A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.

Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n=114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2weeks-3months) serum inflammatory marker load and long-term global outcome 6-12months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6months (adjusted OR=3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p⩽0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1ß and IL-6 levels compared with the low TRAJ group (p⩽0.05). Lastly, injury type (isolated TBI vs. TBI+polytrauma) was associated with IL-6 TRAJ group (χ(2)=5.31, p=0.02). Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated with an increased inflammatory load, and these increases are associated with increased odds for unfavorable global outcomes in the first year following TBI. Future studies should explore additional factors contributing to IL-6 elevations, and therapies to mitigate its detrimental effects on outcome.

The use of blood lactate concentration as an indicator of temperament and its impact on growth rate and tenderness of steaks from Simmental × Angus steers.

The objective of this study was to evaluate the use of blood lactate concentration as an objective measure of beef cattle temperament and determine if the temperament of steers affected growth rate and tenderness of beef steaks. Angus×Simmental steers (n=154) were evaluated for blood lactate (BL), exit velocity (EV) and chute score (CS), and humanely harvested. Carcass characteristics were assessed and loin samples were obtained for tenderness evaluation. All measures of the temperament were significantly correlated to each other (r=0.14-0.47; P≤0.04). Steaks from steers in the medium BL classification were significantly more tender than steaks from steers from the high BL classification. The steers with faster EV tended to result in steaks with higher shear force values (P=0.07). The steers classified as fast growing resulted in steaks with lower shear force values (P=0.02) compared to steaks from steers classified as slow growing. Results suggest that the temperament contributes to variations in growth rate, blood lactate, and tenderness.

Outbreak of extended spectrum beta-lactamase-producing Klebsiella pneumoniae in an intensive care unit (Brest).

INTRODUCTION: We had for aim to describe control and investigation of an outbreak caused by a strain of Extended spectrum beta-lactamase producing Klebsiella pneumoniae in intensive care units of the Brest teaching hospital. PATIENTS AND METHOD: The case definition was a patient infected by or carrying the epidemic strain. Control measures and investigations are presented. A case-control study was conducted in the surgical intensive care unit. Each case was matched with two controls based on admission times in the unit. The study focused on diagnostic and therapeutic procedures, and potential contacts with healthcare workers, in this context of cross transmission. RESULTS: Between February and May 2011, nine cases were reported in the surgical ICU and two in the medical ICU. Eighteen controls were matched with the nine surgical ICU cases. Several factors were found to be statistically associated with infection or colonization by the epidemic strain: the surgical block in which patients had been operated and the ward of first hospitalization; the number of trans-esophageal and trans-thoracic echocardiographies, of central venous catheter insertions, and of surgical operations; intubation. The total number of invasive procedures was also found to be statistically higher among cases. CONCLUSION: This study identified factors associated with colonization or infection by the epidemic strain. These factors might have been involved in the transmission tree, and be vulnerable elements for the prevention of nosocomial infections and colonisations, and their epidemic spread.

Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity.

INTRODUCTION: Elevated levels of tissue factor positive (TF(+)) microparticles (MPs) are observed in plasma from a variety of patients with an increased risk of thrombosis. We and others have described the measurement of TF activity in MPs isolated from plasma. The aim of this study was to investigate the effects of pre-analytical and analytical variables on TF activity of MPs isolated from blood of healthy volunteers either untreated or treated ex vivo with bacterial lipopolysaccharide. MATERIALS AND METHODS: We evaluated the following parameters: use of different centrifugation speeds to isolate the MPs; comparison of TF activity of MPs isolated from platelet poor plasma versus platelet free plasma; effect of freeze/thaw on MP TF activity; and comparison of the MP TF activity assay with the measurement of TF protein by ELISA or flow cytometry. RESULTS: MPs prepared from platelet poor plasma by centrifugation at 20,000×g or 100,000×g for 15 minutes had similar levels of TF activity. However, significantly less TF activity was found in MPs isolated from platelet free plasma compared with platelet poor plasma. Interestingly, freeze/thawing of the plasma showed donor to donor variation in MP TF activity, with a moderate increase in some individuals. CONCLUSION: TF(+) MPs can be quantitatively isolated from platelet poor or platelet free plasma by centrifugation at 20,000×g for 15 minutes. Measurement of MP TF activity in plasma may be used to detect a prothrombotic state in patients with various diseases.

[Acute interstitial lung disease revealing antisynthetase syndrome]. / Pneumopathie interstitielle aiguë révélatrice d'un syndrome des antisynthétases.

INTRODUCTION: The antisynthetase syndrome is characterized by the presence of myositis, interstitial lung disease, arthritis, Raynaud's phenomenon, mechanics hands and anti-Jo1 antibody (histidyl tRNA synthetase). The prognosis of this syndrome is closely related to the severity of lung disease. Myositis can occur several years after lung disease and some patients with interstitial lung disease associated with anti-Jo1 antibodies will not suffer from muscle disease. CASE-REPORT: We report the case of a 69-year-old man admitted to the medical intensive care unit for acute respiratory insufficiency related to rapidly progressive interstitial lung disease. Antisynthetase syndrome was diagnosed the presence of wrists' arthritis, 'mechanic's hands and anti-Jo1 antibodies. Despite the dramatic efficacy of corticosteroid therapy on ventilation parameters, the patient died from a Pseudomonas Aeruginosa nosocomial ventilator-acquired pneumonia. CONCLUSION: Our case emphasizes the importance to search for anti-Jo1 antibodies in the presence of interstitial lung disease. During the course of antisynthetase syndrome, the occurrence of interstitial lung disease is almost always constant and is correlated with poor prognosis.

Investigation and management of an imipenem-resistant oxa-23 Acinetobacter baumannii outbreak in an intensive care unit.

OBJECTIVES: The study objectives were to describe the investigation and management of an imipenem-resistant Acinetobacter baumannii outbreak that occurred in the 15-bed ICU of a tertiary care teaching hospital (Brest, France), during the summer 2008. PATIENTS AND METHODS: Patients harboring an imipenem-resistant A. baumannii strain were defined as case patients. We described case occurrence and steps taken to control the outbreak: contact isolation, reinforcement of hygiene procedures, unit shutdown decision, unit disinfection, and reopening. We also made a case control study and a cost analysis of the outbreak management. RESULTS: During a 10-day period, five patients were positive for a single clone of imipenem-resistant oxa-23 A. baumannii. Four patients presented with ventilation-acquired pneumonia and one was asymptomatic. The first two patients died one day after the first swab which led to the identification of A. baumannii. No additional case was noted in the ICU or in other hospital units after deciding to close the ICU. The cost of outbreak management was estimated at 264,553 euros. The case control study identified several factors associated with infection or colonization: length of stay in the ICU, chronic respiratory disease, number of previous antibiotic classes used, duration of ventilation, prone position, echocardiography, and presence of a nasogastric tube. CONCLUSION: This outbreak occurred during the summer period requiring the shutdown of the ICU and inducing a considerable cost. Rapid reactions of the ICU staff during the outbreak enabled to limit the epidemic.

Role of tissue factor in thrombosis in antiphospholipid antibody syndrome.

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder defined by the presence of an antiphospholipid antibody (aPL) and the occurrence of at least one associated clinical condition that includes venous thrombosis, arterial thrombosis or pregnancy morbidity. The aPL detected in APS have long been thought to have a direct prothrombotic effect in vivo. However, the pathophysiology underlying their coagulopathic effect has not been defined. Emerging data suggest a role for the procoagulant protein tissue factor (TF). In this review we provide an overview of TF, describe mouse models used in the evaluation of the role of TF in thrombosis, as well as summarize recent work on TF and APS.

Effects of late gestation supplementation of rumen undegradable protein, vitamin E, zinc, and chlortetracycline to ewes on indices of immune transfer and productivity.

Late gestation supplementation of feed additives, such as rumen undegradable intake protein (RUIP), vitamin E, Zn, and chlortetracycline, has inconsistently improved ewe/lamb productivity. In 3 experiments, Western white-faced ewes were supplemented for at least 30 d during late gestation with 204 g/(ewe.d) on a DM basis of high (HS; 12.5% RUIP, 880 IU/kg of vitamin E, 176 mg/kg of Zn supplied by an AA complex, and 352 mg/kg of chlortetracycline) or low (LS; 7.56% RUIP and no supplemental vitamin E, Zn, or chlortetracycline) supplements. Ewes of different age (Exp. 1; 3- vs. 6-yr-old; n = 52) and BCS (Exp. 2; good vs. poor BCS; 3.0 and 1.7 +/- 0.5, respectively; n = 40) were supplemented individually in a 2 x 2 factorial arrangement of treatments for 29 d. Thereafter, each ewe was group fed the appropriate supplement until lambing (14 +/- 7 d). Ewe intake, colostral IgG, ewe and lamb parainfluenza type 3 (PI(3)) titers, milk production, ewe BW and BCS change, and lamb production were measured in both experiments. In Exp. 3, approximately 600 ewes were group fed HS or LS over 2 yr. Ewe BW, ewe BCS, lamb production, and lamb survival was measured in Exp. 3 with groups within year as the experimental unit. In Exp. 1, lambs born to 3-yr-old ewes fed the HS had greater (P = 0.01) anti-PI(3) antibody titers than lambs born to 3-yr-old ewes fed the LS. Three-year-old ewes had greater (P < 0.01) DMI than 6-yr-old ewes. In Exp. 1 and 2, d 3 and 10 milk production differences (P

Growth implants reduced tenderness of steaks from steers and heifers with different genetic potentials for growth and marbling.

The objective of this study was to evaluate the effect of growth implants on the carcass characteristics and tenderness of steers and heifers with different genetic potentials for growth, lean meat yield production, and marbling. Two experiments were conducted. Experiment 1 evaluated Angus steers sired by bulls with high EPD for retail product yield or marbling. Implant treatment was imposed randomly within sire groups. Loins (Institutional Meat Purchasing Specifications 180) were collected from each carcass and cut into three 2.54-cm steaks aged for 7, 14 and 21 d to evaluate tenderness. The second experiment evaluated steers and heifers of British and Continental breed descent. Steers and heifers were slaughtered after 120 d on feed. Loin sections were collected, and one 2.54-cm steak aged 7 d was used for tenderness analysis. When implants were used in Angus steers, HCW and LM area increased, whereas internal fat and marbling decreased (P < 0.01). In Angus steers, sire type did not affect shear force values of steaks; however, implant use significantly increased shear force values (P < 0.01). Carcasses from cattle of Continental breed descent were significantly heavier than carcasses of British breed descent with larger LM area, slightly less fat, and a reduced yield grade (P < 0.01). Also, steer carcasses were heavier than heifer carcasses with larger LM (P < 0.05), but no effect of sex on fat depth, internal fat, yield grade or marbling was observed. No significant interactions were seen between growth implant and breed or between growth implant and sex for shear force values. Shear force values were significantly less for steaks from steers and heifers of British decent compared with steers and heifers of Continental descent (P < 0.01). Steaks from implanted steers and heifers had significantly (P < 0.01) greater shear force values than steaks from steers and heifers not implanted. Use of growth implants in growing cattle resulted in significantly heavier carcass weights, larger LM area, and reduced internal fat. However, implant use also reduced the amount of marbling along with contributing to reduced tenderness. Complicating the tenderness issue is the increased shear force values reported for heifers as well as steers of Continental breed descent. Use of implants may contribute to tenderness variability because of different animal responses to implants.

Effect of muscle location, fiber direction, and slice thickness on the processing characteristics and tenderness of beef stir-fry strips from the round and chuck.

The objective was to assess different beef muscles for use as stir-fry. Inside round, outside round, eye of round, knuckle, chuck clod, and chuck tender were obtained from six beef carcasses. Different slice thickness (2, 4, or 8mm) and muscle fiber direction were evaluated. Slices were cooked from frozen on a flat grill and then cut into strips for shear and sensory testing. While meat cut had little effect on shear values of these thin slices, increasing slice thickness greatly affected tenderness and cook yield. The sensory panel found that strips from the knuckle were more tender and juicy, with less connective tissue and with a better flavor than that of slices from the eye of round and outside round. Increasing slice thickness resulted in detection of greater amounts of connective tissue but did not result in a significant difference in the perception of tenderness. Fiber direction was also of importance. Slices removed perpendicular to the fiber direction had shear values up to 50% lower than slices removed parallel.

Weaning from mechanical ventilation.

Weaning covers the entire process of liberating the patient from mechanical support and from the endotracheal tube. Many controversial questions remain concerning the best methods for conducting this process. An International Consensus Conference was held in April 2005 to provide recommendations regarding the management of this process. An 11-member international jury answered five pre-defined questions. 1) What is known about the epidemiology of weaning problems? 2) What is the pathophysiology of weaning failure? 3) What is the usual process of initial weaning from the ventilator? 4) Is there a role for different ventilator modes in more difficult weaning? 5) How should patients with prolonged weaning failure be managed? The main recommendations were as follows. 1) Patients should be categorised into three groups based on the difficulty and duration of the weaning process. 2) Weaning should be considered as early as possible. 3) A spontaneous breathing trial is the major diagnostic test to determine whether patients can be successfully extubated. 4) The initial trial should last 30 min and consist of either T-tube breathing or low levels of pressure support. 5) Pressure support or assist-control ventilation modes should be favoured in patients failing an initial trial/trials. 6) Noninvasive ventilation techniques should be considered in selected patients to shorten the duration of intubation but should not be routinely used as a tool for extubation failure.

Functionality of cow beef in coarse and fine ground model systems.

Patties and sausage batters were made from trimmed brisket, chuck, striploin, hindshank, silverside, thick flank and rib trim from grass-fed Friesian cows. Functionality of each meat cut was determined from cook yield and true stress and strain of cooked sausage batters and cook yield, dimensional changes and peak force of cooked patties. Colour of raw and cooked slices from the meat cuts and cooked batters was evaluated using a colorimeter and a consumer panel. Composition of raw meat from all cuts was similar; chuck and rib trim had higher pH values and were more red than meat from other cuts. Cooked batters from striploin, chuck and hindshank had higher stress and strain values than gels from other cuts. Patties made from thick flank and striploin were the softest and had the highest cook yield. Batters and patties made from meat with higher salt soluble protein content retained more water and fat on cooking, were more cohesive and had higher bind strengths. Manufacturers can use functionality characteristics to select meat for specific products.

Supplemental safflower oil affects the fatty acid profile, including conjugated linoleic acid, of lamb.

The objective of this study was to determine whether increasing levels of dietary safflower oil would alter unsaturated fat (especially CLA) and tocopherol content of lamb, animal performance, carcass characteristics, or color stability of lamb muscle tissue. Targhee x Rambouillet wethers (n = 60) were assigned to one of three diets (four pens per treatment with five lambs per pen) in a completely random design. Diets were formulated with supplemental safflower oil at 0 (control), 3, or 6% (as-fed basis) of the diet. Diets containing approximately 80% concentrate and 20% roughage were formulated, on a DM basis, to be isocaloric and isonitrogenous and to meet or exceed NRC requirements for Ca, P, and other nutrients. A subsample of 12 wethers per treatment was selected based on average BW (54 kg) and slaughtered. Carcass data (LM area, fat thickness, and internal fat content) and wholesale cut weight (leg, loin, rack, shoulder, breast, and foreshank), along with fatty acid, tocopherol, and color analysis, were determined on each carcass. The LM and infraspinatus were sampled for fatty acid profile. Increasing safflower oil supplementation from 0 to 3 or 6% increased the proportion of linoleic acid in the diet from 49.93 to 55.32 to 62.38%, respectively, whereas the percentage of oleic acid decreased from 27.94 to 23.80 to 20.73%, respectively. The percentage of oil in the diet did not (P > or = 0.11) alter the growth and carcass characteristics of lambs, nor did it alter the tocopherol content or color stability of meat. Increasing levels of safflower oil in lamb diets decreased (P < 0.01) the weight percentage of oleic acid in the infraspinatus and LM, and increased linoleic acid (P < 0.01). Oil supplementation increased (P < 0.01) the weight percentage of various isomers of CLA in muscle, with the greatest change in the cis-9,trans-11 isomer. Supplementation of sheep diets with safflower oil, up to 6% of the diet, resulted in increasing levels of unsaturated fatty acids and CLA in the lean tissue, without adversely affecting growth performance, carcass characteristics, or color stability of lamb.

Meat color stability affected by barley variety fed in finishing diet to beef steers.

Angus crossbred steers were assigned randomly to one of four finishing diets based on corn, Chinook, Logan, or H3 barley. Steers were harvested and after a 72-h chill, carcass quality and yield grade data were collected. Beef ribs were removed from 72 carcasses for further analysis. Ribs were aged in vacuum bag at 2°C for 14 days. After aging three adjacent steaks (3.18cm) were removed to determine color stability, tenderness, proximate analysis and pH. Diets fed to steers had no effect on quality and yield grade or tenderness of beef steaks. Steaks from steers fed Logan barley variety were significantly less red at 10 days of storage (Hunter a*=24.06) than steaks from steers fed the other barley varieties (Chinook a*=26.4; H3 a*=28.05) or corn (a*=26.14). Identification of barley varieties that affect color stability could result in designing diets specifically for improved color and increase the use of barley as a finishing grain.

Development of neuronal sensitivity to toxins in cerebrospinal fluid from HIV-type 1-infected individuals.

HIV infection of the immature nervous system generally results in a rapid progression of neurological disease that cannot easily be explained by the severity of encephalitis, viral burden, systemic immune deficiency, or developmental changes in utero. Rather than the viral infection dictating disease progression, we explored the possibility that immature neurons might be particularly sensitive to toxins secreted in response to HIV. Primary cultures of rat cortical neurons were exposed to toxic cerebrospinal fluid (CSF) from HIV-infected individuals (CSF(tox)) and evaluated for changes in intracellular calcium and cell death. CSF(tox) had no detectable effect on early neurite outgrowth, calcium regulation, or cell death during the first few days in culture. Starting at Day 4, delayed increases in intracellular calcium appeared in response to CSF(tox). The magnitude of the delayed calcium rise and cell death increased with the age of the culture and correlated with the appearance of synaptophysin immunoreactive varicosities. A similar gradual development of sensitivity was seen during exposure of feline neurons to toxins generated by choroid plexus macrophages after exposure to feline immunodeficiency virus. The possibility that toxin sensitivity is dependent on the presence of synaptic activity is consistent with the rapid pathogenesis in the CNS seen during the first postnatal year. Emerging synaptic activity coupled with other factors such as high metabolic demand in the young nervous system may combine to increase the likelihood of calcium overload and neuronal dysfunction in response to HIV-associated toxins.