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Synthetic methods have been developed for lead Sortase A inhibitors identified from previous studies. Several derivatives of the lead inhibitor were synthesized to derive preliminary structure activity relationships (SAR). Different regions of the lead inhibitor that are critical for the enzyme activity have been determined by systematic SAR studies. The E stereochemistry of the lead compound was found to be critical for its activity. Replacement of the E double bond with Z double bond or a rigid triple bond reduced the enzyme inhibitory activity in most cases. Reduction of the double bond to a C-C single bond resulted in complete loss of activity. Amide carbonyl and NH groups were also found to be crucial for the activity of this class of inhibitors, as well. The morpholine ring oxygen atom was also found to be an important factor for the activity of the lead inhibitor. Preliminary SAR studies led to the identification of compounds with improved enzyme inhibition. The most active compound was found to have an IC(50) value of 58 microM against the enzyme.

We compare ab initio broad spectrum calculations of the K-edge X-ray absorption spectra of copper and molybdenum against accurate experimental measurements and tabulated standards on an absolute scale. Comparisons are also presented for the fine structure in the spectra.

The limiting uncertainty in recent high accuracy measurements of the mass attenuation coefficient is the measurement of the integrated column density. An improvement in the design of the absorption foil holder is described which reduces the integrated column density uncertainty. The new design allows the edges of the foil to be more accurately mapped by the X-ray beam by reducing the largest source of uncertainty in the foil mapping: the uncertainty in the points along the foil edge. The method is shown to reduce the uncertainty in measurements of the mass attenuation coefficient of zinc foils. The reduced uncertainty in the full-foil mapping will allow the X-ray Extended Range Technique (XERT) to be applied to small non-metallic absorption foils more accurately.

In this article, we have studied and analyzed the statistics of both pristine and distorted bandpass X-ray images. In the past, we have shown that the statistics of natural, bandpass-filtered visible light (VL) pictures, commonly expressed by natural scene statistic (NSS) models, can be used to create remarkably powerful, perceptually relevant predictors of perceptual picture quality. We find that similar models can be developed that apply quite well to X-ray image data. We have also studied the potential of applying these statistical X-ray NSS models to the design of algorithms for automatic image quality prediction of X-ray images, such as might occur in security, medicine, and material inspection applications. As a demonstration of the discrimination power of these models, we devised an application of NSS models to an image modality classification task, whereby VL, X-ray, infrared, and millimeter-wave images can be effectively and automatically distinguished. Our study is conducted on a dataset of X-ray images made available by the National Institute of Standards and Technology.

Transmission X-ray systems are used to image the contents of suspicious packages, luggage, and cargo. The images can have a dynamic range of 1,000:1 or greater, but are typically displayed on consumer-grade displays with a low-dynamic range of less than 255:1. We show that modern tonemapping algorithms can greatly improve the process of displaying X-ray images on low-dynamic-range displays and compare the performance of some popular algorithms for this purpose.

Introduction During surgery on the thoracic and lumbar spine, SEPs to lower limb (LL) stimulation are used to monitor the dorsal column somatosensory pathways from the legs. SEPs to upper limb (UL) stimulation are often also recorded, to monitor for brachial plexus or peripheral nerve dysfunction related to the positioning of the patient’s arms and to serve as a ”control” for the effects of anesthesia on the LL SEPs. The latter use presumes that cortical SEPs to UL and LL stimulation are affected equally by anesthesia. We examined this assumption by measuring amplitude changes in UL and LL SEPs associated with the transition from TIVA (total intravenous anesthesia) with propofol and a narcotic to a halogenated inhalational anesthetic (HIA) during closing in a neurologically normal patient population. Methods We retrospectively identified surgeries for idiopathic scoliosis in adolescents without neuromuscular disease during which there were no adverse SEP or MEP changes and at least 2 runs of both UL and LL SEPs were recorded after the transition to inhalational anesthesia. The average SEP amplitudes were calculated for those runs and for several SEP waveforms immediately preceding the anesthetic change. Percentage amplitude changes were calculated for SEPs for each limb, the results for the left and right sides were averaged together, and the amplitude ratios (amplitudes under HIA divided by amplitudes under TIVA) for UL SEPs were compared to those for LL SEPs. In all cases, the SEPs were elicited by ulnar nerve and posterior tibial nerve stimulation. Results We identified 17 surgeries meeting inclusion criteria; desflurane was used in 9 and sevoflurane in 8. The patients included 12 girls and 5 boys ages 12–17 years. In one patient the UL SEPs were larger after the anesthetic change (amplitude ratio = 118%); in the other patients the amplitude ratio for UL SEPs ranged from 29% to 91%. Overall, the mean amplitude ratio for UL SEPs was 76%. For LL SEPs, the amplitude ratios ranged from 50% to 97% with a mean of 74%. In 10 patients the relative difference between the amplitude ratios for UL SEPs and LL SEPs was ⩽ 15% and in 6 patients it was between 16% and 40%. In the patient with the largest relative difference, the amplitude ratio was 29% for UL SEPs and 55% for LL SEPs. Conclusion Cortical SEPs were almost always smaller under HIA than under TIVA. On average, the anesthetic effects in the UL SEPs were very similar to those in the LL SEPs (mean amplitude ratio 76% vs. 74%). The effects on UL SEPs versus LL SEPs were also similar in most individual patients, but there were some patients in whom the quantitative effects on UL SEPs and LL SEPs differed by more than 15%. In conclusion, in this patient population UL SEPs provide a good anesthetic control for LL SEPs overall, but it should not be assumed that they can accurately predict quantitative amplitude changes in LL SEPs in individual patients.

Objective. The side effects of opioids have been widely investigated, but it is unknown whether the subjective effects of mu agonists and mixed action opioids produce similar symptom profiles. This study examined the structure and predictive validity of somatic and cognitive/affective side-effect profiles of morphine and pentazocine using the Somatic Side Effects Questionnaire and the Cognitive and Affective Side Effects Questionnaire. Design. The subjects were 122 female and 90 male healthy volunteers that received an intravenous bolus administration of either 0.08 mg/kg of morphine or 0.5 mg/kg pentazocine. Pre- and post-drug experimental pain testing was also performed. Exploratory and confirmatory factor analysis resulted in similar factor structures for both drugs. Results. The most frequently reported side effects across both drugs involved feeling relaxed, sedation, and feeling in control. At equianalgesic doses, pentazocine had greater aversive side effects than morphine, whereas morphine was more associated with feelings of control and euphoria. For both drugs, females reported greater frequency of negative side effects than males. Using cluster analysis, we identified similar symptom profiles for each drug. These drug-related side-effect profiles were linked with analgesic responses. Specifically, groups that had a more positive side-effect profile experienced the greatest analgesic effect based on changes in ischemic pain sensitivity. Conclusions. These findings have implications for decisions regarding opioid management of acute, chronic, and malignant pain conditions.

We present a new method for investigating roughness for surface structure and internal inhomogeneity down to the nano-scale for thin, nano-structured and opaque materials. The method uses careful measurements of the X-ray mass-attenuation coefficient and is applied to measure the magnitude of the roughness of gold foils. The technique is unique, providing insight into both surface and internal roughness. We show that moments of the distribution function of surface and internal structure can be investigated using this method, and discuss observable signatures. The approach is non-destructive and very sensitive as a local in situ measurement and as a diagnostic for accurate characterisation.

Five cases of confirmed multiple-drug overdose were previously screened and quantified by the West Virginia Office of the Chief Medical Examiner; 26 different drugs and metabolites were identified and quantified in blood at > or = 10 ng/mL. In this study, whole blood from those five case samples was analyzed by a direct injection multi-stage mass spectrometric (MSn) method to confirm the identity of 26 analytes at or above 10 ng/mL using 16 different deuterium-labeled internal standards. Samples were spiked with internal standards, precipitated with acetonitrile, and centrifuged. Samples were further diluted with either 0.1% formic acid or 0.1% ammonium hydroxide in methanol prior to injection into an electrospray ionization ion trap mass spectrometer (MS). Ions were monitored as MS-MS or MS3 product ions. In all cases, analysis by MS-MS confirmed the presence of the drugs and metabolites when the internal standards were detected. Detection of characteristic MS3 ions was used for further confirmation of the presence of parent drugs in all but three instances. Total analysis time was less than 1 h. Although only useful for qualitative or confirmatory purposes, this direct injection MSn method provides a simple and rapid confirmation of multiple drugs that have been previously identified and quantified by gas chromatographic-MS or liquid chromatographic-MS analytical methods.

Postcolonial modernity has meant the creation of a very unusual set of circumstances for writers of the French‐speaking Caribbean. Called upon to insert themselves forcibly into a space from which, historically, they have been excluded, many of these writers have sharpened their revolutionary horns in Paris, political and cultural capital of the former imperial power. Indeed, throughout the 20th century, Paris has been a veritable inevitability for the francophone elite, a seemingly unavoidable destination that has served at once as a space of painful disillusionment, self‐interrogation, and even community‐building catharsis. While the quandary of negotiating this difficult relationship has been widely discussed, what has been less thoroughly considered is how the very framework in which this tension is negotiated has had an impact on canon formation in the region. In effect, more attention must be paid to the correlation between a refusal of theory and a certain degree of marginalization; to the possibil...

Our prior studies indicated that postural fainting relates to splanchnic hypervolemia and thoracic hypovolemia during orthostasis. We hypothesized that thoracic hypovolemia causes excessive sympathetic activation, increased respiratory tidal volume, and fainting involving the pulmonary stretch reflex. We studied 18 patients 13–21 yr old, 11 who fainted within 10 min of upright tilt (fainters) and 7 healthy control subjects. We measured continuous blood pressure and heart rate, respiration by inductance plethysmography, end-tidal carbon dioxide (ETCO2) by capnography, and regional blood flows and blood volumes using impedance plethysmography, and we calculated arterial resistance with patients supine and during 70° upright tilt. Splanchnic resistance decreased until faint in fainters (44 ± 8 to 21 ± 2 mmHg·l−1·min−1) but increased in control subjects (47 ± 5 to 53 ± 4 mmHg·l−1·min−1). Percent change in splanchnic blood volume increased (7.5 ± 1.0 vs. 3.0 ± 11.5%, P < 0.05) after the onset of tilt. Upright tilt initially significantly increased thoracic, pelvic, and leg resistance in fainters, which subsequently decreased until faint. In fainters but not control subjects, normalized tidal volume (1 ± 0.1 to 2.6 ± 0.2, P < 0.05) and normalized minute ventilation increased throughout tilt (1 ± 0.2 to 2.1 ± 0.5, P < 0.05), whereas respiratory rate decreased (19 ± 1 to 15 ± 1 breaths/min, P < 0.05). Maximum tidal volume occurred just before fainting. The increase in minute ventilation was inversely proportionate to the decrease in ETCO2. Our data suggest that excessive splanchnic pooling and thoracic hypovolemia result in increased peripheral resistance and hyperpnea in simple postural faint. Hyperpnea and pulmonary stretch may contribute to the sympathoinhibition that occurs at the time of faint.

Heating of nanoparticles (NPs) using an AC magnetic field depends on several factors, and optimization of these parameters can improve the efficiency of heat generation for effective cancer therapy while administering a low NP treatment dose. This study investigated magnetic field strength and frequency, NP size, NP concentration, and solution viscosity as important parameters that impact the heating efficiency of iron oxide NPs with magnetite (Fe3O4) and maghemite (γ-Fe2O3) crystal structures. Heating efficiencies were determined for each experimental setting, with specific absorption rates (SARs) ranging from 3.7 to 325.9 W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18 nm), as well as commercially-available iron oxides (with average core sizes of 8, 9, and 16 nm). The experimental magnetic coil system made it possible to isolate the effect of magnetic field parameters and independently study the effect on heat generation. The highest SAR values were found for the 18 nm synthesized particles and the maghemite nanopowder. Magnetic field strengths were applied in the range of 15.1 to 47.7 kA/m, with field frequencies ranging from 123 to 430 kHz. The best heating was observed for the highest field strengths and frequencies tested, with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led to lower heating rates in nanoparticle solutions, which can have significant implications for the application of magnetic fluid hyperthermia in vivo.

Cystic fibrosis (CF) is due to mutations in the CFTR gene, which prevents correct folding, trafficking and function of the mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. The dysfunctional effect of CFTR mutations, principally the F508del-CFTR mutant, is further manifested by hypersecretion of the pro-inflammatory chemokine interleukin-8 into the airway lumen, which further contributes to morbidity and mortality. We have hypothesized that microRNA (miR)-based therapeutics could rescue the dysfunctional consequences of mutant CFTR. Here we report that a miR-16 mimic can effectively rescue F508del-CFTR protein function in airway cell lines and primary cultures, of differentiated human bronchial epithelia from F508del homozygotes, which express mutant CFTR endogenously. We also identify two other miRs, miR-1 and miR-302a, which are also active. Although miR-16 is expressed at basal comparable levels in CF and control cells, miR-1 and miR-302a are undetectable. When miR mimics are expressed in CF lung or pancreatic cells, the expression of the F508del-CFTR protein is significantly increased. Importantly, miR-16 promotes functional rescue of the cyclic AMP-activated apical F508del-CFTR chloride channel in primary lung epithelial cells from CF patients. We interpret these findings to suggest that these miRs may constitute novel targets for CF therapy.

Symptomatic knee osteoarthritis (OA) is a condition commonly associated with increased pain, disability, and functional limitations. Given the poor correspondence between radiographic evidence and clinical pain, central sensitization has been implicated as a potential mechanism underlying pain facilitation in knee OA. Sex may be a moderator of centrally mediated changes in knee OA pain; however, few studies have systematically assessed this. Therefore, the aim of this study was to examine differences in peripheral and central sensitization in men and women with symptomatic knee OA, as well as to determine whether these differences vary across age (middle age versus older age).Participants (n = 288) between the ages of 45 and 85 years completed a battery of quantitative sensory pain procedures assessing sensitivity to contact heat, cold pressor, mechanical pressure, and punctate stimuli. Differences in temporal summation (TS) were examined, as well as measures of clinical pain and functional performance.When compared to men, women exhibited greater sensitivity to multiple pain modalities (i.e., lower heat, cold, pressure thresholds/tolerances, greater TS of pain); however, there were no sex differences in clinical pain, with the exception of greater widespread pain observed in women. Although there were select age-related differences in pain sensitivity, sex differences in pain varied minimally across the age cohort.Overall, these findings provide evidence for greater overall sensitivity to experimental pain in women with symptomatic knee OA compared to men, suggesting that enhanced central sensitivity may be an important contributor to pain in this group.

© 2015 PLOS ONE. The delivery of primary care to homeless individuals with mental health conditions presents unique challenges. To inform healthcare improvement, we studied predictors of favorable primary care experience among homeless persons with mental health conditions treated at sites that varied in degree of homeless-specific service tailoring. This was a multi-site, survey-based comparison of primary care experiences at three mainstream primary care clinics of the Veterans Administration (VA), one homeless-tailored VA clinic, and one tailored non-VA healthcare program. Persons who accessed primary care service two or more times from July 2008 through June 2010 (N = 366) were randomly sampled. Predictor variables included patient and organization characteristics suggested by the patient perception model developed by Sofaer and Firminger (2005), with an emphasis on mental health. The primary care experience was assessed with the Primary Care Quality-Homeless (PCQ-H) questionnaire, a validated survey instrument. Multiple regression identified predictors of positive experiences (i.e. higher PCQ-H total score). Significant predictors of a positive experience included a site offering tailored service design, perceived choice among providers, and currently domiciled status. There was an interaction effect between site and severe psychiatric symptoms. For persons with severe psychiatric symptoms, a homeless-tailored service design was significantly associated with a more favorable primary care experience. For persons without severe psychiatric symptoms, this difference was not significant. This study supports the importance of tailored healthcare delivery designed for homeless persons' needs, with such services potentially holding special relevance for persons with mental health conditions. To improve patient experience among the homeless, organizations may want to deliver services that are tailored to homelessness and offer a choice of providers.

Ultra-thin curved transmission crystals operating in the Cauchois spectrometer geometry were evaluated for the purpose of achieving high spectral resolution in the 6-13 keV x-ray energy range. The crystals were silicon (111) and sapphire R-cut wafers, each 18 μm thick, and a silicon (100) wafer of 50-μm thickness. The W Lα(1) spectral line at 8.398 keV from a laboratory source was used to evaluate the resolution. The highest crystal resolving power, E/ΔE=6300, was achieved by diffraction from the (33-1) planes of the Si(100) wafer that was cylindrically bent to a radius of curvature of 254 mm, where the (33-1) planes have an asymmetric angle of 13.26° from the normal of the crystal surface facing the x-ray source. This work demonstrates the ability to measure highly resolved line shapes of the K transitions of the elements Fe through Kr and the L transitions of the elements Gd through Th using a relatively compact spectrometer optical system and readily available thin commercial wafers. The intended application is as a diagnostic of laser-produced plasmas where the presence of multiple charged states and broadenings from high temperature and density requires high-resolution methods that are robust in a noisy source environment.

A high resolution crystal spectrometer utilizing a crystal in transmission geometry has been developed and experimentally optimized to measure the widths of emission lines in the 10–60 keV energy range with eV accuracy. The spectrometer achieves high spectral resolution by utilizing crystal planes with small lattice spacings (down to 2d = 0.099 nm), a large crystal bending radius and Rowland circle diameter (965 mm), and an image plate detector with high spatial resolution (60 μm in the case of the Fuji TR image plate). High resolution W L-shell and K-shell laboratory test spectra in the 10–60 keV range and Ho K-shell spectra near 47 keV recorded at the LLNL Titan laser facility are presented. The Ho K-shell spectra are the highest resolution hard x-ray spectra recorded from a solid target irradiated by a high-intensity laser.

Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ΔF508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ΔF508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ΔF508-CFTR (t½ ∼10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day.

Responses to painful stimuli are characterized by tremendous interindividual variability, and genetic factors likely account for some proportion of this variability. However, few studies have identified genetic contributions to experimental pain perception in humans. This experiment investigated whether the A118G single nucleotide polymorphism of the mu-opioid receptor gene ( OPRM1 ) was associated with responses to three different experimental pain modalities in a sample of 167 healthy volunteers (96 female, 71 male). Responses to thermal, mechanical, and ischemic pain were assessed in all subjects, and genotyping of OPRM1 was performed, which revealed that the rare A118G allele occurred in 24 females (25%) and 12 males (17%). Statistical analyses indicated that subjects with a rare allele had significantly higher pressure pain thresholds than those homozygous for the common allele. Also, a sex by genotype interaction emerged for heat pain ratings at 49 degrees C, such that the rare allele was associated with lower pain ratings among men but higher pain ratings among women. These data indicate an association of a common single nucleotide polymorphism of OPRM1 with mechanical pain responses and that this genotype may be associated with heat pain perception in a sex-dependent manner. This study examines the association of the A118G SNP of OPRM1 to experimental pain sensitivity. The results indicate that the rare allele is associated with higher pressure pain thresholds. These results support previous contentions that OPRM1 may be a pain-relevant gene; however, replication of these findings is needed.

Objective The purpose of this investigation was to examine the effects of olfactory absorption of two commonly used therapeutic essential oils on sensory and affective responses to experimentally induced pain. Methods A sex-balanced (13 men and 13 women) randomized crossover design was used to obtain pre- and posttreatment change scores for quantitative sensory ratings of contact heat, pressure, and ischemic pain across separate inhalation treatment conditions using essential oil of lavender, essential oil of rosemary, and distilled water (control). Subjective reports of treatment-related changes in pain intensity and pain unpleasantness were obtained for each condition using a visual analog scale. We interpret our findings with respect to the separate dimensions of sensory and affective processing of pain. Results Analyses revealed the absence of changes in quantitative pain sensitivity ratings between conditions. However, retrospectively, subjects' global impression of treatment outcome indicated that both pain intensity and pain unpleasantness were reduced after treatment with lavender and marginally reduced after treatment with rosemary, compared with the control condition. Conclusion These findings suggest that aromatherapy may not elicit a direct analgesic effect but instead may alter affective appraisal of the experience and consequent retrospective evaluation of treatment-related pain.

Phosphodiesterase inhibitors, such as pentoxifylline and aminophylline, may reduce inflammatory cytokine-induced endothelial permeability. We tested the hypothesis that aminophylline treatment may ameliorate the pulmonary and extrapulmonary effects of endotoxemia in a rat model. In anesthetized rats, a tracheotomy was performed along with catheterization of a femoral vein and artery. Anesthesia, fluid balance, and normothermia were maintained throughout the 6-h experiment. A stable hemodynamic and gas-exchange baseline was established at which time the rats were randomly divided into three groups. Group I received aminophylline (1mg/kg) over 30 min followed by 0.5mg/kg/h. Group II received a single dose of endotoxin (4 mg/kg) while Group III received both aminophylline and endotoxin as described for Groups I and II, respectively. Gas-exchange profiles, mean arterial blood pressure, and heart rate were determined every 2h. At hour 6, the rats were euthanized and lung, kidney, and heart tissue were removed for determination of water content. As our control group, we utilized data from our previously published study involving an identical surgical procedure with normal saline. Endotoxemia produced characteristic respiratory and hemodynamic signs of sepsis including hypotension, hyperventilation, tachycardia, and renal and pulmonary edema. Aminophylline treatment failed to prevent these endotoxemia-induced respiratory and hemodynamic manifestations of sepsis, but significantly improved the acid-base imbalance that developed during surgical procedures in saline-treated control rats. Further studies are warranted to determine potentially beneficial doses of aminophylline and resulting theophylline serum concentrations under such septic conditions.

Previous research suggests that women attending gynaecology clinics experience high rates of psychological distress and psychiatric morbidity. Although the reasons for this are poorly understood, certain conditions appear to cause women particularly high levels of anxiety and depression. This paper reports a qualitative study, using Interpretative Phenomenological Analysis (IPA), to examine the illness experiences of women with the common gynaecological condition of fibroids. The study employs semi-structured interviews, guided by Leventhal's self-regulation model, to explore 18 women's understanding and experiences of having fibroids. Qualitative analysis revealed eight themes drawn into two higher-order themes - 'Managing uncertainty' and 'Struggling between defeat and optimism'. These higher-order themes illustrate the multiplicity of experiences and meanings used by women attempting to understand their condition, treatment options and future health outcomes. The differences in women's illness representations may account for differences in their relative distress levels. The findings indicate the importance of considering an individual's illness representations in order to facilitate the provision of appropriate medical and psychological care to women with fibroids.

To determine the mechanisms underlying increased aerobic power in response to exercise training in octogenarians, we studied mildly frail elderly men and women randomly assigned to an exercise group ( n = 22) who participated in a training program of 6 mo of physical therapy, strength training, and walking followed by 3 mo of more intense endurance exercise at 78% of peak heart rate or a control sedentary group ( n = 24). Peak O2 consumption (V̇o2 peak) increased 14% in the exercise group ( P < 0.0001) but decreased slightly in controls. Training induced 14% increase ( P = 0.027) in peak exercise cardiac output (Q̇), determined via acetylene re-breathing, and no change in arteriovenous O2 content difference. The increase in Q̇ was mediated by increases in heart rate ( P = 0.009) and probably stroke volume ( P = 0.096). Left ventricular stroke work also increased significantly. In the men, the increase in V̇o2 peak was exclusively due to a large increase in peak Q̇ (22%). In the women, the gain in V̇o2 peak was due to small increases in Q̇ and O2 extraction from skeletal muscles. Pulse pressure normalized for stroke volume and arterial elastance during peak effort did not change with training. Controls showed no changes. The results suggest that, although frail octogenarians have a diminished capacity for improvement in aerobic power in response to exercise training, this adaptation is mediated mostly by an increase in Q̇ during peak effort. Furthermore, Q̇ likely plays a greater role in the adaptive increase in V̇o2 peak in old men than old women.

This paper explores interconnections between values, theory and practice in psychotherapeutic interventions in women's health. A re-worked biopsychosocial approach is discussed. This draws on a material-discursive psychology that also affirms individual subjective experience. How such an approach translates to clinical practice is illustrated with reference to two clinical vignettes, one describing the process of formulation and the other the process of therapy.

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from κ-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor ( Mc1r ) gene mediates κ-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered κ-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the κ-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.

To evaluate the dosing and safety of intravenous magnesium sulfate administered via continuous infusion for refractory wheezing.All patients admitted to the pediatric intensive care unit (PICU) between January 1998 and March 2001 who were prescribed magnesium sulfate via continuous infusion were identified via retrospective chart review. The patient's medical history, demographic data, vital signs, magnesium dosing history, and concurrent medications were recorded.Forty PICU patients represent our study population. The mean age was 82.6 +/- 64.6 mo; 18 patients were boys.The mean magnesium loading dose (mg/kg) was 29.6 +/- 13.2 with a mean infusion dose (mg/kg/h) of 18.4 +/- 6.5 with a significant difference in dosing noted between patients weighing less than 30 kg and those with a higher weight. The mean magnesium loading dose (mg/kg) in the less than 30 kg group was 35.3 +/- 12.7 compared with 21.9 +/- 9.9 in the higher weight group (P.05). Mean infusion doses (mg/kg/h) were 21.6 +/- 6 and 14.6 +/- 4.2, respectively (P.05). There was no significant difference between the mean concentrations (mg/dL) reported between the 2 groups (less than 30 kg group = 3.9 +/- 0.6; higher weight group = 3.6 +/- 0.5). All patients received nebulized albuterol, ipratropium, and intravenous methylprednisolone before magnesium therapy. Aminophylline and ketamine were prescribed to 28 and 4 patients, respectively. No cardiovascular adverse effects were noted during magnesium therapy.For the treatment of refractory wheezing, intravenous magnesium sulfate administered via continuous infusion represents a safe mode of drug delivery.

The comprehension of 16 pictorial safety symbols was examined using a rapid visual exposure technique and 4 types of prohibitive circle-slash variants (over, under, partial, and translucent). Performance was higher for base pictorial images that appeared to depict more concrete, less complex and familiar concepts. Symbols were better understood with the under and translucent slashes. This research has implications for the design of pictorial symbols on roadways and in other environments where exposure to safety information may be brief.

Postnatal depression carries a significant health burden for mothers and their offspring. However, the majority of screening or treatment studies for postnatal depression have been carried out on white or European populations and clinicians have been appropriately cautious about applying these findings to different cultural groups. This study describes the development and use of a Bengali version of the Edinburgh Postnatal Depression Scale (EPDS). Forty-eight Bangladeshi postnatal women in both Bangladesh and England were interviewed by a Syhletti/Bengali-speaking psychologist. The translated version of the EPDS was presented in the usual way, along with a standardized interview about the degree of social support and a translated version of the General Health Questionnaire (GHQ). Although one item of the EPDS presented some translation difficulties, the majority of items obtained reasonable semantic equivalence and were successfully rated by the women in the study. Preliminary examination of the psychomet...

Background: Sedatives are frequently used to facilitate mechanical ventilation of critically ill pediatric patients. Many of these drugs are used in children before appropriate clinical pharmacology and efficacy/safety trials are performed in the targeted pediatric population. Objective: This study assesses the prescribing patterns and clinical utility of propofol as a sedative before anticipated extubation in mechanically ventilated pediatric patients in the absence of pediatric dosing guidelines. Methods: We conducted a retrospective chart review of patients admitted to the Pediatric Intensive Care Unit at Rainbow Babies and Children's Hospital between January 1993 and July 1994 who received propofol as a sedative to facilitate extubation. Results: Forty-eight patients received propofol as a sedative to facilitate extubation. All patients were immediately sedated after the first propofol loading dose. In their attempts to optimize sedation, clinicians made numerous propofol dose adjustments and administered repeat loading doses. Forty-one of these patients were successfully extubated; deterioration in clinical status unrelated to propofol infusion prevented extubation in the remaining 7 patients. Adverse effects possibly associated with propofol administration included hypotension (24 patients), transient decrease in heart rate (1), hypercholesterolemia (4), hypertriglyceridemia (5), abnormal base excess (3), and neurologic events (3). Propofol was discontinued in only 1 hypotensive patient because of perceived drug-induced adverse effects. Five hypotensive patients were managed with fluid therapy, and all laboratory abnormalities resolved either during propofol infusion or after discontinuation. Most patients with elevated blood lipids had received concurrent intravenous lipid therapy. Conclusions: These data suggest that without effective age-appropriate dose recommendations for new drugs with definite pediatric applications, clinicians must depend on bedside clinical observations and pharmacologic data derived from adult patients to determine drug dosing. This lack of pediatric pharmacologic data delays optimal therapy, leading to unnecessary clinical interventions that affect patient care, patient safety, and cost. Despite these limitations, the results of this study suggest that propofol appears to be well tolerated when used to facilitate extubation in mechanically ventilated pediatric patients.

A selected (non-random) serological survey of cattle for antibodies to the glycoprotein antigen of bovine leukemia virus has been conducted in five states by seven investigators. A total of 1,295 beef and dairy cattle from 74 herds were studied with attention to the following: type of production, number of animals per herd, previous history of bovine leukemia cases in the herd, age of the animal, and serological reaction in the bovine leukemia glycoprotein immunodiffusion test (BL-GID). It was concluded that herd size (1-50, or 50+ animals per herd) exercised no influence on the percent positive BL-GID reactions. However, a previous history of clinical bovine leukemia in the herd and the type of production (beef or dairy) had considerable influence on the percent positive BL-GID reactors. Animals from herds that had a history of bovine leukemia exhibited 52.0% positive BL-GID reactions as compared to 13.7% reactors in animals from herds with no herd history of bovine leukemia. Beef animals exhibited 2.6% positive BL-GID reactions, while dairy animals exhibited 28.2% positive BL-GID reactions. Data were insufficient to determine age trends.

Pain hypervigilance is an important aspect of the fear-avoidance model of pain that may help explain individual differences in pain sensitivity among persons with knee osteoarthritis (OA).The purpose of this study was to examine the contribution of pain hypervigilance to clinical pain severity and experimental pain sensitivity in persons with symptomatic knee OA.We analyzed cross-sectional data from 168 adults with symptomatic knee OA. Quantitative sensory testing was used to measure sensitivity to heat pain, pressure pain, and cold pain, as well as temporal summation of heat pain, a marker of central sensitization.Pain hypervigilance was associated with greater clinical pain severity, as well as greater pressure pain. Pain hypervigilance was also a significant predictor of temporal summation of heat pain.Pain hypervigilance may be an important contributor to pain reports and experimental pain sensitivity among persons with knee OA.

A 55-year-old woman with lung cancer presented with leg numbness. Her systemic disease was well-controlled. MRI was precluded by a metallic cardiac device and spinal CT was unremarkable. On 2 occasions, examination of CSF demonstrated minimally elevated protein, but no abnormal cells. CT myelogram revealed bulky disease and CSF obtained a third time during the procedure confirmed the diagnosis (figure). To detect leptomeningeal carcinomatosis with 90%–98% sensitivity, 3 taps are needed. False-negatives can be minimized by withdrawal of 10.5 mL of CSF and immediate processing.1,2

Enhanced pain facilitation is reportedly an important contributor to the clinical pain experiences of individuals with knee osteoarthritis (OA). Ethnic differences in the prevalence and severity of knee OA in addition to associated pain are also well documented. Temporal summation (TS) of pain is a widely applicable quantitative sensory testing method that invokes neural mechanisms related to pain facilitatory processes. This study tested whether TS of pain, an index of pain facilitation, differentially predicts the clinical pain experiences of African Americans and non-Hispanic whites with symptomatic knee OA.A total of 225 study participants underwent assessment of TS of mechanical and heat pain stimuli applied to their most symptomatic knee and their ipsilateral hand (mechanical) or forearm (heat). Using telephone-based surveys, participants subsequently reported their average and worst clinical pain severity across four consecutive weeks after the assessment of TS.In predicting future clinical pain, ethnicity interacted with TS of mechanical pain (but not heat pain), such that TS of mechanical pain at the knee significantly predicted greater clinical ratings of average (b = 0.02, p = .016) and worst (b = 0.02, p = .044) clinical pain for non-Hispanic whites but not African Americans (p values.30).These results reveal the importance of considering ethnicity when examining pain facilitation and the clinical pain of individuals with symptomatic knee OA. The results of this study are discussed in terms of ethnic differences in the predictors of clinical pain experiences among African Americans and non-Hispanic whites with knee OA.

Betatron x-ray spectra in the 10 keV to 70 keV energy range were recorded by a transmission crystal spectrometer. This work demonstrates for the first time the ability to accurately measure the absolutely-calibrated betatron photon energy distribution using a high-resolution wavelength dispersive crystal spectrometer. The betatron emission was generated by the interaction of intense pulses from the Rutherford Appleton Laboratory Astra-Gemini laser with a gas capillary waveguide. The spectrometer utilized a quartz (101) crystal that was cylindrically bent to a radius of 112 mm.1 The crystal was positioned 2.5 m from the photon source and covered a 12.6 mrad by 9.3 mrad field of view. Single and multiple shot spectra were recorded on an image plate detector. After subtracting the background resulting from energetic (> 300 keV) scattered photons, the energy-dependent shape of the spectrum and the absolute number of photons were measured using the crystal efficiency and image plate calibration curves. The experimental spectra in units of photons/keV/mrad2, averaged over the spectrometer's field of view, were in good agreement with the synchrotron energy distribution. For optimal laser and betatron generation conditions, the fluence of photons having energies > 10 keV was about 3×104 photons/mrad2 per shot, and the critical energy of the fitted synchrotron distribution was 8.8 keV ± 0.5 keV. To further understand and optimize the betatron generation process, it will be necessary to measure the betatron photon distribution with increased accuracy and also with angular resolution in the laser polarization direction and perpendicular to this direction. Improved instrument accuracy and sensitivity can be accomplished by utilizing thicker shielding and improved baffling to reduce the background resulting from > 300 keV scattered photons. Owing to the Bragg condition that must be satisfied along the length of the bent crystal, spectral images present angular and energy dependence in the dispersion plane. Angular resolution in the orthogonal, out-of-plane direction occurs because the fan of x-rays from the small (effectively point) source passes through the crystal with small deflection and is projected onto the image plate.

Study Objective. To evaluate traditional nomogram (TN) versus individualized pharmacokinetic gentamicin dosing practices in neonatal intensive care units, focusing on achieving target therapeutic concentrations (peak > 8 μg/ml, trough < 2 μg/ml), number of dosing changes, number of concentrations obtained, and evidence of nephrotoxicity. Design. Retrospective chart review. Setting. Three neonatal intensive care units. Patients. Three hundred nine infants prescribed gentamicin. Intervention. None. Measurements and Main Results. Sixty-seven percent of patients receiving pharmacokinetic dosing had initial peak concentrations of 8 μ/ml or greater compared with 7% of patients receiving TN dosing (p

Absolute values of the column densities [ ρ t ] c of four gold foils were measured using micrometry combined with the 2D X-ray attenuation profile. The absolute calibration of [ ρ t ] c was made with a reference foil and the [ ρ t ] c of other foils were determined following the thickness transfer method. By this method, we obtain absolute calibration to 0.1% or better which was not possible using only the X-ray map of a single foil over its central region.

The nonoperative management of splenic injury secondary to blunt trauma in older patients remains controversial. We have reviewed our experience from January 1978 to December 1997 with selective nonoperative management of blunt splenic injury in adults 55 years and older. Criteria for nonoperative management included hemodynamic stability with any transient hypotension corrected using less than 2000 cm3 crystalloid infusion, a negative abdominal physical examination ruling out associated injuries, and a blood transfusion requirement of no more than 2 units attributable to the splenic injury. During the study period, 18 patients over age 55 with radiographic confirmation of a splenic injury met the above criteria for nonoperative management. Their mean age was 72 years (range 56–86), and 13 of the 18 were female (72%). The mean Injury Severity Score was 15 (range 4–29), with the mechanism of injury equally divided between automobile crashes (9) and falls (9). During a similar time period, 15 patients 55 years or older with splenic injury composed an operative group; these patients did not differ with respect to age (mean 68 years), sex (60% female), or mechanism of injury. CT scans of 8 patients managed nonoperatively were available and graded using the American Association for the Surgery of Trauma classification, with a mean score of 2.3 (range 2–3). Eight of the 18 nonsurgical patients received blood transfusions. None of the 18 patients who met the criteria for nonoperative management “failed” the protocol, and none were taken to the operating room for abdominal exploration. Two patients (11%) died of associated thoracic injuries after lengthy hospital stays, one at 10 days and one at 24 days. We conclude from our data that nonoperative management of blunt splenic injury in patients age 55 years and older is indicated provided they are hemodynamically stable, do not require significant blood transfusion, and have no other associated abdominal injuries.

Although improved prosthetic graft patency with endothelial cell (EC) seeding has been shown in animal models, the clinical application of this technique requires a convenient source of ECs. We have evaluated EC cultures derived from the mononuclear cell (MNC) fraction obtained during large-volume leukapheresis and compared this with cultures grown from peripheral blood cells obtained by phlebotomy. Leukapheresis was performed in healthy adult volunteers (n = 7) using software designed to increase the percentage of MNCs harvested. Blood (40–293 mL) was drawn from a peripheral vein in healthy adult volunteers (n = 13), and the MNCs were obtained by differential centrifugation using a Lymphoprep gradient. Significantly more MNCs were obtained by leukapheresis than by phlebotomy. Each leukapheresis procedure yielded 12.5 to 23 mL, which contained 2.29 ± 0.35 x 109 MNCs, compared with 2.16 ± 0.50 x 108 MNCs, for each phlebotomy ( P < 0.001). EC colonies developed in significantly more cultures from leukapheresis-derived MNCs (6 of 7) than phlebotomy-derived MNCs (4 of 13; P = 0.008). Leukapheresis-derived cells developed EC morphology at 15.5 ± 2 days compared with 21 ± 3.4 days for cells obtained by phlebotomy ( P = not significant). EC were identified by positive factor VIII and vascular endothelial growth factor receptor immunostaining. Leukapheresis significantly increases the number of progenitor cells available for differentiation into EC compared with phlebotomy and avoids the need for any surgical procedure to harvest a peripheral vein as a direct source of ECs.

Purpose: We have developed techniques to isolate endothelial cell (EC) progenitors from human peripheral and umbilical cord blood. Methods: Human adult peripheral and umbilical cord blood monocytes were isolated by centrifugation, and progenitor cells were separated with the use of magnetic polystyrene beads that were coated with a monoclonal antibody specific for the CD34 cell–membrane antigen. Cells were propagated in selective media, and developing cultures were immunostained for CD31, CD34, factor VIII, and vascular endothelial growth factor cell receptors. ECs that developed were transfected with a gene for prourokinase and used to line ePTFE grafts, which were evaluated in vitro in a pulsatile flow system. Results: Umbilical cord monocyte cultures demonstrated colonies that resembled ECs at approximately 2 weeks, with growth being best supported by EC growth media plus 20% calf serum with iron. Immunostaining of colonies was positive for CD31 and factor VIII. After 18 days in culture, CD34 + cells from adult peripheral blood were noted, which had the typical cobblestone appearance of ECs and immunostained positively for CD31 and factor VIII–related antigens. Cultures of umbilical cord–derived cells and adult peripheral blood–derived cells developed complex line formations within 1 week in culture that stained positively for vascular endothelial growth factor receptor-2. Urokinase-transfected ECs were shown to overexpress urokinase. Prosthetic grafts lined with transfected cells showed 87.33% ± 4.97% cell adherence after 2 hours in a pulsatile flow system at clinically relevant shear stress. Conclusion: We conclude that endothelial progenitor cells can be isolated from human adult peripheral and umbilical cord blood and developed into EC cultures as a source of cells for vascular graft seeding and gene therapy. (J Vasc Surg 2000;31:181-9.)