Predation risk drives long-term shifts in migratory behaviour and demography in a large herbivore population.

Migration is an adaptive life-history strategy across taxa that helps individuals maximise fitness by obtaining forage and avoiding predation risk. The mechanisms driving migratory changes are poorly understood, and links between migratory behaviour, space use, and demographic consequences are rare. Here, we use a nearly 20-year record of individual-based monitoring of a large herbivore, elk (Cervus canadensis) to test hypotheses for changing patterns of migration in and adjacent to a large protected area in Banff National Park (BNP), Canada. We test whether bottom-up (forage quality) or top-down (predation risk) factors explained trends in (i) the proportion of individuals using 5 different migratory tactics, (ii) differences in survival rates of migratory tactics during migration and whilst on summer ranges, (iii) cause-specific mortality by wolves and grizzly bears, and (iv) population abundance. We found dramatic shifts in migration consistent with behavioural plasticity in individual choice of annual migratory routes. Shifts were inconsistent with exposure to the bottom-up benefits of migration. Instead, exposure to landscape gradients in predation risk caused by exploitation outside the protected area drove migratory shifts. Carnivore exploitation outside the protected area led to higher survival rates for female elk remaining resident or migrating outside the protected area. Cause-specific mortality aligned with exposure to predation risk along migratory routes and summer ranges. Wolf predation risk was higher on migratory routes than summer ranges of montane-migrant tactics, but wolf predation risk traded-off with heightened risk from grizzly bears on summer ranges. A novel eastern migrant tactic emerged following a large forest fire that enhanced forage in an area with lower predation risk outside of the protected area. The changes in migratory behaviour translated to population abundance, where abundance of the montane-migratory tactics declined over time. The presence of diverse migratory life histories maintained a higher total population abundance than would have been the case with only one migratory tactic in the population. Our study demonstrates the complex ways in which migratory populations change over time through behavioural plasticity and associated demographic consequences because of individuals balancing predation risk and forage trade-offs.

Ligand exchange and spin state equilibria of Fe(II)(N4Py) and related complexes in aqueous media.

We report the characterization and solution chemistry of a series of Fe(II) complexes based on the pentadentate ligands N4Py (1,1-di(pyridin-2-yl)-N,N-bis(pyridin-2-ylmethyl)methanamine), MeN4Py (1,1-di(pyridin-2-yl)-N,N-bis(pyridin-2-ylmethyl)ethanamine), and the tetradentate ligand Bn-N3Py (N-benzyl-1,1-di(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine) ligands, i.e., [Fe(N4Py)(CH(3)CN)](ClO(4))(2) (1), [Fe(MeN4Py)(CH(3)CN)](ClO(4))(2) (2), and [Fe(Bn-N3Py)(CH(3)CN)(2)](ClO(4))(2) (3), respectively. Complexes 2 and 3 are characterized by X-ray crystallography, which indicates that they are low-spin Fe(II) complexes in the solid state. The solution properties of 1-3 are investigated using (1)H NMR, UV/vis absorption, and resonance Raman spectroscopies, cyclic voltammetry, and ESI-MS. These data confirm that in acetonitrile the complexes retain their solid-state structure, but in water immediate ligand exchange of the CH(3)CN ligand(s) for hydroxide or aqua ligands occurs with full dissociation of the polypyridyl ligand at low (<3) and high (>9) pH. pH jumping experiments confirm that over at least several minutes the ligand dissociation observed is fully reversible for complexes 1 and 2. In the pH range between 5 and 8, complexes 1 and 2 show an equilibrium between two different species. Furthermore, the aquated complexes show a spin equilibrium between low- and high-spin states with the equilibrium favoring the high-spin state for 1 but favoring the low-spin state for 2. Complex 3 forms only one species over the pH range 4-8, outside of which ligand dissociation occurs. The speciation analysis and the observation of an equilibrium between spin states in aqueous solution is proposed to be the origin of the effectiveness of complex 1 in cleaving DNA in water with (3)O(2) as terminal oxidant.

Rupture of an abdominal aortic aneurysm following nonaccidental blunt abdominal trauma.

A 78-year-old woman presented to our trauma center with an initial, erroneous history of a ground-level fall. Further investigation revealed that the patient had been assaulted by her husband immediately prior to presentation. The initial abdominal examination was benign, and the patient was hemodynamically stable. The patient was found to have a large subdural hematoma (SDH). Following open evacuation of the SDH, the patient developed ongoing hemodynamic instability. Further evaluation with computed tomography of the abdomen and pelvis uncovered the diagnosis of a 6 cm abdominal aortic aneurysm (AAA) with a large retroperitoneal hematoma. The patient underwent emergent repair of the ruptured AAA. There were no other significant intra-abdominal injuries, and the patient had an uneventful recovery. This case highlights the need for thorough evaluation of the trauma patient and recognition of the possibility of coexistent AAA in the elderly trauma patient. We believe that this is the first reported case of a ruptured AAA following nonaccidental blunt abdominal trauma.

Management of symptomatic spontaneous isolated visceral artery dissection: is emergent intervention mandatory?

Spontaneous dissection of a visceral artery without associated aortic dissection is rare, although more cases have recently been reported because of the advancement of diagnostic techniques. The risk factors, causes, and natural history of spontaneous isolated visceral artery dissection are unclear. Treatment with open surgery, endovascular stenting, or anticoagulation therapy has been proposed; however, there is no consensus on the optimal management. We present three cases of spontaneous and isolated dissection of visceral arteries. Dissection involved the superior mesenteric artery in one and the celiac artery in two. All three patients presented with acute abdominal pain but lacked any peritoneal irritation. The patients were treated nonoperatively with anticoagulants or antiplatelets. No surgical or endovascular intervention was performed. Follow-up imaging studies demonstrated improvement of the dissection in two patients and no change in one patient. All patients were symptom-free over a mean follow-up of 17 months. Nonoperative treatment with close observation is an acceptable strategy in the management of spontaneous isolated dissection of visceral arteries. Emergent intervention is not mandatory in symptomatic patients without evidence of acute bowel ischemia or hemorrhage.

Gene expression profile in pelvic organ prolapse.

It was hypothesized that the processes contributing to pelvic organ prolapse (POP) may be identified by transcriptional profiling of pelvic connective tissue in conjunction with light microscopy. In order to test this, we performed a frequency-matched case-control study of women undergoing hysterectomy for POP and controls. Total RNA, extracted from uterosacral and round ligament samples used to generate labeled cRNA, was hybridized to microarrays and analyzed for the expression of 32 878 genes. Significance Analysis of Microarrays (Stanford University, CA, USA) identified differentially expressed genes used for ontoanalysis. Quantitative PCR (qPCR) confirmed results. Light microscopy confirmed the tissue type and assessed inflammatory infiltration. The analysis of 34 arrays revealed 249 differentially expressed genes with fold changes (FC) larger than 1.5 and false discovery rates < or =5.2%. Immunity and defense was the most significant biological process differentially expressed in POP. qPCR confirmed the elevated steady-state mRNA levels for four genes: interleukin-6 (FC 9.8), thrombospondin 1 (FC 3.5) and prostaglandin-endoperoxide synthase 2 (FC 2.4) and activating transcription factor 3 (FC 2.6). Light microscopy showed all the samples were composed of fibromuscular connective tissue with no inflammatory infiltrates. In conclusion, genes enriched for 'immunity and defense' contribute to POP independent of inflammatory infiltrates.

Staged endovascular stent grafts for concurrent mobile/ulcerated thrombi of thoracic and abdominal aorta causing recurrent spontaneous distal embolization.

Mobile thrombus of the thoracic aorta is an uncommon pathology with potentially catastrophic complications. Recurrent spontaneous distal embolization may also occur from an ulcerated thrombus of the abdominal aorta. The simultaneous presence of a mobile thrombus in the thoracic aorta and ulcerated thrombus of the abdominal aorta is extremely rare and poses a significant treatment dilemma. Although various approaches have been reported, there is no standard treatment. Direct replacement of the thoracoabdominal aorta is extremely morbid, while continued embolization despite anticoagulation mandate intervention. We herein present the first case report of successful treatment of symptomatic mobile/ulcerated thrombi of the thoracic and abdominal aorta using staged endovascular stent graft repair. Successful treatment of the thoracic component with a thoracic aortic graft (TAG, Gore-Tex, W. L. Gore & Assoc., Flagstaff, Ariz.) was followed one week later by exclusion of the infrarenal aortic lesion with a bifurcated stent graft. Endovascular stent graft exclusion of mobile/ulcerated thoracic and abdominal aortic thrombi is a minimal invasive operation. It can be employed as an alternative procedure in treatment of aortic thrombus with embolization in high risk patients. Long-term follow-up will be necessary to assess the durability of this technique.

A prospective analysis of critical limb ischemia: factors leading to major primary amputation versus revascularization.

In our aging population, primary major amputations (AMP, below-knee or above-knee) continue to be performed despite advances in revascularization. We hypothesized that not only patient comorbidities but also the system of health-care delivery affected the treatment of patients with critical limb ischemia (CLI). A prospective analysis of patients presenting with CLI was undertaken to determine whether patient-specific factors or healthcare delivery factors (system-related) influenced treatment with primary AMP versus lower extremity revascularization (LER). The patient-specific factors age, gender, race/ethnicity, presence of coronary artery disease, cerebrovascular disease, tobacco use, diabetes mellitus (DM), dialysis dependence (end-stage renal disease, ESRD), hypertension, hyperlipidemia, stage of CLI (rest pain, minor or major tissue loss), history of revascularization, and functional status (living situation and ambulatory status) were recorded. The system-related factors time from onset of CLI to vascular surgery evaluation and type of insurance (managed care/other insurance) were also noted. The influence of patient-specific and system-related factors on the primary treatment modality (AMP versus LER) was determined with univariate and multivariate analyses. A total of 224 patients presented with CLI between March 1, 2001, and March 1, 2005. Patients were treated with primary major AMP in 97 cases (43%) and revascularization in 127 cases (57%). On univariate analysis, nonwhite race/ethnicity, DM, ESRD, major tissue loss, dependent living situation, and nonambulatory status were all significant predictors of AMP versus LER (all P < 0.01). On multivariate analysis, major tissue loss, ESRD, DM, and nonambulatory status remained independent predictors of AMP versus LER (all P < 0.05). The system-related factors of time to vascular surgery evaluation (mean 8.6 weeks, 7.1 vs. 9.3 weeks AMP versus LER, P = 0.60) and type of insurance (managed care, 17% vs. 24% AMP vs. LER, P = 0.15) had no influence on treatment. Fifty-four percent of all primary major AMPs were performed due to extensive gangrene or infection present at initial vascular evaluation which precluded limb salvage. Major tissue loss, ESRD, DM, and nonambulatory status are all independent predictors of treatment with primary AMP as opposed to revascularization. Treatment of CLI is determined by patient-specific factors and does not appear to be adversely influenced by system-related factors. Efforts toward improving limb salvage may be best directed at aggressive treatment of medical comorbidities to prevent the late complications of CLI. Earlier recognition of tissue loss and referral to the vascular specialist may lead to improved limb salvage.

Chronic ergot toxicity presenting with bilateral external iliac artery dissection and lower extremity rest pain.

Chronic use of ergot alkaloids has been recognized as a rare cause of lower extremity ischemia. Most patients with ergot toxicity present with symptoms of lower extremity claudication. Herein we present a woman with bilateral lower extremity rest pain and a history of chronic ergot use for migraine headaches. Arteriography demonstrated extensive pruning of the distal arterial tree along with bilateral external iliac artery dissections - a finding that is not often associated with young, normotensive patients with chronic ergot toxicity. This patient was treated with endovascular stenting of the dissections along with cessation of ergot. Her symptoms improved markedly, and follow-up arteriography 6 weeks later demonstrated resolution of the iliac dissections along with restoration of nearly normal lower extremity runoff vessels. Discontinuation of ergot-containing products and cessation of tobacco and caffeine use is the cornerstone of therapy in chronic ergot toxicity. The association of ergot toxicity and iliac dissection has not been previously described. Endovascular or surgical interventions may be considered in patients with ergot toxicity for specific indications or those whose symptoms progress despite conservative management.

Major lower extremity amputation in an academic vascular center.

Major lower extremity amputations continue to be performed despite an aggressive policy of revascularization. Factors leading to amputation were analyzed to determine whether a reduction in the limb loss rate is possible. A retrospective analysis of a prospectively maintained vascular registry was performed to identify patients undergoing above-knee amputation (AKA), below-knee amputation (BKA), and lower extremity revascularization (LER) for limb salvage between January 1, 1999 and January 1, 2002. Patient demographics, comorbidities, insurance carriers, and indications for operative intervention were analyzed. Greater than one-half of all major lower extremity amputations are performed in patients who have failed attempts at revascularization or who are not candidates for LER due to anatomic factors. However, one-quarter of eventual amputees present very late to the vascular surgeon with extensive gangrene or infection that precludes limb salvage. Prompt patient referral and treatment may improve outcome in this group of patients. In our study, insurance issues did not appear to affect treatment. Renal failure continues to play a major role in limb loss.

Routes to regioselective deuteriation of heteroaromatic compounds.

A systematic approach to the deuteriation of polypyridyl type ligands is reported. A range of isotopologues of heteroaromatic compounds containing pyrazyl, pyridyl, 1,2,4-triazole, thienyl, methyl, and phenyl moieties, have been prepared in a cost-effective manner, using a range of methods based on subcritical aqueous media. Selectively and fully deuteriated ligands are characterized by mass spectrometry and(1)H, (2)D, and (13)C NMR spectroscopy. The application of deuteriation to supramolecular chemistry is discussed.

Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia.

Epidemiological studies have been inconsistent regarding a role for folate in the etiology of cervical dysplasia. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, which is involved in the methylation of homocysteine to methionine. A common variant of this enzyme, resulting from a 677C-->T (Ala-->Val) substitution in the gene, has been shown to have reduced activity and is associated with mild hyperhomocysteinemia. A multiethnic case-control study was used to examine the association of dietary folate and MTHFR genotype with the odds ratios (ORs) for cervical dysplasia among women identified from several clinics on Oahu, Hawaii, between 1992 and 1996. We collected blood samples for DNA extraction, cervical smears for cytological diagnosis, exfoliated cervical cells for human papillomavirus (HPV) DNA testing, and personal interviews from 150 women with squamous intraepithelial lesions (SILs) and from 179 women with cytologically normal (Pap) smears. We found a positive, monotonic trend (P = 0.02) in the ORs for cervical SILs associated with the number of variant MTHFR T alleles, after multivariate adjustment. Women with the heterozygous CT genotype had twice the risk of cervical SILs [OR, 2.0; 95% confidence interval (CI), 1.1-3.7], and women with the homozygous TT genotype had almost three times the risk of SILs (OR, 2.9; 95% CI, 1.0-8.8) compared to women with the homozygous MTHFR CC genotype. The dietary intakes of folate, vitamin B(6), and vitamin B(12) were inversely related to the ORs for cervical SILs, after adjustment for HPV DNA and other confounders. The OR among women in the highest quartile compared with women in the lowest quartile of folate intake was 0.3 (95% CI, 0.1-0.7; P for trend = 0.002). Women with the variant T allele and folate intakes below the median were at significantly elevated risk of cervical SILs (OR, 5.0; 95% CI, 2.0-12.2) compared to women with CC alleles and folate intakes above the median. HPV infection was a strong risk factor for cervical dysplasia, particularly among women with the variant T allele (OR, 46.6; 95% CI, 15.9-136.2). All associations of MTHFR genotype with the ORs for cervical SILs were independent of other risk factors under study. These findings suggest that the MTHFR T allele and reduced dietary folate may increase the risk for cervical SILs.

CYP1A1, GSTM1, and GSTT1 polymorphisms and the risk of cervical squamous intraepithelial lesions in a multiethnic population.

OBJECTIVE: In this investigation, we explored the hypothesis that genetic polymorphisms in the cytochrome P4501A1 (T3801C) and glutathione S-transferase classes mu and theta (GSTM1 and GSTT1) gene deletions promote the development of cervical dysplasia by moderating the activation and detoxification of polycyclic hydrocarbons and other compounds that influence oxidative stress and DNA adduct formation. METHODS: A multiethnic, case-control study of 131 women with biopsy-confirmed cervical squamous intraepithelial lesions (SIL) and 180 controls with cytologically normal cervical (Pap) smears was conducted between 1992 and 1996 in Honolulu, Hawaii. We collected in-person interviews, a blood sample to extract genomic DNA, and an exfoliated cervical cell sample to determine the presence and type of human papillomavirus (HPV) using PCR dot-blot hybridization. Genotyping for the CYP1A1 MspI allelic variant and deletion of the GSTM1 and GSTT1 gene loci followed a PCR method. RESULTS: Women who were homozygous, but not heterozygous, for the CYP1A1 MspI variant allele were at significantly increased risk of cervical SIL (odds ratio (OR) = 3.4; 95% confidence interval (CI) = 1.1-10.7) compared to women who were homozygous for the wild-type allele. Subjects with the GSTM1 null genotype had a nonsignificant elevated risk of cervical SIL (OR = 1.6; 95% CI = 0.8-3.0) compared to women with the gene present. No difference in the risk of cervical disease was associated with the GSTT1 null genotype. The combination of the CYP1A1 homozygous variant and the GSTM1 null genotypes increased the odds ratio for cervical SIL to 5.1 (95% CI = 1.3-20.7). There was no evidence for an interaction between genotype and exposure to tobacco smoke, alcohol drinking, or HPV DNA positivity. CONCLUSIONS: These findings, although based on a small number of subjects, suggest that the CYP1A1 MspI polymorphism may be a susceptibility factor for early, premalignant changes in the cervical epithelium.

Rapid enzymatic urine screening test to detect bacteriuria in pregnancy.

OBJECTIVE: To determine the sensitivity, specificity, and positive and negative predictive values of an enzymatic urine screening test for diagnosing bacteriuria in pregnancy. METHODS: Clean-catch midstream urine samples were collected from 383 women who had routine prenatal screening for bacteriuria. Sensitivity, specificity, and positive and negative predictive values for each screening test (enzyme activity, nitrites or leukocytes on dipstick, and bacteria or pyuria on microscopic examination) were estimated using urine culture as the criterion standard. Urine cultures were considered positive if they grew 10(4) colony-forming units of a single uropathogen. Standard deviations used to calculate 95% confidence intervals were based on binomial distribution. A sample of 30 urine specimens was selected to evaluate interrater agreement using Cohen's kappa statistic. RESULTS: Five of 383 samples were contaminated, leaving 378 samples for evaluation. Thirty of 43 specimens with positive urine culture had positive enzyme activity. Of 335 samples with no growth, 150 had negative enzyme activity. Sensitivity, specificity, and positive and negative predictive values for the Uriscreen enzymatic screening test (Bard Patient Care Division, Murray Hill, NJ) were 70%, 45%, 14%, and 92%, respectively. Sensitivity of the Uriscreen was lower than that of bacteria alone. Interrater agreement for Uriscreen testing was high among the three testers (kappa =.86). CONCLUSION: The Uriscreen enzymatic screening test had inadequate sensitivity for rapid screening for bacteriuria in pregnancy.

Cost-effective aortic exposure: a retroperitoneal experience.

In this study we investigated whether the surgical approach to infrarenal aortic aneurysm (IAA) repair significantly affects in-hospital morbidity and cost. The study comprised a consecutive series of 96 patients with elective repair of an IAA by two vascular surgeons using an established protocol from March 1995 to March 1999. The outcomes and costs for 50 patients with transperitoneal (TP) exposure were compared with those for 46 patients with retroperitoneal (RP) exposure, all of whom were in a tertiary care center, in a university hospital. Hospital and ICU days, perioperative complications, and cost were measured. All patients followed the same protocol except for intraoperative aortic exposure. There was no significant difference between TP and RP groups with regard to demographic features (all p-values > 0.12), mean IAA size (p = 0.41) or mean operative blood loss (p = 0.89). Incidence of postoperative complications was similar between the groups (11 in TP and 6 in RP; p = 0.29). However, a trend without statistical significance was noted in the incidence of pulmonary complications (7 in TP and 2 in RP; p = 0.11). Mean ICU days (4 vs. 2; p = 0.004) and hospital days (11 vs. 6; p = 0.002) were significantly longer after TP aortic exposure than after the RP approach. Mean total hospital cost was significantly reduced for patients having RP IAA repair compared to TP IAA repair (mean cost difference = $5,527; p = 0.016). Retroperitoneal exposure for IAA repair is associated with decreased pulmonary complications, significantly shorter ICU and hospital days, and significantly decreased hospital cost compared to transperitoneal aortic exposure. In the future, RP exposure for IAA repair should be the benchmark for comparison of any new techniques.

Urinary and biliary metabolic patterns of chlorothalonil in germ-free and conventional rats.

The metabolic fate of chlorothalonil, a broad spectrum fungicide that is known to be metabolized via glutathione conjugation, was examined through the analysis of urine and bile metabolites. The role of digestive microflora in the metabolism of chlorothalonil was assessed by comparing the metabolic patterns in germ-free and conventional rats. Low urinary and biliary excretion of radioactivity was observed in both conventional and germ-free rats. However, the urinary excretion of radioactivity was higher in conventional than in germ-free rats. Radio-HPLC analysis of urine and bile showed a complex metabolic profile in both conventional and germ-free rats. Methylthio metabolites of chlorothalonil were determined in ethyl acetate extracts of urine and bile of conventional and germ-free rats. These metabolites were excreted in a higher amount in the urine of conventional rats than in the urine of germ-free rats. This study shows the complexity of chlorothalonil metabolism and the role of the digestive microflora in chlorothalonil metabolism.

Vaginal pH and parabasal cells in postmenopausal women.

OBJECTIVE: To determine the vaginal pH level that correlates with elevated parabasal cells in vaginal smears. METHODS: Postmenopausal women presenting to a gynecology office for routine annual and incontinence examinations were studied prospectively. Women were excluded if they had vaginal infections or pelvic organ prolapses past the hymen. pH was measured and cytology smears made from the midvagina. A pathologist who was not aware of pH results evaluated the smears. Spearman rho was used to correlate pH and percentage of parabasal cells. Logistic regression was used to analyze the relationship between pH and increased parabasal cells in vaginal smears. Predictive values were used to select a pH level as a cutoff point to predict increased parabasal cells. RESULTS: Seventy-four women were enrolled and 70 completed the study. The correlation coefficient between pH and percentage of parabasal cells was 0.6 (P < .001). Logistic regression showed association of pH with 20% or more parabasal cells (P < .001). Positive and negative predictive values for pH level above 6.0 as a predictor of 20% or more parabasal cells were 96.3% and 87.5%, respectively. The prevalence of elevated parabasal cells was 22.9%. CONCLUSION: Vaginal pH above 6.0 correlates with high levels of parabasal cells (20% or more) from the midvagina.

Vascular reconstruction and major resection for malignancy.

HYPOTHESIS: Complications of vascular procedures performed for tumor infiltration of major vessels or for the rescue of complex tumor resections may significantly affect perioperative patient outcome and long-term patient survival rate. DESIGN AND PATIENTS: Retrospective review of 39 patients undergoing major resection for malignancy between April 1980 and April 1998; 35 patients underwent major-vessel reconstruction, 3 patients underwent extra-anatomic bypass, and 1 patient underwent major venous thrombectomy. SETTING: University hospital tertiary referral center. MAIN OUTCOME MEASURES: Vascular complications and patient survival rate. RESULTS: Vascular complications included major stroke (3), carotid artery blowout (2), acute graft thrombosis (1), bowel infarction (1), and anastomotic disruption (1). Factors such as patient demographics, preoperative irradiation, tumor stage, resection for recurrent disease, and vessel or graft type had no bearing on the occurrence of a vascular complication (P>.05 in all cases). Eight patients (21%) died within 30 days of surgery, and 2 (5%) died after 30 days but before hospital discharge. Five of these deaths were directly related to vascular problems (P<.001). Cumulative patient survival rate was 44%, 26%, and 10% at 1, 3, and 5 years, respectively. CONCLUSIONS: The long-term patient survival rate is poor when resections for carcinoma are associated with maj or-vessel infiltration or a complication that necessitates an emergent vascular procedure. In this setting, in-hospital mortality is negatively affected by the incidence of a major vascular complication.

Regulating and assessing risks of cholinesterase-inhibiting pesticides: divergent approaches and interpretations.

This document presents a revised framework for conducting worker and dietary risk assessments for less-than-lifetime exposures to organophosphate or carbamate pesticides based on red blood cell (RBC) or brain acetylcholinesterase (AChE) inhibition or the presence of clinical signs and symptoms. The proposals for appropriate uncertainty factors are based on the biological significance of the cholinesterase (ChE) inhibition noted at the lowest-observed-effect level (LOEL) and the degree of uncertainty in the extrapolation between human and animal data. An extensive evaluation of industry data, not previously summarized, and the available literature indicate that the following risk assessment principles are supportable and protective of human health: Plasma ChE inhibition is not an adverse effect, and therefore should not be utilized in risk assessments. Red blood cell AChE is not associated with the nervous system and inhibition is not per se an adverse (neurotoxic) effect. When available, cholinergic effects or brain AChE inhibition data should take precedence over RBC AChE for determining no-observed-effect levels (NOELs). When available, human RBC AChE inhibition or cholinergic effects data should take precedence over animal data for determining NOELs. Due to the lack of adversity associated with inhibition of RBC AChE, the use of a 10-fold (10x) uncertainty factor from the NOEL is adequate when RBC AChE inhibition data from either animal or human studies are used to assess human risk. Due to greater potential for adversity, NOELs for brain AChE inhibition and cholinergic effects identified in animal studies should receive a default uncertainty factor of 100x; lower uncertainty factors may be used on a case-by-case basis. NOELs based on cholinergic effects noted in human studies should only require a 10x uncertainty factor, since an interspecies extrapolation factor from animals to humans is unnecessary. For RBC and brain AChE activity the threshold for defining a NOEL should be less than or equal to 20% difference from control activity in all species. For risk assessment purposes, duration and route of the study should reflect the expected duration and route of exposure for humans (i.e., a 21-d or 28-d dermal study for subchronic occupational dermal exposure assessment). When dermal data are not available, a subchronic oral toxicity study and an appropriate dermal penetration factor should be used. A general default of 10% absorption should be used, analogous to the United Kingdom and German exposure models that are widely used in Europe. The recommendations in this document are generally consistent with current risk assessment procedures used by Canada, the European Community (EC), and the United Kingdom (UK).

Temperature and neuromuscular development in embryos of the trout (Salmo trutta L.).

Myogenesis and neural development were examined in the myotomes of trout (Salmo trutta L.) embryos reared at 2, 6 and 10 degrees C. The relative timings of myotube and muscle fibre formation were similar, with respect to somite stage, at all three temperatures. Myogenesis was seen to begin medially, adjacent to the notochord, and also in separate zones located near the outer surface of the myotomes, believed to be the sites of formation of future slow muscle fibres. Temperature did not affect the relative timings of most aspects of neural development, including HNK-1-immunoreactivity of myosepta, primary motor neuron axonogenesis, Rohon-Beard dendrite outgrowth, and expression of acetylcholinesterase in the spinal chord and at the myosepta. The posterior progression of the lateral line primordium was slightly but significantly delayed relative to somite stage in embryos reared at 10 degrees C compared to 6 and 2 degrees C, while formation of vacuoles in the notochord occurred relatively earlier at higher temperatures. No significant differences in neuromuscular development were observed between offspring of migratory and of non-migratory females.