Mechanism-Based QSAR Modeling of Skin Sensitization.

Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data sets of skin sensitizers, we have allocated each sensitizing chemical to one of 10 mechanistic categories and then developed good QSAR models for the seven categories that have a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.

Scale and pattern of broadnose sevengill shark Notorynchus cepedianus movement in estuarine embayments.

The detailed movements of 32 acoustically tagged broadnose sevengill shark Notorynchus cepedianus were documented in and around north-east Pacific Ocean estuarine embayments from 2005 to 2007. Arrangements of passive acoustic receivers allowed analysis of movement at several spatial scales, with sex and size examined as possible factors influencing the pattern and timing of these movements. Notorynchus cepedianus exhibited a distinctly seasonal pattern of estuary use over three consecutive years, entering Willapa Bay in the spring, residing therein for extended periods of time during the summer and dispersing into nearshore coastal habitats and over the continental shelf during the autumn. Notorynchus cepedianus within Willapa Bay showed spatio-temporal patterns of segregation by size and sex, with males and small females using peripheral southern estuary channels early in the season before joining large females, who remained concentrated in central estuary channels for the entire season. Individuals displayed a high degree of fidelity not only to Willapa Bay (63% were documented returning over three consecutive seasons), but also to specific areas within the estuary, showing consistent patterns of site use from year to year. Cross-estuary movement was common during the summer, with most fish also moving into an adjacent estuarine embayment for some extent of time. Most winter and autumn coastal detections of N. cepedianus were made over the continental shelf near Oregon and Washington, U.S.A., but there were also examples of individuals moving into nearshore coastal habitats further south into California, suggesting the feasibility of broad-scale coastal movements to known birthing and nursery grounds for the species. These findings contribute to a better understanding of N. cepedianus movement ecology, which can be used to improve the holistic management of this highly mobile apex predator in regional ecosystems.

The suppression of Antarctic bottom water formation by melting ice shelves in Prydz Bay.

A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. Here we show new observations from CTD-instrumented elephant seals in 2011-2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf water (salinity 34.65-34.7) is exported through Prydz Channel. This provides a distinct, relatively fresh contribution to Cape Darnley bottom water. Elsewhere, dense water formation is hindered by the freshwater input from the Amery and West Ice Shelves into the Prydz Bay Gyre. This study highlights the susceptibility of Antarctic bottom water to increased freshwater input from the enhanced melting of ice shelves, and ultimately the potential collapse of Antarctic bottom water formation in a warming climate.

Abnormal cortical appearances in pediatric renal allografts.

Renal cortical studies were performed in 19 children with renal transplants. There were 10 normal studies and 9 abnormal studies, 8 of which showed multiple large focal peripheral cortical defects. The following factors showed a positive correlation: (a) the ischemia time of the transplant kidney was significantly shorter in patients with normal studies; (b) cadaver grafts were more likely to have abnormal scan appearances than living related donor grafts; and (c) in four of the five patients with double renal arteries, the scans were abnormal in multiple sites. A possible pathophysiologic mechanism to explain these scan appearances is asymptomatic segmental graft infarction secondary to progressive vascular disease. These infarcts may be a long-term sequela of ischemic insult at the time of or prior to the insertion of the renal allograft.

Left ventricular--right atrial shunt: an unusual cause of hemodynamic deterioration following aortic valve surgery.

Two cases of left ventricular-right atrial shunts inadvertently produced during aortic valve replacement are described. It is surprising that this complication is not more prevalent considering the close proximity of the aortic and mitral valves to the atrioventricular portion of the membranous septum. A left-to-right shunt should be a consideration in patients who fail to improve following aortic valve surgery, especially if the valve and subaortic region were heavily calcified or septal trauma occurred during the surgical procedure.

Pulsatile perfusion versus conventional high-flow nonpulsatile perfusion for rapid core cooling and rewarming of infants for circulatory arrest in cardiac operation.

Thirty consecutive infants undergoing hypothermia and circulatory arrest for repair of ventricular septal defect, transposition of the great vessels, or atrioventricular canal defects were alternately selected for conventional high flow nonpulsatile perfusion or pulsatile perfusion during core cooling and rewarming. All received morphine anesthesia, 30 mg/kg of Solu-Medrol, and 10 to 15 mcg/kg of phentolamine. Those receiving nonpulsatile flow were perfused at a rate of 160 to 180 cc/kg/min with a roller pump and oxygenator with arterial pressure of 50 to 55 mm Hg. In the pulsatile flow group, a roller pump and oxygenator were used, and an especially constructed Datascope PAD (pulsatile assist device) was interposed in the arterial line to provide pulsatile perfusion with 75/40 mm Hg pressure at slightly reduced flow (150 cc/kg/min). The average rectal, esophageal, and tympanic membrane temperatures were reduced to approximately 16 degrees C prior to circulatory arrest. Following repair, perfusion was resumed until these temperatures returned to 37 degrees C. Cooling and rewarming were enhanced by pulsatile perfusion, with over 30% reduction in total pump time. Additionally, the larger patients in the pulsatile group cooled almost as rapidly as the smaller. The rates of decline and subsequent rise of rectal, esophageal, and tympanic membrane temperatures were equal in the pulsatile group, but the rectal temperature lagged far behind in the nonpulsatile group. Urine production during bypass was 100% greater in the pulsatile group. The plasma free hemoglobin was similar in both groups. The average postrewarming pH was 7.31 in the nonpulsatile group and 7.42 in the pulsatile group. Infants receiving pulsatile flow awakened more quickly, were more alert, and required less postoperative mechanical ventilation. We suggest that pulsatile perfusion for core cooling and rewarming of infants is safe and is more rapid and physiological than conventional high-flow nonpulsatile perfusion.

ECLS in pertussis: does it have a role?

OBJECTIVES: To investigate the value of extracorporeal circulatory life support (ECLS) in paediatric patients with severe Bordetella pertussis infection. DESIGN: Single case report and a review of the ECLS database. SETTING: Tertiary referral hospital paediatric intensive care unit. PATIENTS AND PARTICIPANTS: A single case report of an infant with B. pertussis infection is described. Despite receiving ECLS, this infant died from overwhelming cardiac and cerebral insults. Outcome for children receiving ECLS registered on the Extracorporeal Life Support Organization database is reviewed. MEASUREMENTS AND RESULTS: The mortality of infants receiving ECLS for B. pertussis infection is high, with only 5 survivors reported among 22 registered cases. The majority of nonsurvivors had evidence of circulatory collapse in addition to severe respiratory failure, and these patients commonly died of hypoxic-ischaemic cerebral insult. These data suggest the existence of a subgroup of patients with respiratory failure only, who may benefit from ECLS, and a larger subgroup who suffer ischaemic cardiac and cerebral insults which are unlikely to be improved by ECLS. CONCLUSIONS: The value of ECLS in patients with B. pertussis infection who present with major cardiac dysfunction is questionable. Such patients almost invariably have a poor outcome despite maximal therapy.

The relative merits of the heparin-bonded shunt vs. femerofemoral bypass for aortic arch injury.

Six patients with traumatic aortic arch injuries have been repaired with distal aortic perfusion maintained with femerofemoral bypass (three patients) and the heparin-bonded ascending aorta-to-femoral artery shunt (three patients). The two groups are compared regarding pre- and postoperative changes in blood urea nitrogen, creatinine and platelet counts, as well as required blood replacement, days in the hospital, and rapidity of setting up the technique of distal aortic perfusion. No significant difference in the two techniques was demonstrated regarding the above parameters. Both the heparin-bounded shunt and femoral vein-to-femoral artery bypass with the pump oxygenator provide acceptable spinal cord and renal protection. The two techniques should be equally rapid and safe for the larger institution employing cardiopulmonary bypass procedures on a routine basis. The heparin-bounded shunt, however, may provide a more rapid and reliable means of lower aortic perfusion for the smaller institution with less available means of cardiopulmonary bypass support.

Identification of heparin resistance during cardiac and vascular surgery.

An investigation of the response of the activated clotting time to systemic heparinization during cardiopulmonary bypass and peripheral vascular surgery was prompted by the death from clotting of a patient with endocarditis while undergoing valve replacement. The activated clotting time during cardiopulmonary bypass was thereafter maintained at 300 to 400 seconds. Consumption of heparin sodium, derived from an individual dose-response curve, was 0.01 to 3.86 units/kg/min. There was no correlation between initial heparin resistance and the subsequent rate of consumption. Some patients undergoing peripheral vascular surgery required additional heparin after an initial standard dose of 8,000 units so as to maintain their activated clotting time at twice the control values. These data are discussed in relation to previous articles, and recommendations are made for adequate intraoperative heparinization.

Treatment of corrosive burns of the esophagus.

Forty patients with caustic ingestion have been treated between 1955 and 1975. Strong alkali was the corrosive in 95%, and 80% were under 10 years old. Early esophageal stricture developed in 18 patients four weeks after lye ingestion. Among these, esophageal bougienge restored an adequate lumen in two patients with short, soft annular strictures, and right colon interposition was used for esophageal subsitution in ten who had long, dense strictures. We recommend early diagnostic esophagoscopy, to the uppermost level of burn injury only, to determine the presence and severity of the esophageal injury. If esophagoscopy reveals esophageal burn injury, corticosteroid and antibiotic therapy are continued. If no burn injury is visualized, the patient is spared unnecessary treatment. Long, dense strictures unresponsive to bougienage place the patient at risk from instrumental perforation, and these patients should undergo colon interposition through a substernal extrapleural tunnel.

Association between age and blood loss in children undergoing open heart operations.

BACKGROUND: Although recent studies indicated young children are at risk for increased perioperative hemorrhage after open heart operations, the associations between patient age, blood loss and blood product transfusions have not been fully defined in children. METHODS: Perioperative blood loss and blood product transfusion data were recorded for 414 consecutive children undergoing open heart procedures. The children were in the following age groups: 1 month or younger, group 1; older than 1 month to 12 months, group 2; older than 1 year to 5 years, group 3; and older than 5 years, group 4. RESULTS: Postoperative blood loss and blood product transfusions were inversely related to age and differed significantly between the four age groups. Multiple preoperative and intraoperative factors that possibly influence hemostasis also differed significantly between age groups. Median units transfused within 72 hours differed significantly with age (p < 0.0001): group 1, 8 units (range, 1 to 19 units); group 2, 6 units (range, 0 to 21 units); group 3, 2 units (range, 0 to 23 units); and group 4, 0 units (range, 0 to 38 units). CONCLUSIONS: Blood loss and transfusions vary inversely with age. Per kilogram of body weight, neonates bled more and received more donor products than any other age group.

Retrograde venous cardiac perfusion for myocardial revascularization: an experimental evaluation.

This study evaluates cardiac function in dogs during retrograde perfusion through the coronary sinus. Five hearts perfused retrograde in an ex vivo apparatus demonstrated rapid and marked increases in weight and perfusion pressure, became hemorrhagic, and contracted poorly within one hour. Five similarly perfused hearts treated with phenoxybenzamine experienced no increase in weight or perfusion pressure and maintained good color and contractions for up to one hour. Five additional hearts treated with phenoxybenzamine did not develop hemorrhage, edema, increased weight, or increased perfusion pressure but could maintain the systemic circulation for only brief periods after 15 minutes of intermittent cardiopulmonary bypass support. We conclude that cardiac viability can be maintained with retrograde perfusion enhanced with alpha blocking agents. However, hearts so perfused cannot maintain adequate systemic pressure. The data suggests that extensive myocardial revascularization through the retrograde venous route would be ineffective.

A birdcage coil tuned by RF shielding for application at 9.4 T.

The design and performance of an inductively fed low-pass birdcage radiofrequency (RF) coil for applications at 9.4 T are described where tuning is accomplished by mechanically moving a concentric RF shield about the longitudinal axis of an RF coil. Moving the shield about the RF coil effectively changes the mutual inductance of the system, providing a mechanism for adjusting the resonant frequency. RF shield tuning eliminates adjustable capacitors on the legs of the RF coil, eliminates current imbalances and field distortions, and results in improved B1 field homogeneity and high quality (Q) factors. RF shield tuning and inductive matching provide an isolated resonance structure which is both physically and electrically unattached. Experimental analysis of shield position on both B1 field homogeneity and resonant frequency is provided. Computer simulations of B1 field homogeneity as a function of shield position and shield diameter are also presented. Magnetic resonance microimaging substantiates the usefulness of this design.

Cerebral energy metabolism during hypoxia-ischemia correlates with brain damage: a 31P NMR study in unanesthetized immature rats.

The association between the ultimate brain damage resulting from unilateral hypoxic-ischemic insult (HI) and the changes in high-energy metabolites, measured by noninvasive phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy during the insult, was evaluated in 7-day postnatal rats. When the NMR metabolite levels were integrated over the last 1.5 h out of 2.5 h of HI, there was a significant correlation of both the estimator of phosphorylation potential (P < 0.001) and ATP levels (P < 0.01) with histologic score of damage and area morphometry. In particular, the development of cerebral infarction could be predicted from the NMR evaluation (P < 0.005). These findings suggest that a large disturbance in cellular energy metabolism is a prerequisite for the subsequent neuropathological alterations in this model.

Allopurinol preserves cerebral energy metabolism during perinatal hypoxia-ischemia: a 31P NMR study in unanesthetized immature rats.

The effects of high dose allopurinol (ALLOP) pretreatment on the cerebral energy metabolism of unanesthetized 7-day-postnatal rats during exposure to 3 h of cerebral hypoxia-ischemia were serially quantitated using non-invasive 31P NMR spectroscopy. Adenosine triphosphate, integrated over the last 2 h of hypoxia and expressed as a fraction of baseline, was 0.73 +/- 0.16 with ALLOP pretreatment (200 mg/kg s.c.) compared to 0.52 +/- 0.05 for saline pretreatment (P = 0.001). Inorganic phosphate/phosphocreatine (Pi/PCr), integrated over the same time interval, was 2.63 +/- 1.23 relative to baseline with ALLOP versus 5.13 +/- 1.45 for saline-treated pups (P less than 0.0005). We suggest that the neuroprotection achieved with high dose ALLOP pretreatment may be attributed in part to preservation of energy metabolites.

Variations in quantity-frequency measures of alcohol consumption from a general population survey.

This paper examines differences in quantity-frequency (QF) measures of alcohol consumption from the 1988 US National Health Interview Survey. Three methods--global QF, beverage-specific QF, and beverage-specific QF with drink size (QFS)--were used to estimate the average daily ethanol consumption (ADC) of current drinkers. These ADC estimates then were used to categorize drinkers into light, moderate or heavier drinking levels. Total prevalence estimates of heavier drinking were not significantly different among men, but were significantly higher with the QFS measure among women. All mean ADC scores were significantly different for both sexes. The global QF showed the lowest mean consumption, followed by the higher beverage-specific QF and QFS measures. Adding beverage type and drink size to the QF measures increased mean ADC scores for both men and women. However, moderately high correlations (0.84 for men and 0.88 for women) were found with ADC scores from the beverage-specific QF and QFS measures.

Alcohol consumption, gender and self-reported hypertension.

This study examines the relationship of alcohol consumption and self-reported lifetime prevalence of hypertension among 19,284 non-institutionalized civilians in the United States. Cross-sectional data from the 1983 National Health Interview Survey, a national probability sample, were examined for each sex separately. Women who report hypertension consumed significantly less alcohol than women who did not report hypertension. Self-reported hypertensive men consumed equal or greater amounts of alcohol than self-reported normotensive men. Alcohol consumption was significantly associated with greater risk of hypertension among men, but not among women. After controlling for other risk factors significant effects for hypertension were found among males who on average consumed more than one drink/day. Beer consumption and spirits consumption above three drinks/day were significant predictors of male hypertension after adjustment for the confounding effects of other alcoholic beverage consumption and other risk factors. This study suggests that alcohol consumption by men who know that they are hypertensive is an important public health concern, with policy implications for targeting prevention efforts.

Alcoholic beverage type, recall period effects and functional disability: evidence from the 1983 NHIS.

To replicate a Canada Health Survey (CHS) study that found beer drinking was associated with lower morbidity, National Health Interview Survey (NHIS) data for 19,462 persons were used to examine associations between functional disability and beverage specific ethanol consumption. A functional disability index consisting of morbidity and symptom coping events reported for 2 weeks prior to the NHIS interview was constructed. Alcohol consumption was reported for the same period as disability (coincident recall), or for the 2 weeks prior to the respondent's last drink during the past year (antecedent recall). The analysis controlled for confounders using direct standardization and multiple logistic regression. The results of this investigation were not consistent with the CHS study. Former drinkers and antecedent recall drinkers reported greater disability rates than either non-drinkers or coincident recall drinkers. Antecedent recall drinkers exhibiting a preference for beer and wine were, respectively, 40 and 80 percent more likely to be disabled than non-drinkers. Further, this study found no evidence of a protective effect among any subgroup of drinkers. The finding of a significant interaction between alcohol consumption and alcohol recall period suggests that epidemiologic studies should give greater attention to the classification of drinker groups by proximity of alcohol consumption.

Thrombogenic alleles, Escherichia coli O157:H7 infections, and hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) of childhood most commonly follows gastrointestinal infection with Escherichia coli O157:H7. This pathogen elaborates Shiga toxins that are believed to cause microvascular injury and to trigger a thrombogenic response. The exact mechanisms leading to variable disease manifestations are unknown. Allelic variation in genes encoding selected coagulation factors and inhibitors of fibrinolysis were examined to determine whether or not a causal relationship exists between hypercoagulability and the development of HUS. No correlation between the thrombogenic factor V (G1691A), factor II (G20210A), methylenetetrahydrofolate reductase (C677T), or the plasminogen activator inhibitor (PAI)-1 promotor (4G/5G) genotypes and the risk of infection with E. coli O157:H7, or the risk of development of HUS among infected patients, was found. Serum PAI-1 levels did not correlate with the PAI-1 genotype. We conclude that the alleles studied are not major risk factors for the acquisition of E. coli O157:H7 infection, or of E. coli O157:H7-related HUS.

Membrane NMR: a dynamic research area.

Recent NMR relaxation studies of lipid bilayers and biomembranes are explained and briefly discussed. The results of both 2H and 13C NMR investigations suggest that, in addition to rapid local fluctuations of the hydrocarbon chains, slower, more collective motions of the bilayer exist. When the influence of the latter is recognized and properly accounted for, the contribution from local motions can be used to estimate a value for the microviscosity of the bilayer which corresponds to that of a simple n-paraffinic liquid. In general, the dynamic behavior of lipid bilayers as studied by NMR appears quite similar to that of simpler liquid crystals.