Studies on the environmental fate, ecotoxicology and toxicology of 2-methyl 1,3-propanediol.

2-methyl 1,3-propandiol (MPD) is a low molecular weight, colorless glycol used in polymer and coating applications. The log Kow of -0.6 suggests partitioning to aqueous phases with a low concern for possible bioaccumulation. MPD was found to be inherently biodegradable. Ecotoxicological results in several aquatic and terrestrial species found no significant hazard potential. MPD is rapidly absorbed via the oral and dermal routes, metabolized to 3-hydroxybutyrate, and excreted in urine with a half-life of 3.6 h. Acute toxicity testing found low toxicity via all routes. Barely perceptible skin irritation was observed in human volunteers, whereas there was no evidence of irritation in rabbits. Skin sensitization in Guinea pigs was negative. Human skin patch results indicated minimal response in about 1% of individuals. There was no evidence of mutagenicity using bacterial and mammalian test systems. A 90-day oral study in rats found no adverse effects at any dose. Three developmental toxicity studies in rats and rabbits, found no treatment-related maternal toxicity, fetal toxicity or malformations. A two-generation reproduction study in rats found no consistent treatment-related adverse effects on reproduction in either generation. No carcinogenicity studies with MPD were identified. MPD presents a low degree of toxicological and ecotoxicological or environmental hazard.

The Flint Animal Cancer Center (FACC) Canine Tumour Cell Line Panel: a resource for veterinary drug discovery, comparative oncology and translational medicine.

Mammalian cell tissue culture has been a critical tool leading to our current understanding of cancer including many aspects of cellular transformation, growth and response to therapies. The current use of large panels of cell lines with associated phenotypic and genotypic information now allows for informatics approaches and in silico screens to rapidly test hypotheses based on simple as well as complex relationships. Current cell line panels with large amounts of associated drug sensitivity and genomics data are comprised of human cancer cell lines (i.e. NCI60 and GDSC). There is increased recognition of the contribution of canine cancer to comparative cancer research as a spontaneous large animal model with application in basic and translational studies. We have assembled a panel of canine cancer cell lines to facilitate studies in canine cancer and report here phenotypic and genotypic data associated with these cells.

Comparative analysis of MAPK and PI3K/AKT pathway activation and inhibition in human and canine melanoma.

The lack of advanced animal models of human cancers is considered a barrier to developing effective therapeutics. Canine and human melanomas are histologically disparate but show similar disease progression and response to therapies. The purpose of these studies was to compare human and canine melanoma tumours and cell lines regarding MAPK and PI3K/AKT signalling dysregulation, and response to select molecularly targeted agents. Pathway activation was investigated via microarray and mutational analysis. Growth inhibition and cell cycle effects were assessed for pathway inhibitors AZD6244 (MAPK) and rapamycin (PI3K/AKT) in human and canine melanoma cells. Human and canine melanoma share similar differential gene expression patterns within the MAPK and PI3K/AKT pathways. Constitutive pathway activation and similar sensitivity to AZD6244 and rapamycin was observed in human and canine cells. These results show that human and canine melanoma share activation and sensitivity to inhibition of cancer-related signalling pathways despite differences in activating mutations.

Extracorporeal membrane oxygenation: look out for a retrieval team coming to a hospital near you!

In 2011 the Department of Health commissioned five hospitals in England to provide extracorporeal membrane oxygenation (ECMO) to adults with severe respiratory failure. This review will explain the principles underlying ECMO, describe the circuitry used and discuss the care of a patient receiving support. We hope that it will be of use should a patient at your hospital be considered a candidate for ECMO.

Tertiary butyl alcohol in drinking water induces phase I and II liver enzymes with consequent effects on thyroid hormone homeostasis in the B6C3F1 female mouse.

Tertiary butyl alcohol (TBA) was administered to groups of 15 female B6C3F1 mice in drinking water at concentrations of 0, 2.0 or 20 mg TBA ml(-1), for 14 days, for assessment of gross and histological changes in the liver and thyroid, thyroid hormones (T3, T4, and TSH), total hepatic cytochrome P450 (Cyp) content, specific Cyp activities and quantitative PCR analysis of specific Cyp enzymes (Cyp1a1, Cyp2b9, Cyp2b10, Cyp3a11), sulfuryltransferases (ST1a1, ST2a2, and STn) and glucuronyltransferases (UGT1a1, UGT2b1, and UGT2b5). Phenobarbital (PB) was administered to a positive control group by oral gavage at a daily dose of 80 mg kg(-1). TBA caused, on day 14, a reduction in circulating T3 (12-15% decrease) and a dose-dependent reduction in T4 (13-22% decrease), with no evidence of thyroid pathology. Two of five livers examined in the 20 mg TBA ml(-1) dose group showed mild, diffuse centrilobular hypertrophy. On day 14, Cyp 7-benzoxyresorufin-O-debenzylase activity was significantly induced 12-fold by TBA at 20 mg ml(-1), and 1.8-fold at the 2.0 mg TBA ml(-1) concentration. Cyp 7-pentoxyresorufin-O-dealkylase activity was slightly induced (2.1-fold) by 20 mg TBA ml(-1) on day 14. Quantitative PCR analysis of gene transcripts showed a significant induction of Cyp2b10 and ST1a1 with both TBA concentrations, and a slight induction of Cyp2b9 at 20 mg TBA ml(-1) only. PB induced all phase I and phase II gene transcripts except for Cyp1a1 and Cyp2b9. These findings suggest that TBA, at and below doses used in chronic studies, is an inducer of phase I and phase II liver enzymes, with resulting decreases in circulating thyroid hormones in B6C3F1 mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) plasma concentrations in residents of Paritutu, New Zealand: evidence of historical exposure.

An assessment of community exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was undertaken in Paritutu, New Zealand. The suburb lies adjacent to an agrichemical facility that produced 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), between 1962 and 1987. Soil TCDD measurements from 73 nearby addresses demonstrated a pattern of TCDD deposition consistent with an aerial plume following the prevailing local wind patterns and the agrichemical plant as the point source. Blood samples were taken from 52 volunteers having lived for three or more years in Paritutu between 1962 and 1987. Candidate selection focused primarily on individuals who were most likely to show elevated TCDD blood lipid levels when compared to age and gender stratified national average blood concentrations, and secondarily on individuals that provided additional information about specific exposure periods, potential exposures of younger age groups, and specific dietary patterns. A multipathway exposure model was used to estimate serum TCDD levels in each participant. Age and gender-specific TCDD elimination kinetics were also considered. Historical TCDD environmental concentrations were back-calculated from soil concentrations at each residence assuming TCDD releases occurred pre-dominantly between 1962 and 1975. Serum was analysed for chlorinated dibenzodioxins and dibenzofurans, and a subset was analysed for dioxin-like polychlorinated biphenyls. TCDD in serum lipid exceeded two standard deviations above national background levels for 14 participants, and 3 standard deviations for 10 participants. The highest TCDD lipid concentration was 33.3 ng/kg-lipid, or 11 times higher than the comparative 1997 national average. Elevated TCDD concentrations were observed primarily, but not exclusively, in the older study participants who had been in residence in Paritutu before 1968. The study demonstrated TCDD exposure in this community, occurring most likely through the aerial route, and most probably from fugitive emissions during manufacture.

Influence of body heat content on hand function during prolonged cold exposures.

We examined the influence of 1) prior increase [preheating (PHT)], 2) increase throughout [heating (HT)], and 3) no increase [control (Con)] of body heat content (H(b)) on neuromuscular function and manual dexterity of the hands during a 130-min exposure to -20 degrees C (coldEx). Ten volunteers randomly underwent three passive coldEx, incorporating a 10-min moderate-exercise period at the 65th min while wearing a liquid conditioning garment (LCG) and military arctic clothing. In PHT, 50 degrees C water was circulated in the LCG before coldEx until core temperature was increased by 0.5 degrees C. In HT, participants regulated the inlet LCG water temperature throughout coldEx to subjective comfort, while the LCG was not operating in Con. Thermal comfort, rectal temperature, mean skin temperature, mean finger temperature (T(fing)), change in H(b) (DeltaH(b)), rate of body heat storage, Purdue pegboard test, finger tapping, handgrip, maximum voluntary contraction, and evoked twitch force of the first dorsal interosseus muscle were recorded. Results demonstrated that, unlike in HT and PHT, thermal comfort, rectal temperature, mean skin temperature, twitch force, maximum voluntary contraction, and finger tapping declined significantly in Con. In contrast, T(fing) and Purdue pegboard test remained constant only in HT. Generalized estimating equations demonstrated that DeltaH(b) and T(fing) were associated over time with hand function, whereas no significant association was detected for rate of body heat storage. It is concluded that increasing H(b) not only throughout but also before a coldEx is effective in maintaining hand function. In addition, we found that the best indicator of hand function is DeltaH(b) followed by T(fing).

Malleability of human skeletal muscle Na(+)-K(+)-ATPase pump with short-term training.

To investigate the hypothesis that short-term submaximal training would result in changes in Na(+)-K(+)-ATPase content, activity, and isoform distribution in skeletal muscle, seven healthy, untrained men [peak aerobic power (peak oxygen consumption; Vo(2 peak)) = 45.6 ml x kg(-1) x min(-1) (SE 5.4)] cycled for 2 h/day at 60-65% Vo(2 peak) for 6 days. Muscle tissue, sampled from the vastus lateralis before training (0 days) and after 3 and 6 days of training and analyzed for Na(+)-K(+)-ATPase content, as assessed by the vanadate facilitated [(3)H]ouabain-binding technique, was increased (P < 0.05) at 3 days (294 +/- 8.6 pmol/g wet wt) and 6 days (308 +/- 15 pmol/g wet wt) of training compared with 0 days (272 +/- 9.7 pmol/g wet wt). Maximal Na(+)-K(+)-ATPase activity as evaluated by the 3-O-methylfluorescein phosphatase assay was increased (P < 0.05) by 6 days (53.4 +/- 5.9 nmol x h(-1) x mg protein(-1)) but not by 3 days (35.9 +/- 4.5 nmol x h(-1) x mg protein(-1)) compared with 0 days (37.8 +/- 3.7 nmol x h(-1) x mg protein(-1)) of training. Relative isoform distribution, measured by Western blot techniques, indicated increases (P < 0.05) in alpha(2)-content by 3 days and beta(1)-content by 6 days of training. These results indicate that prolonged aerobic exercise represents a potent stimulus for the rapid adaptation of Na(+)-K(+)-ATPase content, isoform, and activity characteristics.

Effects of prolonged exercise and recovery on sarcoplasmic reticulum Ca2+ cycling properties in rat muscle homogenates.

AIM: To examine the effects of exercise and exercise plus active and passive recovery on sarcoplasmic reticulum (SR) Ca2+-handling properties. METHODS: Crude muscle homogenates were prepared from adult rat gastrocnemius muscle from two experiments. In one experiment, the muscle was extracted immediately after prolonged treadmill running (RUN), after a 45 min period of reduced exercise intensity (RUN+) following RUN and compared with controls (CON). In the second experiment, muscle was extracted during passive recovery following the same run protocol at 10 min (REC10), 25 min (REC25) and 45 min (REC45) and compared with CON. RESULTS: Sarcoplasmic reticulum Ca2+-uptake was 31% higher (P < 0.05) in RUN+ compared with CON and RUN. Higher values (P < 0.05) were also found in REC25 (48%) and REC45 (50%) compared with CON. Maximal Ca2+-ATPase was increased by 23% (P < 0.05) in RUN+ compared with CON and RUN and by 65-68% (P < 0.05) in REC25 and REC45 compared with CON. A higher (P < 0.05) Hill coefficient for Ca2+-ATPase activity was observed in RUN+ (2.3 +/- 0.2) compared with CON (1.7 +/- 0.2) or RUN (1.6 +/- 0.2), but not for any REC conditions. In addition, the coupling ratio (Ca2+-uptake/Ca2+-ATPase activity) was higher (P < 0.05) in RUN+ (2.2 +/- 0.10) compared with CON (1.9 +/- 0.05) and RUN (1.9 +/- 0.08). CONCLUSIONS: It is concluded that in crude homogenates, SR Ca2+-uptake and Ca2+-ATPase activity are elevated in recovery following prolonged running and that the elevation in these properties is more pronounced during passive compared with active recovery.

Na+-K+-ATPase in rat skeletal muscle: content, isoform, and activity characteristics.

The purpose of this study was to investigate the hypothesis that muscle Na+-K+-ATPase activity is directly related to Na+-K+-ATPase content and the content of the alpha2-catalytic isoform in muscles of different fiber-type composition. To investigate this hypothesis, tissue was sampled from soleus (Sol), red gastrocnemius (RG), white gastrocnemius (WG), and extensor digitorum longus (EDL) muscles at rest from 38 male Wistar rats weighing 413 +/- 6.0 g (mean +/- SE). Na+-K+-ATPase activity was determined in homogenates (Hom) and isolated crude membranes (CM) by the regenerating ouabain-inhibitable hydrolytic activity assay (ATPase) and the 3-O-methylfluorescein K+-stimulated phosphatase (3-O-MFPase) assay in vitro. In addition, Na+-K+-ATPase content (Bmax) and the distribution of alpha1-, alpha2-, beta1-, and beta2-isoforms were determined by [3H]ouabain binding and Western blot, respectively. For the ATPase assay, differences (P < 0.05) in enzyme activity between muscles were observed in Hom (EDL > WG) and in CM (Sol > EDL = WG). For the 3-O-MFPase assay, differences (P < 0.05) were also found for Hom (Sol > RG = EDL > WG) and CM (Sol = WG > RG). For Bmax, differences in the order of RG = EDL > Sol = WG (P < 0.05) were observed. Isoform distribution was similar between Hom and CM and indicated in CM, a greater density (P < 0.05) of alpha1 in Sol than WG and EDL (P < 0.05), but more equal distribution of alpha2 between muscles. The beta1 was greater (P < 0.05) in Sol and RG, and the beta2 was greater in EDL and WG (P < 0.05). Over all muscles, the correlation (r) between Hom 3-O-MFPase and Bmax was 0.45 (P < 0.05) and between Hom alpha2 and Bmax, 0.59 (P < 0.05). The alpha1 distribution correlated to Hom 3-O-MFPase (r = 0.79, P < 0.05) CM ATPase (r = 0.69, P < 0.005) and CM 3-O-MFPase activity (r = 0.32, P < 0.05). The alpha2 distribution was not correlated with any of the Na+-K+-ATPase activity measurements. The results indicate generally poor relationships between activity and total pump content and alpha2 isoform content of the Na+-K+-ATPase. Several factors, including the type of preparation and the type of assay, appear important in this regard.

Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke.

OBJECTIVE: To provide a hazard prioritisation for reported chemical constituents of cigarette smoke using toxicological risk assessment principles and assumptions. The purpose is to inform prevention efforts using harm reduction. DATA SOURCES: International Agency for Research on Cancer Monographs; California and US Environmental Protection Agency cancer potency factors (CPFs) and reference exposure levels; scientific journals and government reports from the USA, Canada, and New Zealand. STUDY SELECTION: This was an inclusive review of studies reporting yields of cigarette smoke constituents using standard ISO methods. DATA EXTRACTION: Where possible, the midpoint of reported ranges of yields was used. DATA SYNTHESIS: Data on 158 compounds in cigarette smoke were found. Of these, 45 were known or suspected human carcinogens. Cancer potency factors were available for 40 of these compounds and reference exposure levels (RELs) for non-cancer effects were found for 17. A cancer risk index (CRI) was calculated by multiplying yield levels with CPFs. A non-cancer risk index (NCRI) was calculated by dividing yield levels with RELs. Gas phase constituents dominate both CRI and NCRI for cigarette smoke. The contribution of 1,3-butadiene (BDE) to CRI was more than twice that of the next highest contributing carcinogen (acrylonitrile) using potencies from the State of California EPA. Using those potencies from the USEPA, BDE ranked third behind arsenic and acetaldehyde. A comparison of CRI estimates with estimates of smoking related cancer deaths in the USA showed that the CRI underestimates the observed cancer rates by about fivefold using ISO yields in the exposure estimate. CONCLUSIONS: The application of toxicological risk assessment methods to cigarette smoke provides a plausible and objective framework for the prioritisation of carcinogens and other toxicant hazards in cigarette smoke. However, this framework does not enable the prediction of actual cancer risk for a number of reasons that are discussed. Further, the lack of toxicology data on cardiovascular end points for specific chemicals makes the use of this framework less useful for cardiovascular toxicity. The bases for these priorities need to be constantly re-evaluated as new toxicology information emerges.

Coexistence of potentiation and low-frequency fatigue during voluntary exercise in human skeletal muscle.

The role of muscle potentiation in overcoming low-frequency fatigue (LFF) as it developed during submaximal voluntary exercise was investigated in eight males (age 26.4 +/- 0.7 years, mean +/- SE) performing isometric leg extension at approximately 30% of maximal voluntary contraction for 60 min using a 0.5-duty cycle (1 s contraction, 1 s rest). At 5, 20, 40, and 60 min, exercise was interrupted for 3 min, and the maximum positive rate of force development (+dF/dtmax) and maximal twitch force (Pt) were measured in maximal twitch contractions at 0, 1, 2, and 3 min of rest (R0, R1, R2, R3); they were also measured at 15 min of recovery following the entire 60-min exercise period. These measures were compared with pre-exercise (PRE) as an indicator of potentiation. Force at low frequency (10 Hz) was also measured at R0, R1, R2, and R3, and at 15 min of recovery, while force at high frequency (100 Hz) was measured only at R0 and R3 and in recovery. Voluntary exercise increased twitch +dF/dtmax at R0 following 5, 20, 40, and 60 min of exercise, from 2553 +/- 150 N/s at PRE to 39%, 41%, 42%, and 36% above PRE, respectively (P<0.005). Twitch +dF/dtmax decayed at brief rest (R3) following 20, 40, and 60 min of exercise (P<0.05). Pt at R0 following 5 and 20 min of exercise was above that at PRE (P<0.05), indicating that during the early phase of moderate-intensity repetitive exercise, potentiation occurs in the relative absence of LFF. At 40 and 60 min of exercise, Pt at R0 was unchanged from PRE. The LFF (10 Hz) induced by the protocol was evident at 40 and 60 min (R0-R3; P<0.05) and at 15 min following exercise (P<0.05). High-frequency force was not significantly compromised by the protocol. Since twitch force was maintained, these results suggest that as exercise progresses, LFF develops, which can be compensated for by potentiation.

Reduced activity of muscle Na(+)-K(+)-ATPase after prolonged running in rats.

The purpose of this study was to investigate the hypothesis that Na(+)-K(+)-ATPase activity is reduced in muscle of different fiber composition after a single session of aerobic exercise in rats. In one experiment, untrained female Sprague-Dawley rats (weight 275 +/- 21 g; means +/- SE; n = 30) were run (Run) on a treadmill at 21 m/min and 8% grade until fatigue, or to a maximum of 2 h, which served as control (Con), or performed an additional 45 min of low-intensity exercise at 10 m/min (Run+). In a second experiment, utilizing rats of similar characteristics (weight 258 +/- 18 g; n = 32), Run was followed by passive recovery (Rec). Directly after exercise, rats were anesthetized, and tissue was extracted from Soleus (Sol), red vastus lateralis (RV), white vastus lateralis (WV), and extensor digitorum longus (EDL) and frozen for later analysis. 3-O-methylfluorescein phosphatase activity (3-O-MFPase) was determined as an indicator of Na(+)-K(+)-ATPase activity, and glycogen depletion identified recruitment of each muscle during exercise. 3-O-MFPase was decreased (P < 0.05) at Run+ by an average of 12% from Con in all muscles (P < 0.05). No difference was found between Con and Run. Glycogen was lower (P < 0.05) by 65, 57, 44, and 33% (Sol, EDL, RV, and WV, respectively) at Run, and there was no further depletion during the continued low-intensity exercise period. No differences in Na(+)-K(+)-ATPase activity was observed between Con and Rec. The results of this study indicate that inactivation of Na(+)-K(+)-ATPase can be induced by aerobic exercise in a volume-dependent manner and that the inactivation that occurs is not specific to muscles of different fiber-type composition. Inactivation of Na(+)-K(+)-ATPase suggests intrinsic structural modifications by mechanisms that are unclear.

Human neuromuscular fatigue is associated with altered Na+-K+-ATPase activity following isometric exercise.

The purpose of this study was to investigate the hypothesis that reductions in Na+-K+- ATPase activity are associated with neuromuscular fatigue following isometric exercise. In control (Con) and exercised (Ex) legs, force and electromyogram were measured in 14 volunteers [age, 23.4 +/- 0.7 (SE) yr] before and immediately after (PST0), 1 h after (PST1), and 4 h after (PST4) isometric, single-leg extension exercise at ~60% of maximal voluntary contraction for 30 min using a 0.5 duty cycle (5-s contraction, 5-s rest). Tissue was obtained from vastus lateralis muscle before exercise in Con and after exercise in both the Con (PST0) and Ex legs (PST0, PST1, PST4), for the measurements of Na+-K+-ATPase activity, as determined by the 3-O-methylfluorescein phosphatase (3-O-MFPase) assay. Voluntary (maximal voluntary contraction) and elicited (10, 20, 50, 100 Hz) force was reduced 30-55% (P < 0.05) at PST0 and did not recover by PST4. Muscle action potential (M-wave) amplitude and area (measured in the vastus medialis) and 3-O-MFPase activity at PST0-Ex were less than that at PST0-Con (P < 0.05) by 37, 25, and 38%, respectively. M-wave area at PST1-Ex was also less than that at PST1-Con (P < 0.05). Changes in 3-O-MFPase activity correlated to changes in M-wave area across all time points (r = 0.38, P < 0.05, n = 45). These results demonstrate that Na+-K+- ATPase activity is reduced by sustained isometric exercise in humans from that in a matched Con leg and that this reduction in Na+-K+-ATPase activity is associated with loss of excitability as indicated by M-wave alterations.

Assessment of cancer risk from ethylene oxide residues in spices imported into New Zealand.

Quantitative estimates of cancer risks from ethylene oxide (ETO) residues were constructed based on 200 retail samples of various spices in New Zealand. Two samples of cinnamon contained detectable ETO. The highest value encountered was 15 ppm. ETO was not detected in the remaining 198 samples. However, 31 samples had detectable levels of ethylene chlorohydrin (ECH) and/or ethylene bromohydrin (EBH). A conservative estimate of ETO intake, based on average spice consumption, was 3.4 x 10(-6) mg/kg/day. Cancer potency factors for ETO ranging from 0.29 to 0.55 (mg/kg/day)(-1) were used to form cancer risk estimates. The resulting estimates of average lifetime excess cancer risk was 0.8 x 10(-6) to 1.7 x 10(-6). The US 97.5 percentile value for spice consumption (2.8 kg spices per year), gave an extreme upper-end estimate of lifetime cancer risk of approximately 1.4 x 10(-5). These risks are practically negligible considering the conservative assumptions used in estimating exposure to ETO. The exposures to ECH and EBH are 200-300-fold higher than to ETO. These compounds are of lesser potency to ETO in terms of mutagenicity or carcinogenicity in studies to date. However, the precise contribution of these compounds to the cancer risk estimate is uncertain due to large toxicological data gaps, including the absence of a 2-year cancer bioassay by the oral route.

A health risk benchmark for the neurologic effects of styrene: comparison with NOAEL/LOAEL approach.

Benchmark dose (BMD) analysis was used to estimate an inhalation benchmark concentration for styrene neurotoxicity. Quantal data on neuropsychologic test results from styrene-exposed workers [Mutti et al. (1984). American Journal of Industrial Medicine, 5, 275-286] were used to quantify neurotoxicity, defined as the percent of tested workers who responded abnormally to > or = 1, > or = 2, or > or = 3 out of a battery of eight tests. Exposure was based on previously published results on mean urinary mandelic- and phenylglyoxylic acid levels in the workers, converted to air styrene levels (15, 44, 74, or 115 ppm). Nonstyrene-exposed workers from the same region served as a control group. Maximum-likelihood estimates (MLEs) and BMDs at 5 and 10% response levels of the exposed population were obtained from log-normal analysis of the quantal data. The highest MLE was 9 ppm (BMD = 4 ppm) styrene and represents abnormal responses to > or = 3 tests by 10% of the exposed population. The most health-protective MLE was 2 ppm styrene (BMD = 0.3 ppm) and represents abnormal responses to > or = 1 test by 5% of the exposed population. A no observed adverse effect level/lowest observed adverse effect level (NOAEL/LOAEL) analysis of the same quantal data showed workers in all styrene exposure groups responded abnormally to > or = 1, > or = 2, or > or = 3 tests, compared to controls, and the LOAEL was 15 ppm. A comparison of the BMD and NOAEL/LOAEL analyses suggests that at air styrene levels below the LOAEL, a segment of the worker population may be adversely affected. The benchmark approach will be useful for styrene noncancer risk assessment purposes by providing a more accurate estimate of potential risk that should, in turn, help to reduce the uncertainty that is a common problem in setting exposure levels.

Self-referral in point-of-service health plans.

CONTEXT: Most health maintenance organizations offer products with loosened restrictions on patients' access to specialty care. One such product is the point-of-service (POS) plan, which combines "gatekeeping" arrangements with the ability to self-refer at increased out-of-pocket costs. Few data are available from formal evaluations of this new type of plan. OBJECTIVES: To comprehensively describe the self-referral process in POS plans by quantifying rates of self-referral, identifying patients most likely to self-refer, characterizing patients' reasons for self-referral, and assessing satisfaction with specialty care. DESIGN: Retrospective cohort analysis using administrative databases composed of members aged 0 to 64 years who were enrolled in 3 POS health plans in the Midwest (n = 265 843), Northeast (n = 80 292), and mid-Atlantic (n = 39 888) regions for 6 to 12 months in 1996, and a 1997 telephone survey of specialty care users (n = 606) in the midwestern plan. MAIN OUTCOME MEASURES: Self-referred service use and charges, reasons for self-referral, and satisfaction with specialty care. RESULTS: Overall, 8.8% of enrollees in the midwestern POS plan, 16.7% in the northeastern plan, and 17.3% in the mid-Atlantic plan self-referred for at least 1 physician or nonphysician clinician visit. The proportions of enrollees self-referring to generalists (4.7%-8.5%) were slightly higher than the proportions self-referring to specialists (3.7%-7.2%) across all 3 plans. Nine percent to 16% of total charges were due to self-referral. The chances of self-referral to a specialist were increased for patients with chronic and orthopedic conditions, higher cost sharing for physician-approved services, and less continuity with their regular physician. Patients who self-referred to specialists preferred to access specialty care directly (38%), reported relationship problems with their regular physicians (28%), had an ongoing relationship with a specialist (23%), were confused about insurance rules (8%), and did not have a regular physician (3%). Compared with those referred to specialists by a physician, patients who self-referred were more satisfied with the specialty care they received. CONCLUSIONS: Having the option to self-refer is enough for most POS plan enrollees; 93% to 96% of enrollees did not exercise their POS option to obtain specialty care via self-referral during a 1-year interval. The potential downside of uncoordinated, self-referred service use in POS health plans is limited and counterbalanced by higher patient satisfaction with specialist services.

Care-seeking behavior for upper respiratory infections.

BACKGROUND: Many recent efforts to reduce unnecessary medical services have targeted care of upper respiratory infections (URIs). We tested whether patients who seek care very early in their illness differ from those who seek care later and whether they might require a different approach to care. METHODS: We surveyed by telephone 257 adult patients and 249 parents of child patients who called or visited one of 3 primary care clinics within 10 days (adults) or 14 days (parents) of the onset of uncomplicated URI symptoms. Those who contacted the clinic within the first 2 days of illness were compared with those who made contact later. RESULTS: Although 28% of adults and 41% of parents contacted their clinic within the first 2 days of symptom onset, we found very few differences in the characteristics of the caller or patient between those who called early and later. The illnesses of those who called early were not more severe, and they did not have different beliefs, histories, approaches to medical care, or needs. The only clinician-relevant difference was that adult patients calling in the first 2 days had a greater desire to rule out complications (84.7% vs 64.1% calling in 3-5 days and 70.6% calling after 5 days of illness, P < or = .05). CONCLUSIONS: Those who seek medical care very early for a URI do not appear to be different in clinically important ways. If we are going to reduce overuse of medical care and antibiotics for URIs, clinical trials of more effective and efficient strategies are needed to encourage home care and self-management.

The effects of acute passive stretch on muscle protein synthesis in humans.

We examined the effect of an isolated bout of maximal tolerated passive stretch on fractional muscle protein synthetic rate in human soleus muscle. Eight healthy males performed two separate trials with the same leg: one session of passive stretch and one of intermittent active isometric contraction at a force equivalent to that which occurred during the passive stretch trial. This force was approximately 40% of maximum voluntary contraction force and produced volitional fatigue in approximately 27 min. Intermittent passive stretch, for the same duration, elicited a 6.1 degrees increase in joint angle (P<.0005) with silent electromyography. Fractional protein synthetic rate from experimental and control soleus in each trial was assessed from biopsy samples over the period 10-22 hr postexercise by the incorporation rate of L-[1-13C] leucine into muscle. Protein synthesis was elevated in the soleus of the exercised leg following the active contraction trial by 49% (P<.05) but not following the passive stretch trial. Results indicate that a single bout of maximal passive stretch does not significantly elevate fractional muscle protein synthetic rate in humans and thus suggests that muscle stretch per se is not the stimulus for the muscle hypertrophy that occurs with resistance training.

Reduced strength after passive stretch of the human plantarflexors.

The purpose of this study was to assess strength performance after an acute bout of maximally tolerable passive stretch (PS(max)) in human subjects. Ten young adults (6 men and 4 women) underwent 30 min of cyclical PS(max) (13 stretches of 135 s each over 33 min) and a similar control period (Con) of no stretch of the ankle plantarflexors. Measures of isometric strength (maximal voluntary contraction), with twitch interpolation and electromyography, and twitch characteristics were assessed before (Pre), immediately after (Post), and at 5, 15, 30, 45, and 60 min after PS(max) or Con. Compared with Pre, maximal voluntary contraction was decreased at Post (28%) and at 5 (21%), 15 (13%), 30 (12%), 45 (10%), and 60 (9%) min after PS(max) (P < 0.05). Motor unit activation and electromyogram were significantly depressed after PS(max) but had recovered by 15 min. An additional testing trial confirmed that the torque-joint angle relation may have been temporarily altered, but at Post only. These data indicate that prolonged stretching of a single muscle decreases voluntary strength for up to 1 h after the stretch as a result of impaired activation and contractile force in the early phase of deficit and by impaired contractile force throughout the entire period of deficit.