Dietary safety of a dual-enzyme preparation for animal feed: Acute and subchronic oral toxicity and genotoxicity studies.

Animal feed is routinely supplemented with exogenous enzymes to improve nutrient utilization, such as proteases to enhance protein hydrolysis in vivo and xylanases to alleviate feed related anti-nutritional factors. The present studies were conducted to evaluate the potential oral toxicity and genotoxicity of a dual-enzyme preparation, Vegpro® concentrate (VPr-C). Acute oral toxicity studies were conducted in adult male and female Sprague-Dawley Crl CD rats and CHS Swiss ICO:OFI (IOPS Caw) mice. Thirteen week preliminary and final subchronic oral toxicity studies were conducted in male and female rats. Genotoxicity was evaluated through a bacterial reverse mutation test (Ames test), an in-vitro mammalian chromosomal aberration test, and a mammalian micronucleus test. The LD50 was >2000 mg/kg of BW in mice and rats. In the 13-week oral toxicity study, the No Observed Adverse Effects Level (NOAEL) was 1000 mg/kg BW per day for females and 300 mg/kg BW per day for males. VPr-C showed no mutagenic activity in Salmonella typhimurium, did not induce significant chromosomal aberrations in cultured human lymphocytes, and did not increase the frequency or proportion of micronucleated immature erythrocytes in mice. There was no evidence of acute or subchronic toxicity or genotoxicity associated with the test article at these test dosages.

Core competencies for UK occupational health nurses: a Delphi study.

BACKGROUND: Occupational health nurses (OHNs) play a pivotal role in the delivery of occupational health (OH) services. Specific competency guidance has been developed in a number of countries, including the UK. While it is acknowledged that UK OHN practice has evolved in recent years, there has been no formal research to capture these developments to ensure that training and curricula remain up-to-date and reflect current practice. AIMS: To identify current priorities among UK OHNs of the competencies required for OH practice. METHODS: A modified Delphi study undertaken among representative OHN networks in the UK. This formed part of a larger study including UK and international occupational physicians. The study was conducted in two rounds using a questionnaire based on available guidance on training competencies for OH practice, the published literature, expert panel reviews and conference discussions. RESULTS: Consensus among OHNs was high with 7 out of the 12 domains scoring 100% in rating. 'Good clinical care' was the principal domain ranked most important, followed by 'general principles of assessment & management of occupational hazards to health'. 'Research methods' and 'teaching & educational supervision' were considered least important. CONCLUSIONS: This study has established UK OHNs' current priorities on the competencies required for OH practice. The timing of this paper is opportune with the formal launch of the Faculty of Occupational Health Nursing planned in 2018 and should inform the development of competency requirements as part of the Faculty's goals for standard setting in OHN education and training.

An Investigation of the Views of Parents in Otago on Dental Care for Primary School-Aged Children by the Community Oral Health Service Prior to the Introduction of the Hub-Based Clinic System.

BACKGROUND AND OBJECTIVES: Prior to the introduction of the Southern District Health Board's reconfigured Community Oral Health Service in Otago, a project was undertaken with parents to investigate their knowledge, understanding and views of the historical School Dental Service and of the Community Oral Health Service that was being introduced. METHODS: Focus groups were run during 2011 in ten selected schools (parents with children in years 1-8) across two areas in Otago to represent ur ban and rural settings and to represent parents who were already travelling to dental services. RESULTS: Parents valued the traditional School Dental Service in Otago highly, generally agreeing that the service based in schools was accessible and convenient for parents and children. Rural parents who had always taken their children to dental appointments viewed it as a normal process, accepting that there could not be a service located in every school. Parents were aware that facilities were out-of-date. They highlighted the challenges of locating therapists since they started moving from school to school in the later 1990s and felt it was difficult for children seeing different therapists at each recall. There were diverse views on the proposed new system. Some parents felt that school-aged children should go to dental clinics on their own or with peers, while other parents welcomed the opportunity to attend when their child was having health care. CONCLUSION: It appears that the Community Oral Health Services should have an ongoing process to seek the views of parents and children about the service.

Cardiovascular gene therapy: current status and therapeutic potential.

Gene therapy is emerging as a potential treatment option in patients suffering from a wide spectrum of cardiovascular diseases including coronary artery disease, peripheral vascular disease, vein graft failure and in-stent restenosis. Thus far preclinical studies have shown promise for a wide variety of genes, in particular the delivery of genes encoding growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) to treat ischaemic vascular disease both peripherally and in coronary artery disease. VEGF as well as other genes such as TIMPs have been used to target the development of neointimal hyperplasia to successfully prevent vein graft failure and in-stent restenosis in animal models. Subsequent phase I trials to examine safety of these therapies have been successful with low levels of serious adverse effects, and albeit in the absence of a placebo group some suggestion of efficacy. Phase 2 studies, which have incorporated a placebo group, have not confirmed this early promise of efficacy. In the next generation of clinical gene therapy trials for cardiovascular disease, many parameters will need to be adjusted in the search for an effective therapy, including the identification of a suitable vector, appropriate gene or genes and an effective vector delivery system for a specific disease target. Here we review the current status of cardiovascular gene therapy and the potential for this approach to become a viable treatment option.

Evaluating the Antibacterial Properties of Polyacetylene and Glucosinolate Compounds with Further Identification of Their Presence within Various Carrot (Daucus carota) and Broccoli (Brassica oleracea) Cultivars Using High-Performance Liquid Chromatography with a Diode Array Detector and Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry Analyses.

Ongoing consumer concerns over using synthetic additives in foods has strongly influenced efforts worldwide to source suitable natural alternatives. In this study, the antibacterial efficacy of polyacetylene and glucosinolate compounds was evaluated against both Gram positive and Gram negative bacterial strains. Falcarinol [minimum inhibitory concentration (MIC) = 18.8-37.6 µg/mL] demonstrated the best overall antibacterial activity, while sinigrin (MIC = 46.9-62.5 µg/mL) was the most active glucosinolate compound. High-performance liquid chromatography with a diode array detector analysis showed falcarinol [85.13-244.85 µg/g of dry weight (DW)] to be the most abundant polyacetylene within six of the eight carrot (Daucus carota) cultivars investigated. Meanwhile, sinigrin (100.2-244.3 µg/g of DW) was the most abundant glucosinolate present within the majority of broccoli (Brassica oleracea) cultivars investigated using ultra performance liquid chromatography-tandem mass spectrometry analysis. The high abundance of both falcarinol and sinigrin within these respective species suggests that they could serve as potential sources of natural antibacterial agents for use as such in food products.

Examination of the role of cigarette smoke in lung carcinogenesis using multistage models.

The widely used multistage model of Armitage and Doll is fit to the British physician lung cancer data of Doll and Hill under the assumption that cigarette smoke induces the initial and penultimate changes. It is shown that the best fit of this model in continuing smokers gives predictions not in accordance with incidence in ex-smokers and dose-response. A better global fit can be obtained by increasing the number of stages, but this de-emphasizes initiation and is inconsistent with the rise of incidence in nonsmokers. Thus, one should look to other models. A two-stage model with clonal growth in which smoking initiates normal target cells and promotes the clonal growth of just the smoke-initiated cells is proposed. This model is shown to agree with the Doll and Hill data and thus it has empirical plausibility that should encourage biological studies of clonal growth in carcinogenesis.

Clinical pharmacokinetics of nifedipine gastrointestinal therapeutic system. A controlled-release formulation of nifedipine.

The pharmacokinetics of nifedipine following intravenous administration can be represented by an open two-compartment model with a terminal elimination half-life of about two hours. Nifedipine is extensively biotransformed to inactive metabolites, and the total body clearance (450 to 700 ml/minute) is primarily due to hepatic metabolism. Nifedipine undergoes significant tissue distribution in that the steady-state volume of distribution (0.62 to 0.77 liter/kg) is more than twice the volume of distribution of the central compartment (0.25 to 0.29 liter/kg). Although nifedipine is almost completely absorbed from the gastrointestinal tract, oral bioavailability ranges from 45 to 68 percent because of first-pass metabolism. Nifedipine given three times daily shows no accumulation in plasma and no changes in pharmacokinetic behavior during a one-week study period. Pharmacokinetic studies on the gastrointestinal therapeutic system (GITS) show that the bioavailability of the GITS dosage form (relative to the capsule) is about 65 percent after a single dose, but increases to about 86 percent at steady-state because of residual absorption more than 24 hours after dosing. Linear pharmacokinetics are seen following administration of single oral doses of nifedipine GITS as indicated by dose-proportional increases in the area under the plasma drug concentration-time curve over the range of 30 to 180 mg. Administration of the GITS dosage form in the presence of food slightly increases the rate of drug absorption, but does not influence the extent of drug bioavailability. Dose-dumping has not been observed, even with dosing after a meal containing a high level of fat. The GITS tablets provide zero-order delivery of nifedipine, and drug absorption persists beyond the dosing interval of 24 hours. Thus, the GITS dosage form will permit once-a-day dosing and maintain the desired, constant plasma drug concentration with minimal fluctuation.

Synthesis of chiral and achiral pyranenamine derivatives. Potent agents with topical ocular antiallergic activity.

The SS, RR and meso stereoisomers of pyranenamine SK&F 84210 were synthesized stereospecifically starting from commercially available (R)-(-)- or (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol. In addition, two achiral pyranenamines 19 and 26 were also synthesized. When evaluated by intravenous and topical routes in the rat passive ocular anaphylaxis (POA) assay, (SS)- and meso-2 as well as achiral compounds 19 and 26 were found to be more potent antiallergic agents than (RR)-2.

Sex- and age-related antihypertensive effects of amlodipine. The Amlodipine Cardiovascular Community Trial Study Group.

This community-based study assessed whether there were age, sex, or racial differences in response to amlodipine 5 to 10 mg once daily in patients with mild to moderate essential hypertension. This prospective, open-label trial had a 2-week placebo period, a 4-week upward drug titration/efficacy period, and a 12-week drug maintenance period. There were 1,084 evaluable patients (mean age 55.5 years; 65% men and 35% women; 79% white and 21% black; 75% <65 and 25% > or = 65 years old). At the end of the titration/efficacy phase, the mean +/- SD blood pressure (BP) decreased by -16.3 +/- 12.3/-12.5 +/- 5.9 mm Hg, (p < or = 0.0001). Amlodipine produced a goal BP response (sitting diastolic BP < or = 90 mm Hg, or a 10 mm Hg decrease) in 86.0% of patients overall. The BP response was greater in women (91.4%) than in men (83.0%, p < or = 0.001), and greater in those > or = 65 years old (91.5%) than in those < 65 years old (84.1%, p < or = 0.01); however, it was similar between whites and blacks (86.0% vs 85.9%, respectively, p = NS). The sex difference in BP response could not be fully explained by differences in age, weight, dose (mg/kg), race, baseline BP, or compliance, and there were no differences among women based on use of hormone replacement therapy. Amlodipine was well tolerated; mild to moderate edema was the most common adverse effect. Thus, amlodipine was effective and safe as once-a-day monotherapy in the treatment of mild to moderate hypertension in a community-based population. Women had a greater BP response to amlodipine.

Response of negative symptoms of schizophrenia to neuroleptic treatment.

BACKGROUND: In view of the inconclusive reports in the literature about the response to neuroleptics of chronic schizophrenics with negative symptoms, the authors further evaluated this issue. METHOD: A sample of 30 ambulatory chronic schizophrenics meeting DSM-III-R criteria who had to a marked degree at least two negative symptoms of the five on the Scale for the Assessment of Negative Symptoms (SANS) received various therapeutic dosages of thiothixene for 3 months. The average dose was 26.75 mg/day. Subjects were periodically evaluated with the Brief Psychiatric Rating Scale, Negative Symptoms Rating Scale (a modified version of the SANS), and the Randt Memory Test. The time effect on treatment was calculated by repeated measures of analysis of variance. The relationship between the positive and negative symptoms was tested by an analysis of covariance. RESULTS: Both negative and positive symptoms improved with treatment. The negative symptoms tended to respond to treatment predominantly independently of the positive ones. At the end of the study, 63% (N = 19) of patients had improved moderately, 16% (N = 5) had improved slightly, and 20% (N = 6) had not improved. CONCLUSION: The data require further support from a long-term follow-up study that may show the extent to which these gains are maintained over time.

Comparative pharmacokinetics and pharmacodynamics of amlodipine in hypertensive patients with and without type II diabetes mellitus.

Recent clinical trials aimed at attenuating complications in diabetes mellitus have generated interest in the impact of drug formulation and altered pharmacokinetics and pharmacodynamics in diabetes. Specifically, it has been proposed that the diabetic state may alter the pharmacokinetics of several cardiovascular drugs, including some calcium antagonists. The present study investigates the effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of amlodipine in hypertensive subjects with and without diabetes mellitus to determine whether the diabetic state alters these parameters. This trial consisted of a 2-week placebo washout phase, a 2-week titration phase, and a 2-week maintenance phase. Study patients included 18 hypertensive patients with type II diabetes mellitus and 10 nondiabetic hypertensive patients. Blood samples were collected after administration of amlodipine and AUC, Cmax, and tmax were determined. The acute 24-hour pharmacodynamic response to amlodipine was assessed by blood pressure and telemetric heart rate measurements. There were no significant differences for either amlodipine 5 or 10 mg in AUC (p = 0.40 for 5 mg; p = 0.59 for 10 mg), Cmax (p = 0.41 for 5 mg; p = 0.45 for 10 mg), and tmax (p = 0.79 for 5 mg; p = 0.67 for 10 mg) between diabetic and nondiabetic hypertensive subjects. Similarly, the 24-hour pharmacodynamic effects of amlodipine on systolic blood pressure, diastolic blood pressure, and heart rate did not differ between diabetic and nondiabetic subjects as assessed by repeated-measures analysis of variance. Because of the theoretical basis for anticipating that diabetes mellitus may provoke important pharmacokinetic and pharmacodynamic alterations, our study provides an important database in clearly demonstrating that the diabetic milieu did not alter the pharmacokinetics or pharmacodynamics of amlodipine.

Intravascular ultrasound to assess anastomotic patency after lung transplantation.

Pulmonary arterial anastomotic stenosis is an unusual complication after single-lung transplantation. Intravascular ultrasound, performed at the bedside with an introducer sheath and guidewire, is a new technique that provides high-resolution tomographic images of the anastomotic site. This modality was used early in the postoperative course of a 58-year-old man to exclude significant pulmonary arterial anastomotic narrowing after right single-lung transplantation for primary pulmonary hypertension.

Internalizing and externalizing behavior of children with enlisted Navy mothers experiencing military-induced separation.

OBJECTIVES: To examine whether children with Navy mothers exhibit higher levels of internalizing and externalizing behavior than children in civilian families and whether deployment affects children's internalizing and externalizing behavior. METHOD: Navy mothers who experienced deployment completed a measure assessing children's internalizing and externalizing behavior before and after a deployment (and at similar intervals for the Navy and civilian comparison groups). Data collection took place between 1996 and 1998. RESULTS: Navy children with deployed mothers exhibited higher levels of internalizing behavior than children with nondeployed Navy mothers. Navy children whose mothers experienced deployment were more likely to exhibit clinical levels of internalizing behavior than Navy children with nondeployed mothers or civilian children. Group differences, however, were modest and overall mean scores were in the normal range. CONCLUSIONS: Findings do not suggest greater pathology in children of Navy mothers; however, findings do indicate we should be particularly attentive of deployed mothers and their children.

Clinical correlation of maximal urinary flow rate and plasma doxazosin concentrations in the treatment of benign prostatic hyperplasia. Multicenter Study Group.

OBJECTIVES: To investigate the relationship among doxazosin dose, plasma concentration, and clinical response in 248 hypertensive men with benign prostatic hyperplasia (BPH) in a 16-week, placebo-controlled, double-blind study. METHODS: After a 2-week placebo run-in period, patients were randomized to treatment with either doxazosin (titrated to doses of 2, 4, 8, or 12 mg once daily) or placebo. After 6, 10, and 14 weeks, plasma concentrations of doxazosin were measured at 2 to 6 hours (peak) and approximately 24 hours (trough) after dosing. Changes in maximal urinary flow rate (Qmax) compared with baseline were measured at the same time points. Patients recorded their symptoms in a daily diary and completed a questionnaire at weeks 2, 8, and 16 to assess both obstructive and irritative BPH symptoms. In addition, BPH symptoms were assessed by the investigator at each study visit. RESULTS: Steady-state peak and trough plasma doxazosin concentrations were achieved by 6 weeks of therapy and were maintained between 6 and 14 weeks of active treatment. Peak and trough plasma concentrations increased linearly within the dose range of 2 to 12 mg and were positively correlated with a corresponding mean improvement in Qmax (P = 0.001 and P = 0.008, respectively), consistent with a 24-hour once-daily dosing of doxazosin. Clinical response to doxazosin plateaued at peak and trough plasma concentrations of between 60 and 80 ng/mL and 25 ng/mL, respectively, corresponding to a dose of 8 mg daily. Patient assessment of obstructive BPH symptoms showed significant improvement in the 4- and 8-mg doxazosin treatment groups compared with placebo. CONCLUSIONS: In patients with BPH, both doxazosin plasma concentration and Qmax increased linearly with increasing dose, in the range of 2 to 8 mg daily. The maximal therapeutic dosage of doxazosin would appear to be 8 mg in this group of BPH patients. Further studies are required to support these findings.

Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine.

Methamphetamine (m-AMPH) or saline was repeatedly administered to rats. One week later, the caudate-putamen of the m-AMPH-treated rats revealed a decrease in both [3H]mazindol-labeled dopamine uptake sites and tissue dopamine content. Moreover, the resulting pattern of decline in these measures was regionally heterogeneous. The ventral caudate-putamen displayed the greatest decrease in both [3H]mazindol binding and dopamine content while the neighboring nucleus accumbens and the dorsal caudate-putamen remained relatively intact. These results indicate a regional difference in the susceptibility of striatal dopaminergic terminals to the neurotoxic effects of methamphetamine.

Effect of HER2/neu expression on survival in non-small-cell lung cancer.

Major prognostic factors for early-stage non-small-cell lung cancer (NSCLC) are tumor size and nodal status. It has been suggested that HER2/neu overexpression may be related to poor prognosis in NSCLC. We evaluated the significance of HER2/neu overexpression on survival in patients with NSCLC. Data were collected on 239 patients treated surgically for stage I/II NSCLC between 1987 and 1996. None of the patients received adjuvant chemotherapy or radiation. Formalin-fixed, paraffin-embedded tumor tissue samples were stained with p185/HER2 receptor antibody. Results were reported as positive (2+, 3+) or negative (0, 1+) (Group A). A separate analysis considered only 3+ as positive (Group B). HER2/neu overexpression was seen in 18% in Group A (43 of 239) and 6% in Group B (15 of 239). HER2/neu overexpression was highest in bronchoalveolar cell carcinoma and adenocarcinoma. More stage I tumors were positive than stage II in both groups, but this was significant only in Group A (21% vs. 7%, P = 0.02). No difference was seen with age, gender, or grade for either group. In Group A, the relapse rate was 55% for HER2/neu-overexpressing tumors and 31% for HER2/neu-negative tumors (P = 0.003). Median time to relapse in patients with HER2/neu-positive tumors was 2.9 years; it was not reached in patients with HER2/neu-negative tumors. Median survival of patients with HER2/neu-positive tumors was 3.6 years compared to 5 years in patients with HER2/neu-negative tumors (P = 0.66). In Group B, the relapse rate was 60% for HER2/neu-overexpressing tumors and 33% for negative tumors (P = 0.036). Median time to relapse was 3.4 years in HER2/neu positive and had not been reached in negative tumors. There was no difference in 5-year survival rates for both groups (47% for HER2/neu positive and 50% for negative, P = 0.66).

Soft-tissue injury as an indication of child abuse.

We reviewed the hospital records of 371 children who were suspected of having been physically abused. Our purpose was to determine specific features that might be used to distinguish injuries resulting from abuse from accidental injuries. Soft-tissue injuries were found in 341 (92 per cent) of these children. Ecchymoses were most common, accounting for 555 (62 per cent) of 892 soft-tissue injuries, and very few had a suspicious pattern. Only thirty-four (9 per cent) of the children had a radiographically documented fracture, but radiography was performed for only thirty-seven (10 per cent) of the patients and it rarely was done unless a fracture was clinically obvious. The patterns of injury were age-specific. The forty-four children who were nine months old or less had an average of only one soft-tissue injury; thirty soft-tissue injuries involved the head or face, and seven (16 per cent) of the children had a burn. These children were the most severely injured: two (5 per cent) died and twenty (45 per cent) had a fracture. The sixty-one children who were ten months to two years and eleven months old had an average of two soft-tissue injuries; fifty-four soft-tissue injuries involved the head or face, and nine (15 per cent) of the children had a burn. A fracture was found in eight (13 per cent) of these children.(ABSTRACT TRUNCATED AT 250 WORDS)

Variance components in comparative bioavailability studies.

Variance components in comparative bioavailability studies are examined. Assay measurement error is shown to be negligible relative to other variance components, and hence, repeat assay does not appreciably increase study precision and is unnecessary. More important is the finding that repeat administration of each formulation to each subject may substantially decrease the variance of the formulation difference and may allow the use of fewer subjects in a study. The benefit of repeat administration depends on the relative sizes of the within-subject variance component and the subject-formulation interaction component. In addition, repeat administration allows separate estimation of the within-subject component and the subject-formulation component. The former component is important for assessing bioequivalence, and the latter component, for assessing interchangeability of formulations.