Multi-phase volcanic resurfacing at Loki Patera on Io.

The Jovian moon Io hosts the most powerful persistently active volcano in the Solar System, Loki Patera. The interior of this volcanic, caldera-like feature is composed of a warm, dark floor covering 21,500 square kilometres surrounding a much cooler central 'island'. The temperature gradient seen across areas of the patera indicates a systematic resurfacing process, which has been seen to occur typically every one to three years since the 1980s. Analysis of past data has indicated that the resurfacing progressed around the patera in an anti-clockwise direction at a rate of one to two kilometres per day, and that it is caused either by episodic eruptions that emplace voluminous lava flows or by a cyclically overturning lava lake contained within the patera. However, spacecraft and telescope observations have been unable to map the emission from the entire patera floor at sufficient spatial resolution to establish the physical processes at play. Here we report temperature and lava cooling age maps of the entire patera floor at a spatial sampling of about two kilometres, derived from ground-based interferometric imaging of thermal emission from Loki Patera obtained on 8 March 2015 ut as the limb of Europa occulted Io. Our results indicate that Loki Patera is resurfaced by a multi-phase process in which two waves propagate and converge around the central island. The different velocities and start times of the waves indicate a non-uniformity in the lava gas content and/or crust bulk density across the patera.

Effect of web-based training for Department of Motor Vehicle staff on donor designation rates: results of a statewide randomized trial.

On approach to addressing the continual shortage of organ donors is to encourage people to join a state donor registry. Joining the registry saves time and assures family members that organ donation is what their loved one would want. However, fewer than half of adults have taken this step. We tested a brief, web-based training program for department of motor vehicles (DMV) staff that educates them about organ and tissue donation and also models the correct way to interact with customers. The intervention was developed with extensive input and active participation from DMV staff. After a small-scale pilot test, all DMV offices across the state of West Virginia (WV) were randomized to receive the training or serve as a comparison group. The results showed that customers of DMV staff who had received the training were 7.5% more likely to register as organ donors. A conservative estimate is that this generates approximately 800 additional donor designations per month. An important aspect of web-based training is that once it has been deployed, it can continue to be used without incurring additional cost; the state of WV currently requires all new employees to complete the training program. This type of training can be adopted nationwide.

The national DBS brain tissue network pilot study: need for more tissue and more standardization.

Over 70,000 DBS devices have been implanted worldwide; however, there remains a paucity of well-characterized post-mortem DBS brains available to researchers. We propose that the overall understanding of DBS can be improved through the establishment of a Deep Brain Stimulation-Brain Tissue Network (DBS-BTN), which will further our understanding of DBS and brain function. The objectives of the tissue bank are twofold: (a) to provide a complete (clinical, imaging and pathological) database for DBS brain tissue samples, and (b) to make available DBS tissue samples to researchers, which will help our understanding of disease and underlying brain circuitry. Standard operating procedures for processing DBS brains were developed as part of the pilot project. Complete data files were created for individual patients and included demographic information, clinical information, imaging data, pathology, and DBS lead locations/settings. 19 DBS brains were collected from 11 geographically dispersed centers from across the U.S. The average age at the time of death was 69.3 years (51-92, with a standard deviation or SD of 10.13). The male:female ratio was almost 3:1. Average post-mortem interval from death to brain collection was 10.6 h (SD of 7.17). The DBS targets included: subthalamic nucleus, globus pallidus interna, and ventralis intermedius nucleus of the thalamus. In 16.7% of cases the clinical diagnosis failed to match the pathological diagnosis. We provide neuropathological findings from the cohort, and perilead responses to DBS. One of the most important observations made in this pilot study was the missing data, which was approximately 25% of all available data fields. Preliminary results demonstrated the feasibility and utility of creating a National DBS-BTN resource for the scientific community. We plan to improve our techniques to remedy omitted clinical/research data, and expand the Network to include a larger donor pool. We will enhance sample preparation to facilitate advanced molecular studies and progenitor cell retrieval.

A critical assessment of the mechanism by which hyperoxia attenuates exercise-induced asthma.

Recent data demonstrate that the magnitude of the heat loss that occurs from the respiratory tract during exercise correlates with the degree of post-exertional obstruction that develops in asthmatics. Respiratory heat loss relates directly to the minute ventilation and heat capacity of the inspired gas and inversely to its water content and temperature. Because it has been shown that inhaling 100% oxygen during exercise blunts the obstructive response, we wondered if this effect could be accounted for by differing values of heat exchange with air and oxygen breathing. To examine this question, we studied 10 asthmatics by measuring multiple aspects of pulmonary mechanics before and after four bouts of exhausting leg work during which the subjects inhaled either air or oxygen conditioned to provide widely differing thermal burdens on their airways. Under all inspired gas conditions, oxygen breathing produced significantly less obstruction than air. Minute ventilation was also significantly less with oxygen as was the total heat lost. As the latter fell, so did the magnitude of the postexercise obstruction. When the differences in ventilation and respiratory heat loss between air and oxygen were eliminated by eucapnic hyperventilation, the differences in the obstructive responses also disappeared. Thus, the effects of hyperoxia on exercise-induced asthma can be accounteed for solely by alterations in heat exchange.

Ammonia inhibits cAMP-regulated intestinal Cl- transport. Asymmetric effects of apical and basolateral exposure and implications for epithelial barrier function.

The colon, unlike most organs, is normally exposed to high concentrations of ammonia, a weak base which exerts profound and diverse biological effects on mammalian cells. The impact of ammonia on intestinal cell function is largely unknown despite its concentration of 4-70 mM in the colonic lumen. The human intestinal epithelial cell line T84 was used to model electrogenic Cl- secretion, the transport event which hydrates mucosal surfaces and accounts for secretory diarrhea. Transepithelial transport and isotopic flux analysis indicated that physiologically-relevant concentrations of ammonia (as NH4Cl) markedly inhibit cyclic nucleotide-regulated Cl- secretion but not the response to the Ca2+ agonist carbachol. Inhibition by ammonia was 25-fold more potent with basolateral compared to apical exposure. Ion substitution indicated that the effect of NH4Cl was not due to altered cation composition or membrane potential. The site of action of ammonia is distal to cAMP generation and is not due simply to cytoplasmic alkalization. The results support a novel role for ammonia as an inhibitory modulator of intestinal epithelial Cl- secretion. Secretory responsiveness may be dampened in pathological conditions associated with increased mucosal permeability due to enhanced access of lumenal ammonia to the basolateral epithelial compartment.

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles.

Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with 'paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.

Immunochemical studies of a purified antigen from Micropolyspora faeni.

A pure antigen fraction was isolated from the crude culture filtrate of Micropolyspora faeni by gel filtration and affinity chromatography. The isolated antigen has a mol. wt of approximately 16,000 and an isoelectric point of pH 3.8. The major amino acid content of this fraction includes glycine, glutamic acid, aspartic acid and alanine. This antigen fraction reacted with the sera of all 15 farmer's lung patients and 20 asymptomatic farmers with circulating anti-M. faeni antibodies. An ELISA method was developed using the purified antigen to detect specific circulating antibodies against M. faeni in farmer's lung patients.

Plasma melatonin circadian rhythms during the menstrual cycle and after light therapy in premenstrual dysphoric disorder and normal control subjects.

The aim of this study was to replicate and extend previous work in which the authors observed lower, shorter, and advanced nocturnal melatonin secretion patterns in premenstrually depressed patients compared to those in healthy control women. The authors also sought to test the hypothesis that the therapeutic effect of bright light in patients was associated with corrective effects on the phase, duration, and amplitude of melatonin rhythms. In 21 subjects with premenstrual dysphoric disorder (PMDD) and 11 normal control (NC) subjects, the authors measured the circadian profile of melatonin during follicular and luteal menstrual cycle phases and after 1 week of light therapy administered daily, in a randomized crossover design. During three separate luteal phases, the treatments were either (1) bright (> 2,500 lux) white morning (AM; 06:30 to 08:30 h), (2) bright white evening (PM; 19:00 to 21:00 h), or (3) dim (< 10 lux) red evening light (RED). In PMDD subjects, during the luteal phase compared to the follicular menstrual cycle phase, melatonin onset time was delayed, duration was compressed, and area under the curve, amplitude, and mean levels were decreased. In NC subjects, melatonin rhythms did not change significantly during the menstrual cycle. After AM light in PMDD subjects, onset and offset times were advanced and both duration and midpoint concentration were decreased as compared to RED light. After PM light in PMDD subjects, onset and offset times were delayed, midpoint concentration was increased, and duration was decreased as compared to RED light. By contrast, after light therapy in NC subjects, duration did not change; onset, offset, and midpoint concentration changed as they did in PMDD subjects. When the magnitude of advance and delay phase shifts in onset versus offset time with AM, PM, or RED light were compared, the authors found that in PMDD subjects light shifted offset time more than onset time and that AM light had a greater effect on shifting melatonin offset time (measured the following night in RED light), whereas PM light had a greater effect in shifting melatonin onset time. These findings replicate the authors' previous observation that nocturnal melatonin concentrations are decreased in women with PMDD and suggest specific effects of light therapy on melatonin circadian rhythms that are associated with mood changes in patient versus control groups. The differential changes in onset and offset times during the menstrual cycle, and in response to AM and PM bright light compared with RED light, support a two-oscillator (complex) model of melatonin regulation in humans.

Early versus late partial sleep deprivation in patients with premenstrual dysphoric disorder and normal comparison subjects.

OBJECTIVE: The aim of this study was to compare the clinical effects of early-night and late-night partial sleep deprivation in patients with premenstrual dysphoric disorder and normal comparison subjects. METHOD: In the premenstrual phase of two menstrual cycles, 23 subjects with DSM-IV premenstrual dysphoric disorder and 18 normal comparison subjects underwent a randomized crossover trial of 1) early-night sleep deprivation, in which subjects slept from 3:00 a.m. to 7:00 a.m., followed by a night of recovery sleep (11:00 p.m. to 7:00 a.m.), and 2) late-night sleep deprivation, in which subjects slept from 9:00 p.m. to 1:00 a.m., followed by a night of recovery sleep. RESULTS: For the subjects with premenstrual dysphoric disorder, in both partial sleep deprivation conditions the Hamilton and Beck depression ratings were significantly lower after recovery sleep than at baseline. Ratings on the day after early or late partial sleep deprivation tended to be lower than at baseline but were not statistically different. The normal comparison subjects showed no clinically important mood changes. A factor analytic approach used with the Hamilton depression scores showed that depressive retardation symptoms were the most responsive to sleep deprivation in the premenstrual dysphoric disorder subjects. CONCLUSIONS: These results are consistent with the reported efficacy of sleep deprivation for major depressive disorder. However, the premenstrual dysphoric disorder subjects improved after the recovery sleep rather than directly after partial sleep deprivation. That late-night sleep deprivation did not have greater benefit than did the hypothesized sham treatment, early-night sleep deprivation, also suggests that placebo effects cannot be ruled out.

Antisense inhibition of striatal GABAA receptor proteins decreases GABA-stimulated chloride uptake and increases cocaine sensitivity in rats.

The functional status of striatal GABAA receptors appears to be inversely related to the magnitude of cocaine-induced behaviors. Exposure of striatum to antisense oligodeoxynucleotides (ASODNs) targeted to the mRNAs for the alpha 2 and the beta 3 subunits of the GABAA receptor should decrease expression of receptor proteins and therefore might be expected to increase cocaine sensitivity. ASODNs, scrambled ODNs or saline were injected into right lateral ventricle of rats and behavioral responses to cocaine were tested 18-20 h after treatment. Animals injected separately with alpha 2 or beta 3 ASODNs exhibited increased behavioral sensitivity to cocaine compared to rats injected with saline or scrambled ODNs including performing more 360 degrees turns to the left than to the right. There was significantly less GABA-stimulated Cl uptake in right striatum compared to left striatum of ASODN-treated rats with no significant difference between sides in control animals. Specific binding to benzodiazepine and convulsant sites on the GABAA receptor was not selectively altered by ASODN treatment. Combined alpha 2 beta 3 ASODN treatment did not affect either cocaine sensitivity or GABAA receptor function. There was no difference between the density of Nissl stained cells in the left and right edges of striatum in control or ASODN-treated rats indicating the absence of significant neurotoxic effects of the ASODN treatment. Injection of fluorescein-conjugated ASODNs indicated that ASODN is present in striatum at times during which behavioral and neurochemical indices of GABA receptor function are decreased. Thus, the functional status of GABAA receptors in striatum may be involved in determining cocaine sensitivity.

Aspergillus fumigatus peptides differentially express Th1 and Th2 cytokines.

Relevant allergens from Aspergillus fumigatus associated with allergic bronchopulmonary aspergillosis (ABPA) have been cloned and expressed. The pathogenesis of ABPA probably depends on specific cytokines and immunoglobulins secreted by lymphocytes on stimulation with different epitopes of those allergens. In the present study, we synthesized peptides of 12-16 amino acids from the sequence of Asp fI and compared their immunological responses in four mice strains (BALB/c, C57BL/6, AKR, and CBA). Of the five peptides studied for their cytokine profile, one showed a clear Th1, whereas another showed a Th2 response. The remaining three peptides varied in their immunoreactivity. The results suggest that a number of epitopes of diverse activities are present in individual molecules and may be involved in the pathogenesis of ABPA through differential cytokine secretions.

Neuropsychological performance across the menstrual cycle in women with and without Premenstrual Dysphoric Disorder.

This study examined neuropsychological performance across the menstrual cycle in women with varying levels of premenstrual symptomatology. Following a 2-month period of prospective symptom documentation, there were 19 women who met DSM-IV criteria for Premenstrual Dysphoric Disorder (PMDD group) and 18 women with mild to moderate symptoms. Neuropsychological functioning was evaluated at the late follicular (pre-ovulatory) and late luteal (premenstrual) phases across the domains of psychomotor speed, attention, and verbal learning and memory. Repeated measures analysis of variance yielded significant group x phase differences on the psychomotor index, with women in the PMDD group demonstrating significant psychomotor slowing in the late luteal phase. This psychomotor slowing was subtle, however, and scores remained within the normal range across testing sessions. No group or phase differences were found on indices of attention or verbal learning and memory. These results suggest that with the exception of subtle psychomotor slowing in the late follicular relative to the late luteal phase, there is no discernible difference in cognitive functioning between women with and without PMDD.

Serological investigation of refractory human adult periodontitis.

This study examined the difference between the serum antibody profiles in refractory adult periodontitis patients (group A), and compared to those (group B) who responded well to conventional periodontal treatment. The levels of specific IgG antibody to Actinobacillus actinomycetemcomitans, Bacteroides gingivalis, Fusibacteriumnucleatum, and Eikenella corrodens were assessed in a group of 19 patients (group A) and 11 patients (group B). Specific IgG serum antibody levels were estimated using biotin-avidin linked immunosorbent assay (BALISA). Results indicated that Actinobacillus actinomycetemcomitans, and Bacteroides gingivalis had very high levels of specific circulating antibody in the sera of both groups of patients; whereas, Fusobacterium nucleatum and Eikenella corrodens showed considerable lower levels of antibody than the other two antigens. However, the differences between the two groups with regard to the antibody levels against different bacterial antigens were not statistically significant.

The use of mouse models to investigate shear bond strength in amelogenesis imperfecta.

Patients with amelogenesis imperfecta (AI) have defective enamel; therefore, bonded restorations of patients with AI have variable success rates. To distinguish which cases of AI may have good clinical outcomes with bonded materials, we evaluated etching characteristics and bond strength of enamel in mouse models, comparing wild-type (WT) with those having mutations in amelogenin (Amelx) and matrix metalloproteinase-20 (Mmp20), which mimic 2 forms of human AI. Etched enamel surfaces were compared for roughness by scanning electron microscopy (SEM) images. Bonding was compared through shear bond strength (SBS) studies with 2 different systems (etch-and-rinse and self-etch). Etched enamel surfaces of incisors from Amelx knock-out (AmelxKO) mice appeared randomly organized and non-uniform compared with WT. Etching of Mmp20KO surfaces left little enamel, and the etching pattern was indistinguishable from unetched surfaces. SBS results were significantly different when AmelxKO and Mmp20KO enamel surfaces were compared. A significant increase in SBS was measured for all samples when the self-etch system was compared with the etch-and-rinse system. We have developed a novel system for testing shear bond strength of mouse incisors with AI variants, and analysis of these data may have important clinical implications for the treatment of patients with AI.

The state of general surgery training: a different perspective.

BACKGROUND: Much has been written about the influences of Accreditation Council for Graduate Medical Education (ACGME) work restrictions, the litigious climate in American medicine, and the proliferation of subspecialty fellowships on general surgery training. Few previous studies have addressed general surgical residents' perceptions of surgical training on a national level. METHODS: A 38-question Institutional Review Board-approved survey was sent via e-mail to the program directors at all ACGME-approved general surgical training programs for distribution to categorical general surgery residents. Voluntary responses to statements focusing on job satisfaction, quality of life, and the influences of operative experience, work hours, fellows, physician extenders, as well as faculty and administration on resident training were solicited. RESULTS: Overall, 997 responses were received from residents of all clinical levels from 40 states. Most respondents were from university-based programs (79%) with a broad representation of program sizes (mean of 6 graduates per year; range 2 to 11). Residents believe that they will be prepared to enter clinical practice at the conclusion of their training (86%), that the duration of surgical training is adequate (85%), and that they are exposed to sufficient case volume and complexity (85% and 84%, respectively). Only 360 respondents (36%) believe that they are financially compensated appropriately. Although most respondents support the ACGME work-hour restrictions (70%), far fewer feel that they improve their training or patient care (46.6% and 46.8%, respectively). Most respondents are proud to be surgical residents (88%), view surgery as a rewarding profession (87%), and would choose surgery as a profession again (77%). CONCLUSIONS: Surgical residents are positive regarding the quality of their training and life, although they feel poorly compensated for their work. Most residents intend to pursue fellowship training. Survey responses were consistent irrespective of gender, ethnicity, and program type.

Increased embolic risk in patients with left ventricular thrombi.

Although left ventricular thrombi are associated with an increased embolic risk in the first few weeks after acute myocardial infarction, the long-term risk remains undefined. To ascertain the incidence of strictly defined systemic emboli, we followed 85 patients with echocardiographically documented left ventricular thrombi. At the time of the entry echocardiogram, most patients (n = 57) had remote myocardial infarction, while 19 had recent (less than 1 month) infarction, and nine had idiopathic cardiomyopathy. Because of the difficulty in classifying events as embolic in patients with advanced atherosclerosis, a matched control group of 91 patients without thrombi was also studied. The thrombus and control groups were similar with regard to recent myocardial infarction, remote infarction, anterior infarction, ejection fraction, atrial fibrillation, echocardiographic referral for source of emboli, and warfarin therapy. During a mean follow-up of 22 months after echocardiography, embolic events occurred in 13% (11 of 85) of patients with thrombi compared with 2% (two of 91) control patients (p less than .01). The actuarial probability of being embolus free at 2 years after echocardiography was 86% in patients with thrombi compared with 97% in control patients (p less than .01). All embolic events occurred greater than 1 month after myocardial infarction (range 1 to 96 months). The only clinical or echocardiographic features predictive of embolization were protrusion and mobility of thrombus (both p less than .02). We conclude that the incidence of embolic events is definitely increased in patients with left ventricular thrombi compared with control subjects during long-term follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

L-Asparaginase of Klebsiella aerogenes. Activation of its synthesis by glutamine synthetase.

An L-asparaginase has been purified some 250-fold from extracts of Klebsiella aerogenes to near homogeneity. The enzyme has a molecular weight of 141,000 as measured by gel filtration and appears to consist of four subunits of molecular weight 37,000. The enzyme has high affinity for L-asparagine, with a Km below 10(-5) M, and hydrolyzes glutamine at a 20-fold lower rate, with a Km of 10(-3) M. Interestingly, the enzyme exhibits marked gamma-glutamyltransferase activity but comparatively little beta-aspartyl-transferase activity. A mutant strain lacking this asparaginase has been isolated and grows at 1/2 to 1/3 the rate of the parent strain when asparagine is provided in the medium as the sole source of nitrogen. This strain grows as well as the wild type when the medium is supplemented with histidine or ammonia. Glutamine synthetase activates the formation of L-asparaginase. Mutants lacking glutamine synthetase fail to produce the asparaginase, and mutants with a high constitutive level of glutamine synthetase also contain the asparaginase at a high level. Thus, the formation of asparaginase is regulated in parallel with that of other enzymes capable of supplying the cell with ammonia or glutamate, such as histidase and proline oxidase. Formation of the asparaginase does not require induction by asparaginase and is not subject to catabolite repression.

A corticosteroid program for prevention of hospitalization for status asthmaticus in children.

This study assessed the efficacy of an outpatient course of prednisone in the treatment of acute asthma, as a method of preventing hospitalization for status asthmaticus. From September-November 1984, 181 courses of prednisone were utilized by children for acute exacerbations of asthma inadequately controlled by bronchodilators and inhaled beclomethasone dipropionate or cromolyn. The dose of prednisone was 1 mg/kg/day for five days with a maximum of 40 mg/day. Only ten children required hospitalization for status asthmaticus. Privately insured patients and non-privately insured patients accounted for 61 and 120 of the prednisone courses, respectively, of which five children from each group required hospitalization. The data suggest that short-term administration of prednisone for exacerbations of asthma was valuable in decreasing the need for hospitalization for asthma among bronchodilator-treated asthmatics. Further, patients from families without private hospitalization insurance appear as amenable to prednisone-intervention as privately insured patients.

Polarized Emissivity and Kirchhoff's law.

An expression for the polarized emissivity of a material is obtained with the Stokes vector-Mueller matrix polarization formalism. The result obtained is that thermally emitted radiance might have a circular polarization component. In addition, the emissivity depends only on the reflectance matrix.