A randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of BTH1677 (1,3-1,6 beta glucan; Imprime PGG) in combination with cetuximab and chemotherapy in patients with advanced non-small cell lung cancer.

Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m2 and subsequent doses 250 mg/m2, weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m2, Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles; patients who responded or remained stable received maintenance therapy with BTH1677/cetuximab (BTH1677 arm) or cetuximab (Control arm). Investigator and blinded central radiology reviews were conducted. Efficacy assessments included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, time-to-progression and overall survival (OS); safety was assessed by adverse events (AEs). Potential biomarker analysis for BTH1677 response was also conducted. Results Compared to control treatment, the addition of BTH1677 numerically increased ORR by both investigator (47.8% vs 23.1%; p=0.0468) and central (36.6% vs 23.1%; p=0.2895) reviews. No other endpoints differed between arms. PK was consistent with previous studies. BTH1677 was well tolerated, with AEs expected of the backbone therapy predominating. Biomarker-positive patients displayed better ORR and OS than negative patients. Conclusions BTH1677 combined with cetuximab/carboplatin/paclitaxel was well tolerated and improved ORR as first-line treatment in patients with advanced NSCLC. Future patient selection by biomarker status may further improve efficacy ClinicalTrials.gov Identifier: NCT00874848.

A 12-week randomized clinical trial investigating the potential for sucralose to affect glucose homeostasis.

The discovery of gut sweet taste receptors has led to speculations that non-nutritive sweeteners, including sucralose, may affect glucose control. A double-blind, parallel, randomized clinical trial, reported here and previously submitted to regulatory agencies, helps to clarify the role of sucralose in this regard. This was primarily an out-patient study, with 4-week screening, 12-week test, and 4-week follow-up phases. Normoglycemic male volunteers (47) consumed ∼333.3 mg encapsulated sucralose or placebo 3x/day at mealtimes. HbA1c, fasting glucose, insulin, and C-peptide were measured weekly. OGTTs were conducted in-clinic overnight, following overnight fasting twice during screening phase, twice during test phase, and once at follow-up. Throughout the study, glucose, insulin, C-peptide and HbA1c levels were within normal range. No statistically significant differences between sucralose and placebo groups in change from baseline for fasting glucose, insulin, C-peptide and HbA1c, no clinically meaningful differences in time to peak levels or return towards basal levels in OGTTs, and no treatment group differences in mean glucose, insulin, or C-peptide AUC change from baseline were observed. The results of other relevant clinical trials and studies of gastrointestinal sweet taste receptors are compared to these findings. The collective evidence supports that sucralose has no effect on glycemic control.

A Randomized, Blinded Study to Validate the Merz Hand Grading Scale for Use in Live Assessments.

BACKGROUND: The Merz Hand Grading Scale (MHGS) is a 5-point scale used to grade appearance of the dorsum of the hand. The MHGS has been previously validated for assessment of photographed hands but not for live assessment. OBJECTIVE: The purpose of this randomized, blinded study was to validate the MHGS for live assessment of the hands in the clinical setting. METHODS: Three physician raters completed a scale qualification program that included MHGS training, ratings of standardized hand photographs, and statistical analysis for reliability. Eighty-four subjects (28 males, 30% Fitzpatrick skin Types IV-VI, mean age of 42 years), randomized to 2 live assessment sessions for independent and blinded observation of dorsa of their right hands, completed the study. RESULTS: Overall MHGS intrarater weighted Kappa value was 0.74 (0.68-0.79 [CI 95%]). First- and second-time hand-rating agreement scores ranged from 64% to 75%. Interrater weighed Kappa values ranged from 0.59 to 0.71, representing between-rater paired results of each combination of raters. CONCLUSION: High-weighted Kappa values and agreements demonstrate that consistency at different time points can be achieved individually and by different raters for live assessments. The MHGS is a suitable instrument for live assessment in the clinical setting.

Forced to be right.

In "Forced to be Free", Neil Levy surveys the raft of documented decision-making biases that humans are heir to, and advances several bold proposals designed to enhance the patient's judgment. Gratefully, Levy is moved by the psychological research on judgment and decision-making that documents people's inaccuracy when identifying courses of action will best promote their subjective well-being. But Levy is quick to favour the patient's present preferences, to ensure they get "final say" about their treatment. I urge the opposite inclination, raising doubts about whether the patient's "present preferences" are the best expression of their "final say". When there is adequate evidence that people, by their own lights, overemphasize their present preferences about the future, we should carefully depreciate those preferences, in effect biasing them to make the right decision by their own lights.

Seduction without cause: uncovering explanatory neurophilia.

Credibility is a cherished currency in science, but its cues can be counterfeit. A novel series of experiments by Weisberg and her colleagues show that non-expert consumers of behavioral explanations assign greater standing to explanations that contain neuroscientific details, even if these details provide no additional explanatory value. Here, we discuss the part that this 'placebic' information might play in producing a potentially misleading sense of intellectual fluency and, consequently, an unreliable sense of understanding.

Fecundity of Cryptosporidium parvum is correlated with intracellular levels of the viral symbiont CPV.

Differences in the virulence and fecundity of Cryptosporidium parvum isolates have been observed by several researchers studying cryptosporidiosis. The purpose of the present study was to determine if there was a correlation between intracellular levels of the viral symbiont CPV in C. parvum and fecundity of two isolates of the parasite, namely C. parvum Beltsville (B) and C. parvum Iowa (I). Dairy calves infected with 10(6)C. parvum-B excreted 5-fold more oocysts compared with calves infected with the same number of C. parvum-I oocysts. The increased fecundity of the former strain was corroborated by semi-quantitative PCR assay of DNA isolated from cell cultures infected with either C. parvum-B or C. parvum-I. Quantitative reverse transcriptase-PCR analysis of viral RNA revealed a 3-fold greater number of CPV in C. parvum-B compared with C. parvum-I oocysts. These findings may indicate a role for CPV in fecundity and possibly virulence of C. parvum.

A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer.

BACKGROUND: BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomized to the BTH1677 arm (N = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W) or Control arm (N = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. RESULTS: ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. CONCLUSIONS: Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov registration ID: NCT00874107 . Registered 2 April 2009. First participant was enrolled on 29 September 2009.

Polyamines mediate uncontrolled calcium entry and cell damage in rat heart in the calcium paradox.

Brief perfusion of heart with calcium-free medium renders myocardial cells calcium-sensitive so that readmission of calcium results in uncontrolled Ca2+ entry and acute massive cell injury (calcium paradox). We investigated the hypothesis that polyamines may be involved in the mediation of abnormal Ca2+ influx and cell damage in the calcium paradox. The isolated perfused rat heart was used for these studies. Calcium-free perfusion promptly (less than 5 min) decreased the levels of polyamines and the activity of their rate-regulating synthetic enzyme, ornithine decarboxylase (ODC), and calcium reperfusion abruptly (less than 15-180 s) increased these components. alpha-Difluoromethylornithine (DFMO), a specific suicide inhibitor of ODC, suppressed the calcium reperfusion-induced increase in polyamines and the concomitant increase in myocardial cellular 45Ca influx, loss of contractility, release of cytosolic enzymes, myoglobin, and protein, and structural lesions. Putrescine, the product of ODC activity, nullified DFMO inhibition and restored the calcium reperfusion-induced increment in polyamines and the full expression of the calcium paradox. Putrescine itself enhanced the reperfusion-evoked release of myoglobin and protein in the absence of DFMO. Hypothermia blocked the changes in heart ODC and polyamines induced by calcium-free perfusion and calcium reperfusion and prevented the calcium paradox. These results indicate that rapid Ca2+-directed changes in ODC activity and polyamine levels are essential for triggering excessive transsarcolemmal transport of Ca2+ and explosive myocardial cell injury in the calcium paradox.

Enterocytozoon bieneusi in mature dairy cattle on farms in the eastern United States.

Fecal specimens were obtained from mature milking cows on farms in Vermont, New York, Pennsylvania, Maryland, Virginia, North Carolina, and Florida. Polymerase chain reaction (PCR)-positive specimens for Enterocytozoon bieneusi were found in 24 of 541 cows examined (4.4%) and on 12 of 14 farms. The prevalence of E. bieneusi varied considerably from farm to farm, with the lowest prevalence (2.3%) on FL-2 and the highest prevalence (12.5%) on VT-2. None of the cows exhibited signs of diarrhea. All PCR-positive specimens were sequenced to determine the genotype of E. bieneusi. Five genotypes were identified. Three were identified as cattle-specific genotypes previously reported as BEB1, BEB2, and BEB4, and two new genotypes, BEB 6 and BEB7, were found. None have been reported to infect humans.

Gap junction assembly and endocytosis correlated with patterns of growth in a cultured adrenocortical tumor cell (SW-13).

After seeding at subconfluent densities, human adrenocortical adenocarcinoma cells (SW-13) proliferate to form a typical epithelial monolayer upon the culture vessel substratum. Single cells of the confluent monolayer are spontaneously released into the medium, however, where they may remain isolated or reaggregate with other floating cells. In this study, we examined the growth patterns of these cells in culture and analyzed alterations of their most prominent intercellular contact specialization, the gap junction, as cellular relationship changed during growth and development of the cell culture. We report here details of gap junction assembly during cellular aggregation and correlate the apparent endocytosis of gap junctions with the spontaneous release of single cells from the monolayer into the medium.

Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial.

PURPOSE: Recombinant human erythropoietin (rHuEPO) is the standard of care for patients with chemotherapy-related anemia. Intravenous (IV) iron improves hemoglobin (Hb) response and decreases dosage requirements in patients with anemia of kidney disease, but its effect has not been studied in randomized trials in cancer patients. METHODS: This prospective, multicenter, open-label, randomized trial enrolled 157 patients with chemotherapy-related anemia (Hb

Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States.

BACKGROUND: Hypertension is common in chronic hemodialysis patients, yet there are limited data on the epidemiology of hypertension in these patients in the United States. METHODS: We assessed the prevalence, treatment, and control of hypertension in a cohort of 2535 clinically stable, adult hemodialysis patients who participated in a multicenter study of the safety and tolerability of an intravenous iron preparation. Hypertension was defined as an average predialysis systolic blood pressure >150 mm Hg or diastolic blood pressure >85 mm Hg, or the use of antihypertensive medications. RESULTS: Hypertension was documented in 86% (n = 2173) of patients. The prevalence of hypertension, in contrast to that observed in the general population, did not increase linearly with age and was not affected by sex or ethnicity. Hypertension was controlled adequately in only 30% (n = 659) of the hypertensive patients. In the remaining patients, hypertension was either untreated (12% [252/2173]) or treated inadequately (58% [1262/2173]). CONCLUSION: Control of hypertension, particularly systolic hypertension, in chronic hemodialysis patients in the United States is inadequate, despite recognition of its prevalence and the frequent use of antihypertensive drugs. Optimizing the use of medications and closer attention to nonpharmacologic interventions, such as adjustment of dry weight, a low-sodium diet, and exercise, may improve control.

The biological basis of speech: what to infer from talking to the animals.

Speech perception and production are uniquely human adaptations. The mechanisms and laws that these adaptations implicate are tuned to linguistic rather than general auditory phenomena, leading to the view that speech is special (SiS). Despite the progress made by proponents of SiS, a small but growing "auditorist" program critical of SiS conscripts nonhuman animals such as quail and chinchilla and, using discrimination tasks on speech stimuli, incorrectly infers a common mechanism from similar cross-species performance. The author argues that the auditorist's refutation project must demonstrate not just cross-species isomorphisms of behavior but also either a common biological mechanism or common functional organization. The refutation project does neither. The author argues further that the auditorist's appeal to the principle of parsimony fails. Respect for the total available evidence undermines auditorism and bolsters SiS.

Changes in the profiles of circulating white blood cells, corticosterone, T3 and T4 during the initiation of humoral immunity in immature male chickens.

Eight-week-old male White Leghorn chickens were injected intravenously with either 0.1 ml of Brucella abortus (BA) or saline. Blood samples were collected before injection, 1 hr, 3 hr, 6 hr, 12 hr, 24 hr, and then daily for the following 6 days after the injection. Total white blood cells (WBC), differential counts and corticosterone (CS), T3 and T4 levels were measured in all blood samples. These data represented the results obtained from the primary response. To obtain data for the secondary response, the same birds were injected 4 weeks following the first challenge and the same procedure was followed. During primary and secondary responses, circulating lymphocytes and monocytes decreased significantly 3 hr following BA injection and then increased steadily and reached a peak approximately 5 days post-BA injection, however, circulating heterophils increased significantly 6-12 hr and returned to normal levels 2 days post-BA injection. Serum corticosterone increased significantly 3 hr following BA injection. Serum T3 decreased significantly 3 to 12 hr then increased significantly 2 days following BA injection. There were no significant changes in any of the measurements following saline injection. Correlations between circulating hormones and white blood cells were calculated and are reported. These results indicate that an early step in the initiation of humoral immunity is probably an increase in serum CS. This increase in CS is followed by a decrease in circulating lymphocyte and monocyte numbers. These decreases may be the result of lymphocyte trapping in secondary lymphoid organs. This series of events may occur to modulate and activate the immune response.

Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy.

BACKGROUND: Cystic fibrosis causes exocrine pancreatic insufficiency, leading to malabsorption. Supplemental pancreatic enzyme therapy alleviates the concomitant malnutrition experienced by cystic fibrosis patients. It is recognized that patients experience variations in clinical response to different brands of enzymes. This has prompted the US Food and Drug Administration to require that enzyme supplements be subjected to New Drug Applications. AIM: To investigate the safety and efficacy of supplemental pancreatic enzyme therapy in cystic fibrosis subjects. METHODS: We compared two doses of one formulation of enteric-coated pancreatic enzymes: Ultrase MT12 (12,000 lipase units per capsule) and Ultrase MT20 (20,000 lipase units per capsule), to placebo in two separate safety and efficacy studies. RESULTS: Mean total fat, protein and carbohydrate intake did not differ significantly between the groups. A significant difference in both fat and protein absorption occurred with the enzyme therapy groups. The Ultrase MT12 and Ultrase MT20 groups experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. CONCLUSIONS: This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

Adipocyte size distribution in fa/fa rats during development.

Epididymal fat pad adipocyte frequency distributions of obese (fa/fa) and nonobese (non-fa/fa) Zucker rats were determined from 2 to 20 wk of age. The fa/fa rats consistently displayed a higher proportion of larger adipocytes than the non-fa/fa rats of all ages studied. Increased adipocyte size preceded an increase in the number of adipocytes during the early phases of obese development. Among the fa/fa rats, the frequency of small cells continued to increase, which resulted in a bimodal distribution by 20 wk of age. Discriminant analysis suggests that the differences in adipocyte size frequency distributions at 2 wk of age may be another useful means to identify fa/fa and non-fa/fa pups prior to expression of overt obesity. Increased fat storage may reflect the lower energy expended by the very young fa/fa rats.

Mechanical transport and transmission of Cryptosporidium parvum oocysts by wild filth flies.

Over the course of six months wild filth flies were collected from traps left for 7-10 days in a barn with or without a calf shedding Cryptosporidium parvum Genotype 2 oocysts in diarrheic feces. The oocysts of C. parvum transported on the flies' exoskeletons and eluted from their droplets left on visited surfaces were infectious for mice. The mean number of oocysts carried by a fly varied from 4 to 131, and the total oocyst number per collection varied from 56 to approximately 4.56 x 10(3). Fly abundance and intensity of mechanical transmission of infectious C. parvum oocysts were positively correlated, and both increased significantly when an infected calf was in the barn. Molecular data showed that the oocysts shed by infected calves were carried by flies for at least 3 weeks. Filth flies can acquire infectious C. parvum oocysts from unsanitary sites, deposit them on visited surfaces, and therefore may be involved in human or animal cryptosporidiosis.

Effects of yohimbine on autonomic measures are determined by individual values for area under the concentration-time curve.

A study was conducted to examine tolerability and pharmacodynamics of single doses of yohimbine in healthy volunteers using measures of mood, heart rate, blood pressure, and serum catecholamine levels. Participants were given single oral doses of yohimbine hydrochloride as high as 21.6 mg. Plasma concentrations of yohimbine, epinephrine, norepinephrine, and MHPG (3-methoxy-4-hydroxyphenylethylene-glycol) were quantified by means of high-performance liquid chromatography with electrochemical detection. Mood was assessed by visual analogue scale (VAS), the Profile of Mood States, and the Spielberger State Anxiety Index. Yohimbine was well tolerated and rapidly absorbed and eliminated. Dose-related increases in area under the concentration-time curve (AUC) were observed. Administration of yohimbine in the presence of a high fat meal diminished both the rate and extent of drug absorption. Significant intersubject variability in the pharmacokinetic parameters of yohimbine was observed, with some individuals exhibiting greatly increased oral bioavailability of yohimbine. Increases in blood pressure, respiratory rate, plasma catecholamine levels, and total VAS score were observed in participants with elevated AUC values. The AUC of yohimbine had the largest effect on total VAS score. The results indicate that higher doses of yohimbine are both well tolerated and produce dose-related increases in AUC, which are associated with more pronounced autonomic effects. Increases in respiratory rate and plasma MHPG appear to be the most reliable pharmacodynamic measures for single oral doses of yohimbine. Individual differences in the pharmacokinetics of yohimbine are important in determining pharmacodynamic effects and should be considered in evaluations of its clinical effectiveness.

Plant and marine n-3 fatty acids inhibit experimental metastasis of rat mammary adenocarcinoma cells.

The effectiveness of dietary n-3 plant and marine fatty acids and n-6 gamma-linolenic acid (GLA) was tested as an antimetastatic modality in the experimental model of metastasis of 13762MAT:B mammary adenocarcinoma cells. Weanling female Fischer 344 rats were placed on one of the following diets: 1-23.52% blackcurrant oil (BCO), II-23.52% corn oil (CO), III-15.52% BCO + 8% fish oil (FO), IV-20.52% FO + 3% CO, and V-5% CO. After 8 weeks, 15 rats per group were injected i.v. with 10(5) cells and diets were continued until sacrifice. In the 23.52% CO group (II), the number of small (< 2 mm) and large (> 2 mm) lung metastatic foci and their total volume were significantly greater than the BCO- and/or FO-fed groups (I, II and IV). Although the number of small metastatic foci was comparable in the 5% and 23.52% CO groups, the number of large foci and the total tumor volume were reduced in the 5% CO group. These results suggest that, compared to a low-corn oil diet or a high-fat diet containing a mixture of marine and plant n-3 fatty acids plus n-6 GLA, a 23.52% corn oil diet can enhance experimental metastasis of mammary adenocarcinoma cells. Total number of metastatic foci and tumor volume were the smallest in group III, receiving a combination of plant and marine n-3 fatty acids.

Capillary NMDA receptors regulate blood-brain barrier function and breakdown.

Polyamines and their regulatory synthetic enzyme ornithine decarboxylase (ODC) have been implicated in blood-brain barrier (BBB) breakdown following cryogenic injury. ODC activation and BBB breakdown are prevented by MK-801, indicating involvement of NMDA receptors. Studies in isolated rat cerebral capillaries supports the presence of NMDA receptors linked to ODC. NMDA (1-50 microM) stimulated capillary uptake of horseradish peroxidase, 2-deoxy-[14C]glucose, and 45 Ca in a receptor-, concentration-, polyamine- and Ca(2+)-dependent manner. We suggest that NMDA receptors may couple capillary transport of nutrients to glutamate-mediated neuronal excitation, and when overestimated disrupt normal BBB function.