Recent attempted and actual weight change in relation to pregnancy loss: a prospective cohort study.

OBJECTIVE: To assess weight change and attempted weight loss during the 12-18 months before spontaneous conception in relation to the risk of pregnancy loss. DESIGN: Prospective cohort study. SETTING: United States, 2007-2011. METHODS: Women (n = 629) who were attempting pregnancy reported at baseline any weight loss attempts over the past 12 months, and their minimum and maximum weights during that time. Follow up lasted one to six menstrual cycles and throughout pregnancy. Using bodyweight measured at 4 weeks' gestation, participants were categorised as having weight loss ≥5%, weight gain ≥5%, both, or neither, over the previous 12-18 months. Log-binomial models adjusted for potential confounders. MAIN OUTCOME MEASURES: Risk ratio (RR) and 95% confidence interval (CI) of pregnancy loss. RESULTS: Attempted weight loss was reported by 44% of women and actual weight loss by 11%, but neither was consistently associated with pregnancy loss. The RR for recent weight gain ≥5% was 1.65 (CI 1.09, 2.49). CONCLUSIONS: Weight gain over the period spanning 12-18 months pre-conception to 4 weeks' gestation may increase the risk of pregnancy loss among fertile women with prior pregnancy losses. Attempted and actual weight loss were not associated with pregnancy loss; however, replication is needed from larger studies with data on particular weight-loss methods. TWEETABLE ABSTRACT: Recent weight gain before and around the time of conception may increase the risk of pregnancy loss.

Methyl isobutyl ketone-induced hepatocellular carcinogenesis in B6C3F1 mice: A constitutive androstane receptor (CAR)-mediated mode of action.

In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis. To further investigate the MOA for MIBK-induced murine liver tumors, male and female B6C3F1, C57BL/6, and CAR/PXR Knockout (KO) mice were exposed to either 0 or 1800 ppm MIBK for 6 h/day, 5 days/week for a total of 10 days. On day 1, mice were implanted with osmotic mini-pumps containing 5-Bromo-2-deoxyuridine (BrdU) 1 h following exposure and humanely euthanized 1-3 h following the final exposure. B6C3F1 and C57BL/6 mice had statistically significant increases in liver weights compared to controls that corresponded with hepatocellular hypertrophy and increased mitotic figures. Hepatocellular proliferation data indicated induction of S-phase DNA synthesis in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to control, and no increase was observed in MIBK exposed CAR/PXR KO mice. Liver gene expression changes indicated a maximally-induced Cyp2b10 (CAR-associated) transcript and a slight increase in Cyp3a11(PXR-associated) transcript in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to controls, but not in Cyp1a1 (AhR-associated) or Cyp4a10 (PPAR-α-associated) transcripts. CAR/PXR KO mice exposed to 1800 ppm MIBK showed no evidence of activation of AhR, CAR, PXR or PPAR-α nuclear receptors via their associated transcripts. MIBK induced hepatic effects are consistent with a phenobarbital-like MOA where the initiating events are activation of the CAR and PXR nuclear receptors and resultant hepatocellular proliferation leading to rodent liver tumors.

Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice.

AIMS: To investigate the antidiabetic actions of three dogfish glucagon peptide analogues [known glucagon-like peptide-1 and glucagon receptor co-agonists] after chronic administration in diet-induced high-fat-diet-fed diabetic mice. MATERIALS AND METHODS: National Institutes of Health Swiss mice were pre-conditioned to a high-fat diet (45% fat) for 100 days, and control mice were fed a normal diet (10% fat). Normal diet control and high-fat-fed control mice received twice-daily intraperitoneal (i.p.) saline injections, while the high-fat-fed treatment groups (n = 8) received twice-daily injections of exendin-4(1-39), [S2a]dogfish glucagon, [S2a]dogfish glucagon exendin-4(31-39) or [S2a]dogfish glucagon-Lys(30) -γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days. RESULTS: After dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and an associated insulinotropic effect (analysis of variance, p < .05 to <.001) compared with saline-treated high-fat-fed controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared with saline-treated high-fat-fed controls (p <.05 to <.001). After chronic treatment, no receptor desensitization was observed but insulin sensitivity was enhanced for all peptide-treated groups (p < .01 to <.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglyceride concentrations compared with those found in lean controls (p = .0105 and p = .0048, respectively). Pancreatic insulin content was not affected by peptide treatments but [S2a]dogfish glucagon and [S2a]dogfish glucagon exendin-4(31-39) decreased pancreatic glucagon by 28%-34% (p = .0221 and p = .0075, respectively). The percentage of ß-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with high-fat-fed controls and the ß-cell area decreased (p < .05 to <.01). CONCLUSIONS: Overall, dogfish glucagon co-agonist analogues had several beneficial metabolic effects, showing therapeutic potential for type 2 diabetes.

Novel dual agonist peptide analogues derived from dogfish glucagon show promising in vitro insulin releasing actions and antihyperglycaemic activity in mice.

The antidiabetic potential of thirteen novel dogfish glucagon derived analogues were assessed in vitro and in acute in vivo studies. Stable peptide analogues enhanced insulin secretion from BRIN-BD11 ß-cells (p < 0.001) and reduced acute glycaemic responses following intraperitoneal glucose (25 nmol/kg) in healthy NIH Swiss mice (p < 0.05-p<0.001). The in vitro insulinotropic actions of [S2a]dogfish glucagon, [S2a]dogfish glucagon-exendin-4(31-39) and [S2a]dogfish glucagon-Lys(30)-γ-glutamyl-PAL, were blocked (p < 0.05-p<0.001) by the specific GLP-1 and glucagon receptor antagonists, exendin-4(9-39) and (desHis(1)Pro(4)Glu(9))glucagon amide but not by (Pro(3))GIP, indicating lack of GIP receptor involvement. These analogues dose-dependently stimulated cAMP production in GLP-1 and glucagon (p < 0.05-p<0.001) but not GIP-receptor transfected cells. They improved acute glycaemic and insulinotropic responses in high-fat fed diabetic mice and in wild-type C57BL/6J and GIPR-KO mice (p < 0.05-p<0.001), but not GLP-1R-KO mice, confirming action on GLP-1 but not GIP receptors. Overall, dogfish glucagon analogues have potential for diabetes therapy, exerting beneficial metabolic effects via GLP-1 and glucagon receptors.

Hospital-acquired Anemia in Critically Ill Dogs and Cats: A Multi-Institutional Study.

BACKGROUND: Hospital-acquired anemia is commonly described in people but limited information currently is available regarding its prevalence in animals. HYPOTHESIS/OBJECTIVES: Assess the prevalence of hospital-acquired anemia in hospitalized critically ill dogs and cats, and examine its relationship with phlebotomy practices, transfusion administration, and survival to discharge. ANIMALS: Eight hundred and fifty-one client-owned animals (688 dogs and 163 cats). METHODS: A multicenter, observational study was conducted in which packed cell volume (PCV) was recorded at the time of admission and on subsequent hospitalization days. Signalment, number of blood samples obtained, underlying disease, whether or not blood products were administered, duration of hospitalization, and survival to discharge were recorded. RESULTS: Admission anemia prevalence was 32%, with overall prevalence during the hospitalization period of 56%. The last recorded PCV was significantly lower than the admission PCV for both dogs (admission PCV, 42% [range, 6-67%]; last recorded PCV, 34% [range, 4-64%], P < .0001) and cats (admission PCV, 31% [range, 6-55%]; last recorded PCV, 26% [range, 10-46%], P < .0001). Patients that developed anemia had significantly more blood samples obtained (nonanemic, 5 blood samples [range, 2-54]; anemic, 7 blood samples [range, 2-49], P < .0001). Hospitalized cats were significantly more likely to develop anemia compared to dogs (P < .0001), but anemic dogs were significantly less likely to survive to discharge (P = .0001). Surgical patients were at higher risk of developing hospital-acquired anemia compared to medical patients (OR, 0.63; 95% CI, 0.4-0.9; P = .01). CONCLUSIONS AND CLINICAL RELEVANCE: Hospital-acquired anemia occurred frequently, especially in surgical patients. Additional studies focused on the direct effect of phlebotomy practices on the likelihood of anemia development in hospitalized animals are warranted.

Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice.

The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-γ-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8-oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3ß. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-γ-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice.

Massive haemorrhage associated with inadvertent incision of a suspected carotid artery pseudoaneurysm in a cat.

A 12-year-old, castrated male, domestic long-haired cat experienced massive haemorrhage associated with an incision of a swelling on the neck 2 weeks after right-sided ventral bulla osteotomy. Emergent control of haemorrhage was gained through unilateral carotid artery ligation. Cardiopulmonary resuscitation was provided in conjunction with massive blood transfusion. The cat made an unremarkable recovery. Carotid artery pseudoaneurysm due to surgical disruption of the carotid artery during ventral bulla osteotomy, specifically through the use of self-retaining retractors, was suspected. This case highlights the development of pseudoaneurysm as a potential complication of head and neck surgery, and additionally describes a case of massive transfusion in a cat.

Methyl isobutyl ketone exposure-related increases in specific measures of α2u-globulin (α2u) nephropathy in male rats along with in vitro evidence of reversible protein binding.

Chronic exposure to methyl isobutyl ketone (MIBK) resulted in an increase in the incidence of renal tubule adenomas and occurrence of renal tubule carcinomas in male, but not female Fischer 344 rats. Since a number of chemicals have been shown to cause male rat renal tumors through the α2u nephropathy-mediated mode of action, the objective of this study is to evaluate the ability of MIBK to induce measures of α2u nephropathy including renal cell proliferation in male and female F344 rats following exposure to the same inhalation concentrations used in the National Toxicology Program (NTP) cancer bioassay (0, 450, 900, or 1800ppm). Rats were exposed 6h/day for 1 or 4 weeks and kidneys excised approximately 18h post exposure to evaluate hyaline droplet accumulation (HDA), α2u staining of hyaline droplets, renal cell proliferation, and to quantitate renal α2u concentration. There was an exposure-related increase in all measures of α2u nephropathy in male, but not female rat kidneys. The hyaline droplets present in male rat kidney stained positively for α2u. The changes in HDA and α2u concentration were comparable to d-limonene, an acknowledged inducer of α2u nephropathy. In a separate in vitro study using a two-compartment vial equilibration model to assess the interaction between MIBK and α2u, the dissociation constant (Kd) was estimated to be 1.27×10(-5)M. This Kd is within the range of other chemicals known to bind to α2u and cause nephropathy. Together, the exposure-related increase in measures of α2u nephropathy, sustained increase in renal cell proliferation along with an indication of reversible binding of MIBK to α2u, support the inclusion of MIBK in the category of chemicals exerting renal effects through a protein droplet α2u nephropathy-mediated mode of action (MoA).

A multicenter cohort study of pregnancy outcomes among women with laboratory-confirmed H1N1 influenza.

OBJECTIVE: To evaluate associations between laboratory-confirmed 2009 H1N1 influenza infection and obstetric and neonatal outcomes. STUDY DESIGN: A multicenter cohort study was performed comparing laboratory-confirmed cases of 2009 H1N1 infection during pregnancy (N=142) with matched controls (N=710). Subanalysis was also performed comparing severely infected (hospitalized) women with controls. RESULT: No outcome differences were noted in comparing all women with H1N1 with controls. Women with severe infection had a higher incidence of delivering a small for gestational age (SGA) infant: 18.8% (6/32) versus 7.4% (52/707), adjusted odds ratio 2.35 (95% confidence interval 1.03, 5.36, P=0.02). Mean birth weight was 3013.0 g among severely infected women and 3223.3 g in controls (P=0.08), and incidence of preterm delivery was 25.0% (8/32) and 11.6% (82/710) (P=0.08), respectively. CONCLUSION: Pregnant women with mild clinical illness secondary to 2009 H1N1 were not at a greater risk of adverse pregnancy outcomes. However, severely infected women were more likely to deliver SGA infants.

Genotoxicity screening via the γH2AX by flow assay.

The measurement of serine139-phosphorylated histone H2AX (γH2AX) provides a biomarker of DNA double-strand breaks (DSBs) and may identify potential genotoxic activity. In order to evaluate a flow cytometry assay for γH2AX detection (hereafter termed the γH2AX by flow assay), 6 prototypical (3 pro- and 3 proximate) genotoxins, i.e. dimethylbenz[a]anthracene (DMBA), 2-acetylaminofluorene (2-AAF), benzo[a]pyrene (B[a]P), methyl methane sulphonate (MMS), methyl nitrosourea (MNU) and 4-nitroquinoline oxide (4NQO), were selected to define assay evaluation criteria. In addition, 3 non-genotoxic cytotoxins (phthalic anhydride, n-butyl chloride and hexachloroethane) were included to investigate the influence of cytotoxicity on assay performance. At similar cytotoxicity levels (relative cell counts; RCC 75-40%) all prototypical genotoxins induced marked concentration-dependent increases in γH2AX compared with the non-genotoxins. As a result, assay evaluation criteria for a positive effect were defined as >1.5-fold γH2AX @ RCC >25%. Twenty five additional chemicals with diverse structures and genotoxic activity were selected to evaluate the γH2AX by flow assay. Results were compared with Ames bacterial and in vitro mammalian genotoxicity tests (mouse lymphoma assay and/or chromosome aberration assay). γH2AX by flow assay results were highly predictive of Ames (sensitivity 100%; specificity 67%; concordance 82%) and in vitro mammalian genotoxicity tests (sensitivity 91%; specificity 89%; concordance 91%) and provide additional evidence that γH2AX is a biomarker of potential genotoxic activity, underpinned mechanistically by the cellular response to DSBs. Discordant findings were predominately attributed to differences in specificity for some mammalian cell genotoxins that are Ames non-mutagens or for "biologically-irrelevant" positives in the mammalian tests. Simple anilines were classified as genotoxic following rat liver S9-mediated bioactivation, however, effects on γH2AX were atypical and limited to a small sub-population of S-phase nuclei. Nevertheless, the γH2AX by flow assay represents a novel genotoxicity assay with the potential to flag both pro- and proximate genotoxins.

Postoperative haemorrhage associated with active suction drains in two dogs.

This article describes two dogs in which an active suction drain was placed to manage dead space at the surgical site and acute haemorrhage and hypovolaemia occurred postoperatively. In both instances, fluid resuscitation and temporary discontinuation of drainage resulted in resolution of clinical signs. Although the underlying cause of haemorrhage was not definitively identified, the use of low-pressure drainage systems and avoidance of interference with local blood vessels should be considered. This is a previously undocumented complication of active suction drain use in veterinary patients.

Dysregulated complement activation as a common pathway of injury in preeclampsia and other pregnancy complications.

The complement system protects the host against invading organisms, initiates inflammation and dispose of immune complexes and the products of inflammatory injury. The complement system provides an important link between the innate and adaptive immune systems. Experimental observations suggest that increased complement activation causes and/or perpetuates inflammation during pregnancy. Recent studies suggest a link between complement activation and preeclampsia. Excessive activation or insufficient regulation of complement recruits leukocytes and unleashes potent inflammatory and anti-angiogenic mediators associated with placental insufficiency and maternal endothelial dysfunction characteristic of preeclampsia. We review the animal and human studies that link complement activation and pathogenic events in preeclampsia, present evidence that activation of the complement system is associated with the development of preeclampsia and provides new targets to prevent its complications.

The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia.

OBJECTIVE: To determine the interrelationships during early pregnancy of complement-activation fragments Bb, C3a and sC5b-9, and angiogenesis-related factors placental growth factor (PiGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and their associations with pre-eclampsia. DESIGN: Prospective cohort study. SETTING: Denver complement study (June 2005-June 2008). POPULATION: A total of 668 pregnant women with singleton gestations, recruited between 10 and 15 weeks of gestation. METHODS: Using univariable and multivariable logistic regression analysis, concentrations of complement-activation fragments and angiogenesis-related factors were compared between 10 and 15 weeks of gestation in women who subsequently did or did not develop pre-eclampsia. Interrelationships between these variables were tested using the non-parametric Spearman rank correlation coefficient. MAIN OUTCOME MEASURE: Pre-eclampsia. The association of complement-activation fragments and angiogenesis-related factors with obesity was also examined. RESULTS: The mean (+/-SD) levels of complement Bb in early pregnancy among women who did and did not develop pre-eclampsia were 0.84 (+/-0.26) microg/ml and 0.69 (+/-0.2) microg/ml, respectively (P = 0.001). Concentrations of PiGF were significantly (P = 0.01) lower (31 +/- 12 pg/ml) in early pregnancy in the pre-eclamptic group of women, as compared with the normotensive group (39 +/- 32 pg/ml). The adjusted odds ratio (AOR) of Bb and PiGF were 2.1 (CI = 1.4-3.1, P < 0.0003) and 0.2 (CI = 0.07-0.7, P = 0.01), respectively. There was no significant difference in the levels of C3a, sC5b-9, sFlt-1 and sEng in early pregnancy among women who developed pre-eclampsia, compared with women who remained normotensive during pregnancy. Higher levels of Bb (P = 0.0001) and C3a (P = 0.03), and lower levels of sFlt-1 (P = 0.0002) and sEng (P = 0.0001) were found among women with obesity, compared with non-obese controls. No meaningful relationships were found between the complement-activation fragments and the angiogenesis-related factors. CONCLUSIONS: In this cohort during early pregnancy, increased concentrations of complement-activation factor Bb and lower concentrations of PiGF were associated with the development of pre-eclampsia later in pregnancy.

Effectiveness and safety of a structured swimming program in previously sedentary women during pregnancy.

OBJECTIVE: To determine whether undertaking a swimming program in sedentary women during pregnancy would improve maternal fitness without adverse fetal consequences. METHODS: Prospective observational investigation of healthy sedentary pregnant women participating in a monitored swimming program. RESULTS: Twenty-three women attended swimming sessions from 16 to 28 weeks of gestation resulting in increasing distances swum and improved aerobic fitness as measured by physical work capacity (PWC170) (p = 0.003). Resting maternal heart rate decreased (p = 0.041) and resting systolic (p = 0.092) and diastolic (p = 0.971) blood pressures remained unchanged over gestation. The mean fetal heart rates decreased with advancing gestational age (p = 0.001), consistent with normal physiology. Non-stress tests and umbilical artery systolic/diastolic ratios were similar before and after swimming sessions, providing evidence that fetal well-being was unchanged. CONCLUSIONS: A structured swimming program in sedentary pregnant women increases maternal fitness without any alteration in maternal and fetal well-being.

How much does physical appearance say about the psychological adjustment of competent and dysfunctional children?

Presents a study in which three sets of photographs of socially competent, aggressive, and anxious preschoolers were rated by college students (n = 150 raters per set), blind to the children's group membership. This was done to assess the extent to which adults are able to make valid and reliable evaluations of children's psychological adjustment on the basis of physical appearance alone. Sets 1 and 2 were photographs of different children taken under the same conditions and providing both facial and nonfacial cues. Sets 2 and 3 were of the same children taken under conditions that varied as to the amount of nonfacial cues they provided. Results showed that (a) socially competent children were judged to be better adjusted than their dysfunctional peers (i.e., more competent, less aggressive, less anxious, and less likely to have emotional or behavioral problems); (b) within the dysfunctional group, aggressive and anxious children were distinguished in ways that correspond closely to what is known about them from behavioral and clinical research; (c) irrespective of group membership, girls and boys were generally distinguished in ways that reflect normative beliefs about gender differences from social and developmental research; (d) group differences in ratings of psychological adjustment were generally comparable across photograph sets and could not be accounted for by differences in the children's perceived physical attractiveness; and (e) raters reported that they relied mainly on the children's expression, eyes, and posture to make their judgments of adjustment. These results replicate and extend earlier findings based on 1 of the 3 photograph sets (Serketich & Dumas, 1997). They suggest that when first impressions matter, competent children are at an advantage and their dysfunctional peers at a disadvantage even before their actual behavior comes to confirm or to invalidate these impressions. Theoretical and clinical implications of the findings are discussed.

Flow cytometric enumeration of micronucleated reticulocytes: high transferability among 14 laboratories.

This laboratory previously described a single-laser flow cytometric method, which effectively resolves micronucleated erythrocyte populations in rodent peripheral blood samples. Even so, the rarity and variable size of micronuclei make it difficult to configure instrument settings consistently and define analysis regions rationally to enumerate the cell populations of interest. Murine erythrocytes from animals infected with the malaria parasite Plasmodium berghei contain a high prevalence of erythrocytes with a uniform DNA content. This biological model for micronucleated erythrocytes offers a means by which the micronucleus analysis regions can be rationally defined, and a means for controlling interexperimental variation. The experiments described herein were performed to extend these studies by testing whether malaria-infected erythrocytes could also be used to enhance the transferability of the method, as well as control intra- and interlaboratory variation. For these studies, blood samples from mice infected with malaria, or treated with vehicle or the clastogen methyl methanesulfonate, were fixed and shipped to collaborating laboratories for analysis. After configuring instrumentation parameters and guiding the position of analysis regions with the malaria-infected blood samples, micronucleated reticulocyte frequencies were measured (20,000 reticulocytes per sample). To evaluate both intra- and interlaboratory variation, five replicates were analyzed per day, and these analyses were repeated on up to five separate days. The data of 14 laboratories presented herein indicate that transferability of this flow cytometric technique is high when instrumentation is guided by the biological standard Plasmodium berghei.

Food-derived heterocyclic amine mutagens: variable metabolism and significance to humans.

The cooking of meat has been found to generate compounds that possess extreme mutagenicity when examined in short term tests. This observation led to the isolation and identification of a family of mutagenic chemicals, all of which are heterocyclic amines. These amines are potent bacterial and eukaryotic cell mutagens, and all of those tested have been found to induce tumors in laboratory animals. Metabolic activation of the heterocyclic amines predominantly involves CYP1-mediated N-hydroxylation and then O-esterification by phase II enzymes. In contrast, carbon oxidation, glucuronidation, and sulfation reactions at sites other than the hydroxylamine yield detoxication metabolites. In humans, the activities of these pathways are known to vary between individuals and are likely to influence susceptibility to the genetic toxicity of the heterocyclic amines. Clearly, accurate determination of human exposure to the heterocyclic amines and identification of the key enzyme systems involved and their regulation will be required for rational assessment of the risk and will help devise strategies to reduce such risk.

Promoting intervention fidelity. Conceptual issues, methods, and preliminary results from the EARLY ALLIANCE prevention trial.

Fidelity refers to the demonstration that an experimental manipulation is conducted as planned. In outcome research, an intervention can be said to satisfy fidelity requirements if it can be shown that each of its components is delivered in a comparable manner to all participants and is true to the theory and goals underlying the research. Demonstrating the fidelity of an intervention is a key methodologic requirement of any sound prevention trial. This paper summarizes key conceptual and methodologic issues associated with intervention fidelity, and describes the steps taken to promote fidelity in EARLY ALLIANCE, a large-scale prevention trial currently testing the effectiveness of family, peer, and school interventions to promote competence and reduce risk for conduct disorder, substance abuse, and school failure. The paper presents preliminary results (Trial Year 1) that demonstrate content and process fidelity for two of these interventions, and discusses how the EARLY ALLIANCE methodology may be generalized to address fidelity issues in other prevention studies.

Effectiveness of a teaching programme in pain and symptom management for junior house officers.

The objectives of this study were (i) to assess the level of knowledge with respect to pain and symptom management among doctors in their first year after graduation and (ii) to measure the impact of a structured teaching programme on their level of knowledge. All 34 newly qualified junior house officers in one teaching hospital were offered a six-session teaching programme in pain and symptom management. A multiple-choice questionnaire was used to assess their level of knowledge at the beginning and at the end of a 6-month period over which the teaching sessions took place. Attendance at and satisfaction with the programme were high. There was a significant improvement in the level of knowledge at the end of the programme, with the greatest improvement in those who attended most sessions. The low scores recorded for the questionnaire administered before the teaching programme suggest that there is a critical need for improved education in palliative care amongst newly qualified doctors. We have shown that a simple in-service case-based teaching programme can meet this need effectively.

Effect of dietary vitamin E supplementation on cholesterol oxidation in vacuum packaged cooked beef steaks.

The effect of dietary vitamin E supplementation on cholesterol oxidation in vacuum packaged, cooked, refrigerated and frozen beef steaks, was investigated. Steers (Friesian×Charolais×Black Hereford) were fed diets providing 20 or 3000 mg α-tocopheryl acetate/head/day for 135 days prior to slaughter. α-Tocopherol concentrations in M. psoas major (PM) and M. longissimus dorsi (LD) were significantly (p<0.05) increased by supplementation and were significantly (p<0.05) higher in PM than LD. Cholesterol oxidation (monitored by measuring 7-ketocholesterol formation) increased during refrigerated and frozen storage in some, but not all, groups, and tended to be higher in PM than LD. Dietary vitamin E did not affect 7-ketocholesterol formation in LD, but significantly (p<0.05) reduced concentrations in PM during refrigerated and frozen storage. Supplementation significantly (p<0.05) reduced TBARS in PM and LD, indicating that vitamin E improved oxidative stability in both muscles. The results show that dietary vitamin E supplementation inhibits cholesterol oxidation in vacuum packaged, cooked beef during refrigerated and frozen storage, but may be influenced by muscle type.