Paraoxon sensitive phenylvalerate hydrolase in assessing the severity of acute paraoxon poisoning

INTRODUCTION: Intoxications with organophosphorous compounds, especially paraoxon, are frequent. Organophosphorous compounds inhibit serine hydrolases such as acetylcholine, butyrilcholine, and carboxyl esterases although acetylcholine and butyrylcholine are too sensitive to paraoxon to be useful markers of severity. They cannot show a dose-dependent inhibition during an acute organophosphorous compounds exposure because maximal enzyme inhibition is reached at very low organophosphorous compounds concentrations. PURPOSE: To determine in vitro the dose-effect relationship between the activity of the paraoxon-sensitive phenylvalerate hydrolase, a member of the carboxvl esterases family, and the paraoxon dose, and to assess its utility as a putatively less sensitive enzyme marker to monitor the severity of an acute paraoxon intoxication. MATERIALS AND METHODS: Phenylvalerate hydrolase and butyrylcholine activities were determined in serum of nine healthy human volunteers before and after addition of different concentrations of paraoxon. The determination of phenyl-valerate hydrolase activity was carried out using a modification of the method described by Johnson. A commercially available kit was used to measure butyrylcholine activity. RESULTS: Paraoxon inhibits phenyl-valerate hydrolase activity at concentrations above 10 M. Maximal inhibition (approximately 50% of baseline) is achieved at concentrations above 2.5 x 10(-7) M. The IC50 value of paraoxon for phenyl-valerate hydrolase is 34+/-2 nM. The uninhibited phenyl-valerate hydrolase activity is due to paraoxon-resistent isoforms. Paraoxon begins inhibiting butyrylcholine activity at concentrations above 10(-9) M. At concentrations above 5 x 10(-5) M, no butyrylcholine activity is measulrable. The IC50 value of paraoxon for butyrylcholine is 150+/-23 nM. CONCLUSION: The paraoxon-sensitive subunit of phenyl-valerate hydrolase shows dose-dependent inhibition when exposed to paraoxon in vitro, but it is even more sensitive than butyrylcholine to paraoxon inhibition. Determinations of phenyl-valerate hydrolase activity to assess the severity of an acute organophosphorous compounds poisoning cannot be recommended, but phenyl-valerate hydrolase may have utility in worker surveillance.     

Long-term follow-up of a 10-month programme in curriculum development for medical educators: a cohort study

Context  There is an ongoing need for curriculum development (CD) in medical education. However, only a minority of medical teaching institutions provide faculty development in CD. This study evaluates the long-term impact of a longitudinal programme in curriculum development.
Methods  We surveyed eight cohorts of participants ( n  =   64) and non-participants ( n  =   64) from 1988 to 1996 at baseline and at 6–13 years after completion of a 10-month, one half-day per week programme offered annually, which included a mentored CD project, workshops on CD steps, a final paper and a presentation.
Results  Fifty-eight participants (91%) and 50 non-participants (78%) returned completed follow-up surveys. In analyses, controlling for background characteristics and baseline self-rated proficiencies, participants were more likely than non-participants at follow-up to report having developed and implemented curricula in the past 5 years (65.5% versus 43.7%; odds ratio [OR] 2.41, 95% confidence interval [CI] 1.03–5.66), to report having performed needs assessment when planning a curriculum (86.1% versus 58.8%; OR 5.59, 95% CI 1.20–25.92), and to rate themselves highly in developing (OR 3.57, 95% CI 1.36–9.39), implementing (OR 3.04, 95% CI 1.16–7.93) and evaluating (OR 2.74, 95% CI 1.10–6.84) curricula. At follow-up, 86.2% of participants reported that the CD programme had made a moderate or great impact on their professional careers. Responses to an open-ended question on the impact confirmed continued involvement in CD work, confidence in CD skills, application of CD skills and knowledge beyond CD, improved time management, and lasting relationships formed because of the programme.
Conclusions  Our results suggest that a longitudinal faculty development programme that engages and supports faculty in real CD work can have long-lasting impact.     

The impact of prompted narrative writing during internship on reflective practice: a qualitative study

Narrative writing has been used to promote reflection and increased self-awareness among physicians. The purpose of this study was to determine the impact of prompted narrative writing on reflection. Thirty-two interns at 9 internal medicine residency programs participated in a year-long qualitative study about personal growth beginning in July of 2002. Interns wrote narratives every 8 weeks. At study completion, interns wrote a final narrative describing the affect that being in the study had on them. Responses were reviewed and organized into domains. Writing throughout the year resulted in reflection and encouraged interns to reconsider their core values and priorities. Some found that the exercise promoted greater self-awareness and provided an emotional outlet. Writing about difficult experiences coupled with reflection motivated some interns to want to improve. Prompted narrative writing led to reflection among interns and promoted self-awareness. Educators may consider incorporating narrative writing into residency education.     

Evidence,Theory and Context: Using intervention mapping to develop a worksite physical activity intervention

Background  

The workplace is an ideal setting for health promotion. Helping employees to be more physically active can not only improve their physical and mental health, but can also have economic benefits such as reduced sickness absence. The current paper describes the development of a three month theory-based intervention that aims to increase levels of moderate intensity physical activity amongst employees in sedentary occupations.     

Transfected MCF-7 cells as a model for breast cancer progression

Summary The MCF-7 human breast carcinoma cell line has been used as a recipient for eukaryotic plasmid expression vectors to determine the effects of growth factor and growth factor receptor overexpression on the estrogen-dependent, antiestrogen sensitive and poorly metastatic phenotypes exhibited by this line. Overexpression of some members of the erbB family of ligands and receptors were found to have some effects on these pheno-types. However, only when two members of the fibroblast growth factor family, FGF-1 and FGF-4, were overexpressed was progressivein vivo growth observed is either ovariectomized nude mice without estrogen supplementation or in mice that received tamoxifen treatment. FGF transfected cells also exhibited an increased ability to form micrometastases. The implications of these results with regard to the possible role of the paracrine and autocrine effects of angiogenic growth factor production in breast cancer progression are discussed.     

Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome

BACKGROUND: Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) germline mutations. METHODS: Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM-pancreatic carcinoma (FAMMM-PC) association in concert with a CDKN2A germline mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics, reduced penetrance of CDKN2A mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS: Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early-onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later-onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A mutation. CONCLUSIONS: The authors suggest that these tumors may collectively, in concert with CDKN2A mutations, constitute a "new" putative hereditary carcinoma syndrome referred to as FAMMM-PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required.     

Health-risk behaviour in Croatia

OBJECTIVE: To identify the health-risk behaviour of various homogeneous clusters of individuals. STUDY DESIGN: The study was conducted in 13 of the 20 Croatian counties and in Zagreb, the Croatian capital. In the first stage, general practices were selected in each county. The second-stage sample was created by drawing a random subsample of 10% of the patients registered at each selected general practice. METHODS: The sample was divided into seven homogenous clusters using statistical methodology, combining multiple factor analysis with a hybrid clustering method. RESULTS: Seven homogeneous clusters were identified, three composed of males and four composed of females, based on statistically significant differences between selected characteristics (P<0.001). Although, in general, self-assessed health declined with age, significant variations were observed within specific age intervals. Higher levels of self-assessed health were associated with higher levels of education and/or socio-economic status. Many individuals, especially females, who self-reported poor health were heavy consumers of sleeping pills. Males and females reported different health-risk behaviours related to lifestyle, diet and use of the healthcare system. Heavy alcohol and tobacco use, unhealthy diet, risky physical activity and non-use of the healthcare system influenced self-assessed health in males. Females were slightly less satisfied with their health than males of the same age and educational level. Even highly educated females who took preventive healthcare tests and ate a healthy diet reported a less satisfactory self-assessed level of health than expected. CONCLUSION: Sociodemographic characteristics, life style, self-assessed health and use of the healthcare system were used in the identification of seven homogeneous population clusters. A comprehensive analysis of these clusters suggests health-related prevention and intervention efforts geared towards specific populations.     

Minimum alveolar concentration for halothane in children with cerebral palsy and severe mental retardation

Children with cerebral palsy and severe mental retardation who present for operation may require lower concentrations of inhalational anaesthetics than healthy children. The minimum alveolar concentration (MAC) for halothane was measured in 36 children and adolescents, aged 4–18 years, who underwent orthopaedic surgery. The control group consisted of 12 healthy children (group 1). Children with cerebral palsy and severe mental retardation were allocated to one of two groups: those taking chronic anticonvulsant medication (group 2) ( n  = 12) and those who did not take any drugs (group 3) ( n  = 12). The mean (SEM) MAC value for halothane (expressed in volume per cent) was 0.90 (0.02) for healthy children. Children with cerebral palsy had significantly lower MAC values whether they took anticonvulsant drugs or not (0.62 (0.03) and 0.71 (0.10), respectively).     

A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia

The entorhinal cortex (ERC) has been implicated in schizophrenia by a number of studies. There is anatomical observation of neuronal heterotopias in the rostral ERC, which is consistent with a hypothesis of neurodevelopmental abnormalities in this disease. In view of the significant cytoarchitectonic variation of the ERC throughout its rostro-caudal extent, we performed a detailed subareal analysis of the rostral two-thirds of the entorhinal cortex (ERCr) in 14 postmortem schizophrenic brains and 14 matched controls (mean ages of 48 and 47 respectively). This systematic evaluation included both a qualitative microscopic analysis of morphogenetic anomalies that would be consistent with neurodevelopmental pathology and quantitative measurements of total neuronal number, average neuronal density, laminar volume and laminar depth from the cortical surface in cytoarchitectonically matched subareas of schizophrenic and control brains. Parcellation of the entire ERC on the basis of cytoarchitectonic criteria identified five distinct regions, similar to those described in the macaque, except that in the human brain three of the regions were further divisible into two or three subareas, yielding nine distinct cellular compartments. Five rostral areas, prorhinal (Pr), lateral (28L), intermediate rostral and caudal (281r and 281c), and sulcal (28S), comprise the ERCr. Gross and microscopic examination of these subdivisions throughout the ERCr failed to reveal laminar disorganization in any of the schizophrenic brains. The brains also did not differ significantly with respect to total neuronal number, total volume and neuronal density per laminar and subareal subdivision, or laminar thickness per entorhinal subarea. However, neuronal number and density were reduced by 12-18% in Pr and 28L, suggesting that mild quantitative abnormalities may exist in the ERCr and might possibly be revealed in a larger sample of schizophrenic brains. We have failed to confirm previous reports of laminar disorganization in the ERCr in brains of patients with schizophrenia; to the extent that this region is implicated in schizophrenia, the structural changes are likely to consist of more subtle cellular disturbances.      

Inhibition of cigarette smoke-related lipophilic DNA adducts in rat tissues by dietary oltipraz

The present study investigated the effects of dietary oltipraz on cigarette smoke-related lipophilic DNA adduct formation. Female Sprague- Dawley rats were exposed daily to sidestream cigarette smoke in a whole- body exposure chamber 6 h/day for 4 consecutive weeks. One group of rats was maintained on control diet while another group received the same diet supplemented with either a low (167 p.p.m.) or high (500 p.p.m.) dose of oltipraz, starting 1 week prior to initiation of smoke exposure until the end of the experiment. Analysis of lipophilic DNA adducts by the nuclease P1-mediated 32P-post-labeling showed up to five smoke-related adducts. Adduct no. 5 predominated in both the lung and the heart while adduct nos 3 and 2 predominated in the trachea and bladder, respectively. Quantitative analysis revealed that the total adduct level was the highest in lungs (270+/-68 adducts/10(10) nucleotides), followed by trachea (196+/-48 adducts/10(10) nucleotides), heart (141+/-22 adducts/10(10) nucleotides) and bladder (85+/-16 adducts/10(10) nucleotides). High dose oltipraz treatment reduced the adduct levels in lungs and bladder by >60%, while the reduction in lungs in the low-dose group was approximately 35%. In trachea, the effect of low and high dietary oltipraz on smoke DNA adduction was equivocal, while smoke-related DNA adducts in the heart were minimally inhibited by high-dose oltipraz. In a repeat experiment that employed a 3-fold lower dose of cigarette smoke, oltipraz (500 p.p.m.) was found to inhibit the formation of DNA adducts in rat lungs and trachea by 80 and 65%, respectively. These data clearly demonstrate a high efficacy of oltipraz in inhibiting the formation of cigarette smoke-induced DNA adducts in the target tissues.