Anthelmintic activity and chemical profile of native plant extracts from the Yucatan Peninsula against Toxocara canis.

Toxocara canis can produce the "larva migrans" syndrome in humans, and in puppies, it can cause severe digestive disorders. The most used treatments are based on anthelmintics, although there are reports of anthelmintic (AH) resistance. The Yucatan Peninsula has a great variety of plant species whose AH properties are still unknown. The objective of this study was to evaluate the in vitro AH activity of ethanolic (EE), methanolic (ME) and aqueous (AE) extracts from the leaves of five native plant species of the Yucatan Peninsula on T. canis eggs of dogs from Merida, Yucatan. As part of a screening, the EE of the plants Alseis yucatanensis, Calea jamaicensis, Cameraria latifolia, Macrocepis diademata, and Parathesis cubana were evaluated at doses of 2400 and 3600 µg/ml. The EE and AE of A. yucatanensis and M. diademata presented high percentages (≥ 91.3%) of inhibition of the larval development of T. canis after six days of exposure. The lowest LC50 and LC99 was presented by the ME from A. yucatanensis (255.5 and 629.06 µg/ml, respectively) and the ME from M. diademata (222.4 and 636.5 µg/ml, respectively), and the AE from A. yucatanenesis (LC50 of 535.9 µg/ml). Chemical profiling of the most potent AH extract (Alseis yucatanensis) was carried out by LC-UV-HRMS. Data from the ME and AE from this plant indicated the presence of the known glucosylngoumiensine, kaempferol 3,7-diglucosyde, uvaol, linoleic acid and linolenic acid together with unknown alkaloids. The EE, ME and AE from leaves of M. diademata and A. yucatanensis could be developed as natural alternatives to control T. canis.

Prophylaxis and Treatment of Inflammation with Pentacyclic Chemotype of Uncaria tomentosa.

Context: Anti-inflammatory drugs and biologics can effectively treat inflammatory conditions and diseases but can also cause burdensome side effects. Many patients prefer to use time-tested, traditional medicinal products and dietary supplements, but such products seldom receive the rigorous testing required for regulatory approvals of drugs and biologics. Thus, it is advantageous to demonstrate by experimentation the pharmacological and toxicological properties of unapproved natural products and compared to benchmark approved drugs or biologics. Objective: The studies intended to evaluate Samento®, a commercial hydro-alcoholic extract of the pentacyclic chemotype of Uncaria Tomentosa (Willd.) DC, for the prophylactic and treatment effects of irritant-induced inflammation and antigen-induced arthritic inflammation in two rat models. The studies were also intended to create a clinical bridge rationale for the use of Samento® in the treatment of inflammation in humans, with a suggested allometrically scaled starting dose. Design: The research team performed two in vivo animal model studies of induced inflammation in rats. Setting: The studies took place at the Universidad Peruana Cayetano Heredia in Lima, Peru. Prophylaxis Model of Irritant-Induced Inflammation: Holtzman rats in five groups (five each per group) were administered 14 daily doses of Samento® at 250, 500, and 1000 mg/kg of wet weight, or 40 mg/kg of naproxen sodium as a positive control, or nothing as a negative control. At 14 days the right legs of the rats were challenged by injection into the connective tissue by the chemical irritant carrageenan. Two hours thereafter the weight of the irritant-injected right leg was compared to the non-injected left leg of each rat, to determine the level of irritant-induced inflammation. Treatment Model of Antigen-Induced Arthritic Inflammation: Arthritic inflammation was induced in five groups of Lewis rats (five each per group) by intradermal injection of the tail with non-allogeneic, bovine type II collagen in incomplete Freund's adjuvant. A sixth group was not injected with collagen antigen as a non-induced control. Ten days after the induction of arthritic inflammation in the five injected groups, individual groups were treated with Samento® at 250, 500, and 1000 mg/kg of wet weight daily for 21 days, or 0.2 mg/kg of methotrexate twice per week as a positive control, or nothing as a negative control. At 21 days the animals were assessed for antigen-induced arthritic inflammation and assigned an analog score ranging from 0 to 4. Results: The research team confirmed the presence of pentacyclic oxindoles and the absence of tetracyclic oxindoles within Samento®. In the prophylactic model, 14 days of pretreatment with oral Samento® produced dose-dependent, statistically significant reductions in inflammation in the rats' leg weights between the carrageenan induction and postintervention, for the 250, 500, and 1000 mg/kg Samento® groups (P < .05 for all groups). The 1000 mg/kg group had a 74% anti-inflammatory effect versus 97% with the 40 mg/kg of naproxen sodium in the positive control group. In the treatment model, 21 days of oral administration of Samento® produced dose-dependent, statistically significant reductions in arthritic inflammation postintervention, for the 250, 500, and 1000 mg/kg Samento® groups (P < .05 for all groups). Treatment with the highest tested dose of the extract (1000 mg/kg) yielded an 85% anti-inflammatory effect versus 90% with 0.2 mg/kg of methotrexate in the positive control group. Conclusions: The two rat models revealed that the Uncaria phytotherapy Samento® was an effective prophylactic as well as a treatment for induced inflammation in rats. The highest dose of the pentacyclic chemotype of Uncaria approached the anti-inflammatory activities of the established benchmark pharmaceutical positive controls. The results in the two rat models suggest an allometrically scaled starting dose of Samento® of 4 g daily in humans.

GlucoMedix®, an extract of Stevia rebaudiana and Uncaria tomentosa, reduces hyperglycemia, hyperlipidemia, and hypertension in rat models without toxicity: a treatment for metabolic syndrome.

BACKGROUND: The objective of this in vivo study is to evaluate in five rat models the pharmacologic effects and toxicity of a commercial hydro-alcoholic extract, GlucoMedix®, derived from Stevia rebaudiana and the pentacyclic chemotype of Uncaria Tomentosa (Willd.) DC, for use as a treatment for metabolic syndrome. The extract contains phytochemicals of Stevia (e.g., steviol glycosides) and Uncaria (e.g., pentacyclic oxindole alkaloids, but lacks tetracyclic oxindole alkaloids). METHODS: The pharmacologic assessments in three rat models include reductions in chemically induced hyperglycemia, hyperlipidemia (cholesterol and triglycerides), and hypertension, all of which are comorbidities of metabolic syndrome. Acute toxicity and 28-day subacute toxicity were assessed in rat models at doses higher than those used in the efficacy models. RESULTS: The acute oral toxicity was evaluated in Holtzman rats and the extract did not produce acute toxic effects or lethality, with the LD50 > 5000 mg/kg (extract wet weight). Furthermore, subacute oral toxicity was evaluated in rats for 28 days at daily doses as high as 2000 mg/kg without toxicity or abnormal clinical chemistry or hematological effects. Daily oral doses of 250 - 1000 mg/kg were used to evaluate the treatment effects in hyperglycemic (alloxan-induced and glibenclamide-controlled), hyperlipidemic (cholesterol-induced and atorvastatin-controlled), and hypertensive (L-NAME-induced and enalapril-controlled) rat models. Alloxan-induced hyperglycemia was reduced in a dose-dependent manner within 28 days or less. Cholesterol-induced hyperlipidemic rats exhibited dose-dependent reductions in cholesterol and triglycerides at 21 days. Furthermore, GlucoMedix® produced a dose-dependent decrease in systolic and diastolic arterial blood pressure in L-NAME-induced hypertensive rats at 28 days. CONCLUSIONS: The five in vivo rat models revealed that the all-natural phytotherapy GlucoMedix® is a safe and effective treatment for hyperglycemia, hyperlipidemia, and hypertension. This extract is expected to affect multiple comorbidities of metabolic syndrome, without any acute or subacute oral toxicity in humans. Although multiple prescription drugs are well known for the treatment of individual comorbidities of metabolic syndrome, no drug monotherapy concurrently treats all three comorbidities.

Effect of tomato (Solanum lycopersicum L.) lycopene-rich extract on the kinetics of rancidity and shelf-life of linseed (Linum usitatissimum L.) oil.

The effect of tomato lycopene-rich extract (TLE) addition on shelf-life of linseed oil was evaluated. Linseed oil was extracted by cold pressing and TLE by supercritical CO2. Linseed oils with and without TLE addition were characterized for moisture, color, refractive index, fatty acid composition and antioxidants. Adding TLE to 80 mg lycopene/kg oil improved linseed oil stability, showing the same induction time at 110 °C (by Rancimat) of control linseed oil with 200 mg/kg butylhydroxytoluene. The increase of free fatty acid, peroxide value, p-anisidine value, K232 and K268 at 40, 50, and 60 °C until 90 days followed first-order kinetics. Rancidity rate augmented with temperature. TLE addition slowed oil degradation without changing the mechanism since the Arrhenius lines were parallel. Mean Ea were respectively 38.2, 24.7, 38.0, 38.2, 41.5 kJ/mol. TLE addition increased linseed oil shelf-life by 31% (Rancimat) and by 42% (stability kinetics during storage).

Protective effect of supplementation with biotin against high-fructose-induced metabolic syndrome in rats.

Several reports have demonstrated that pharmacological concentrations of biotin reduce hyperglycemia, hypertriglyceridemia, and hypertension. We hypothesized that biotin could exert a protective effect on some illness-associated metabolic syndrome. To test this hypothesis, male Wistar rats were fed a diet containing 30% fructose in drinking water and classified into four groups: C, the control group; B, the group receiving biotin (intraperitoneal injection, 2 mg/kg); F, the group receiving fructose (30% w/v); and FB, the group receiving fructose-biotin. The administration of biotin began after the rats had been on a high-fructose diet for 12 weeks and continued for 4 weeks. Our results showed that food and fluid intake were diminished in the F and FB groups. However, the final body weights were similar between the groups. A significant increase in hepatic triglyceride and cholesterol content, plasma cholesterol, triglycerides, transaminases, low-density lipoprotein cholesterol (LDL-c), systolic blood pressure, and vasocontraction, as well as a decrease in high-density lipoprotein cholesterol (HDL-c) were observed in the F group. Glucose tolerance and insulin tolerance were also impaired in the F group. The administration of biotin ameliorated all these changes. Hepatic oxidative stress as well as macrovesicular fatty changes in hepatocytes caused by a high-fructose diet were also improved by biotin. Our findings demonstrate that biotin has a protective role against metabolic syndrome by improving insulin resistance associated with normal hepatic and serum levels of triglyceride and cholesterol, blood pressure, and the prevention of steatosis and hepatic oxidative damage. Therefore, biotin could be used as a therapeutic strategy in the pharmacological treatment of metabolic syndrome.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

BACKGROUND: Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer. METHODS: In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points. RESULTS: In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76). CONCLUSIONS: Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257 ; EudraCT number, 2006-003466-34 .).

ALD1613, a Novel Long-Acting Monoclonal Antibody to Control ACTH-Driven Pharmacology.

Adrenocorticotropic hormone (ACTH) is the primary regulator of adrenal glucocorticoid production. Elevated levels of ACTH play a critical role in disease progression in several indications, including congenital adrenal hyperplasia and Cushing disease. We have generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1613) to ACTH. In vitro, ALD1613 neutralizes ACTH-induced signaling via all 5 melanocortin receptors and inhibited ACTH-induced cyclic adenosine monophosphate accumulation in a mouse adrenal cell line (Y1). ALD1613 administration to wild-type rats significantly reduced plasma corticosterone levels in a dose-dependent manner. In rodent models with either chronic infusion of ACTH or acute restraint stress-induced ACTH, corticosterone levels were significantly reduced by ALD1613. Administration of ALD1613 to nonhuman primates on days 1 and 7 stably reduced plasma cortisol levels >50% for 57 days. ALD1613 demonstrates the potential of a monoclonal antibody to be an effective therapeutic for conditions with elevated ACTH levels.

Hermangioma intraóseo: reto diagnóstico. Presentación de un caso y revisión de la literatura / Intraosseous hemangioma: a diagnostic challenge. Report of a case and review of the literature

Los hemangiomas son neoplasias benignas de origen endotelial, formadoras de vasos. Los hemangiomas intraóseos son condiciones raras que comprenden del 0.5 a 1% de todos los tumores intraóseos. Su localización más común es la columna vertebral y los huesos del cráneo. Aquéllos que se presentan en los maxilares son tumores muy raros. Dos tercios de éstos se localizan en la mandíbula, con una proporción de mujer a hombre de 2:1. El objetivo de este artículo es reportar un caso signifi cativo de un hemangioma central de grandes dimensiones de la rama de la mandíbula del lado derecho, el cual fuetratado exitosamente con resección quirúrgica y ligadura de vasos nutricionales. Caso clínico: Paciente de 14 años que presenta un área radiolúcida unilocular en la rama mandibular del lado derecho. Clínicamente se observa aumento de la cara difuso, que causa asimetría facialasintomática de tres años de evolución. Conclusiones: La importancia del hemangioma intraóseo de los maxilares radica en su proximidad con los dientes, lo que representa un alto riesgo de sangrado debido a cualquier traumatismo por intento de extracción. El diagnóstico de hemangioma intraóseo, debido a su baja incidencia e inusual manera de presentación, es un reto diagnóstico...

Management of Chronic Hand Eczema.

Management of hand eczema is complex because of the broad range of different pathogeneses, courses, and prognoses. Furthermore, the efficacy of most available treatments is not well established and the more severe forms can have a major impact on the patient's quality of life. Patient education, preventive measures, and the use of emollients are the mainstays in the management of hand eczema. High-potency topical corticosteroids are the treatment of choice, with calcineurin inhibitors used for maintenance. Phototherapy or systemic treatments are indicated in patients who do not respond to topical treatments. Switching from topical treatments should not be delayed to avoid sensitizations, time off work, and a negative impact on quality of life. Alitretinoin is the only oral treatment approved for use in chronic hand eczema.

Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻5) and rs828054 (OR = 1.06; p = 1 × 10⁻4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Evaluation of linalool, a natural antimicrobial and insecticidal essential oil from basil: effects on poultry.

Linalool is a natural plant-product used in perfumes, cosmetics, and flavoring agents. Linalool has proven antimicrobial and insect-repellent properties, which indicate it might be useful for control of enteropathogens or insect pests in poultry production. However, there are no published reports that linalool may be safely administered to or tolerated by chickens. Linalool was added to the diets of day-of-hatch chicks, and they were fed linalool-supplemented diets for 3 wk. We studied the effects of linalool on serum chemistry, gross pathology, feed conversion, and relative liver weights. Linalool had a dramatic negative dose-dependent effect on feed conversion at concentrations in the feed exceeding 2% linalool, but not on gross pathology. Liver weights were significantly increased in the 5% linalool-treated birds. There was a statistical effect on blood glucose, but this parameter remained below the cut-offs for elevated serum glucose, and the result is likely of no biological significance. Linalool caused serum aspartate aminotransferase (AST) levels to increase, but it did not increase serum gamma-glutamyl transferase levels. The linalool effect on AST was dose-dependent, but in linalool doses between 0.1 and 2% of the feed, AST was not elevated beyond normal parameters. Linalool at 2% or less may be safely added to chicken feed. We suggest future studies to evaluate the addition of linalool to the litter, where it may be used as an antimicrobial or an insect repellent or to produce a calming effect.

Cytoreductive surgery followed by chemotherapy versus chemotherapy alone for recurrent platinum-sensitive epithelial ovarian cancer (SOCceR trial): a multicenter randomised controlled study.

BACKGROUND: Improvement in treatment for patients with recurrent ovarian cancer is needed. Standard therapy in patients with platinum-sensitive recurrent ovarian cancer consists of platinum-based chemotherapy. Median overall survival is reported between 18 and 35 months. Currently, the role of surgery in recurrent ovarian cancer is not clear. In selective patients a survival benefit up to 62 months is reported for patients undergoing complete secondary cytoreductive surgery. Whether cytoreductive surgery in recurrent platinum-sensitive ovarian cancer is beneficial remains questionable due to the lack of level I-II evidence. METHODS/DESIGN: Multicentre randomized controlled trial, including all nine gynecologic oncologic centres in the Netherlands and their affiliated hospitals. Eligible patients are women, with first recurrence of FIGO stage Ic-IV platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, who meet the inclusion criteria. Participants are randomized between the standard treatment consisting of at least six cycles of intravenous platinum based chemotherapy and the experimental treatment which consists of secondary cytoreductive surgery followed by at least six cycles of intravenous platinum based chemotherapy. Primary outcome measure is progression free survival. In total 230 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Where the role of cytoreductive surgery is widely accepted in the initial treatment of ovarian cancer, its value in recurrent platinum-sensitive epithelial ovarian cancer has not been established so far. A better understanding of the benefits and patients selection criteria for secondary cytoreductive surgery has to be obtained. Therefore the 4th ovarian cancer consensus conference in 2010 stated that randomized controlled phase 3 trials evaluating the role of surgery in platinum-sensitive recurrent epithelial ovarian cancer are urgently needed. We present a recently started multicentre randomized controlled trial that will investigate the role of secondary cytoreductive surgery followed by chemotherapy will improve progression free survival in selected patients with first recurrence of platinum-sensitive epithelial ovarian cancer.

Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study.

BACKGROUND: Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. AIM: To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. METHODS: This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. RESULTS: No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. CONCLUSIONS: Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.

OBJECTIVES: In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1-mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease. METHODS: In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG. RESULTS: LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge-placebo arm compared with the placebo-placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection. CONCLUSIONS: LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge.

Successful centralisation of patients with vulvar carcinoma: a population-based study in The Netherlands.

INTRODUCTION: In general, centralisation of care for patients with rare malignancies is advised in order to improve outcome with respect to prognosis and treatment related morbidity. Therefore, centralisation of women with vulvar squamous cell carcinoma (SCC), which is an extremely rare tumour, has been advocated by the national guidelines of the Dutch Society of Obstetrics and Gynaecology in 2000. The objective of this study was to determine whether this advice has been adapted and has led to improved survival. METHODS: All patients diagnosed with vulvar malignancies between 1989 and 2008 in the Eastern part of the Netherlands were retrieved from the population-based cancer registry held by the Comprehensive Cancer Centre, The Netherlands. Patient- and tumour characteristics and vital status until January 2011 were retrieved. Data of patients diagnosed in two periods (before and after release of the guideline; 1989-1999 and 2000-2008) were compared. Relative survival rates were calculated as a good approximation of cause-specific survival. RESULTS: A total number of 382 patients with vulvar SCC with invasion > 1mm, who had an indication for groin surgery, were included in the analysis. In the first decade 62% (123 of 198 patients) were treated in a specialised oncology centre, which increased to 93% (172 of 184 patients) in the more recent period. Overall, the 5 year relative survival improved slightly from 69% (95% confidence interval (CI) 60-77%) to 75% (95% CI 65-83%). After adjustment for age and stage, being treated in a specialised oncology centre was an independent prognostic factor for survival. CONCLUSION: Centralisation of care for vulvar SCC patients has been well adopted in the Eastern part of the Netherlands. Being treated in a specialised oncology centre was associated with a better survival after adjustment for age and stage.

Examining the auditory nerve fiber response to high rate cochlear implant stimulation: chronic sensorineural hearing loss and facilitation.

Neural prostheses, such as cochlear and retinal implants, induce perceptual responses by electrically stimulating sensory nerves. These devices restore sensory system function by using patterned electrical stimuli to evoke neural responses. An understanding of their function requires knowledge of the nerves responses to relevant electrical stimuli as well as the likely effects of pathology on nerve function. We describe how sensorineural hearing loss (SNHL) affects the response properties of single auditory nerve fibers (ANFs) to electrical stimuli relevant to cochlear implants. The response of 188 individual ANFs were recorded in response to trains of stimuli presented at 200, 1,000, 2,000, and 5,000 pulse/s in acutely and chronically deafened guinea pigs. The effects of stimulation rate and SNHL on ANF responses during the 0-2 ms period following stimulus onset were examined to minimize the influence of ANF adaptation. As stimulation rate increased to 5,000 pulse/s, threshold decreased, dynamic range increased and first spike latency decreased. Similar effects of stimulation rate were observed following chronic SNHL, although onset threshold and first spike latency were reduced and onset dynamic range increased compared with acutely deafened animals. Facilitation, defined as an increased nerve excitability caused by subthreshold stimulation, was observed in both acute and chronic SNHL groups, although the magnitude of its effect was diminished in the latter. These results indicate that facilitation, demonstrated here using stimuli similar to those used in cochlear implants, influences the ANF response to pulsatile electrical stimulation and may have important implications for cochlear implant signal processing strategies.

A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints.

BACKGROUND: Most neonates less than 1.0 kg birth weight need red blood cell (RBC) transfusions. Delayed clamping of the umbilical cord 1 minute after delivery transfuses the neonate with autologous placental blood to expand blood volume and provide 60 percent more RBCs than after immediate clamping. This study compared hematologic and clinical effects of delayed versus immediate cord clamping. STUDY DESIGN AND METHODS: After parental consent, neonates not more than 36 weeks' gestation were randomly assigned to cord clamping immediately or at 1 minute after delivery. The primary endpoint was an increase in RBC volume/mass, per biotin labeling, after delayed clamping. Secondary endpoints were multiple clinical and laboratory comparisons over the first 28 days including Score for Neonatal Acute Physiology (SNAP). RESULTS: Problems with delayed clamping techniques prevented study of neonates of less than 30 weeks' gestation, and 105 neonates 30 to 36 weeks are reported. Circulating RBC volume/mass increased (p = 0.04) and weekly hematocrit (Hct) values were higher (p < 0.005) after delayed clamping. Higher Hct values did not lead to fewer RBC transfusions (p > or = 0.70). Apgar scores after birth and daily SNAP scores were not significantly different (p > or = 0.22). Requirements for mechanical ventilation with oxygen were similar. More (p = 0.03) neonates needed phototherapy after delayed clamping, but initial bilirubin levels and extent of phototherapy did not differ. CONCLUSIONS: Although a 1-minute delay in cord clamping significantly increased RBC volume/mass and Hct, clinical benefits were modest. Clinically significant adverse effects were not detected. Consider a 1-minute delay in cord clamping to increase RBC volume/mass and RBC iron, for neonates 30 to 36 weeks' gestation, who do not need immediate resuscitation.

In vivo wound-healing activity of oleanolic acid derived from the acid hydrolysis of Anredera diffusa.

Anredera diffusa is used as a wound-healing agent in traditional Peruvian medicine. Acid hydrolysis of the bioactive ethanolic extract, followed by in vivo activity-guided fractionation, yielded oleanolic acid, with a wound-healing activity equivalent to 42.9% (p < 0.01) above the control. The highest cicatrizant activity in mice was obtained by applying 40 microg of oleanolic acid per gram of body weight.

Early identification of resistance to first-line single-agent methotrexate in patients with persistent trophoblastic disease.

PURPOSE: A generally accepted definition for resistance to first-line single-agent chemotherapy for persistent trophoblastic disease (PTD) is lacking. In the present study, a normogram for serum human chorionic gonadotropin (hCG) from patients with normalization of serum hCG after first-line single-agent chemotherapy for PTD was constructed to identify patients resistant to this chemotherapy. PATIENTS AND METHODS: Between 1987 and 2004, data from 2,132 patients were registered at the Dutch Central Registry for Hydatidiform Moles. A normal serum hCG regression corridor was constructed for 79 patients with low-risk PTD who were cured by single-agent methotrexate (MTX) chemotherapy (control group). Another group of 29 patients with low-risk PTD needed additional alternative therapies (dactinomycin and multiagent chemotherapy) for failure of serum hCG to normalize with single-agent chemotherapy (study group). RESULTS: Serum hCG measurement preceding the fourth and sixth single-agent chemotherapy course proved to have excellent diagnostic accuracy for identifying resistance to single-agent chemotherapy, with an area under the curve (AUC) for receiver operating characteristic curve analysis of 0.949 and 0.975, respectively. At 97.5% specificity, serum hCG measurements after 7 weeks showed 50% sensitivity. CONCLUSION: In the largest study to date, we describe the regression of serum hCG levels in patients with low-risk PTD successfully treated with MTX. At high specificity, hCG levels in the first few courses of MTX can identify half the number of patients who are extremely likely to need alternative chemotherapy to cure their disease and for whom further treatment with single-agent chemotherapy will be ineffective.