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Purpose:Cancer treatments can paradoxically appear to reduce the risk of noncancer mortality in observational studies, due to residual confounding. Here we introduce a method, Bias Reduction through Analysis of Competing Events (BRACE), to reduce bias in the presence of residual confounding.Experimental Design:BRACE is a novel method for adjusting for bias from residual confounding in proportional hazards models. Using standard simulation methods, we compared BRACE with Cox proportional hazards regression in the presence of an unmeasured confounder. We examined estimator distributions, bias, mean squared error (MSE), and coverage probability. We then estimated treatment effects of high versus low intensity treatments in 36,630 prostate cancer, 4,069 lung cancer, and 7,117 head/neck cancer patients, using the Veterans Affairs database. We analyzed treatment effects on cancer-specific mortality (CSM), noncancer mortality (NCM), and overall survival (OS), using conventional multivariable Cox and propensity score (adjusted using inverse probability weighting) models, versus BRACE-adjusted estimates.Results:In simulations with residual confounding, BRACE uniformly reduced both bias and MSE. In the absence of bias, BRACE introduced bias toward the null, albeit with lower MSE. BRACE markedly improved coverage probability, but with a tendency toward overcorrection for effective but nontoxic treatments. For each clinical cohort, more intensive treatments were associated with significantly reduced hazards for CSM, NCM, and OS. BRACE attenuated OS estimates, yielding results more consistent with findings from randomized trials and meta-analyses.Conclusions:BRACE reduces bias and MSE when residual confounding is present and represents a novel approach to improve treatment effect estimation in nonrandomized studies.

Supplementary Data from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data

Supplementary Figure from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data

Supplementary Table from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data

Purpose: Cancer treatments can paradoxically appear to reduce the risk of noncancer mortality in observational studies, due to residual confounding. Here we introduce a method, Bias Reduction through Analysis of Competing Events (BRACE), to reduce bias in the presence of residual confounding. Experimental Design: BRACE is a novel method for adjusting for bias from residual confounding in proportional hazards models. Using standard simulation methods, we compared BRACE with Cox proportional hazards regression in the presence of an unmeasured confounder. We examined estimator distributions, bias, mean squared error (MSE), and coverage probability. We then estimated treatment effects of high versus low intensity treatments in 36,630 prostate cancer, 4,069 lung cancer, and 7,117 head/neck cancer patients, using the Veterans Affairs database. We analyzed treatment effects on cancer-specific mortality (CSM), noncancer mortality (NCM), and overall survival (OS), using conventional multivariable Cox and propensity score (adjusted using inverse probability weighting) models, versus BRACE-adjusted estimates. Results: In simulations with residual confounding, BRACE uniformly reduced both bias and MSE. In the absence of bias, BRACE introduced bias toward the null, albeit with lower MSE. BRACE markedly improved coverage probability, but with a tendency toward overcorrection for effective but nontoxic treatments. For each clinical cohort, more intensive treatments were associated with significantly reduced hazards for CSM, NCM, and OS. BRACE attenuated OS estimates, yielding results more consistent with findings from randomized trials and meta-analyses. Conclusions: BRACE reduces bias and MSE when residual confounding is present and represents a novel approach to improve treatment effect estimation in nonrandomized studies.

OBJECTIVES: Visual cognitive performance (VCP) is an important factor in high-speed interactions with the environment such as sports or driving, however, the testing, training and determination of factors that influence this ability are scarce. The purpose of the Nutrition, Vision and Cognition in Sport Studies (IONSport) is to determine the nutritional factors that explain large variance in VCP and training responses. The objective of this study is to determine if daily beef or vegetable protein consumption affect VCP training responses. METHODS: Thirty-seven women (age 18–35 years) were randomized to either one serving of beef (90% lean ground sirloin, 3 oz) or one serving of vegetable protein (Morningstar prime veggie burgers, 3 oz) per day for 30 days. These foods were equivalent in serving size, calories, protein and fat but distinct in micronutrients. At the end of the dietary intervention, they performed 15 visual cognitive training sessions (Neurotracker) in 10 visits to the laboratory. On the days of training, all food intake was documented for 18 days (Three prior to starting, five from day zero to 15 and 10 from day 15–30). Mean nutritional intakes were calculated for the 15 days of food records during the intervention. RESULTS: Both groups significantly (P

OBJECTIVES: High levels of visual cognitive performance (VCP) are required for complex daily activities including driving and participating in sports. Many cognitive tests use simple measures of social cognition or memory that lack the dynamic complexity needed for daily living. Healthy fats including mono- and polyunsaturated fats have been shown to improve cognition and brain health due to the need for fatty acids for neurotransmitter production and myelin sheath insulation. The effects of specific fats on specific cognitive functions is still poorly understood. The Nutrition, Vision, and Cognition in Health Study (IONHealth) investigates nutritional and behavioral factors that influence cognition in 3-dimensional multiple objects tracking test (3DMOT). It was hypothesized that monounsaturated fats would affect cognitive performance. METHODS: 104 men and women adults age 50–75 years recorded 15 food logs and completed 15 training sessions (Neurotracker) during 10 lab visits over 15 days. Food logs were used to represent typical eating patterns for each individual and means over 15 days were used for analyses. RESULTS: Monounsaturated fat intake was significantly associated to VCP, however, this affect was not distinct from overall fat intake where higher fat intake (114.7, 99.8, 71.8, 62.9 g/day mean) was significantly associated (P

In the last decade, the number of full-time registered dietitians (RDs) serving intercollegiate athletes in the United States has more than quadrupled. However, many student athletes may be at increased risk of nutrition-related problems that impact physical and academic performance, which include inadequate macronutrients, inadequate micronutrients, and excessive macronutrients. This narrative review reports the current literature to date on nutrition-related knowledge in collegiate athletes and the impact of sports RDs on student athletes’ nutrition knowledge and behaviors. To date, only observational and quasi-experimental studies have been published with regard to changes in nutrition knowledge and behaviors in NCAA athletes. While these studies report benefits of the RD as a member of the interdisciplinary student athlete support team, more well-designed randomized control trials are warranted to determine benefits related to health outcomes and sport-specific performance outcomes.

Background Zonulin is observed in animal models to regulate intestinal permeability and influenced by dietary intake, gut microbiota, and inflammation. We conducted a secondary analysis of a randomized controlled crossover trial (NCT03582306) in individuals with a BMI greater than 30 kg/m2 and high habitual red meat intake and low habitual green leafy vegetable (GLV) intake. Methods Participants were provided with frozen GLV during the first or last four weeks (immediate or delayed intervention) of the twelve-week trial. Biological and anthropometric measures were taken at the beginning and at each four-week interval. A subset of 20 participants was selected for this secondary analysis of the intestinal permeability and inflammation-related biomarkers: serum and fecal zonulin; serum lipopolysaccharide binding protein (LBP), Alpha-1-acid glycoprotein 1 (ORM-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C-reactive protein; 8-hydroxy-2'-deoxyguanosine (8OHdG) and plasma Vitamin K1 as a marker of protocol adherence. Nutrient and food group intake from two-24-h dietary recalls collected at each time point were assessed. Fecal microbiota was measured by 16 s rRNA PCR sequencing. Changes in biological markers, dietary factors, and microbial taxa were assessed with Wilcoxon Sign Ranks Tests. Exploratory analyses of the relationship between changes in outcome variables were conducted with Spearman correlations. Results No changes in serum and fecal zonulin and serum LBP were observed. Plasma Vitamin K (p = 0.005) increased, while plasma 8OHdG (p = 0.023) decreased during the intervention compared to the control. The only dietary factors that changed significantly were increases during intervention in Vitamin K and Dark GLV (p p = 0.001) in females and Bifidobacterium (ρ = − 0.838, p = 0.009) and Bacteroidaceae (ρ = 0.871, p = 0.005) in men. Conclusions A high GLV dietary intervention increased serum zonulin levels and had no effect on fecal zonulin. Lack of concordance between several inflammation-associated biomarkers and zonulin corroborate recent reports of limited utility of zonulin in obese adults free of lower gastrointestinal disease. Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT03582306 (NCT03582306) registered on 07/11/2018.

Green leafy vegetables (GLV) may reduce the risk of red meat (RM)-induced colonic DNA damage and colorectal cancer (CRC). We previously reported the primary outcomes (feasibility) of a 12-week randomized controlled crossover trial in adults with habitual high RM and low GLV intake with body mass index (BMI) &gt, 30 kg/m2 (NCT03582306). Herein, our objective was to report a priori secondary outcomes. Participants were recruited and enrolled in 2018, stratified by gender, and randomized to two arms: immediate intervention group (IG, n = 26) or delayed intervention group (DG, n = 24). During the 4 week intervention period, participants were provided with frozen GLV and counseled to consume 1 cooked cup equivalent daily. Participants consumed their normal diet for the remaining 8 weeks. At each of four study visits, anthropometrics, stool, and blood were taken. Overall, plasma Vitamin K1 (0.50 ± 1.18 ng/mL, p &lt, 0.001) increased, while circulating 8OHdG (−8.52 ± 19.05 ng/mL, p &lt, 0.001), fecal 8OHdG (−6.78 ± 34.86 ng/mL, p &lt, 0.001), and TNFα (−16.95 ± 60.82 pg/mL, p &lt, 0.001) decreased during the GLV intervention compared to control periods. Alpha diversity of fecal microbiota and relative abundance of major taxa did not differ systematically across study periods. Further investigation of the effects of increased GLV intake on CRC risk is warranted.

Preclinical and observational research suggests green leafy vegetables (GLVs) may reduce the risk of red meat (RM)-induced colonic DNA damage and colon cancer (CC). We sought to determine the feasibility of a high GLV dietary intervention in adults with an increased risk of CC (NCT03582306) via a 12-week randomized controlled crossover trial. Participants were randomized to immediate or delayed (post-4-week washout) intervention groups. During the 4-week intervention period, participants were given frozen GLVs and counseled to consume one cooked cup equivalent daily. The primary outcomes were: accrual&mdash, recruiting 50 adults in 9 months, retention&mdash, retaining 80% of participants at completion, and adherence&mdash, meeting GLV intake goals on 90% of days. Adherence data were collected twice weekly and 24-h dietary recalls at each time point provided nutrient and food group measures. The Food Acceptability Questionnaire (FAQ) was completed to determine acceptability. On each of the four study visits, anthropometrics, stool, saliva, and blood were obtained. Fifty adults were recruited in 44 days. Participants were 48 &plusmn, 13 years of age, 62% female, and 80% Caucasian, with an average BMI at screening of 35.9 &plusmn, 5.1. Forty-eight (96%) participants were retained and completed the study. During the intervention phase, participants consumed GLVs on 88.8% of days, the adherence goal of one cup was met on 73.2% of days. Dietary recall-derived Vitamin K and GLVs significantly increased for all participants during the intervention periods. Overall satisfaction did not differ between intervention and control periods (p = 0.214). This feasibility trial achieved accrual, retention and acceptability goals, but fell slightly short of the benchmark for adherence. The analysis of biological specimens will determine the effects of GLVs on gut microbiota, oxidative DNA damage, and inflammatory cytokines.

Background: Vildagliptin is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control and pancreatic β-cell function in patients with Type 2 diabetes. Vildagliptin may be an appropriate agent to combine with other antihyperglycemic agents in patients requiring combination therapy to achieve optimal glycemic control. Two studies were performed to determine the potential for pharmacokinetic and pharmacodynamic interactions between vildagliptin and the sulfonylurea, glyburide, or pioglitazone in patients with Type 2 diabetes. Methods: Two open-label, multiple-dose, 3-period, randomized, crossover studies in patients with Type 2 diabetes were carried out. Steady state drug pharmacokinetics and postprandial plasma glucose and insulin responses were assessed during treatment with vildagliptin 100 mg b.i.d. alone and in combination with glyburide 10 mg q.d. (n = 17) or with vildagliptin 100 mg q.d. alone or in combination with pioglitazone 45 mg q.d. (n = 15). Results: Coadministration of vildagliptin with either glyburide or pioglitazone had no clinically significant effect on the pharmacokinetics of any of the 3 drugs. Changes in AUC and C max during combination treatment were small (≤ 15%), and 90% confidence intervals for the geometric mean ratios (drug coadministration/monotherapy) were generally contained within the acceptance range for bioequivalence (0.80 - 1.25). Vildagliptin/glyburide coadministration significantly reduced the area under the plasma glucose-time curve compared with glyburide alone (AUE 0-5h reduced by 12% (p = 0.005) and AUE 0-15h by 13% (p = 0.003)), and increased the area under the plasma insulin-time curve (AUE 0-15h increased by 12% (p = 0.041)). Vildagliptin/pioglitazone coadministration also significantly reduced postprandial glucose exposure compared with pioglitazone alone (AUE 0.5-5.5h reduced by 11% (p - 0.029) and AUE 0-15.5h by 10% (p = 0.019)). Vildagliptin was generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and was not associated with hypoglycemia. Conclusions: Coadministration of vildagliptin with either glyburide or pioglitazone in patients with Type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics.

Imatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (Cmins) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (± SD, CV%) steady-state Cmin for imatinib and CGP74588 were 979 ng/mL (± 530 ng/mL, 54.1%) and 242 ng/mL (± 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). Cmin of imatinib was significantly higher in patients who achieved CCyR (1009 ± 544 ng/mL vs 812 ± 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT00333840.

Obtaining a biowaiver for topical drugs used in veterinary species faces many of the same challenges associated with human topicals. However, the skin of domestic animals varies anatomically and biochemically and experimental approaches to assess bioequivalence (BE) in veterinary species have challenges that are not often encountered with human skin. This is especially the situation with locally acting drugs. The focus of this paper is to address several of the challenges associated with (i) determining the BE of these locally acting drugs and (ii) critically examine the current technological advances that can act as a surrogate for clinical trials.

Data on abortions, stillbirths and kid mortality from an experimental herd, used for the development of the Yaez, were analyzed. Total number of embryos was 960. Mortality was divided according to kids' age, to early mortality (during first 48 h), mortality before weaning at 70 d (BWA) and after weaning up to 180 d (AWA). There were more abortions among primiparous does (11 %) than among older ones (5.3%). More triplets were aborted (13.4% vs. 6.2%) and/or born dead (15.5% vs. 5.3%) than kids in smaller litters. Season affected mortality of kids before, as well as after, weaning. Rates were 7%, 25.3% and 12.8% BWA for winter, spring and summer born kids, respectively. After weaning 8%, 22.6% and 9.5% died out of winter, spring and summer kids, respectively. Day of birth in season was a significant factor of mortality of kids before and after weaning. Of the kids born during the first 10 d of season, 7.7% died BWA and 8.9% AWA; out of kids that were born from 11 to 20 days, 17.5% died BWA and 16.5% AWA, while 27.2% of the kids that were born after 20 d died BWA and 20.7% died AWA. Mortality rate before and after weaning increased corresponding to the percentage of ibex genes in the dam, the sire and the kid. Combination of low birth weight with hybridization of goat and ibex resulted in increased mortality in all three ages. During the first 48 h of their life average mortality was 4.5%; of kids born up to 1.5 kg with 10–30% ibex genes, 17.6% died; and from the group with more than 30% ibex genes, 33.3% died.

To address the variability challenges inherent to 45 and 32nm as early as possible, a model-based variability analysis has been implemented to predict lithography induced electrical variability in standard cell libraries, and this analysis was used optimize the cell layout and decrease variability by up to 40%.

In recent years, various DFM techniques are developed and adopted by the designers to improve circuit yield and reliability. The benefits from applying a DFM technique to a circuit often come at the expense of degrading other process or design attributes. In this paper, we discuss two widely deployed techniques: double vias and wire spreading/widening, show the benefits and trade-offs of their usage, and practical ways to implement them in SoC designs.

Cloned cDNA copies of the genomic RNA of melon necrotic spot virus (MNSV) have been sequenced and the sizes and locations of predicted viral proteins have been deduced. The genome consists of at least 4262 nucleotides and the positive strand contains three to five open reading frames (ORFs) which may be expressed. The 5' proximal ORF encodes a 29K protein (p29) and terminates with an amber codon which may be read through to produce an 89K protein (p89). Two small centrally located ORFs each encode a 7K protein (p7A and p7B). As p7A is in frame with p7B, readthrough of the amber codon terminating p7A may occur, producing a 14K protein (p14). The 3' proximal ORF encodes the 42K coat protein. The genomic organization of MNSV, its probable translation strategy and the amino acid sequences of its putative proteins closely resemble those of known carmoviruses, suggesting that MNSV should be classified as a member of the carmovirus group. Unusual properties of the putative MNSV replicase (p89) suggest that MNSV should be classified in a new virus supergroup with several other viruses sharing these properties.

As lithography and other patterning processes become more complex and more non-linear with each generation, the task of physical design rules necessarily increases in complexity also. The goal of the physical design rules is to define the boundary between the physical layout structures which will yield well from those which will not. This is essentially a rule-based pre-silicon guarantee of layout correctness. However the rapid increase in design rule requirement complexity has created logistical problems for both the design and process functions. Therefore, similar to the semiconductor industry's transition from rule-based to model-based optical proximity correction (OPC) due to increased patterning complexity, opportunities for improving physical design restrictions by implementing model-based physical design methods are evident. In this paper we analyze the possible need and applications for model-based physical design restrictions (MBPDR). We first analyze the traditional design rule evolution, development and usage methodologies for semiconductor manufacturers. Next we discuss examples of specific design rule challenges requiring new solution methods in the patterning regime of low K1 lithography and highly complex RET. We then evaluate possible working strategies for MBPDR in the process development and product design flows, including examples of recent model-based pre-silicon verification techniques. Finally we summarize with a proposed flow and key considerations for MBPDR implementation.

The difficult insertion of a right subclavian catheter in a 63-year-old patient resulted in a pseudoaneurysm of the brachiocephalic artery requiring a resection-suture. The preventive measures of that complication are reminded.

The author proposes that the subject chosen for psychoanalytical investigation bears a relationship to autobiographical experiences. Aspects of the life of the British psychoanalyst, Joan Riviere (1883-1962), are examined and related to her investigation into a form of pathological femininity presented in her paper 'Womanliness as a masquerade'. Information about her formative years is gained from a diary kept by her mother that gives details of Joan Riviere's early months and years as well as further information about her as a young adult. Riviere's own diary, which lists events and activities in which she took part throughout more than a decade before she became a psychoanalyst, gives valuable insights into her life at that time. The author examines the descriptions of the patient in Riviere's paper and relates it to many facets of the latter's life. The defensive femininity shown by her patient is characterised by appeasement and denial of intellectual and professional attributes to escape detection and the retribution feared as a consequence of having, in phantasy, stolen potency from men. It is suggested that Riviere's own life experiences, particularly in relation to men, are represented in her paper.

The possible involvement of nitric oxide in the regulation of intestinal ion transport induced by neuropeptide Y (NPY) was investigated by evaluating the effects of NG-methyl-L-arginine (L-NMA), L-arginine and S-nitroso-N-acetylpenicillamine (SNAP) on NPY activity in mouse ileum mounted in Ussing chambers in vitro. Serosal NPY (10 nM) produced a sustained decrease in basal transmural short circuit current (Isc) and potential difference without altering the tissue conductance. Pretreatment of tissues with L-arginine (3 mM), but not D-arginine (10 mM), blocked the NPY-mediated changes in Isc. This L-arginine effect on NPY activity was reversed by L-NMA (3 mM), and not by NG-methyl-D-arginine (10 mM). The L-arginine effect on NPY activity was concentration-related with an A50 (95% CL) value of 1.6 (0.9-2.3) mM. In contrast to L-arginine, L-NMA (1 mM) pretreatment of tissues produced an enhancement of NPY activity, resulting in a 3.8-fold leftward displacement of the NPY concentration-response curve; NG-methyl-D-arginine was without effect. The effect of L-NMA on NPY activity was concentration-related with an A50 (95% CL) value of 45.3 (23.2-68.8) microM. Serosal application of SNAP, a nitric oxide donor, produced a concentration-related decrease in basal Isc and potential difference without altering tissue conductance with an A50 (95% CL) value of 22.5 (11.1-40.5) microM. Pretreatment of tissue with SNAP (100 microM) reduced the NPY activity with rightward displacement of NPY concentration-response curve. Pretreatment of tissues with L-arginine also blocked the reduction of Isc by [D-Pen2, D-Pen5]enkephalin (10-30 nM), H2N-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 (10-30 nM) and somatostatin (0.3-1.0 microM), but had no effect on norepinephrine (0.1-0.3 microM)-induced decrease in mouse ileal Isc. These results show that [fgc]l-arginine and SNAP block NPY-mediated changes in ion transport, suggesting that nitric oxide may play a role in the regulation of NPY-mediated ion transport in the mouse ileum.

Two cases of infra renal vena cava leiomyosarcoma are reported. Their locoregional extension resulted in a joint resection of the aorta and the vena cava. The follow-up of the two cases is of respectively 34 months and 32 months. We think that large resections are necessary, due to the microscopic characteristics of such tumors in order to try to improve the prognosis.

Inflammatory aneurysms of the abdominal aorta raise particular problems, as they are often detected as a result of their complications. In the light of one case presenting with anuria, the authors discuss the various treatment options and the value of preoperative corticosteroids.

The difficult insertion of a right subclavian catheter in a 63-year-old patient resulted in a pseudoaneurysm of the brachiocephalic artery requiring a resection-suture. The preventive measures of that complication are reminded.

Two kappa agonists, fedotozine and trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolydinyl)-cyclohexyl ]- benzeneacetamide methanesulfonate [(+/-)U-50,488H] were used to reverse the gastrointestinal transit inhibition induced by either peritoneal irritation (PI) or intracisternal (i.c.) administration of corticotropin releasing factor (CRF). PI was induced by acetic acid given i.p. Gastric emptying and intestinal transit were estimated with a 51Cr-labeled test meal. PI inhibited both gastric emptying (-50.9%) and intestinal transit (-48.8%). These inhibitions were prevented in a dose-dependent manner by the CRF antagonist, alpha-helical-CRF9-41 at doses (1-10 nmol/rat i.c.) that had no effect in control animals. CRF (300 pmol/rat i.c.) reproduced the gastrointestinal transit inhibitions seen under PI. The CRF effects were blocked by alpha-helical-CRF9-41 (10 nmol/rat) given i.c. but not i.v. Fedotozine (1-10 mg/kg s.c. but not 300 micrograms/rat i.c.v. or intrathecally) and (+/-)U-50,488H (0.3-3 mg/kg s.c. but not 100 micrograms/kg i.c.v.) reversed PI- but not CRF-induced ileus. Neither PI-induced ileus nor the fedotozine response was affected by perivagal capsaicin treatment. It was concluded that the PI-induced ileus depends on central CRF receptors. This result is consistent with the activation of an extrinsic inhibitory reflex. The reversal by kappa agonists of PI- but not CRF-induced ileus suggests that kappa agonists do not act after but before the CRF receptors. A possible peripheral action on nonvagal sensory afferents is suggested.

The possible role of nitric oxide (NO) in the regulation of intestinal ion transport was studied in isolated sheets of mouse ileum mounted in Ussing flux chambers. The competitive NO-synthase inhibitors NG-methyl-L-arginine (L-NMA), and NG-nitro-L-arginine (L-NNA) and the effects of NO released from acidified sodium nitrite solution were evaluated in tissues pretreated with guanethidine and atropine. Serosal L-NMA or L-NNA (10-300 microM), but not NG-methyl-D-arginine (D-NMA), produced a sustained concentration-related increase in short-circuit current (Isc) and potential difference (PD) with maximal Isc increases of 50.8 +/- 8.2 and 45.5 +/- 5.8 microAmps/cm2, respectively; mucosal application of L-NMA or L-NNA produced transient increases in Isc. The A50 (and 95% CL) values for serosal L-NMA and L-NNA were 25.6 (15.7-41.9) and 8.7 (5.1-14.9) microM, respectively. L-Arginine (0.1-10 mM), but not D-arginine, produced both a concentration-related reversal of L-NMA or L-NNA-induced increases in Isc. Additionally, pretreatment with L-arginine blocked the L-NMA or L-NNA effects, suggesting a competitive interaction. L-NMA-mediated increases in Isc were unaffected by bicarbonate-free buffer, whereas replacement of chloride ions with gluconate ions almost completely attenuated the response to L-NMA. Further, the effects of L-NMA or L-NNA were blocked by tetrodotoxin or chlorisondamine, suggesting neural actions involving ganglionic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

e15130 Background: A first set of US-guided biopsy does not exclude prostate cancer in men with elevated PSA. Repeated biopsy detection rate is only 10 to 30% and increases risks of complications. Localization of suspected targets on MRI with subsequent sonography may be difficult. Therefore, we addressed the ability of contrast-enhanced US-guided biopsies in detecting prostate cancer after MRI localization. Methods: 79 patients (mean age 62y) with elevated PSA value (mean = 12.9 ng/ml) and prior negative biopsy (1-5, mean 2.3) were included in a prospective study. They underwent prostate MRI examination: T1-weighted, T2-weighted, diffusion-weighted and dynamic contrast-enhanced sequences. A single physician performed a first set of targeted biopsies (TB) on MRI-suspected lesion and identified on contrast-enhanced US as well, and subsequently performed a set of sextant randomized “non targeted biopsies” (NTB). Diagnostic efficacy of each biopsy approach – TB or NTB- was evaluated regards to pathological r...

The effects of putative sigma ligands and two neuropeptides on intestinal ion transport were evaluated in isolated sheets of whole mouse jejunum mounted in Ussing flux chambers. Serosal administration of neuropeptide Y (NPY), peptide YY (PYY), (+)-N-cyclopropylmethyl-N-methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO 1784), di(ortho-tolyl)guanidine (DTG) and (+)- or (-)-N-allyl-normetazocine (NANM) produced concentration-related decreases in short-circuit current (Isc) without changes in tissue conductance. Although NPY and PYY were active in nanomolar concentrations, JO 1784, DTG and (+)- and (-)-NANM were active in micromolar concentrations; the rank order of potency in inhibiting Isc was PYYNPYJO 1784 = (-)-N- cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochlorideDTG(+)-NANM = (-)-NANM. Serosal application of tetrodotoxin effectively blocked the decrease in Isc associated with all of the ligands tested. The activity of the serosally applied ligands was blocked by prior application of chlorisondamine, a ganglionic blocker. The effects of JO 1784 and NPY were evaluated using antagonists of several receptor types. Although application of serosal haloperidol had no effect alone up to concentrations of 1 microM, this compound produced a rightward displacement in both the NPY and JO 1784 concentration-effect curves. In contrast, sulpiride, SCH-23390, naloxone, yohimbine and prazosin failed to antagonize the effects of NPY or JO 1784.(ABSTRACT TRUNCATED AT 250 WORDS)

A series of letters that Freud wrote to Joan Riviere in the period from 12-8-1921 to 22-1-1939 has been transcribed, translated into French and published here for the first time in the original text. They were given by Joan Riviere to the Sigmund Freud Archives and deposited at the Library of Congress in Washington where access to them had been restricted. Through the efforts of Dr. Harold Blum, the present Executive Director of the Freud Archives, the restriction was lifted. The letters concern arrangements that Freud made for his analysis of Joan Riviere; his (and her) relationship to Ernest Jones; the translation into English and the publication of his works in England. They also concern Freud's reaction to the reception in England of Anna Freud's book on The Technique of Child Analysis (1927) and his view of Melanie Klein's approach to the theory and practice of child analysis.