2013 multistate outbreaks of Cyclospora cayetanensis infections associated with fresh produce: focus on the Texas investigations.

The 2013 multistate outbreaks contributed to the largest annual number of reported US cases of cyclosporiasis since 1997. In this paper we focus on investigations in Texas. We defined an outbreak-associated case as laboratory-confirmed cyclosporiasis in a person with illness onset between 1 June and 31 August 2013, with no history of international travel in the previous 14 days. Epidemiological, environmental, and traceback investigations were conducted. Of the 631 cases reported in the multistate outbreaks, Texas reported the greatest number of cases, 270 (43%). More than 70 clusters were identified in Texas, four of which were further investigated. One restaurant-associated cluster of 25 case-patients was selected for a case-control study. Consumption of cilantro was most strongly associated with illness on meal date-matched analysis (matched odds ratio 19·8, 95% confidence interval 4·0-∞). All case-patients in the other three clusters investigated also ate cilantro. Traceback investigations converged on three suppliers in Puebla, Mexico. Cilantro was the vehicle of infection in the four clusters investigated; the temporal association of these clusters with the large overall increase in cyclosporiasis cases in Texas suggests cilantro was the vehicle of infection for many other cases. However, the paucity of epidemiological and traceback information does not allow for a conclusive determination; moreover, molecular epidemiological tools for cyclosporiasis that could provide more definitive linkage between case clusters are needed.

The 2008 ACVP role delineation survey and initial data analysis: from the Role Delineation Task Force.

The American College of Veterinary Pathologists commissioned a role delineation survey to define the specialized tasks, knowledge, and tools that define the current practice of veterinary clinical pathology and veterinary anatomic pathology. The survey also identified when competence was acquired for each task (i.e., before certification or after certification). The response rate by diplomates was high, with approximately 50% of practicing pathologists within each specialty responding to each survey. Using the survey results, all tasks for each specialty were classified as either appropriate or unsuitable for testing in the certifying examinations. The role delineation survey data will facilitate the creation of test plans that objectively define the content in each certifying examination, the evaluation and enhancement of training curricula, and the optimization of continuing education opportunities for practicing veterinary pathologists.

A procedure for the safety evaluation of natural flavor complexes used as ingredients in food: essential oils.

A scientifically based guide has been developed to evaluate the safety of naturally occurring mixtures, particularly essential oils, for their intended use as flavor ingredients. The approach relies on the complete chemical characterization of the essential oil and the variability of the composition of the oil in the product intended for commerce. Being products of common plant biochemical pathways, the chemically identified constituents are organized according to a limited number of well-established chemical groups called congeneric groups. The safety of the intake of the each congeneric group from consumption of the essential oil is evaluated in the context of data on absorption, metabolism, and toxicology of members of the congeneric group. The intake of the group of unidentified constituents is evaluated in the context of the consumption of the essential oil as a food, a highly conservative toxicologic threshold, and toxicity data on the essential oil or an essential oil of similar chemotaxonomy. The flexibility of the guide is reflected in the fact that high intake of major congeneric groups of low toxicologic concern will be evaluated along with low intake of minor congeneric groups of significant toxicological concern (i.e., higher structural class). The guide also provides a comprehensive evaluation of all congeneric groups and constituents that account for the majority of the composition of the essential oil. The overall objective of the guide is to organize and prioritize the chemical constituents of an essential oil in order that no reasonably possible significant risk associated with the intake of essential oil goes unevaluated. The guide is, however, not intended to be a rigid checklist. The Flavor and Extract Manufacturers Association (FEMA) Expert Panel will continue to evaluate each essential oil on a case by case basis applying their scientific judgment to insure that each natural flavor complex is exhaustively evaluated.

Safety evaluation of natural flavour complexes.

Natural flavour complexes (NFCs) are chemical mixtures obtained by applying physical separation methods to botanical sources. Many NFCs are derived from foods. In the present paper, a 12-step procedure for the safety evaluation of NFCs, 'the naturals paradigm', is discussed. This procedure, which is not intended to be viewed as a rigid check list, begins with a description of the chemical composition of the commercial product, followed by a review of the data on the history of dietary use. Next, each constituent of an NFC is assigned to one of 33 congeneric groups of structurally related substances and to one of three classes of toxic potential, each with its own exposure threshold of toxicological concern. The group of substances of unknown structure is placed in the class of greatest toxic potential. In subsequent steps, for each congeneric group the procedure determines the per capita intake, considers metabolic pathways and explores the need and availability of toxicological data. Additional toxicological and analytical data may be required for a comprehensive safety evaluation. The procedure concludes with an evaluation of the NFC in its entirety, also considering combined exposure to congeneric groups. The first experiences with the use of this procedure are very promising. Future safety evaluations of larger numbers of NFCs will indicate the usefulness of the system, either in its present form or in a form modified on the basis of experience.

Haematological safety of antipsychotic drugs.

Haematological abnormalities are frequently encountered during treatment with antipsychotic drugs. Most of these are mild and of no clinical significance. In the case of many, there is often difficulty in establishing a cause-and-effect relationship between the drug and the abnormality. However, in a small minority of patients, hazardous, potentially life-threatening haematological effects can occur due to a combination of pharmacological and host factors. These include leucopenia and agranulocytosis. Although such effects are rare, it is essential that they are diagnosed and managed promptly. In this paper, the authors review the haematological adverse effects and safety of antipsychotic drugs and present a strategy for prevention.

Na+ transport in normal and CF human bronchial epithelial cells is inhibited by BAY 39-9437.

To test the hypothesis that Na+ transport in human bronchial epithelial (HBE) cells is regulated by a protease-mediated mechanism, we investigated the effects of BAY 39-9437, a recombinant Kunitz-type serine protease inhibitor, on amiloride-sensitive short-circuit current of normal [non-cystic fibrosis (CF) cells] and CF HBE cells. Mucosal treatment of non-CF and CF HBE cells with BAY 39-9437 decreased the short-circuit current, with a half-life of approximately 45 min. At 90 min, BAY 39-9437 (470 nM) reduced Na+ transport by approximately 70%. The inhibitory effect of BAY 39-9437 was concentration dependent, with a half-maximal inhibitory concentration of approximately 25 nM. Na+ transport was restored to control levels, with a half-life of approximately 15 min, on washout of BAY 39-9437. In addition, trypsin (1 microM) rapidly reversed the inhibitory effect of BAY 39-9437. These data indicate that Na+ transport in HBE cells is activated by a BAY 39-9437-inhibitable, endogenously expressed serine protease. BAY 39-9437 inhibition of this serine protease maybe of therapeutic potential for the treatment of Na+ hyperabsorption in CF.

Acquired Factor VIII autoantibody: four cases demonstrating the heterogenous nature of this condition and problems involved in diagnosis and treatment.

The development of an autoantibody to human Factor VIII is rare and presents many problems for diagnosis and treatment. We have seen several cases at our institution recently with widely heterogenous clinical and laboratory presentations. A wide range of treatment modalities were used in these cases with no gold standard of treatment or widely accepted guidelines existing. This has prompted us to examine all cases of this condition presenting at Fremantle Hospital over the last decade. We describe four cases which demonstrate the heterogeneity of this condition and its treatment and review the recent literature on the subject.

52-Week oral gavage chronic toxicity study with ubiquinone in rats with a 4-week recovery.

Potential ubiquinone (CoQ10; a natural fermentation product) toxicity was assessed in rats administered CoQ(10) by oral gavage for 1 year at 100, 300, 600, and 1200 mg/(kg day). No adverse changes in mortality, clinical signs, body weight, food consumption, or clinical pathology results occurred. CoQ(10) had elimination half-lives ranging from 10.7 to 15.2 h. At 1200 mg/(kg day), a high incidence of orange, granular, lumenal exudate in nasal turbinates occurred; microscopically, findings similar to those in the turbinates were occasionally observed in small granulomas within lung alveoli. A dose-related increased incidence of vacuolated macrophages (mesenteric lymph nodes) and vacuolated hepatic periportal cells was noted. Neither were associated with tissue damage or organ dysfunction, so they were not considered to be adverse. The nasal turbinate and lung findings were probably secondary to incidental exposure to crystallized test material. Overall, CoQ(10) was well tolerated by male and female rats at dose levels up to 1200 mg/(kg day).

Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody.

Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) is a monoclonal IgG1 antibody that is being developed as an antiangiogenic agent for use in treating a variety of solid tumors. Preclinical safety studies included an immunohistochemical tissue cross-reactivity study, in vitro hemolytic potential and blood compatibility studies, and multiple dose toxicity studies. Toxicity studies were conducted in cynomolgus monkey because rhuMAbVEGF is pharmacologically active in this species and does not bind rat or mouse vascular endothelial growth factor (VEGF). Following twice weekly administration of rhuMAbVEGF for 4 or 13 wk, young adult cynomolgus monkeys exhibited physeal dysplasia characterized by a dose-related increase in hypertrophied chondrocytes, subchondral bony plate formation, and inhibition of vascular invasion of the growth plate. In addition, decreased ovarian and uterine weights and an absence of corpora lutea were observed in females receiving 10 and 50 mg/kg/dose in the 13-wk study. Both the physeal and ovarian changes were reversible with cessation of treatment. No other treatment-related effects were observed following rhuMAbVEGF administration at doses up to 50 mg/kg. These findings indicate that VEGF is required for longitudinal bone growth and corpora lutea formation and that rhuMAbVEGF can reversibly inhibit physiologic neovascularization at these sites.

Hydrodynamic properties of mucins secreted by primary cultures of guinea-pig tracheal epithelial cells: determination of diffusion coefficients by analytical ultracentrifugation and kinetic analysis of mucus gel hydration and dissolution.

We have used two different approaches to determine hydrodynamic parameters for mucins secreted by guinea-pig tracheal epithelial cells in primary culture. Cells were cultured under conditions that promote mucous cell differentiation. Secreted mucins were isolated as the excluded fraction from a Sepharose CL-4B gel filtration column run under strongly dissociating conditions. Biochemical analysis confirmed the identity of the high molecular weight material as mucins. Analytical ultracentrifugation was used to study the physical properties of the purified mucins. The weight average molecular mass (Mw) for three different preparations ranged from 3.3 x 10(6) to 4.7 x 10(6) g/mol (corresponding to an average structure of 1-2 subunits), and the sedimentation coefficient from 25.5 to 35 S. Diffusion coefficients ranging from 4.5 x 10(-8) to 6.4 x 10(-8) cm2/s were calculated using the Svedberg equation. A polydispersity index (Mz/Mw) of approximately 1.4 was obtained. Diffusivity values were also determined by image analysis of mucin granule exocytosis captured by videomicroscopy. The time course of hydration and dissolution of mucin was measured and a relationship is presented which models both phases, each with first order kinetics, in terms of a maximum radius and rate constants for hydration and dissolution. A median diffusivity value of 8.05 x 10(-8) cm2/s (inter-quartile range = 1.11 x 10(-7) to 6.08 x 10(-8) cm2/sec) was determined for the hydration phase. For the dissolution phase, a median diffusivity value of 6.98 x 10(-9) cm2/s (inter-quartile range = 1.47 x 10(-8) to 3.25 x 10(-9) cm2/sec) was determined. These values were compared with the macromolecular diffusion coefficients (D20,w) obtained by analytical ultracentrifugation. When differences in temperature and viscosity were taken into account, the resulting D37,g was within the range of diffusivity values for dissolution. Our findings show that the physicochemical properties of mucins secreted by cultured guinea-pig tracheal epithelial cells are similar to those of mucins of the single or double subunit type purified from respiratory mucus or sputum. These data also suggest that measurement of the diffusivity of dissolution may be a useful means to estimate the diffusion coefficient of mucins in mucus gel at the time of exocytosis from a secretory cell.