogenic activity of bone marrow-derived cells. TRPM8+ mucosal fibers expressed CGRP in human and mouse colon. Furthermore, neuronal CGRP contents were increased in colons from naive and DSS-treated Trpm8(-/-) mice, suggesting deficient CGRP release in the absence of TRPM8 triggering. Finally, treatment of Trpm8(-/-) mice with CGRP reversed their hyperinflammatory phenotype. These results suggest that TRPM8 signaling in mucosal sensory neurons is indispensable for the regulation of innate inflammatory responses via the neuropeptide CGRP.

Pegvisomant and cabergoline combination therapy in acromegaly.

Combination with cabergoline may offer additional benefits to acromegalic patients on pegvisomant monotherapy. We evaluated the safety and efficacy profile of this combination and investigated the determinants of response. An observational, retrospective, cross-sectional study. Fourteen acromegalic patients (9 females), who were partially resistant to somatostatin analogs and on pegvisomant monotherapy. Cabergoline was added because of the presence of persistent mildly increased IGF-I. The mean follow-up time was 18.3 ± 10.4 months. The efficacy and safety profile was assessed. The influence of clinical and biochemical characteristics on treatment efficacy was studied. IGF-I levels returned to normal in 4 patients (28%) at the end of the study. In addition, some decline in IGF-I levels was observed in a further 5 patients. The % IGF-I decreased from 158 ± 64% to 124 ± 44% (p = 0.001). The average change in IGF-I was -18 ± 27% (range -67 to +24%). Lower baseline IGF-I (p = 0.007), female gender (p = 0.013), lower body weight (p = 0.031), and higher prolactin (PRL) levels (p = 0.007) were associated with a better response to combination therapy. There were no significant severe adverse events. Significant tumour shrinkage was observed in 1 patient. Combination therapy with pegvisomant and cabergoline could provide better control of IGF-I in some patients with acromegaly. Baseline IGF-I levels, female gender, body weight, and PRL levels affect the response to this combination therapy.

A randomized, clinical trial of ketorolac tromethamine vs ketorolac trometamine plus complex B vitamins for cesarean delivery analgesia.

BACKGROUND: Ketorolac is widely used for postoperative analgesia in patients who undergo cesarean delivery. In countries where the use of opioids is considerably restricted, alternatives to narcotics are required. AIM: We hypothesize that the addition of complex B synergize the analgesic effect of ketorolac in postoperative cesarean patients, thus requiring a smaller dose of the anti-inflammatory agent, and therefore decreasing the potential side effects of ketorolac. METHODS: A randomized clinical trial with 100 patients undergoing a primary elective cesarean delivery enrolled in the study. Pain was assessed in the recovery room and then they were randomized to receive ketorolac 30 mg intramuscular (i.m.) or 15 mg of ketorolac plus complex B vitamin (CBV). The pain score with an analog scale was assessed 1, 2, 6, 12, 18, and 24 h after the baseline. The student's t test was performed to compare the demographic differences between the 2 means. RESULTS: 100 patients were included in the study, showing no statistical differences in the demographics. The patient's pain score at 1, 2, 6, 12, 18 and 24 hours showed no statistical differences between the control group (ketorolac 30mg) compared to the group of ketorolac 15mg and complex B vitamins. No changes in the coagulation studies were found in both groups. CONCLUSION: The present study demonstrates that ketorolac 30 mg and ketorolac 15 mg plus complex B vitamins can provide acceptable analgesia in many patients with severe pain.

Somatotroph tumor progression during pegvisomant therapy: a clinical and molecular study.

CONTEXT: There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown. OBJECTIVE: The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant. DESIGN AND SETTING: This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain. PATIENTS: Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months. MAIN OUTCOME MEASURES: Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew. RESULTS: A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P < 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R(2) = 0.334, P < 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = -4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group. CONCLUSIONS: No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.

Hepatic nuclear factor 1-alpha directs nucleosomal hyperacetylation to its tissue-specific transcriptional targets.

Mutations in the gene encoding hepatic nuclear factor 1-alpha (HNF1-alpha) cause a subtype of human diabetes resulting from selective pancreatic beta-cell dysfunction. We have analyzed mice lacking HNF1-alpha to study how this protein controls beta-cell-specific transcription in vivo. We show that HNF1-alpha is essential for the expression of glut2 glucose transporter and L-type pyruvate kinase (pklr) genes in pancreatic insulin-producing cells, whereas in liver, kidney, or duodenum tissue, glut2 and pklr expression is maintained in the absence of HNF1-alpha. HNF1-alpha nevertheless occupies the endogenous glut2 and pklr promoters in both pancreatic islet and liver cells. However, it is indispensable for hyperacetylation of histones in glut2 and pklr promoter nucleosomes in pancreatic islets but not in liver cells, where glut2 and pklr chromatin remains hyperacetylated in the absence of HNF1-alpha. In contrast, the phenylalanine hydroxylase promoter requires HNF1-alpha for transcriptional activity and localized histone hyperacetylation only in liver tissue. Thus, different HNF1-alpha target genes have distinct requirements for HNF1-alpha in either pancreatic beta-cells or liver cells. The results indicate that HNF1-alpha occupies target gene promoters in diverse tissues but plays an obligate role in transcriptional activation only in cellular- and promoter-specific contexts in which it is required to recruit histone acetylase activity. These findings provide genetic evidence based on a live mammalian system to establish that a single activator can be essential to direct nucleosomal hyperacetylation to transcriptional targets.

L-Arginine administration prevents reperfusion-induced cardiomyocyte hypercontracture and reduces infarct size in the pig.

OBJECTIVE: Stimulation of cGMP synthesis protects cardiomyocytes against reoxygenation-induced hypercontracture. The purpose of this study was to determine whether L-arginine supplementation has a protective effect against reperfusion-induced hypercontracture and necrosis in the intact animal. METHODS: Twenty-four Large-White pigs were randomized to receive either 100 mg/kg of L-arginine i.v. or vehicle 10 min before 48 min of coronary occlusion and 2 h of reperfusion. Hemodynamic variables, coronary blood flow and myocardial segment length changes (piezoelectric crystals) were monitored. Postmortem studies included quantification of myocardium at risk (in vivo fluorescein), infarct size (triphenyltetrazolium reaction), myocardial myeloperoxidase activity and histological analysis. Systemic, coronary vein, and myocardial cGMP concentration were measured in additional animals. RESULTS: Administration of L-arginine had no significant effect in hemodynamics or coronary blood flow. During reperfusion, myocardial cGMP content was reduced in the LAD as compared to control myocardium (P=0.02). L-Arginine increased myocardial cGMP content and caused a transient increase in plasma cGMP concentration during the initial minutes of reperfusion (P=0.02). The reduction in end-diastolic segment length induced by reperfusion, reflecting hypercontracture, was less pronounced in the L-arginine group (P=0.02). Infarct size was smaller in pigs receiving L-arginine (47.9+/-7.2% of the area at risk) than in controls (62.9+/-4.9%, P=0.047). There were no differences between groups in leukocyte accumulation in reperfused myocardium (P=0.80). CONCLUSION: L-Arginine supplementation reduces myocardial necrosis secondary to in situ ischemia-reperfusion by a direct protective effect against myocyte hypercontracture.

Urodilatin limits acute reperfusion injury in the isolated rat heart.

OBJECTIVES: Hypercontracture is an important mechanism of myocyte death during reperfusion. cGMP modulates the sensitivity of contractile myofilaments to Ca2+, and increasing cGMP concentration during the last minutes of anoxia prevents reoxygenation-induced hypercontracture in isolated cardiomyocytes. The purpose of this study was to determine whether stimulation of particulate guanylyl cyclase with the natriuretic peptide urodilatin, given at the time of reperfusion, reduces myocardial necrosis in the rat heart submitted to transient ischemia. METHODS: Isolated rat hearts (n = 38) were submitted to either 40 or 60 min of no-flow ischemia and 2 h of reperfusion, and were allocated to receive or not receive 0.05 microM urodilatin during the first 15 min of reperfusion or non-reperfusion treatment. RESULTS: A marked reduction in myocardial cGMP concentration was observed in control hearts during reperfusion after 40 or 60 min of ischemia. Urodilatin significantly attenuated cGMP depletion during initial reperfusion, markedly improved contractile recovery after 40 min of ischemia (P < 0.0309), and reduced reperfusion-induced increase in left ventricular end-diastolic pressure (P = 0.0139), LDH release (P = 0.0263), and contraction band necrosis (P = 0.0179) after 60 min of ischemia. The beneficial effect of urodilatin was reproduced by the membrane permeable cGMP analog 8-Bromo-cGMP. CONCLUSIONS: These results indicate that reduced cGMP concentration may impair myocyte survival during reperfusion. Stimulation of particulate guanylyl cyclase may appear as a new strategy to prevent immediate lethal reperfusion injury.

L-arginine limits myocardial cell death secondary to hypoxia-reoxygenation by a cGMP-dependent mechanism.

The objective of this study was to investigate the effect of L-arginine supplementation on myocardial cell death secondary to hypoxia-reoxygenation. Isolated rat hearts (n = 51) subjected to 40 min of hypoxia and 90 min of reoxygenation received 3 mM L-arginine and/or 1 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a selective inhibitor of soluble guanylyl cyclase) throughout the experiment or during the equilibration, hypoxia, or reoxygenation periods. The incorporation of L-[3H]arginine into myocytes during energy deprivation was investigated in isolated adult rat myocytes. The addition of L-arginine to the perfusate throughout the experiment resulted in higher cGMP release (P < 0.05), reduced lactate dehydrogenase release (P < 0.05), and increased pressure-rate product (P < 0.05) during reoxygenation. These effects were reproduced when L-arginine was added only during equilibration, but addition of L-arginine during hypoxia or reoxygenation had no effect. Addition of ODQ either throughout the experiment or only during reoxygenation reversed the beneficial effects of L-arginine. L-[3H]arginine was not significantly incorporated into isolated myocytes subjected to energy deprivation. We conclude that L-arginine supplementation protects the myocardium against reoxygenation injury by cGMP-mediated actions. To be effective during reoxygenation, L-arginine must be added before anoxia.

[Induction of labor with misoprostol]. / Inducción del trabajo de parto con misoprostol.

The results obtained with the induction of labor with a synthetic analogue of prostaglandin E1: misoprostol, are presented. We reviewed 149 cases of patients admitted to this hospital (The "Policlínico Escuela Eva Perón") for induction of labor throughout a 13-month period of time since 06/01/92 until 06/30/93. All patients had a medical indication for induction of labor, a single pregnancy, cephalic - vertex presentation, no previous surgical scars on uterus, no contraindications for vaginal delivery, Bishop score below 7, gestational age over 37 weeks, and a reactive NST (Non Stress Test). Misoprostol was used intravaginally in the posterior fornix, in one dose of 100 mcg. In those patients where the spontaneous rupture of membranes was not the cause of induction itself, these were artificially ruptured at the moment of admission if possible depending on obstetric conditions, or no longer than 2 hours afterward. All patients underwent continuous fetal hart rate monitoring, during the active phase of labor. There were no failures of induction since all patients reached the active phase of labor without using oxytocin. There was an extremely high percentage of vaginal deliveries being this figure 96.6%. Only 5 patients had to undergo a cesarean section, 2 because of arrest of labor and 3 because acute fetal distress. Four cases of acute intrauterine fetal distress were registered but none of them were caused by tachysystole or hypercontractility. The mean time from the beginning of induction to delivery was 5 hours and 20 minutes (+/- 2 hs, 40') 70.5% of patients giving birth before 6 hours since admittance.(ABSTRACT TRUNCATED AT 250 WORDS)

Critical control points for foods prepared in households whose members had either alleged typhoid fever or diarrhea.

Hazard analysis of food preparation practices were conducted in four households and eleven others were visited to survey both food preparation practices and environmental conditions. Households selected had members who were suffering from either diarrhea of unknown etiology or alleged typhoid fever. Hazard analyses and sanitary surveys included gathering data on time-temperature exposures of foods, collecting samples of food and drinking water, sampling sewage or drains, and obtaining stool specimens from persons with diarrhea and from family controls. Food samples were tested for aerobic mesophilic colony counts and common foodborne pathogens; specimens were tested for Salmonella, Shigella, Campylobacter and Yersinia. Campylobacter was isolated from two persons purported to have diarrhea, but neither Salmonella, Shigella nor Yersinia were recovered from alleged cases or controls. Salmonella agona was recovered from a latrine. Most foods were cooked to internal temperatures to or near to boiling. Those not promptly eaten were held at ambient room or outside temperatures until a subsequent meal, until a family member returned home, or until lunch time when taken to the fields. During these intervals, microorganisms multiplied and mesophilic aerobic organisms increased often reaching 10(8)/g or greater before consumption. None of these foods were reheated before eating. Bacillus cereus was isolated from 4 of 10 samples; one sample of 'moro' (beans and rice) exceeded 10(6)/g, two other samples exceeded 10(3)/g. Staphylococcus aureus was isolated from 7 of 14 samples, one exceeded 10(5)/g. Fecal coliforms were isolated from 8 of 14 food samples, five exceeded 10(5)/g. Neither Salmonella nor Shigella were isolated from any food, the community water supplies or from vessels of water within houses. Fecal coliform counts of water were less than 3/ml, except one sample from a clay vessel (9/ml). Risks associated with cooked foods which were not promptly eaten appeared to be greater than that associated with water.

Comparacion de dos tecnicas de Knott y filtro nucleopore en el diagnostico de filariasis Brancrofti / Comparative study of the Knott and nucleopore filter techniques for diagnosis of Bancroft's filiarasis

En una muestra aleatoria de 1.657 personas, se compararon las tecnicas de Knott y filtro nucleopore, sin que se hallaran diferencias significativas. La tradicional tecnica de Knott demostro ser tan eficaz para la deteccion de portadores de microfiliarias como los modernos filtros de membrana