Reduced response of human meniscal cells to Osteogenic Protein 1 during osteoarthritis and pro-inflammatory stimulation.

OBJECTIVE: Many cell types lose responsiveness to anabolic factors during inflammation and disease. Osteogenic Protein 1 (OP1/BMP7) was evaluated for the ability to enhance extracellular matrix synthesis in healthy and OA meniscus cells. Mechanisms of cell response to OP1 were explored. DESIGN: Meniscus and cartilage tissues from healthy tissue donors and osteoarthritis (OA) patients undergoing total knee arthroplasties were acquired. Primary cell cultures were stimulated with OP1 and/or inflammatory factors (IL1α, IL1ß, or fibronectin fragments (FnF)) and cellular responses were analyzed by RT-qPCR and immunoblots. Frozen section immunohistochemistry (IHC) was conducted to assess OP1 and receptor proteins in normal and OA meniscus. RESULTS: OP1 treatment of normal meniscus cells resulted in significant, dose-dependent increases in ACAN (aggrecan) and COL2A1, and decreased MMP13 gene transcription, while only ACAN was upregulated (P < 0.01) at the highest dose of OP1 in OA meniscus cells. OP1 induced significantly more ACAN gene transcription in normal meniscus than normal articular cartilage (P = 0.05), and no differences between normal and OA cartilage were detected. Receptor expression and kinetics of canonical signaling activation were similar between normal and OA specimens. Normal meniscus cells treated with inflammatory factors were refractory to OP1 stimulation. Smad1 phosphorylation at an inhibitory site was induced (P = 0.01 for both normal and OA meniscus) by inflammatory cytokine treatment. CONCLUSIONS: The meniscus demonstrates resistance to OP1 stimulation in OA and in the presence of inflammatory mediators. MAPK-mediated Smad1 linker phosphorylation is a possible mediator of the loss of anabolic extracellular matrix production in the inflammatory cytokine affected meniscus.

Standardised survey method for identifying catchment risks to water quality.

This paper describes the development and application of a systematic methodology to identify and quantify risks in drinking water and recreational catchments. The methodology assesses microbial and chemical contaminants from both diffuse and point sources within a catchment using Escherichia coli, protozoan pathogens and chemicals (including fuel and pesticides) as index contaminants. Hazard source information is gathered by a defined sanitary survey process involving use of a software tool which groups hazards into six types: sewage infrastructure, on-site sewage systems, industrial, stormwater, agriculture and recreational sites. The survey estimates the likelihood of the site affecting catchment water quality, and the potential consequences, enabling the calculation of risk for individual sites. These risks are integrated to calculate a cumulative risk for each sub-catchment and the whole catchment. The cumulative risks process accounts for the proportion of potential input sources surveyed and for transfer of contaminants from upstream to downstream sub-catchments. The output risk matrices show the relative risk sources for each of the index contaminants, highlighting those with the greatest impact on water quality at a sub-catchment and catchment level. Verification of the sanitary survey assessments and prioritisation is achieved by comparison with water quality data and microbial source tracking.

How strict is galactose restriction in adults with galactosaemia? International practice.

Dietary management of 418 adult patients with galactosaemia (from 39 centres/12 countries) was compared. All centres advised lactose restriction, 6 restricted galactose from galactosides ± fruits and vegetables and 12 offal. 38% (n=15) relaxed diet by: 1) allowing traces of lactose in manufactured foods (n=13) or 2) giving fruits, vegetables and galactosides (n=2). Only 15% (n=6) calculated dietary galactose. 32% of patients were lost to dietetic follow-up. In adult galactosaemia, there is limited diet relaxation.

Osteoarthritic changes in vervet monkey knees correlate with meniscus degradation and increased matrix metalloproteinase and cytokine secretion.

OBJECTIVE: Meniscus injury increases osteoarthritis risk but its pathobiology in osteoarthritis is unclear. We hypothesized that older adult vervet monkeys would exhibit knee osteoarthritic changes and the degenerative menisci from these animals would secrete matrix metalloproteinases (MMPs) and pro-inflammatory cytokines that contribute to the development of osteoarthritis. DESIGN: In a cross sectional analysis of healthy young adult (9-12 years) and old (19-26 years) adult female vervet monkeys, knees were evaluated in vivo with computed tomography (CT) imaging, and joint tissues were morphologically graded at necropsy. Meniscus explants were subsequently cultured to evaluate meniscal MMP and cytokine secretion. RESULTS: CT images revealed significant bony osteoarthritic changes in 80% of older monkeys which included increases in osteophyte number and meniscal calcification. Meniscus and cartilage degradation scores were greater in the older monkeys and were positively correlated (r > 0.7). Menisci from older animals exhibiting osteoarthritic changes secreted significantly more MMP-1, MMP-3, and MMP-8 than healthy menisci from younger monkeys. Older menisci without significant osteoarthritic changes secreted more IL-7 than healthy young menisci while older osteoarthritic menisci secreted more IL-7 and granulocyte-macrophage colony-stimulating factor than healthy older menisci. CONCLUSIONS: Aged vervets develop naturally occurring knee osteoarthritis that includes involvement of the meniscus. Degenerative menisci secreted markedly increased amounts of matrix-degrading enzymes and inflammatory cytokines. These factors would be expected to act on the meniscus tissue and local joint tissues and may ultimately promote osteoarthritis development. These finding also suggest vervet monkeys are a useful animal model for studying the progression of osteoarthritis.

Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration.

FIG4 is a ubiquitously expressed phosphatase that, in complex with FAB1/PIKFYVE and VAC14, regulates the biosynthesis of the signaling lipid PI(3,5)P(2). Null mutation of Fig4 in the mouse results in spongiform degeneration of brain and peripheral ganglia, defective myelination and juvenile lethality. Partial loss-of-function of human FIG4 results in a severe form of Charcot-Marie-Tooth neuropathy. Neurons from null mice contain enlarged vacuoles derived from the endosome/lysosome pathway, and astrocytes accumulate proteins involved in autophagy. Other cellular defects include astrogliosis and microgliosis. To distinguish the contributions of neurons and glia to spongiform degeneration in the Fig4 null mouse, we expressed Fig4 under the control of the neuron-specific enolase promoter and the astrocyte-specific glial fibrillary acidic protein promoter in transgenic mice. Neuronal expression of Fig4 was sufficient to rescue cellular and neurological phenotypes including spongiform degeneration, gliosis and juvenile lethality. In contrast, expression of Fig4 in astrocytes prevented accumulation of autophagy markers and microgliosis but did not prevent spongiform degeneration or lethality. To confirm the neuronal origin of spongiform degeneration, we generated a floxed allele of Fig4 and crossed it with mice expressing the Cre recombinase from the neuron-specific synapsin promoter. Mice with conditional inactivation of Fig4 in neurons developed spongiform degeneration and the full spectrum of neurological abnormalities. The data demonstrate that expression of Fig4 in neurons is necessary and sufficient to prevent spongiform degeneration. Therapy for patients with FIG4 deficiency will therefore require correction of the deficiency in neurons.

Pro-inflammatory stimulation of meniscus cells increases production of matrix metalloproteinases and additional catabolic factors involved in osteoarthritis pathogenesis.

OBJECTIVE: Meniscus injury increases the risk of osteoarthritis; however, the biologic mechanism remains unknown. We hypothesized that pro-inflammatory stimulation of meniscus would increase production of matrix-degrading enzymes, cytokines and chemokines which cause joint tissue destruction and could contribute to osteoarthritis development. DESIGN: Meniscus and cartilage tissue from healthy tissue donors and total knee arthroplasties (TKAs) was cultured. Primary cell cultures were stimulated with pro-inflammatory factors [IL-1ß, IL-6, or fibronectin fragments (FnF)] and cellular responses were analyzed by real-time PCR, protein arrays and immunoblots. To determine if NF-κB was required for MMP production, meniscus cultures were treated with inflammatory factors with and without the NF-κB inhibitor, hypoestoxide. RESULTS: Normal and osteoarthritic meniscus cells increased their MMP secretion in response to stimulation, but specific patterns emerged that were unique to each stimulus with the greatest number of MMPs expressed in response to FnF. Meniscus collagen and connective tissue growth factor (CTGF) gene expression was reduced. Expression of cytokines (IL-1α, IL-1ß, IL-6), chemokines (IL-8, CXCL1, CXCL2, CSF1) and components of the NF-κB and tumor necrosis factor (TNF) family were significantly increased. Cytokine and chemokine protein production was also increased by stimulation. When primary cell cultures were treated with hypoestoxide in conjunction with pro-inflammatory stimulation, p65 activation was reduced as were MMP-1 and MMP-3 production. CONCLUSIONS: Pro-inflammatory stimulation of meniscus cells increased matrix metalloproteinase production and catabolic gene expression. The meniscus could have an active biologic role in osteoarthritis development following joint injury through increased production of cytokines, chemokines, and matrix-degrading enzymes.

Blood lactate clearance after maximal exercise depends on active recovery intensity.

AIM: High-intensity exercise is time-limited by onset of fatigue, marked by accumulation of blood lactate. This is accentuated at maximal, all-out exercise that rapidly accumulates high blood lactate. The optimal active recovery intensity for clearing lactate after such maximal, all-out exercise remains unknown. Thus, we studied the intensity-dependence of lactate clearance during active recovery after maximal exercise. METHODS: We constructed a standardized maximal, all-out treadmill exercise protocol that predictably lead to voluntary exhaustion and blood lactate concentration>10 mM. Next, subjects ran series of all-out bouts that increased blood lactate concentration to 11.5±0.2 mM, followed by recovery exercises ranging 0% (passive)-100% of the lactate threshold. RESULTS: Repeated measurements showed faster lactate clearance during active versus passive recovery (P<0.01), and that active recovery at 60-100% of lactate threshold was more efficient for lactate clearance than lower intensity recovery (P<0.05). Active recovery at 80% of lactate threshold had the highest rate of and shortest time constant for lactate clearance (P<0.05), whereas the response during the other intensities was graded (100%=60%>40%>passive recovery, P<0.05). CONCLUSION: Active recovery after maximal all-out exercise clears accumulated blood lactate faster than passive recovery in an intensity-dependent manner, with maximum clearance occurring at active recovery of 80% of lactate threshold.

Dietary practices in pyridoxine non-responsive homocystinuria: a European survey.

BACKGROUND: Within Europe, the management of pyridoxine (B6) non-responsive homocystinuria (HCU) may vary but there is limited knowledge about treatment practice. AIM: A comparison of dietetic management practices of patients with B6 non-responsive HCU in European centres. METHODS: A cross-sectional audit by questionnaire was completed by 29 inherited metabolic disorder (IMD) centres: (14 UK, 5 Germany, 3 Netherlands, 2 Switzerland, 2 Portugal, 1 France, 1 Norway, 1 Belgium). RESULTS: 181 patients (73% >16 years of age) with HCU were identified. The majority (66%; n=119) were on dietary treatment (1-10 years, 90%; 11-16 years, 82%; and >16 years, 58%) with or without betaine and 34% (n=62) were on betaine alone. The median natural protein intake (g/day) on diet only was, by age: 1-10 years, 12 g; 11-16 years, 11 g; and >16 years, 45 g. With diet and betaine, median natural protein intake (g/day) by age was: 1-10 years, 13 g; 11-16 years, 20 g; and >16 years, 38 g. Fifty-two percent (n=15) of centres allocated natural protein by calculating methionine rather than a protein exchange system. A methionine-free l-amino acid supplement was prescribed for 86% of diet treated patients. Fifty-two percent of centres recommended cystine supplements for low plasma concentrations. Target treatment concentrations for homocystine/homocysteine (free/total) and frequency of biochemical monitoring varied. CONCLUSION: In B6 non-responsive HCU the prescription of dietary restriction by IMD centres declined with age, potentially associated with poor adherence in older patients. Inconsistencies in biochemical monitoring and treatment indicate the need for international consensus guidelines.

Dietary management of urea cycle disorders: European practice.

BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Workplace oral health promotion activities among community-aged care workers: A qualitative exploration.

BACKGROUND: The workplace is an ideal-and priority-setting for health promotion activities. Developing and implementing workplace health promotion interventions, including oral health promotion activities, can help create health-supporting workplace environments. OBJECTIVE: To pilot workplace oral health promotion activities among staff working in the aged care sector, report their impact and explore participants' views on the factors that contribute to participation and effectiveness. METHODS: This study comprised three phases: (i) the development and face validation of the resources, (ii) a 3-h educational session and (iii) five interview sessions with participants 4-6 weeks following the education session. The recorded interviews were transcribed verbatim and analysed thematically. RESULTS: Eleven community-aged care workforce were invited to five feedback sessions. Ten participants were female and ranged in age from 18 to 64. All participants gave favourable comments about the content and delivery of the training session and accompanying resources. The participants felt that the benefits of WOHP include improved staff knowledge, awareness and oral care routine, the ability to share (and put into practice) the gained knowledge and information with their dependants, a lower risk of having poor oral health that adversely affects their well-being and work tasks, and potentially beneficial impacts on the organization's staff roster. Their attendance in the WOHP was facilitated by being paid to attend and scheduling the sessions during work time. Future WOHP suggestions include the possibility of a one-stop dental check-up at the workplace or staff dental care discounts from local dental practitioners and combining oral health with other health promotion activities. CONCLUSIONS: Planning and implementing WOHP was deemed acceptable and feasible in this study context and successfully achieved short-term impacts among community-aged care workers. Appropriate times and locations, organizational arrangements and a variety of delivery options contributed to successful programme planning and implementation.

Differential effects of nicotine treatment and ethanol self-administration on CYP2A6, CYP2B6 and nicotine pharmacokinetics in African green monkeys.

In primates, nicotine is metabolically inactivated in the liver by CYP2A6 and possibly CYP2B6. Changes in the levels of these two enzymes may affect nicotine pharmacokinetics and influence smoking behaviors. This study investigated the independent and combined effects of ethanol self-administration and nicotine treatment (0.5 mg/kg b.i.d. s.c.) on hepatic CYP2A6 and CYP2B6 levels (mRNA, protein, and enzymatic activity), in vitro nicotine metabolism, and in vivo nicotine pharmacokinetics in monkeys. CYP2A6 mRNA and protein levels and in vitro coumarin (selective CYP2A6 substrate) and nicotine metabolism were decreased by nicotine treatment but unaffected by ethanol. CYP2B6 protein levels and in vitro bupropion (selective CYP2B6 substrate) metabolism were increased by ethanol but unaffected by nicotine treatment; CYP2B6 mRNA levels were unaltered by either treatment. Combined ethanol and nicotine exposure decreased CYP2A6 mRNA and protein levels, as well as in vitro coumarin and nicotine metabolism, and increased CYP2B6 protein levels and in vitro bupropion metabolism, with no change in CYP2B6 mRNA levels. Chronic nicotine resulted in higher nicotine plasma levels achieved after nicotine administration, consistent with decreased CYP2A6. Ethanol alone, or combined with nicotine, resulted in lower nicotine plasma levels by a mechanism independent of the change in these enzymes. Thus, nicotine can decrease hepatic CYP2A6, reducing the metabolism of its substrates, including nicotine, whereas ethanol can increase hepatic CYP2B6, increasing the metabolism of CYP2B6 substrates. In vivo nicotine pharmacokinetics are differentially affected by ethanol and nicotine, but when both drugs are used in combination the effect more closely resembles ethanol alone.

Histopathology of naturally occurring and surgically induced osteoarthritis in mice.

OBJECTIVE: The morphology of lesions in mouse models of osteoarthritis (OA) has not been comprehensively characterized, in part because current histological assessments of OA focus primarily on articular cartilage (AC). In the present study, sections of murine stifle joints with naturally occurring (aged animals) and surgically induced (destabilized medial meniscus, DMM) OA were examined using a newly developed histological grading scheme that includes quantitative measurements and semiquantitative grades to evaluate multiple joint tissues. DESIGN: The data collected was analyzed using Principal Components Analysis (PCA); factor scores for each joint were generated. Individual parameters and factor scores were compared between surgical groups and among age groups. For comparison, the original Mankin Histological-Histochemical Grading System (HHGS) also was applied. RESULTS: Overall, lesions were most severe in the medial tibial plateaus. Significant changes in AC and neighboring bone were identified in surgically induced models and in naturally occurring disease. Mean factor scores provided a comprehensive evaluation of joint changes. An important new finding was that chondrocyte cell death within the AC was a commonly identified lesion and its extent significantly increased with age. While the Mankin HHGS detected significant overall differences in OA severity between surgical groups, it was not sensitive in detecting age-related differences, nor did it provide information regarding changes in individual tissues. CONCLUSION: These results demonstrate the utility of this newly developed murine OA grading scheme in identifying lesions in AC and in other joint tissues. Surgically induced changes were similar to those occurring naturally with aging.

A point prevalence survey of antibiotic use in four acute-care teaching hospitals utilizing the European Surveillance of Antimicrobial Consumption (ESAC) audit tool.

The objective of this research was to assess current patterns of hospital antibiotic prescribing in Northern Ireland and to determine targets for improving the quality of antibiotic prescribing. A point prevalence survey was conducted in four acute teaching hospitals. The most commonly used antibiotics were combinations of penicillins including ß-lactamase inhibitors (33·6%), metronidazole (9·1%), and macrolides (8·1%). The indication for treatment was recorded in 84·3% of the prescribing episodes. A small fraction (3·9%) of the surgical prophylactic antibiotic prescriptions was for >24 h. The results showed that overall 52·4% of the prescribed antibiotics were in compliance with the hospital antibiotic guidelines. The findings identified the following indicators as targets for quality improvement: indication recorded in patient notes, the duration of surgical prophylaxis and compliance with hospital antibiotic guidelines. The results strongly suggest that antibiotic use could be improved by taking steps to address the identified targets for quality improvement.

Dietary management of urea cycle disorders: UK practice.

BACKGROUND: There is no published data describing UK dietary management of urea cycle disorders (UCD). The present study describes dietary practices in UK inherited metabolic disorder (IMD) centres. METHODS: Cross-sectional data from 16 IMD centres were collected by a questionnaire describing the management of UCD patients on prescribed protein-restricted diets. RESULTS: One hundred and seventy-five patients [N-acetylglutamate synthase deficiency, n = 3; carbamoyl phosphate synthase deficiency (CPS), n = 8; ornithine transcarbamoylase deficiency (OTC), n = 75; citrullinaemia, n = 41; argininosuccinic aciduria (ASA), n = 36; arginase deficiency, n = 12] were reported; 70% (n = 123) aged 0-16 years; 30% (n = 52) >16 years. Prescribed median protein intake decreased with age (0-6 months: 2 g kg(-1) day(-1); 7-12 months: 1.6 g kg(-1) day(-1); 1-10 years: 1.3 g kg(-1) day(-1); 11-16 years: 0.9 g kg(-1) day(-1) and >16 years: 0.8 g kg(-1) day(-1)) with little variation between disorders. Adult protein prescription ranged 0.4-1.2 g kg(-1) day(-1) (40-60 g day(-1)). In the previous 2 years, 30% (n = 53) were given essential amino acid supplements (EAAs) (CPS, n = 2; OTC, n = 20; citrullinaemia, n = 15; ASA, n = 7; arginase deficiency, n = 9). EAAs were prescribed for low plasma quantitative essential amino acids (n = 13 centres); inadequate natural protein intake (n = 11) and poor metabolic control (n = 9). From diagnosis, one centre prescribed EAAs for all patients and one centre for severe defects only. Only 3% (n = 6) were given branch chain amino acid supplements. Enteral feeding tubes were used by 25% (n = 44) for feeds and 3% (n = 6) for medications. Oral energy supplements were prescribed in 17% (n = 30) of cases. CONCLUSIONS: In the UK, protein restriction based on World Health Organization 'safe intakes of protein', is the principle dietary treatment for UCD. EAA supplements are prescribed mainly on clinical need. Multicentre collaborative research is required to define optimal dietary treatments.

Vaccinating health care workers during an influenza pandemic.

BACKGROUND: In response to the 2009 H1N1 influenza pandemic, health care workers (HCWs) were offered immunization with H1N1 vaccine in addition to seasonal flu vaccine. Previously, low rates of influenza vaccine uptake in HCWs have been attributed to concerns about vaccine clinical effectiveness, side effects and access difficulties. AIMS: To explore H1N1 influenza vaccination of HCWs in London during 2009-10 and examine reasons for vaccine refusal. METHODS: An online questionnaire survey of doctors and nurses working in two primary care trust (PCT) areas and one acute trust area was carried out in London. RESULTS: Only 59% of the 221 respondents had been immunized with H1N1 influenza vaccine and 43% with seasonal influenza vaccine. The commonest reasons for remaining unvaccinated were 'side effects', 'swine flu not severe' and 'concerns about clinical effectiveness of the vaccine'. Respondents who had been vaccinated that season gave positive feedback on their experience. CONCLUSIONS: While uptake among HCWs was greater for the pandemic vaccine than is usually seen with seasonal influenza vaccine, this survey suggests that in this area of London during the 2009 pandemic, HCWs refused H1N1 vaccination due to concerns about clinical effectiveness, side effects and perceptions that H1N1 infection was not generally severe. We found no evidence to suggest poor access was a barrier to H1N1 vaccination of HCWs. If good access is maintained, the key barrier to improving seasonal flu vaccine uptake lies with informing the personal risk assessment made by the HCW.

Bio-monitoring for uranium using stream-side terrestrial plants and macrophytes.

This study evaluated the abilities of various plant species to act as bio-monitors for environmental uranium (U) contamination. Vegetation and soil samples were collected from a U processing facility. The water-way fed from facility storm and processing effluents was the focal sample site as it represented a primary U transport mechanism. Soils and sediments from areas exposed to contamination possessed U concentrations that averaged 630 mg U kg(-1). Aquatic mosses proved to be exceptional accumulators of U with dry weight (dw) concentrations measuring as high as 12,500 mg U kg(-1) (approximately 1% of the dw mass was attributable to U). The macrophytes (Phragmites communis, Scripus fontinalis and Sagittaria latifolia) were also effective accumulators of U. In general, plant roots possessed higher concentrations of U than associated upper portions of plants. For terrestrial plants, the roots of Impatiens capensis had the highest observed levels of U accumulation (1030 mg kg(-1)), followed by the roots of Cyperus esculentus and Solidago speciosa. The concentration ratio (CR) characterized dry weight (dw) vegetative U levels relative to that in associated dw soil. The plant species that accumulated U at levels in excess of that found in the soil were: P. communis root (CR, 17.4), I. capensis root (CR, 3.1) and S. fontinalis whole plant (CR, 1.4). Seven of the highest ten CR values were found in the roots. Correlations with concentrations of other metals with U were performed, which revealed that U concentrations in the plant were strongly correlated with nickel (Ni) concentrations (correlation: 0.992; r-squared: 0.984). Uranium in plant tissue was also strongly correlated with strontium (Sr) (correlation: 0.948; r-squared: 0.899). Strontium is chemically and physically similar to calcium (Ca) and magnesium (Mg), which were also positively-correlated with U. The correlation with U and these plant nutrient minerals, including iron (Fe), suggests that active uptake mechanisms may influence plant U accumulation.

Independent and combined effects of ethanol self-administration and nicotine treatment on hepatic CYP2E1 in African green monkeys.

Cytochrome P450 2E1 metabolizes ethanol and also bioactivates many toxins and procarcinogens. Elevated levels of hepatic CYP2E1 are associated with an increased susceptibility to chemical toxicity and carcinogenesis. This study investigated the induction of hepatic CYP2E1 by ethanol and nicotine, alone and in combination, in a nonhuman primate model. Monkeys that self-administered ethanol and that received subcutaneous injections of nicotine (0.5 mg/kg b.i.d.), alone and in combination, were compared with control animals (four groups, n = 10/group). Chlorzoxazone (CZN) was used as a probe drug to phenotype in vivo CYP2E1 activity before and after chronic ethanol and/or nicotine exposure. CYP2E1 protein levels and in vitro chlorzoxazone metabolism were assessed in liver microsomes. Average daily ethanol consumption was ≈3.0 g/kg (blood ethanol levels ≈24 mM) and was unaffected by nicotine treatment. Ethanol self-administration and nicotine treatment, alone and in combination, significantly increased in vivo CZN disposition compared with that in control animals. The effect of ethanol was only observed at higher levels of intake. Ethanol and nicotine increased CYP2E1 protein levels and in vitro CZN metabolism, with combined exposure to both drugs resulting in the greatest increase. The effect of ethanol was also dependent on level of intake. Chronic exposure to ethanol and nicotine induced hepatic CYP2E1 activity and protein levels, particularly when both drugs were used in combination and when ethanol intake was high. These results have important implications for public health, given the association between elevated CYP2E1 and disease, and the large proportion of individuals who are exposed to ethanol and nicotine, often in combination.

Transtracheal jet ventilation in 50 patients with severe airway compromise and stridor.

BACKGROUND: Management of the airway is difficult in patients with pharyngeal or laryngeal pathology caused by malignancy, extensive surgery, or radiotherapy scarring, particularly when undergoing pharyngolaryngeal surgery. Tracheal intubation, with or without fibreoptic guidance, is often impractical because of the severe glottic stenosis and primary tracheostomy under local anaesthesia has been the preferred technique. However, complication rates as high as 30% have been reported after primary tracheostomy and there is the potential for long-term morbidity. High-frequency jet ventilation (HFJV) has several advantages over other techniques in the management of the difficult airway and can be delivered by supraglottic and infraglottic routes. To date, no large series has described the use of transtracheal HFJV (TTHFJV) in adult patients with stridor and critical airway obstruction. METHODS: We report a prospective, descriptive audit of the safe use of TTHFJV in patients with severe airway compromise and stridor undergoing pharyngolaryngeal surgery (50 consecutive procedures in 44 patients). RESULTS: TTHFJV was successful in all 50 cases. There were no major complications and the incidence of minor complications was 20% with no subsequent morbidity. CONCLUSIONS: We attribute this low incidence to the use of an automated jet ventilator with airway pressure monitoring and control, and the alteration of ventilator parameters by an experienced anaesthetist.

Non-traumatic dental presentations at emergency departments in New Zealand.

INTRODUCTION: Many low-income New Zealanders attend emergency departments (EDs) for relief of dental pain and infection. This places a substantial burden on EDs. Better understanding of non-traumatic dental presentations (NTDPs) will aid the development of relevant health policy and clinical management strategies. AIM: To explore the nature, context and impact of NTDPs on New Zealand EDs. METHODS: A mixed-methods approach was used. Routinely collected data on NTDPs to ED at four New Zealand hospitals were analysed descriptively, and semi-structured interviews with ED and dental personnel (n=20) from the four hospitals were conducted and analysed thematically. RESULTS: Young adults (20-39 years), and Maori and Pacific people, were frequent ED attenders for NTDPs; repeat visits were common. Most were seen by non-dental health practitioners. Cost and access were identified as barriers to dental care. Management of NTDPs generally involved analgesics for relief of pain and antibiotics for infection management. All participants said definitive care pathways for NTDPs were lacking. There is potential to improve staff training in diagnosis and anaesthetic administration. However, participants were more interested in referral pathways and public funding for dental care. CONCLUSIONS: Accessible and equitable dental care pathways and policies are urgently required to enable timely and appropriate care for NTDPs.