Fasting ghrelin but not PYY(3-36) is associated with insulin-resistance independently of body weight in Wistar rats.
The objective of this study was to evaluate the association between insulin-resistance and fasting levels of ghrelin and PYY in Wistar rats. A total of 25 male Wistar rats, weighing 200-300 g, was included in this study. The animals were maintained in cages with a 12/12h light-dark cycle and fed standard chow and water ad libitum. After 12-h overnight fasting, ghrelin, PYY, insulin and glucose values were determined. Insulin resistance was assessed by means of the HOMA-IR, which was ranked and the median was used as a cut-off value to categorize insulin-resistance. HOMA-IR values equal and above 2.62 were considered insulin-resistant (IR) while values below 2.62 were considered insulin sensitive (IS). Differences between means were determined using the Student t-test. Multiple regression and Pearson's correlation test were used to evaluate the association between variables. HOMA-IR median IQ range values for IS and IR groups were, respectively, 1.56 (0.89 - 2.16) vs. [4.06 (3.50 - 4.61); p < 0.001]. The IR group presented increased levels of fasting ghrelin, PYY and insulin respectively: [50.35 (25.99 - 74.71) pg/mL vs. 12.33 (8.77 - 15.89) pg/mL; p = 0.001]; [54.38 (37.50 - 71.26) pg/mL vs. 33.17 (22.34 - 43.99) pg/mL; p = 0.016]; [18.04 (14.48 - 21.60) uU/mL vs. 7.09 (4.83 - 9.35) uU/mL; p = 0.001]. Ghrelin, but not PYY, correlated linearly and positively with HOMA-IR: ghrelin vs. HOMA-IR (r = 0.52; p = 0.008), and PYY vs. HOMA-IR (r = 0.22; p = 0.200). This correlation was independent of body weight. Fasting ghrelin and PYY serum levels are increased in lean, relatively insulin resistant Wistar rats, and this increase is independent of weight.


Enterobacteriaceae Growth Promotion by Intestinal Acylcarnitines, a Biomarker of Dysbiosis in Inflammatory Bowel Disease.
Altered plasma acylcarnitine levels are well-known biomarkers for a variety of mitochondrial fatty acid oxidation disorders and can be used as an alternative energy source for the intestinal epithelium when short-chain fatty acids are low. These membrane-permeable fatty acid intermediates are excreted into the gut lumen via bile and are increased in the feces of patients with inflammatory bowel disease (IBD). Herein, based on studies in human subjects, animal models, and bacterial cultures, we show a strong positive correlation between fecal carnitine and acylcarnitines and the abundance of Enterobacteriaceae in IBD where they can be consumed by bacteria both in vitro and in vivo. Carnitine metabolism promotes the growth of Escherichia coli via anaerobic respiration dependent on the cai operon, and acetylcarnitine dietary supplementation increases fecal carnitine levels with enhanced intestinal colonization of the enteric pathogen Citrobacter rodentium. In total, these results indicate that the increased luminal concentrations of carnitine and acylcarnitines in patients with IBD may promote the expansion of pathobionts belonging to the Enterobacteriaceae family, thereby contributing to disease pathogenesis.


Effective Disease Control After Combinatorial Treatment with a PD-1 Antibody and an mTOR Inhibitor for Recurrent Ovarian Clear Cell Carcinomas: A Case Report and Literature Review.
Ovarian clear cell carcinoma (OCCC) is a rare type of epithelial ovarian cancer characterized by a chemoresistant phenotype and high-grade tumor. Conventional therapies for OCCC include surgery and chemotherapy. However, these OCCC treatment approaches are characterized by a high risk of relapse and drug resistance resulting in poor prognosis. Therefore, alternative therapeutic approaches are required to achieve better outcomes. In this study, a PIK3CA p.R88Q mutation and PD-L1 expression with a tumor proportion score of 10% was explored in a patient who presented with rapid recurrence after surgery and unsuccessful postoperative chemotherapy. Based on the clinical condition and the patient preference, she was administered a novel combinatorial therapy comprising mTOR inhibitor everolimus, which is a well-known and potent inhibitor of the PI3K/AKT signaling pathway, and the anti-PD-1 antibody toripalimab. Treatment with this combinatorial therapy showed good prognosis, with more than eight months of disease control, and no severe adverse events were observed. The findings of this study provide a novel and effective strategy for OCCC patients. To the best of our knowledge, this is the first study to report a new combination regimen of immunotherapy (everolimus plus toripalimab) for solid tumors. Everolimus is not only an antitumor targeted drug but also an immunosuppressant; it's combination with immunotherapy is controversial. This is the first report to demonstrate that it has a synergistic effect.


Epicardial activation times after defibrillation in open-chest dogs using unipolar DC-coupled activation recordings.
The widespread clinical application of implantable electrical defibrillation devices has engendered considerable interest into the mechanism of action of such devices. In addition, better means of rapid detection of postshock efficacy have been sought. The authors performed this study to test the following hypotheses: (1) postshock epicardial activation times may be used to differentiate successful from unsuccessful defibrillation attempts; and (2) successful defibrillation can be characterized by whether two or more activation wavefronts are simultaneously present on the epicardium after a defibrillation attempt. Unipolar Ag/AgCl sintered electrodes were directly coupled from 120 recording sites that covered both right and left ventricular surfaces. This technique was applied to 203 defibrillation attempts in 6 open-chest dogs during electrically induced ventricular fibrillation. There were 139 successful and 64 unsuccessful defibrillation attempts. The difference between the first and second post-shock activation times was significantly different between the successful and unsuccessful attempts. This difference was secondary to the activation time delay of the second post-shock activation cycle relative to the first post-shock activation cycle. When the first-to-second post-shock time delay was greater than 140 ms, the defibrillation attempt was found to be uniformly successful. In no case of successful defibrillation accompanied by total termination of ventricular fibrillation were more than two wavefronts simultaneously present on the heart after shock. In contrast, successful defibrillation accompanied by transient residual fibrillating activity or unsuccessful defibrillation attempts were observed to present with either two simultaneous activation wavefronts or an activation wavefront in temporal isolation.(ABSTRACT TRUNCATED AT 250 WORDS)


Conspicuity and bicycle crashes: preliminary findings of the Taupo Bicycle Study.
To describe the methods, characteristics of participants, and report on the preliminary findings of a longitudinal study of cyclists. Web-based survey to establish a cohort of cyclists. Participants in the largest mass-participation bicycle event in New Zealand, the Wattyl Lake Taupo Cycle Challenge. 2469 riders who had enrolled online in the 2006 Wattyl Lake Taupo Cycle Challenge. Self-reported crashes in preceding 12 months. Of 5653 eligible riders, 2469 (44%) completed the study questionnaire. Mean age was 44 years, 73% were male, and the average number of kilometers cycled per week in the preceding 12 months was 130. The annual incidence of crashes leading to injury that disrupted usual daily activities for at least 24 h was 0.5 per cyclist/year. About one-third of these crashes resulted in presentation to a health professional. The mean number of days absent from work attributable to bicycle crashes was 0.39 per cyclist/year. After adjustment for potential confounders and exposure (kilometers cycled per year), the rate of days off work from bicycle crash injury was substantially lower among riders who reported always wearing fluorescent colors (multivariate incidence rate ratio 0.23, 95% CI 0.09 to 0.59). Low cyclist conspicuity may increase the risk of crash-related injury and subsequent time off work. Increased use of high-visibility clothing is a simple intervention that may have a large impact on the safety of cycling.


The metabolic syndrome, cardiopulmonary fitness, and subcutaneous trunk fat as independent determinants of arterial stiffness: the Amsterdam Growth and Health Longitudinal Study.
The mechanisms that link the metabolic syndrome to increased cardiovascular risk are incompletely understood, especially in young people. We therefore examined whether the metabolic syndrome was associated with arterial stiffness and whether any such associations were independent of cardiopulmonary fitness and subcutaneous trunk fat. Cross-sectional analyses of data on 364 men and women aged 36 years from the Amsterdam Growth and Health Longitudinal Study (ninth follow-up measurement, year 2000). The prevalence of the metabolic syndrome was defined by a slightly modified National Cholesterol Education Program (NCEP) definition. Arterial stiffness was ultrasonically estimated by distensibility and compliance of the carotid, femoral, and brachial arteries and by the carotid elastic modulus. The prevalence of the metabolic syndrome in this young adult population was 18.3% in men and 3.2% in women. Individuals with the syndrome compared with individuals without risk factors had 11.2% and 17.0% less distensibility and 9.0% and 18.2% less compliance of the carotid and femoral arteries, respectively, and 15.9% higher carotid elastic modulus. After adjustment for cardiopulmonary fitness and subcutaneous trunk fat, the metabolic syndrome remained significantly associated with stiffness of the carotid but not the femoral artery. In addition, poor cardiopulmonary fitness and high subcutaneous trunk fat were associated with arterial stiffness, and this was independent of the metabolic syndrome. A modified NCEP definition of the metabolic syndrome identified young individuals with increased arterial stiffness. The mechanisms that link the metabolic syndrome, poor cardiopulmonary fitness, and high subcutaneous trunk fat to greater arterial stiffness overlap but are partly independent of each other.


Encapsulated papillary carcinoma with and without frank invasion: Comparison of clinicopathologic features and role of axillary staging.
To investigate clinical and pathologic features of encapsulated papillary carcinomas (EPCs) that may be associated with invasive disease and characterize the axillary staging practices for EPCs at our institution. A pathology database search for cases containing "papillary carcinoma" was performed. Slides were reviewed by two pathologists. Clinicopathological features and axillary staging practices of EPCs with and without invasion were compared. Twenty-five cases of EPCs were identified. Fifteen cases contained a frank invasive tumor (60%), which were all pT1 (0.7 ± 0.56 cm), and the majority were ER-positive, HER2-negative, low-grade IDC-NST. Seventeen patients underwent sentinel lymph node biopsies (SLNB). No nodal metastases were identified. Follow-up was available for 24 patients (mean = 39 ± 29 months); 23 had no NED. Patients that presented with a self-palpated mass (versus screening) were more likely to have an invasive component; however, no pathologic or radiologic features differentiated EPCs with and without frank invasion. Pathologic and radiologic characteristics did not differentiate EPCs with and without frank invasion. EPCs have an excellent prognosis supported by the notable disease-free survival and negative nodal status in our cohort, which supports the notion that patients with EPCs may forgo axillary staging.


η2-Alkene Complexes of [Rh(PONOP-iPr)(L)]+ Cations (L = COD, NBD, Ethene). Intramolecular Alkene-Assisted Hydrogenation and Dihydrogen Complex [Rh(PONOP-iPr)(η-H2)].
Rhodium-alkene complexes of the pincer ligand κ3-C5H3N-2,6-(OPiPr2)2 (PONOP-iPr) have been prepared and structurally characterized: [Rh(PONOP-iPr)(η2-alkene)][BArF4] [alkene = cyclooctadiene (COD), norbornadiene (NBD), ethene; ArF = 3,5-(CF3)2C6H3]. Only one of these, alkene = COD, undergoes a reaction with H2 (1 bar), to form [Rh(PONOP-iPr)(η2-COE)][BArF4] (COE = cyclooctene), while the others show no significant reactivity. This COE complex does not undergo further hydrogenation. This difference in reactivity between COD and the other alkenes is proposed to be due to intramolecular alkene-assisted reductive elimination in the COD complex, in which the η2-bound diene can engage in bonding with its additional alkene unit. H/D exchange experiments on the ethene complex show that reductive elimination from a reversibly formed alkyl hydride intermediate is likely rate-limiting and with a high barrier. The proposed final product of alkene hydrogenation would be the dihydrogen complex [Rh(PONOP-iPr)(η2-H2)][BArF4], which has been independently synthesized and undergoes exchange with free H2 on the NMR time scale, as well as with D2 to form free HD. When the H2 addition to [Rh(PONOP-iPr)(η2-ethene)][BArF4] is interrogated using pH2 at higher pressure (3 bar), this produces the dihydrogen complex as a transient product, for which enhancements in the 1H NMR signal for the bound H2 ligand, as well as that for free H2, are observed. This is a unique example of the partially negative line-shape effect, with the enhanced signals that are observed for the dihydrogen complex being explained by the exchange processes already noted.


Integration of visual and auditory information in bimodal neurones in the guinea-pig superior colliculus.
We have investigated the responses of neurones in the guinea-pig superior colliculus to combinations of visual and auditory stimuli. When these stimuli were presented separately, some of these neurones responded only to one modality, others to both and a few neurones reliably to neither. To bimodal stimulation, many of these neurones exhibited some form of cross-modality interaction, the degree and nature of which depended on the relative timing and location of the two stimuli. Facilitatory and inhibitory interactions were observed and, occasionally, both effects were found in the same neurone at different inter-stimulus intervals. Neurones whose responses to visual stimuli were enhanced by an auditory stimulus were found in the superficial layers. Although visual-enhanced and visual-depressed auditory neurones were found throughout the deep layers, the majority of them were recorded in the stratum griseum profundum. Neurones that responded to both visual and auditory stimuli presented separately and gave enhanced or depressed responses to bimodal stimulation were found throughout the deep layers, but were concentrated in the stratum griseum intermediale and extended into the stratum opticum.


[Human immunodeficiency virus (HIV) infection. The effectiveness of different diagnostic sequences in suspected pulmonary infection].
Assessment of different diagnostic sequences, in patients VIH(+) with a suspected pulmonary infection. A cross-sectional descriptive study of 76 HIV(+) patients with suspected respiratory infection. It has been determined the validity and the pretest and post-test probability of the radiology (Rx) of thorax, 67Ga pulmonary scintigraphy and seric LDH levels, in order to design four different diagnostic algorithms. The diagnostic sequence Rx-LDH-scintigraphy with normal results involved an infection probability of 58.0%. Pathological Rx with successively normal LDH and scintigraphy, implied a likelihood of 97.0%. The LDH elevation in sequence with scintigraphy and Rx rose to 96.1% if both were abnormal and diminished to 8.3% if normal. The LDH elevation associated with the sequence of normal Rx and scintigraphy suggests a low infection likelihood. On the contrary, associated with pathological Rx and scintigraphy in sequence, practically assures the pulmonary infection.


Endothelin activation of reactive oxygen species mediates stress-induced pressor response in Dahl salt-sensitive prehypertensive rats.
Experiments were designed to test the hypothesis that endothelin (ET) and/or reactive oxygen species contribute to the pressor response induced by acute air jet stress in normotensive Dahl salt-sensitive rats maintained on a normal salt diet (prehypertensive). Mean arterial pressure was chronically monitored by telemetry before and after 3-day treatment with the free radical scavenger 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol) or ET receptor antagonists ABT-627 (ET A antagonist) or A-182086 (ET A/B antagonist) supplied in the drinking water. Rats were restrained and subjected to pulsatile air jet stress (3 minutes). Plasma samples at baseline and during acute stress were analyzed for 8-isoprostane (measure of reactive oxygen species production) and ET. Neither Tempol nor ET receptor antagonist treatment had an effect on baseline mean arterial pressure or plasma 8-isoprostane. The pressor response to acute stress was accompanied by significant increases in plasma 8-isoprostane and ET. Tempol significantly reduced both the total pressor response (area under the curve) and the stress-mediated increase in plasma 8-isoprostane; conversely, Tempol had no effect on the stress-induced increase in plasma ET. Combined ET(A/B) antagonism, but not selective ET(A) receptor blockade, similarly suppressed the pressor response to stress and stress-mediated rise in 8-isoprostane. Together these results indicate that reactive oxygen species contribute to the pressor response to acute air jet stress. Furthermore, the increase in reactive oxygen species occurs downstream of ET(B) receptor activation.


Development of a multitarget tracking system for paramecia.
This investigation develops a multitarget tracking system for the motile protozoa, paramecium. The system can recognize, track, and record the orbit of swimming paramecia within a 4 mm diameter of a circular experimental pool. The proposed system is implemented using an optical microscope, a charge-coupled device camera, and a software tool, Laboratory Virtual Instrumentation Engineering Workbench (LABVIEW). An algorithm for processing the images and analyzing the traces of the paramecia is developed in LABVIEW. It focuses on extracting meaningful data in an experiment and recording them to elucidate the behavior of paramecia. The algorithm can also continue to track paramecia even if they are transposed or collide with each other. The experiment demonstrates that this multitarget tracking design can really track more than five paramecia and simultaneously yield meaningful data from the moving paramecia at a maximum speed of 1.7 mm/s.


A review of the efficacy of smoking-cessation pharmacotherapies in nonwhite populations.
Cigarette smoking continues to be the leading cause of preventable morbidity and mortality in the United States. Research suggests that behavioral support strategies and pharmacotherapy can improve abstinence rates. However, both approaches, especially pharmacotherapy, have been understudied in nonwhite US populations. The aim of this review was to evaluate the efficacy of smoking-cessation pharmacotherapy in nonwhite US populations. Using search terms smoking cessation, nicotine replacement therapy, bupropion SR, varenicline, minority, ethnicity, African American, black, Hispanic, American Indian, and Alaska Native, a literature search was conducted to identify English-language studies that evaluated the use of smoking-cessation pharmacotherapies in nonwhite patients in MEDLINE (1966\2-December 2007), International Pharmaceutical Abstracts (1980\2-January 2008), Database of Abstracts of Reviews of Effectiveness (1990\2-December 2007), and EMBASE Drugs & Pharmacology (1991\2-third quarter 2007). Nine studies were identified and assessed. Six studies looked at smoking-cessation pharmacotherapy in black smokers, 1 in Hispanic smokers, 1 in Native American smokers, and 1 in white and nonwhite smokers. In black smokers (N = 410; mean cigarettes per day [cpd], 20.4) who received the nicotine patch versus placebo, the 30-day self-reported abstinence rates were 21.5% versus 13.7% (P = 0.03) at 10 weeks and 17.1% versus 11.7% (P = NS) at 6 months. In black smokers (N = 600; mean [SD] cpd, 16.1 [7.5]) who received sustained-release (SR) bupropion 150 mg BID versus placebo for 7 weeks, the 7-day biochemically verified abstinence rates at weeks 6 and 26 were 36.0% versus 19.0% (Delta, 17%; 95% CI, 9.7\2-24.4; P < 0.001) and 21.0% versus 13.7% (Delta, 7.3%; 95% CI, 1.0\2-13.7; P = 0.02). Predictors of smoking cessation included use of bupropion SR (abstinence rate, 41.5% vs 21.1%; P<0.001); smoking nonmentholated cigarettes (abstinence rate, 28.3% in mentholated smokers [n = 417] vs 41.5% in nonmentholated smokers [n = 118]; P = 0.006); not smoking within 30 minutes of awakening (abstinence rate, 26.4% [n = 420] in those who did vs 48.7% [n = 115] in those who did not; P < 0.001); and lower baseline salivary cotinine levels (256.8 [137.0] ng/mL in those who became abstinent vs 305.6 [143.4] ng/mL in those who remained smokers; P < 0.001). In black light (<or=10 cpd) smokers (N = 753) who received nicotine gum 2 mg, the biochemically verified 7-day abstinence rates at weeks 8 and 26 in mentholated versus nonmentholated smokers were 22.6% versus 26.8% (P = NS) and 11.2% versus 18.8% (P = 0.015), respectively; at week 26, the abstinence rates in those who received gum + mentholated cigarettes (n = 309) versus gum + nonmentholated cigarettes (n = 67) were 14% versus 24% (P = 0.031). In Hispanic smokers (N = 108; mean [SD] cpd, 18.8 [10.2]) who received nicotine patch versus placebo for 10 weeks, 46% versus 26% (chi(2) = 4.01; P = 0.05) were abstinent from weeks 2 to 10 (completed all doses of patch); patients who were more acculturated and received active treatment had a higher abstinence rate than less acculturated patients (63% vs 47%; P value not provided). In Native American smokers (N = 252; cpd not provided) who received nicotine patch + counseling and were followed up at 3, 6, 9, and 12 months, selfreported abstinence rates were 31% (49/156), 30% (21/71), 24% (13/55), and 21% (4/19), respectively (P values not provided). In a 6-month study in white (n = 191) and nonwhite (n = 108) smokers (mean [SD] cpd, 21 [11]) randomized to receive a nicotine patch (n = 144) versus nasal spray (n = 155) for 8 weeks, the carbon monoxide\2-verified 7-day abstinence rates were 34.7% versus 29.0%; at 6 months, these rates were 18.1% versus 15.5% (P = NS). In nonwhite patients, logistic regression analysis at 6 months found that a higher proportion of patients randomized to receive nasal spray did not smoke for >or=7 consecutive days (odds ratio, 0.20; 95% CI, 0.05-0.77; P = 0.02). Data from the studies in this review support the use of smoking-cessation pharmacotherapy (nicotine patch and bupropion SR) in nonwhite patients. Black patients, who smoked within 30 minutes of awakening, smoked mentholated cigarettes, and had high salivary cotinine levels may have difficulty quitting regardless of the number of cigarettes smoked per day; therefore, determining the type of cigarettes smoked (mentholated vs nonmentholated) and salivary cotinine levels may be helpful in assessing the severity of smoking addiction and guide pharmacotherapy (eg, starting at higher doses of nicotine-replacement therapy in a light smoker). Other than smoking-cessation behavioral studies, there is a lack of congruent smoking-cessation pharmacotherapy studies in American Indian/Alaska Native, Hispanic, and other ethnic populations.


Repair of the defect in spondylolysis. Durable fixation with pedicle screws and laminar hooks.
Direct repair of a defect in the pars interarticularis was performed with use of bone-grafting and internal fixation with a pedicle screw, rod, and laminar hook in order to achieve a higher prevalence of osseous union than that achieved with commonly used procedures. The configuration of the head of the screw, which is designed to allow it to connect with the rod at the necessary angle, simplified the placement of the rod. The procedure was performed in sixteen patients who had a bilateral defect of the pars interarticularis with or without grade-I or II spondylolisthesis, had had failure of non-operative treatment, and had had temporary relief of pain after the area of the defect in the pars interarticularis had been infiltrated with lidocaine. Concomitant degeneration of a disc was not a criterion for exclusion. The patients were followed for an average of twenty-five months (range, twenty-four to twenty-eight months). The average age at the time of the operation was thirty-two years (range, twelve to sixty years). Six patients had findings of nerve-root compression on myelography with computerized tomographic scanning, and the bone spurs overlying the affected nerve root around the defect in the pars interarticularis were removed with an ultrasonic osteotome through a small window. The implant was removed about one year after the operation. Oblique radiographs showed osseous union in the previous defect bilaterally in all sixteen patients. Thirteen patients were free of symptoms, and three had major improvement with occasional low-back pain. None had a complication, such as infection, breakage of the implant, or irritation of a nerve root. The method used for direct repair of the defect of the pars interarticularis in these patients proved to be simple and effective. Relief of symptoms appeared to depend on decompression of the affected nerve root, if one was involved, and on preoperative prediction of the locus of the symptoms by infiltration of the pars interarticularis with lidocaine.


Impact of epoxyeicosatrienoic acids in lung ischemia-reperfusion injury.
Epoxyeicosatrienoic acids (EETs) are protective in both myocardial and brain ischemia, variously attributed to activation of K(ATP) channels or blockade of adhesion molecule upregulation. In this study, we tested whether EETs would be protective in lung ischemia-reperfusion injury. The filtration coefficient (K(f)), a measure of endothelial permeability, and expression of the adhesion molecules vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) were measured after 45 minutes ischemia and 30 minutes reperfusion in isolated rat lungs. K(f) increased significantly after ischemia-reperfusion alone vs time controls, an effect dependent upon extracellular Ca(2+) although not on the EET-regulated channel TRPV4. Inhibition of endogenous EET degradation or administration of exogenous 11,12- or 14,-15-EET at reperfusion significantly limited the permeability response to ischemia-reperfusion. The beneficial effect of 11,12-EET was not prevented by blockade of K(ATP) channels nor by blockade of TRPV4. Finally, 11,12-EET-dependent alteration in adhesion molecules expression is unlikely to explain its beneficial effect, since the expression of the adhesion molecules VCAM and ICAM in lung after ischemia-reperfusion was similar to that in controls. EETs are beneficial in the setting of lung ischemia-reperfusion, when administered at reperfusion. However, further study will be needed to elucidate the mechanism of action.


The biomolecular era for thoracic surgeons: the example of the ESTS Biology Club.
Understanding basic mechanisms of lung disease may help to move forward the management of our patients. Molecular biology has affected our diagnostic and therapeutic pathways in the direction of personalized medicine not only for thoracic malignancies. Accordingly, thoracic surgeons are becoming increasingly aware that specific knowledge of genetic and epigenetic alterations may influence their clinical behavior-from the ward to the operating room (OR). In this continuously evolving scenario, surgical societies have perceived the increasing relevance of biomolecular medicine in the practice of modern thoracic surgery. More recently, in the spirit of mutual collaboration between sister societies, the European Society of Thoracic Surgeons (ESTS) has adopted the concept of the American Association for Thoracic Surgery (AATS) incorporating one session dedicated to the Biology Club within the Annual Meeting Program. The aim of the ESTS Biology Club is to outline and sponsor the new profile of the surgeon scientist during the only world meeting exclusively focused on general thoracic surgery. The following article will summarize the significance of this and give an update on molecular biology tools for thoracic malignancies.


Molecular characterization of the Smyth chicken sublines and their parental controls by RFLP and DNA fingerprint analysis.
The Smyth line (SL) chicken, a model for autoimmune human vitiligo, is characterized by a spontaneous posthatch epidermal pigment loss (vitiligo). Even though the immunological and morphological changes accompanying the vitiligo process have been well studied, the genetics of this phenomenon remains elusive. The SL lines have been maintained by nonpedigreed matings since their inception, and therefore, the inbreeding status is unknown. The present study was designed to provide an estimate of the inbreeding coefficients and the molecular genetic profiles of the SL sublines, each homozygous for a different MHC haplotype and their MHC-matched parental control (BL) sublines. The DNA fingerprint analysis revealed that there is a moderate level of inbreeding within the SL and BL parental sublines. Of the two SL sublines studied, SL101 had the highest level of inbreeding (0.948). Similarly, its parental control line (BL101) was more inbred than the parental subline of SL102 (BL102). The very high level of similarity between the SL sublines and their respective parental control lines is shown further by the similarity index (SI) estimates (SI between SL101 and BL101 was 0.949 and that between SL102 and BL102 was 0.932). Restriction fragment length polymorphism (RFLP) analysis of the endogenous viral genes (avian leukosis virus subgroup E, ALVE) showed that five ALVE-related BamH1 fragments were present in the SL101 and four in SL102 sublines, whereas the parental BL101 and BL102 sublines had five and six fragments, respectively. SL101 and SL102 shared two fragments, but the frequencies were different. Similarly, BL101 and BL102 shared two fragments. SL101 and BL101 shared three fragments, and SL102 and BL102 also shared three fragments.


Face preference detection task based on EEG energy analysis in the source domain.
Facial stimulation can produce specific event-related potential (ERP) component N170 in the fusiform gyrus region. However, the role of the fusiform gyrus region in facial preference tasks is not clear at present, and the current research of facial preference analysis based on EEG signals is mostly carried out in the scalp domain. This paper explores whether the region of the fusiform gyrus is involved in processing face preference emotions in terms of the distribution of energy over the source domain, and finds that the pars orbitalis cortex is most energetically active in the face preference task and that there are significant differences between the left and right hemispheres.Clinical Relevance- The role of pars orbitalis in facial preference may help doctors determine whether the pars orbitalis cortex is lost in clinical practice.


Structure-function analyses of cytochrome P450revI involved in reveromycin A biosynthesis and evaluation of the biological activity of its substrate, reveromycin T.
Numerous cytochrome P450s are involved in secondary metabolite biosynthesis. The biosynthetic gene cluster for reveromycin A (RM-A), which is a promising lead compound with anti-osteoclastic activity, also includes a P450 gene, revI. To understand the roles of P450revI, we comprehensively characterized the enzyme by genetic, kinetic, and structural studies. The revI gene disruptants (ΔrevI) resulted in accumulation of reveromycin T (RM-T), and revI gene complementation restored RM-A production, indicating that the physiological substrate of P450revI is RM-T. Indeed, the purified P450revI catalyzed the C18-hydroxylation of RM-T more efficiently than the other RM derivatives tested. Moreover, the 1.4 Å resolution co-crystal structure of P450revI with RM-T revealed that the substrate binds the enzyme with a folded compact conformation for C18-hydroxylation. To address the structure-enzyme activity relationship, site-directed mutagenesis was performed in P450revI. R190A and R81A mutations, which abolished salt bridge formation with C1 and C24 carboxyl groups of RM-T, respectively, resulted in significant loss of enzyme activity. The interaction between Arg(190) and the C1 carboxyl group of RM-T elucidated why P450revI was unable to catalyze both RM-T 1-methyl ester and RM-T 1-ethyl ester. Moreover, the accumulation of RM-T in ΔrevI mutants enabled us to characterize its biological activity. Our results show that RM-T had stronger anticancer activity and isoleucyl-tRNA synthetase inhibition than RM-A. However, RM-T showed much less anti-osteoclastic activity than RM-A, indicating that hemisuccinate moiety is important for the activity. Structure-based P450revI engineering for novel hydroxylation and subsequent hemisuccinylation will help facilitate the development of RM derivatives with anti-osteoclast activity.


[Electroacupuncture Relieves Pain by Down-regulating Expression of Hippocampal High Mobility Group Protein 1 and Contents of TNF-α and IL-1 β in Rats with Chronic Neuropathic Pain].
To observe the effect of electroacupuncture (EA) on expression of high mobility group protein 1 (HMGB 1) and related downstream effectors of proinflammatory cytokines in the hippocampus in chronic neuropathic pain rats, so as to investigate its mechanism underlying neuropathic pain relief. Male SD rats were randomized into sham, model, and EA groups, with 12 rats in each group. The neuropathic pain model was established by ligature of the left sciatic nerve to induce chronic constriction injury (CCI). EA was applied to bilateral "Zusanli"(ST 36) and "Yanglingquan"(GB 34) for 30 min, once daily for 7 days. The mechanical withdrawal threshold (WMT) was detected using an electronic von Frey anesthesiometer. The expression level of HMGB 1 in the hippocampus was determined using quantitative RT-PCR and Western blot, separately, and the contents of hippocampal TNF-α and IL-1 β were detected by ELISA. Compared with the sham group, the MWT values were markedly decreased on day 7, 10 and 14 after modeling in the model group (P<0.001). On day 10 and 14 after modeling, the MWT values were significantly up-regulated in the EA group relevant to those of the model group (P<0.05, P<0.01). The expression levels of HMGB1 mRNA and protein, and the contents of hippocampal TNF-α and IL-1 β were markedly increased in the model group relevant to the sham group (P<0.001), and significantly down-regulated in the EA group relevant to the model group (P<0.001, P<0.01, P<0.05). EA stimulation of ST 36-GB 34 can relieve pain in chronic neuropathic pain rats, which may be related to its actions in down-regulating the levels of HMGB 1 and its downstream proinflammatory cytokines TNF-α and IL-1 β in the hippocampus.


Olfactory and gustatory dysfunction in COVID-19 patients: A meta-analysis study.
COVID-19, caused by a novel coronavirus, is a persistent global pandemic. It is crucial to examine existing reports to effectively summarize and characterize its clinical course. We used a large-scale meta-analysis to establish prevalence rates for loss of olfaction and gustation in COVID-19 positive patients. PubMed/Medline, Embase, and Web of Sciences were searched for articles published until April 30, 2020. Furthermore, to avoid missing papers, more searches were carried out in the reference lists of covered studies. Articles that mentioned olfactory and/or gustatory disorder in patients with COVID-19 were included for further analysis. Articles that did not report the aforementioned information were excluded. Duplicated articles, reviews, and meta-analysis were excluded as well. The quality of the references was assessed according to the checklist provided by JBI (Joanna Briggs Institute). We used independent extraction of data by multiple observers. The pooled frequency with 95% confidence intervals (CI) was assessed using random effect model. The main outcome measures reported were the pooled frequency of olfaction and pooled frequency of gustation disorder in patients with COVID-19 calculated using a random effect model weighted by the study population. The 15 included studies had 3,739 participants which all had confirmed COVID-19. Olfactory and gustatory disorders were assessed and a total number of 1,354 and 1,729 were reported to have taste or smell impairment, respectively. The estimated rate of taste disorder in patients with COVID-19 was 49.0% [95% confidence interval (CI) 34.0-64.0, I2: 96%] (Figure 2). The estimated rate of olfactory disorder in patients with COVID-19 was 61.0% (95% CI 44.0%-75.0%). Our meta-analysis demonstrated high rates of taste (49.0%) and smell (61.0%) disorders in patients with confirmed COVID-19. Results increase the power of recent reports-loss of olfactory and loss of gustation should now routinely be considered in the setting of COVID-19 infection.


Opposing roles of prostaglandin D2 receptors in ulcerative colitis.
Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of dextran sulfate sodium colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared with control subjects. In contrast, CRTH2 was decreased in eosinophils, NK, and CD3(+) T cells but not in monocytes and CD3(+)/CD4(+) T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydro TXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved, whereas the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue, where it may contribute to inflammation, whereas DP most likely promotes anti-inflammatory actions.


Submerged culture mycelium and broth of Grifola frondosa improve glycemic responses in diabetic rats.
Grifola frondosa, an edible fungus with a large fruiting body and overlapping caps, has been demonstrated to be a natural source of health-promoting substances, mainly due to its polysaccharides beta-glucan. By using male Wistar rats injected with saline (normal rats) or nicotinamide plus streptozotocin (diabetic rats), we investigated the effects of an orally ingested placebo (CON and STZ groups), culture mycelium (CGM and SGM groups), broth (CGB and SGB groups), and mycelium plus broth (CGX and SGX groups) of Grifola frondosa on glycemic responses. During the experimental period (from day 0 to day 15), the STZ group had significantly lower body weight compared to the CON group (one-way ANOVA, p<0.05). Moreover, the STZ group had significantly higher blood glucose concentrations at 2 hour-postprandial periods on days 0, 7, and 14 and in an oral glucose tolerance test (OGTT) on day 10, as well as significantly higher serum fructosamine and triglyceride on day 15 compared to the CON group. These diabetes-induced increases were significantly attenuated by administrations of mycelium and/or broth, i.e., the SGM, SGB, and SGX groups. The results of repeated-measures analysis and three-way ANOVA indicated that diabetes mellitus significantly increases, and mycelium administration significantly decreases postprandial blood glucose; diabetes mellitus significantly increases, and mycelium and broth administrations significantly decrease serum triglyceride, fructosamine, and blood glucose concentrations; moreover, in the area under the curve in OGTT, p<0.05. Our results revealed that submerged-culture mycelia and broth of Grifola frondosa have bioactivities for improving glycemic responses.


Inhibition of 72 kDa inositol polyphosphate 5-phosphatase E improves insulin signal transduction in diet-induced obesity.
The 72 kDa inositol polyphosphate 5-phosphatase E (72k-5ptase) controls signal transduction through the catalytic dephosphorylation of the 5-position of membrane-bound phosphoinositides. The reduction of 72k-5ptase expression in the hypothalamus results in improved hypothalamic insulin signal transduction and reduction of food intake and body mass. Here, we evaluated the tissue distribution and the impact of obesity on the expression of 72k-5ptase in peripheral tissues of experimental animals. In addition, insulin signal transduction and action were determined in an animal model of obesity and insulin resistance treated with an antisense (AS) oligonucleotide that reduces 72k-5ptase expression. In lean Wistar rats, 72k-5ptase mRNA and protein are found in highest levels in heart, skeletal muscle, and white adipose tissue. In three distinct models of obesity, Wistar rats, Swiss mice fed on high-fat diet, and leptin-deficient ob/ob mice, the expression of 72k-5ptase is increased in skeletal muscle and adipose tissue. The treatment of obese Wistar rats with an anti-72k-5ptase AS oligonucleotide results in significant reduction of 72k-5ptase catalytic activity, which is accompanied by reduced food intake and body mass and improved insulin signal transduction and action as determined by immunoblotting and clamp studies respectively. 72k-5ptase expression is increased in obesity and its AS inhibition resulted in a significant improvement in insulin signal transduction and restoration of glucose homeostasis.


Role of Toll-like receptors in natural killer cell function in acute lymphoblastic leukemia.
Natural killer (NK) cells are specialized lymphocytes primarily involved in the response to infection and tumors. NK cells are characterized by the presence of specific surface molecules, as well as a wide repertoire of receptors that impart microenvironment-dependent effector functions. Among these receptors, Toll-like receptors (TLRs) can be activated to condition the NK response to either a cytotoxic or immunoregulatory phenotype. However, cellular function is frequently impaired during disorders such as cancer. In the last decade, it has become increasingly evident that the stimulation of NK cells is a requirement for their increased cytotoxic activity. TLR activation has been suggested as an alternative route for reestablishing the antitumor activity of NK cells. The present review summarizes the characteristics of NK cells, their receptors, the expression and function of NK cell TLRs, and their functional status in cancer, primarily acute lymphoblastic leukemia.


Randomised double-blind comparison of bolus phenylephrine or ephedrine for treatment of hypotension in women with pre-eclampsia undergoing caesarean section.
Treatment of post-spinal hypotension during caesarean section assumes special concern in pre-eclamptic patients due to a compromised fetoplacental circulation and increased risk of placental hypoperfusion. Phenylephrine and ephedrine are the most commonly used vasopressors, although the best choice is still not clear. We studied 80 pre-eclamptic women with a singleton pregnancy who underwent caesarean section with spinal anaesthesia, and who developed hypotension defined as a decrease in systolic arterial pressure ≥ 20% from baseline or absolute value < 100 mmHg. Women were randomly allocated to receive phenylephrine 50 μg or ephedrine 4 mg boluses for treatment of hypotension. Blood pressure changes following vasopressor administration were similar in both groups, but heart rate remained higher after ephedrine at all time-points. The primary outcome measure of umbilical artery pH was 7.26 (0.11) in the phenylephrine group and 7.25 (0.09) in the ephedrine group (p = 0.86). The incidence of neonatal acidosis (umbilical artery pH < 7.20) was 9 (22.5%) in the phenylephrine group and 11 (27.5%) in the ephedrine group (p = 0.80). Other secondary outcome measures were comparable. In conclusion, phenylephrine 50 μg and ephedrine 4 mg, administered as intravenous boluses to treat post-spinal hypotension during caesarean section in pre-eclamptic patients, resulted in similar fetal acid-base values, were equally effective in treating hypotension and were associated with good maternal and neonatal outcome.


The anesthetic record: accuracy and completeness.
To evaluate if anesthesia training and experience influenced chart completion and accuracy. One hundred and twenty-four subjects, including medical students, anesthesia residents and community and university based clinical anesthesiologists, were given a standardized patient in a simulator environment and asked to conduct induction and maintenance of anaesthesia. Three critical events were introduced resulting in changes in BP, HR, PETCO2 and SpO2. Subjects were instructed to manage the patient and the anesthetic chart, as was their customary practice. Discrepancy, calculated as the difference between the actual and charted values divided by the actual physiological value was compared by level of training with a two-way repeated measures analysis of variance (ANOVA) for all four physiological variables. The completeness of charting, defined as at least one data point recorded for each of the four physiological variables of the three critical events, was compared across level of training, age of participants and number of years in practice. The overall completeness of charting remained low (< 37%) with no relationship based on the anesthesiologist's age, level of training or number of years in practice. There was discrepancy in charting for all physiological variables (HR, BP, PETCO2 and SpO2, P < 0.0001), with a marked difference in the degree of discrepancy within each level of training. Training resulted in no differences in charting discrepancy. Charting of data to the anesthetic record remained incomplete and inaccurate in all groups based on level of training, age and number of years in practice.


Mixture cure model with random effects for clustered interval-censored survival data.
The mixture cure model is an effective tool for analysis of survival data with a cure fraction. This approach integrates the logistic regression model for the proportion of cured subjects and the survival model (either the Cox proportional hazards or accelerated failure time model) for uncured subjects. Methods based on the mixture cure model have been extensively investigated in the literature for data with exact failure/censoring times. In this paper, we propose a mixture cure modeling procedure for analyzing clustered and interval-censored survival time data by incorporating random effects in both the logistic regression and PH regression components. Under the generalized linear mixed model framework, we develop the REML estimation for the parameters, as well as an iterative algorithm for estimation of the survival function for interval-censored data. The estimation procedure is implemented via an EM algorithm. A simulation study is conducted to evaluate the performance of the proposed method in various practical situations. To demonstrate its usefulness, we apply the proposed method to analyze the interval-censored relapse time data from a smoking cessation study whose subjects were recruited from 51 zip code regions in the southeastern corner of Minnesota.


Rehabilitation and respiratory management in the acute and early post-acute phase. "Instant paper from the field" on rehabilitation answers to the COVID-19 emergency.
COVID-19 is a respiratory infectious disease that can cause respiratory, physical and psychological long-term dysfunctions in patients. First recommendations on respiratory management were published, but they were not based on the specific needs due to COVID-19. In this paper we share the early experiences from the clinical field in Northern Italy, where the epidemic started in February. This paper summarizes the second webinar on COVID-19 (230 live attendees, 11,600 viewers of the recorded version) organized by the Italian Society of Physical and Rehabilitation Medicine about rehabilitation and in particular respiratory management in the acute (Intensive Care Unit [ICU]) and immediate post-acute phases. There is the need to prepare for the post-acute phase. ICU length of stay is relatively long, with immobilization in prone position. Some specific problems are described, including severe muscle weakness and fatigue, joint stiffness, dysphagia, (neuro)psychological problems, impaired functioning concerning mobility, activities of daily life and work. A lot is yet unknown and patients can experience long-term consequences as we know from the literature on the postintensive care syndrome, but COVID-19 has unique features to be investigated and understood. As a colleague stated during the Covinar: this is a marathon, not a sprint….


Genome-Wide Identification of Calcium Dependent Protein Kinase Gene Family in Plant Lineage Shows Presence of Novel D-x-D and D-E-L Motifs in EF-Hand Domain.
Calcium ions are considered ubiquitous second messengers in eukaryotic signal transduction pathways. Intracellular Ca(2+) concentration are modulated by various signals such as hormones and biotic and abiotic stresses. Modulation of Ca(2+) ion leads to stimulation of calcium dependent protein kinase genes (CPKs), which results in regulation of gene expression and therefore mediates plant growth and development as well as biotic and abiotic stresses. Here, we reported the CPK gene family of 40 different plant species (950 CPK genes) and provided a unified nomenclature system for all of them. In addition, we analyzed their genomic, biochemical and structural conserved features. Multiple sequence alignment revealed that the kinase domain, auto-inhibitory domain and EF-hands regions of regulatory domains are highly conserved in nature. Additionally, the EF-hand domains of higher plants were found to contain four D-x-D and two D-E-L motifs, while lower eukaryotic plants had two D-x-D and one D-x-E motifs in their EF-hands. Phylogenetic analysis showed that CPK genes are clustered into four different groups. By studying the CPK gene family across the plant lineage, we provide the first evidence of the presence of D-x-D motif in the calcium binding EF-hand domain of CPK proteins.


Medication review: fluconazole.
Fluconazole is an antifungal agent available for the treatment of oropharyngeal and esophageal candida and cryptococcal meningitis. It has been found to be equal to or more efficacious than amphotericin B in treating oral and esophageal candidiasis and in providing maintenance therapy for cryptococcal meningitis. It still remains to be seen if it can be equally effective in treating acute cryptococcal infections and systemic candidiasis. In these fungal infections, amphotericin B remains the clinically proven drug of choice. To its advantage, it does not cause acute renal failure, bone marrow depression, or suppress corticosteroid production which are significant drawbacks to other available agents. It is a drug with great promise for its specific indications, but more studies in renal failure and organ transplant patients are needed to firmly establish its efficacy in these populations.


Identification of the same polyomavirus species in different African horseshoe bat species is indicative of short-range host-switching events.
Polyomaviruses (PyVs) are considered to be highly host-specific in different mammalian species, with no well-supported evidence for host-switching events. We examined the species diversity and host specificity of PyVs in horseshoe bats (Rhinolophus spp.), a broadly distributed and highly speciose mammalian genus. We annotated six PyV genomes, comprising four new PyV species, based on pairwise identity within the large T antigen (LTAg) coding region. Phylogenetic comparisons revealed two instances of highly related PyV species, one in each of the Alphapolyomavirus and Betapolyomavirus genera, present in different horseshoe bat host species (Rhinolophus blasii and R. simulator), suggestive of short-range host-switching events. The two pairs of Rhinolophus PyVs in different horseshoe bat host species were 99.9 and 88.8 % identical with each other over their respective LTAg coding sequences and thus constitute the same virus species. To corroborate the species identification of the bat hosts, we analysed mitochondrial cytb and a large nuclear intron dataset derived from six independent and neutrally evolving loci for bat taxa of interest. Bayesian estimates of the ages of the most recent common ancestors suggested that the near-identical and more distantly related PyV species diverged approximately 9.1E4 (5E3-2.8E5) and 9.9E6 (4E6-18E6) years before the present, respectively, in contrast to the divergence times of the bat host species: 12.4E6 (10.4E6-15.4E6). Our findings provide evidence that short-range host-switching of PyVs is possible in horseshoe bats, suggesting that PyV transmission between closely related mammalian species can occur.


The human insulin gene and diabetes mellitus.
The recombinant DNA technology is a useful tool to characterize the insulin gene and adjacent areas. A highly polymorphic region near the human insulin gene was detected and its possible relation to certain types of diabetes mellitus is discussed. In three cases the synthesis of a structurally abnormal insulin of lower biological activity leads to hyperglycemia. These mutant insulin gene sequences can be identified with the help of restriction endonuclease cleavage analysis. Insulin gene expression is regulated mainly at translational level. Elements near or within the insulin gene seem to be required for a sufficient and cell-specific expression. But the role of the polymorphic locus is not yet clear. First results on gene transplantation by administration of liposome entrapped insulin gene sequences are surprising, but at this time only of speculative value for medical research.


A self-replicating peptide nucleic acid.
While the non-enzymatic ligation and template-directed synthesis of peptide nucleic acids (PNA) have been reported since 1995, a case of self-replication of PNA has not been achieved yet. Here, we present evidence for autocatalytic feedback in a template directed synthesis of a self-complementary hexa-PNA from two trimeric building blocks. The course of the reaction was monitored in the presence of increasing initial concentrations of the product by RP-HPLC. Kinetic modeling with the SimFit program revealed parabolic growth characteristics. The observed template effect, as well as the rate of ligation, was significantly influenced by nucleophilic catalysts, pH value, and uncharged co-solvents. Systematic optimization of the reaction conditions allowed us to increase the autocatalytic efficiency of the system by two orders of magnitude. Our findings contribute to the hypothesis that PNA may have served as a primordial genetic molecule and was involved in a potential precursor of a RNA world.


Hypersensitivity pneumonitis reaction to Mycobacterium avium in household water.
Hypersensitivity pneumonitis has been described with exposure to aerosolized Mycobacterium avium complex (MAC) in indoor hot tubs (hot tub lung). To describe a case of MAC-associated hypersensitivity pneumonitis-like reaction possibly from showering and review previous hot tub lung reports. For the case report, we investigated a patient with histologically diagnosed hypersensitivity pneumonitis and MAC-positive sputum culture findings. Mycobacterial cultures were obtained from his home and workplace. Isolates were typed using pulsed-field gel electrophoresis. For the review, MEDLINE and EMBASE were searched for hot tub lung reports, which were reviewed and summarized. A 50-year-old man had progressive dyspnea and episodic fever and myalgias. Pulmonary function testing results revealed obstruction and impaired diffusion; a chest CT scan found diffuse, centrilobular, ground-glass nodules, and air trapping, and a lymphocytic alveolitis with an elevated CD4/CD8 ratio. Transbronchial biopsy showed multiple well-formed nonnecrotizing granulomas. Multiple respiratory samples and shower and bathtub specimens grew MAC, with matching pulsed-field gel electrophoresis patterns. The patient changed from showering to tub bathing. Prednisone and antimycobacterial drugs were administered for approximately 1 year. His symptoms, pulmonary function abnormalities, and CT scan findings resolved. The literature review yielded 36 cases of hot tub lung. Clinical features included dyspnea (97%), cough (78%), and fever (58%). Pulmonary function testing showed obstruction (67%), restriction (55%), and impaired diffusion (75%). A chest CT scan showed ground-glass opacification (95%) and nodules (67%). Granulomas were well-formed in 95%. Treatments included discontinuation of hot tub use and prednisone, antimycobacterial drugs, or both. Outcomes were favorable. A hypersensitivity pneumonitis-like reaction to mycobacteria can occur from exposures other than hot tubs. There are key differences between classic hypersensitivity pneumonitis and MAC-associated hypersensitivity pneumonitis. Antimycobacterial therapy may be required. The possibility of MAC hypersensitivity pneumonitis from showering raises potential implications in the investigation of patients with hypersensitivity pneumonitis.


[Comparative effectiveness of the enteral and intravenous administration of rifampicin in treating experimental tuberculosis in rabbits].
The efficacy of intravenous and enteral administration of rifampicin was studied comparatively in treatment of hematogenic diseminated tuberculosis in rabbits. The drugs were administered in a dose of 10 mg/kg for 60 days. The functional state of the liver was studied in the time course by activity of urokinase, a hepatospecific enzyme and transaminases. Monotherapy with rifampicin capsules administered enterally resulted in death of 66.6 per cent of the animals due to tuberculosis during the first month of the treatment. Completion of the treatment course in 4 rabbits did not result in abacillation. When rifampicin was administered intravenously no deaths of the animals due to tuberculosis were recorded. Complete abacillation of the internal organs was observed in 37.5 per cent of the rabbits. The changes in activity of the indicator enzymes were transient and after discontinuation of the treatment came to normal.


Psychosocial factors and psychological well-being: a study from a nationally representative sample of Korean workers.
This study was conducted to examine how each psychosocial factor on working conditions is related to a worker's well-being. Data from the 2011 Korean Working Conditions Survey were analyzed for 33,569 employed workers aged ≥15 years. Well-being was evaluated through the WHO-5 questionnaire and variables about occupational psychosocial factors were classified into eight categories. The prevalence ratios were estimated using Poisson regression model. Overall, 44.3% of men and 57.4% of women were in a low well-being group. In a univariate analysis, most of the psychosocial factors on working conditions are significantly related with a worker's low well-being, except for insufficient job autonomy in both genders and job insecurity for males only. After adjusting for sociodemographic and structural factors on working conditions, job dissatisfaction, lack of reward, lack of social support, violence and discrimination at work still showed a statistically significant association with a worker's low well-being for both genders. We found that psychosocial working conditions were associated with the workers' well-being.


HIV Care Providers' Role Legitimacy as Supporters of Their Patients' Alcohol Reduction.
Although HIV care providers are strategically situated to support their patients' alcohol reduction efforts, many do not do so, sometimes failing to view this support as consistent with their roles. Using data collected from 112 HIV providers in 7 hospital-based HIV Care Centers in the NYC metropolitan area, this paper examines the correlates of providers' role legitimacy as patients' alcohol reduction supporters. Results indicate that providers (1) responsible for a very large number of patients and (2) those with limited confidence in their own ability to give this assistance, but high confidence in their program's ability to do so, were less likely to have a high level of role legitimacy as patients' alcohol reduction supporters. Findings suggest the types of providers to target for alcohol reduction support training.


Irritable pouch syndrome is characterized by visceral hypersensitivity.
Irritable pouch syndrome (IPS) is a functional disorder in patients with ileal pouch-anal anastomosis (IPAA), which presents with symptoms in the absence of structural abnormalities of the pouch. Thus, it resembles other functional disorders, such as irritable bowel syndrome characterized by visceral hypersensitivity in the presence of normal rectal biomechanics. The aim was to assess pouch biomechanics and perception of balloon distension in different groups of subjects with IPAA and to correlate the findings with clinical features. Pouch tone, compliance, and sensation to balloon distension were measured in 18 patients with IPS, 11 patients with active pouch inflammation (pouchitis or Crohn's disease of the pouch), and 12 asymptomatic subjects with normal pouches. All patients were recruited from a subspecialty Pouchitis Clinic. Scores of sensation of gas, urge to defecate, and pain measured by visual analog scales at various distension pressures were significantly higher in IPS than pouchitis and normal pouch patients. Pouch tone was comparable among the groups and compliance was reduced in the pouchitis group. The visual analog scale showed a trend of correlation with the Pouchitis Disease Activity Index symptom scores in IPS. IPS, like other gut functional disorders, is characterized by visceral hypersensitivity, with normal pouch biomechanics.


Psychosocial Effect of Newborn Genomic Sequencing on Families in the BabySeq Project: A Randomized Clinical Trial.
Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families. To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units. In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019. Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group). Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents' relationship (Kansas Marital Satisfaction Scale), and parents' psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale). A total of 519 parents (275 women [53.0%]; mean [SD] age, 35.1 [4.5] years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean [SE] Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 [0.15]; 3 months, -0.18 [0.18]; 10 months, -0.07 [0.20]; joint P = .57) or parents' psychological distress (between-group ratio of adjusted mean [SE] Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 [0.08]; 3 months, 1.07 [0.11]; joint P = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents' relationship measure differed between groups over time (between-group difference in adjusted mean [SE] Kansas Marital Satisfaction Scale scores: postdisclosure, -0.19 [0.07]; 3 months, -0.04 [0.07]; and 10 months, -0.01 [0.08]; joint P = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain. In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant. ClinicalTrials.gov Identifier: NCT02422511.


Bacterial and fungal pneumonias.
Bacterial pneumonias occur with increased frequency and can be associated with increased morbidity in the HIV-infected population compared with normals. The pathogens that most frequently cause community-acquired pneumonias are S. pneumoniae, H. influenzae, and occasionally S. aureus. These pneumonias usually respond to appropriate antibiotic therapy; however, patients diagnosed with bacterial pneumonias are at increased risk for subsequent episodes. Nosocomial pneumonias, by contrast, are usually caused by gram-negative organisms and have a high mortality. Fungal pneumonias also have an increased incidence in AIDS patients, and usually occur in the setting of disseminated disease. Infections caused by C. neoformans, H. capsulatum, and C. immitis often recur despite a good initial response to amphotericin B. Maintenance therapy with an antifungal agent is therefore recommended.


A case study of nurse practitioner role implementation in primary care: what happens when new roles are introduced?
At the time of this study (2009) the role of the nurse practitioner was new to the province of British Columbia. The provincial government gave the responsibility for implementing the role to health authorities. Managers of health authorities, many of whom were unfamiliar with the role, were responsible for identifying the need for the NP role, determining how the NP would function, and gaining team members' acceptance for the new role. The purpose of the study was to explain the process of nurse practitioner role implementation as it was occurring and to identify factors that could enhance the implementation process. An explanatory, single case study with embedded units of analysis was used. The technique of explanation building was used in data analysis. Three primary health care settings in one health authority in British Columbia were purposively selected. Data sources included semi-structured interviews with participants (n=16) and key documents. The results demonstrate the complexity of implementing a new role in settings unfamiliar with it. The findings suggest that early in the implementation process and after the nurse practitioner was hired, team members needed to clarify intentions for the role and they looked to senior health authority managers for assistance. Acceptance of the nurse practitioner was facilitated by team members' prior knowledge of either the role or the individual nurse practitioner. Community health care providers needed to be involved in the implementation process and their acceptance developed as they gained knowledge and understanding of the role. The findings suggest that the interconnectedness of the concepts of intention, involvement and acceptance influences the implementation process and how the nurse practitioner is able to function in the setting. Without any one of the three concepts not only is implementation difficult, but it is also challenging for the nurse practitioner to fulfill role expectations. Implications for research, policy, practice and education are discussed.


Enhanced phase regression with Savitzky-Golay filtering for high-resolution BOLD fMRI.
Phase regression exploits the temporal evolution of phase in individual voxels to suppress blood oxygenation level dependent (BOLD) signal fluctuations caused by larger vessels and draining veins while preserving signal changes from microvascular effects. However, this process does not perform well when phase time series have low signal-to-noise ratios because of high levels of physiological noise. We demonstrate that Savitzky-Golay filters may be used to recover the underlying change in phase and completely restore the efficacy of phase regression. We do not make a priori assumptions regarding phase evolution and perform a data-driven exploration of parameter space to select the Savitzky-Golay filter parameters that minimize temporal variance in each voxel after phase regression. This approach is shown to work well on data acquired with single-shot and multi-shot pulse sequences, and should therefore be useful for both human and animal gradient-echo fMRI at high spatial resolutions at high fields. The ability to improve the spatial specificity of BOLD activation may be especially advantageous for clinical applications of fMRI that rely upon the accuracy of individual subject's activation maps to assist with presurgical planning and clinical decision-making. Enhanced phase regression with Savitzky-Golay filtering may also find other uses in analyses of resting state functional connectivity.


Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes.
For many years, adipose tissue has been mainly considered as an inert reservoir for storing triglycerides. Since the discovery that adipocytes may secrete a variety of bioactive molecules (hormones, chemokines, and cytokines), an endocrine and paracrine role for white adipose tissue (WAT) in the regulation of energy balance and other physiological processes has been established, particularly with regard to brain and muscle. In contrast, little is known about the interactions of WAT with liver. Hence, we examined the effect of the secretory products of WAT on hepatocytes. Conditioned medium of human WAT explants induced significant steatosis in hepatocyte cell lines. Factor(s) responsible for the conditioned medium-induced steatosis were screened by a battery of blocking antibodies against different cytokines/chemokines shown to be secreted by WAT. In contrast to interleukin-8 and interleukin-6, the monocyte chemoattractant protein-1 was capable of inducing steatosis in hepatocytes in a time-dependent manner at concentrations similar to those found in conditioned medium. Incubation of conditioned medium with antimonocyte chemoattractant protein-1 antibodies prevented triglyceride accumulation. Investigation of the mechanism leading to the triglyceride accumulation showed that both a diminution of apolipoprotein B secretion and an increase in phosphoenolpyruvate carboxykinase messenger RNA may be involved. The monocyte chemoattractant protein-1 secreted by adipose tissue may induce steatosis not only recruiting macrophages but also acting directly on hepatocytes.


Classification and strength measurement of stationary-phase promoters by use of a newly developed promoter cloning vector.
When an Escherichia coli culture changes from exponential growth to the stationary phase, expression of growth-related genes levels off, while a number of stationary-phase-specific genes are turned on. To gain insight into the growth phase-dependent global regulation of genome transcription, we analyzed the strength and specificity of promoters associated with the stationary-phase genes. For the in vivo assay of promoter activity, 300- to 500-bp DNA fragments upstream from the translation initiation codon were isolated and inserted into a newly constructed doubly fluorescent protein (DFP) vector. The activity of test promoters was determined by measuring the green fluorescent protein (GFP). To avoid the possible influence of plasmid copy number, the level of transcription of reference promoter lacUV5 on the same plasmid was determined by measuring the red fluorescent protein (RFP). Thus, the activities of test promoters could be easily and accurately determined by determining the GFP/RFP ratio. Analysis of the culture time-dependent variation of 100 test promoters indicated that (i) a major group of the stationary-phase promoters are up-regulated only in the presence of RpoS sigma; (ii) the phase-coupled increase in the activity of some promoters takes place even in the absence of RpoS; and (iii) the activity of some promoters increases in the absence of RpoS. This classification was confirmed by testing in vitro transcription by using reconstituted RpoD and RpoS holoenzymes.


Public trust and accountability for clinical performance: lessons from the national press reportage of the Bristol hearing.
The General Medical Council hearing into events at the Bristol Royal Infirmary resulted in verdicts of serious professional misconduct against three senior doctors. After the longest-running hearing in the GMC's history the press response was fierce. This paper reviews the reporting of the Bristol case (and issues arising from it) in the main broadsheet and tabloid national newspapers (dailies and Sundays) in the 5-week period around the GMC's delivery of the verdicts and subsequent sentencing. The aim was to describe the main themes emerging from the press coverage and to assess the implications for future debates over clinical performance and accountability. Media interest in the Bristol case was intense (184 published items in 5 weeks). The reporting was emotive and largely hostile, raising doubts about not just isolated lapses of care but also the possibility of more systematic failings. Diminished trust and reduced public confidence were recurrent themes, powerfully expressed. Professional self-regulation received scathing criticism, with calls for more public access to individual performance data. Future debates about clinical governance will need to take account of the new public context in the wake of Bristol. Arguments about the relative merits of self-regulation or data-driven performance management systems now need to be played out for a knowing and openly sceptical print media.


Vitellogenin and Vitellogenin-Like Genes in the Brown Planthopper.
Vitellogenin (Vg) is precursor of vitellin. Here, we identified a Vg (NlVg) and two Vg-likes (NlVg-like1 and NlVg-like2) in the brown planthopper, Nilaparvata lugens. Phylogenetic analyses showed that NlVg-like1 and NlVg-like2 are not clustered with the conventional insect Vgs associated with vitellogenesis. Temporo-spatial expression analyses showed that the NlVg and NlVg-like2 transcript levels increased significantly 24 h after emergence and were primarily expressed in female adults. However, NlVg-like1 was expressed during all stages, and in both genders. Tissue-specific analyses showed that all three genes were most highly expressed in the fat body. The injection of double-stranded RNA targeting NlVg showed that NlVg is essential not only for oocyte development but also for nymph development. The knockdown of NlVg-like1 in female adults resulted in failure to hatch or death before eggshell emergence in 18% of offspring embryos, suggesting that NlVg-like1 plays an important role during late embryogenesis. Approximately 65% of eggs laid by females that were treated with double-stranded RNA targeting NlVg-like2 failed to hatch, indicating that NlVg-like2 plays a role in nutrition absorption during oocyte, or embryonic development. Our results illustrate the structural and functional differences among the Vg and Vg-like genes and provide potential targets for RNA-interference-based insect pest management strategies.


Monolithically integrated reflective SOA-EA carrier re-modulator for broadband access nodes.
We propose and experimentally demonstrate a monolithically integrated circuit composed of a reflective concatenated semiconductor optical amplifier (SOA) and electro-absorber (EA) for high bit-rate carrier re-modulation. Simultaneous erasure and re-modulation of intensity modulated (IM) signals are shown. Although the experimental results are performed at 5 Gb/s, reflective SOA-EA re-modulators have the potential for operation at higher bit-rates.


Combined hepatocellular-cholangiocarcinoma after tetralogy of Fallot repair: a case report and review of literature.
Liver fibrosis and cancer are serious hepatic complications for patients with congenital heart diseases. We present a rare case of combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) (cHCC-CCA) after the repair of tetralogy of Fallot (TOF). A 54-year-old Japanese woman had undergone biventricular repair for TOF at 7 years old. She presented with abdominal distension. Abdominal CT revealed ascites and a 90-mm tumor involving the liver's left lobe. Tumor marker values were: alpha-fetoprotein, 16,208 ng/mL and des-gamma-carboxy prothrombin, 33,920 mAU/mL. The preoperative diagnosis was malignant tumor of the liver (e.g., HCC or intrahepatic CCA). We performed a left lobectomy of the liver. Histopathologically, the tumor was composed of two components growing in trabecular and irregular tubular patterns accompanied by a transitional area; the tumor was diagnosed as cHCC-CCA. The non-cancerous area showed fibrous change mainly surrounding a central vein and sinusoid, expanding toward the portal area without inflammation. We provide the details of our patient's cHCC-CCA that developed from fibrous congestive liver associated with right-sided heart failure after TOF repair, diagnosed based on histopathological features. We discuss liver fibrosis as a hepatic complication and a careful follow-up maneuver for improving the outcomes of patients with chronic hepatic congestion.


Influence of limit-setting and participation in physical activity on youth screen time.
To examine the associations of demographics, rules associated with television-viewing, and physical activity with daily screen time (including television, non-school-related computer use, and video games) in children and adolescents. We analyzed data from a telephone survey of 7415 youth aged 9 to 15 years from the Youth Media Campaign Longitudinal Survey. We used logistic regression models to calculate odds of exceeding recommended screen-time limits (>120 minutes/day) according to demographics, rules, and physical activity. Odds that children would exceed recommended screen-time limits were positively associated with age and black race/ethnicity and negatively associated with income level. Children and adolescents who reported that they really agreed that their parents had rules about time spent watching television and playing video games were less likely to exceed recommended limits than those who strongly disagreed that their parents had rules. Similarly, when parents reported always or very often having limits on television watching (versus rarely or never) and when parents correctly identified the recommended limits, children were less likely to exceed recommended limits. Children whose parents reported consistent limits and who themselves reported consistent rules about time spent watching television had the lowest prevalence of exceeding recommended limits. Odds that children would exceed recommended limits decreased as physical activity in the previous week increased. Parental rules regarding screen time and participation in physical activity play a role in the amount of screen time among children and adolescents. Programs that encourage limit-setting by parents and promote physical activity may reduce screen time among youth.


We Are What We Eat: A Stoichiometric and Ecometabolomic Study of Caterpillars Feeding on Two Pine Subspecies of Pinus sylvestris.
Many studies have addressed several plant-insect interaction topics at nutritional, molecular, physiological, and evolutionary levels. However, it is still unknown how flexible the metabolism and the nutritional content of specialist insect herbivores feeding on different closely related plants can be. We performed elemental, stoichiometric, and metabolomics analyses on leaves of two coexisting Pinus sylvestris subspecies and on their main insect herbivore; the caterpillar of the processionary moth (Thaumetopoea pityocampa). Caterpillars feeding on different pine subspecies had distinct overall metabolome structure, accounting for over 10% of the total variability. Although plants and insects have very divergent metabolomes, caterpillars showed certain resemblance to their plant-host metabolome. In addition, few plant-related secondary metabolites were found accumulated in caterpillar tissues which could potentially be used for self-defense. Caterpillars feeding on N and P richer needles had lower N and P tissue concentration and higher C:N and C:P ratios, suggesting that nutrient transfer is not necessarily linear through trophic levels and other plant-metabolic factors could be interfering. This exploratory study showed that little chemical differences between plant food sources can impact the overall metabolome of specialist insect herbivores. Significant nutritional shifts in herbivore tissues could lead to larger changes of the trophic web structure.


Regenerative potential of human skeletal muscle during aging.
In this study, we have investigated the consequences of aging on the regenerative capacity of human skeletal muscle by evaluating two parameters: (i) variation in telomere length which was used to evaluate the in vivo turn-over and (ii) the proportion of satellite cells calculated as compared to the total number of nuclei in a muscle fibre. Two skeletal muscles which have different types of innervation were analysed: the biceps brachii, a limb muscle, and the masseter, a masticatory muscle. The biopsies were obtained from two groups: young adults (23 +/- 1.15 years old) and aged adults (74 +/- 4.25 years old). Our results showed that during adult life, minimum telomere lengths and mean telomere lengths remained stable in the two muscles. The mean number of myonuclei per fibre was lower in the biceps brachii than in the masseter but no significant change was observed in either muscle with increasing age. However, the number of satellite cells, expressed as a proportion of myonuclei, decreased with age in both muscles. Therefore, normal aging of skeletal muscle in vivo is reflected by the number of satellite cells available for regeneration, but not by the mean number of myonuclei per fibre or by telomere lengths. We conclude that a decrease in regenerative capacity with age may be partially explained by a reduced availability of satellite cells.


Taxonomic reappraisal of Antithamnion sparsum Tokida (Ceramiaceae, Rhodophyta).
The taxonomic criterion of Antithamnion sparsum was reappraised in comparison with A. densum and A. defectum based on crossing experiments, morphological observation, chromosome study and Random Amplified Polymorphic DNA (RAPD) analysis. These species had a very similar morphology but were sexually isolated. The chromosome number was n = ca. 24 for A. densum, n = ca. 21 for A. defectum, and n = ca. 44 for A. sparsum. All isolates of A. sparsum and A. densum showed polysiphonia-type life history Asexual reproduction was induced by favorable environmental conditions. In A. sparsum, 1-2% of male plants developed mitotic tetrasporangia together with spermatangia. In A. densum, 5-10% of tetraspores developed into asexual tetrasporophytes. Phylogenetic relationships between these species were examined using RAPD analysis, and A. glanduliferum was used as an outgroup. A total of 167 polymorphic RAPD markers amplified from 15 different primers were analyzed. Results suggested that these species were closely related, with A. defectum placed in the middle of A. sparsum and A. densum. Chromosome study and RAPD analysis implied that A. sparsum first separated from A. defectum through polyploidization and later A. densum evolved. These species may present another example of the narrow species concept in the genus Antithamnion.


Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial.
Ten- to 15-year survival results were analyzed from a prospective multi-institutional randomized surgical trial that involved 740 stages I and II melanoma patients with intermediate thickness melanomas (1.0 to 4.0 mm) and compared elective (immediate) lymph node dissection (ELND) with clinical observation of the lymph nodes as well as prognostic factors that independently predict outcomes. Eligible patients were stratified according to tumor thickness, anatomical site, and ulceration, and then prerandomized to either ELND or nodal observation. By using Cox stepwise multivariate regression analysis, the independent predictors of outcome were tumor thickness (P < .001), the presence of tumor ulceration (P < .001), trunk site (P = .003), and patient age more than 60 years (P = .01). Overall 10-year survival was not significantly different for patients who received ELND or nodal observation (77% vs. 73%; P = .12). Among the prospectively stratified subgroups of patients, 10-year survival rates favored those patients with ELND, with a 30% reduction in mortality rate for the 543 patients with nonulcerated melanomas (84% vs. 77%; P = .03), a 30% reduction in mortality rate for the 446 patients with tumor thickness of 1.0 to 2.0 mm (86% vs. 80%; P = .03), and a 27% reduction in mortality rate for 385 patients with limb melanomas (84% vs. 78%; P = .05). Of these subgroups, the presence or absence of ulceration should be the key factor for making treatment recommendations with regard to ELND for patients with intermediate thickness melanomas. These long-term survival rates from patients treated at 77 institutions demonstrate that ulceration and tumor thickness are dominant predictive factors that should be used in the staging of stages I and II melanomas, and confer a survival advantage for these subgroups of prospectively defined melanoma patients.


Effect on dental caries of a stannous fluoride-calcium pyrophosphate dentrifice in an adult population: one-year results.
The first year of a two-year double-blind clinical trial of the anticaries effectiveness of a stannous fluoride-calcium pyrophosphate (SnF2-CPP) dentifrice as compared to a placebo control dentifrice involved 1,337 adult subjects, 18 to 78 years of age. Adult subjects were examined for dental caries at a baseline examination and after one year of ad lib dentifrice usage by an experienced clinical examiner using a visual-tactile examination and a radiographic evaluation. Results of the study after one year indicate a significant (P < 0.05) 33.3% difference in new caries formation with use of the SnF2-CPP dentifrice as compared to the placebo control based on the DMFS score.


Cancer molecular imaging: radionuclide-based biomarkers of the epidermal growth factor receptor (EGFR).
Overexpression of the epidermal growth factor receptor tyrosine kinase (EGFR-TK) has been documented in numerous human cancers of epithelial origin, and was found to correlate with resistance to treatment and poor prognosis. Recognizing the central role that this receptor plays in cancer development and progression, various approaches have been developed to target it in order to more specifically eradicate cancer cells. These methods include, among others, low-molecular weight inhibitors of the TK domain that are commonly designed to treat those tumors that overexpress the EGFR. Nevertheless, no currently available assay provides non-invasive, longitudinal and sensitive quantitation of receptor levels in tumors so as to better identify candidate patients for EGFR-targeted therapies. Hence, attempts have been made to develop radiolabeled molecular imaging agents as potential bioprobes to quantitatively monitor treatment efficiency. Such EGFR-targeted bioprobes could not only improve patient selection and treatment monitoring, but also allow a direct delivery of radionuclides for radiotherapy. In this review, the role that EGFR plays in cancer development and therapy is briefly presented, followed by a short review of prominent milestones in the development of EGFR-TK inhibitors. These inhibitors constitute the fundamental core structure for the development of radiolabeled probes to visualize the EGFR in vivo. The considerations that need to be taken into account for the development of such probes will be presented, along with a critical examination on the progress that has been made thus far in the field.


Serological Detection of SARS-CoV-2 Antibodies in Naturally-Infected Mink and Other Experimentally-Infected Animals.
The recent emergence of SARS-CoV-2 in humans from a yet unidentified animal reservoir and the capacity of the virus to naturally infect pets, farmed animals and potentially wild animals has highlighted the need for serological surveillance tools. In this study, the luciferase immunoprecipitation systems (LIPS), employing the spike (S) and nucleocapsid proteins (N) of SARS-CoV-2, was used to examine the suitability of the assay for antibody detection in different animal species. Sera from SARS-CoV-2 naturally-infected mink (n = 77), SARS-CoV-2 experimentally-infected ferrets, fruit bats and hamsters and a rabbit vaccinated with a purified spike protein were examined for antibodies using the SARS-CoV-2 N and/or S proteins. From comparison with the known neutralization status of the serum samples, statistical analyses including calculation of the Spearman rank-order-correlation coefficient and Cohen's kappa agreement were used to interpret the antibody results and diagnostic performance. The LIPS immunoassay robustly detected the presence of viral antibodies in naturally infected SARS-CoV-2 mink, experimentally infected ferrets, fruit bats and hamsters as well as in an immunized rabbit. For the SARS-CoV-2-LIPS-S assay, there was a good level of discrimination between the positive and negative samples for each of the five species tested with 100% agreement with the virus neutralization results. In contrast, the SARS-CoV-2-LIPS-N assay did not consistently differentiate between SARS-CoV-2 positive and negative sera. This study demonstrates the suitability of the SARS-CoV-2-LIPS-S assay for the sero-surveillance of SARS-CoV-2 infection in a range of animal species.


Effects of intrabrachial arterial infusion of pyruvate on forearm tissue metabolism. Interrelationships between pyruvate, lactate, and alanine.
Postabsorptive release of alanine from forearm skeletal muscle is large relative to other amino acids, suggesting new synthesis by transamination of pyruvate. This hypothesis was tested and the pathway quantified in six subjects, each given two 30 min intrabrachial arterial pyruvate infusions. The first (12 mumoles/min) supplied approximately that amount of pyruvate produced endogenously by glycolysis in resting muscle. The second (36 mumoles/min) approximated endogenous pyruvate production by glycolysis during moderate exercise. Changes in balance across forearm tissues of pyruvate, glucose, lactate, and amino acids were measured. The time-course of pyruvate equilibration across fore-arm muscles was detailed in three additional subjects. The two infusions increased arterial pyruvate from 64 to 674 and 1776 mumoles/liter respectively. Muscle consumed 72% of the exogenous pyruvate during both infusions. Outputs of lactate and alanine increased, accounting respectively for 30.3 and 6.7% of the pyruvate at the low infusion rate, and 17.1 and 3.8% at the high rate. The remaining pyruvate probably was oxidized. Muscle release of valine, isoleucine, and leucine decreased during the high dose infusion. Additionally, adipose tissue plus skin released more alanine and lactate during the high dose infusion. Other metabolies were unchanged.Thus, both muscle and adipose tissue plus skin synthesize alanine from pyruvate. Lactate production considerably exceeds that of alanine. In muscle, increased availability of intracellular pyruvate serving as a nitrogen acceptor may facilitate branched chain amino acid oxidation. Muscle consumption of infused pyruvate is rapid, and detailed studies of its equilibration suggest that passage across the muscle cell membrane is rate limiting.


Safe Care for Pediatric Patients: A Scoping Review Across Multiple Health Care Settings.
Children are particularly vulnerable to patient safety concerns due to pediatric-specific and general health care challenges. This scoping review identifies and describes the vulnerabilities of those aged 0 to 18 years to iatrogenic harm in various health care settings. Six databases were searched from 1991 to 2012. Primary studies were categorized using predetermined groupings. Categories were tallied and descriptive statistics were employed. A total of 388 primary studies exploring interventions that improved patient safety, deficiencies, or errors leading to safety concerns were included. The most common issues were medication (189 studies, 48.7%) and general medical (81 studies, 20.9%) errors. Sixty studies (15.5%) evaluated or described patient safety interventions, 206 studies (53.1%) addressed health care systems and technologies, 17 studies (4.4%) addressed caregiver perspectives and 20 studies (5.2%) discussed analytic models for patient safety. Further work is needed to ensure consistency of definitions in patient safety research to facilitate comparison and collation of results.


Regional odontodysplasia (Ghost teeth). A case report.
Regional odontodysplasia is a rare development anomaly affecting the teeth with an unknown etiology. This dental abnormality involves the hard tissues of the teeth that are derived from both epithelial (enamel) and mesenchymal (dentine & cementum) components of the tooth forming apparatus. Teeth in a region or quadrant of maxilla or mandible are affected to the extent that they exhibit short roots, wide open apical foramen and large pulp chamber, the thinness and poor mineralisation qualities of th enamel and dentine layers have given rise to a faint radiolucent image, hence the term "Ghost teeth". Both the permanent teeth and the deciduous teeth are affected. Females are more commonly affected than males. There is a maxillary predominance (2.5:1) with a predilection for the anterior teeth. Eruption of the affected teeth is delayed or does not occur. Because of the poor quality of the affected teeth, they cannot be rehabilitated for functional use therefore the treatment of choice is extraction with prosthetic replacement. However, necrosis and facial cellulitis appear to be a complication if these teeth are retained. A unique case of regional odontodysplasia affecting the entire right quadrant of mandible is reported here.


Dialysis Modalities and HDL Composition and Function.
Lipid abnormalities may have an effect on clinical outcomes of patients on dialysis. Recent studies have indicated that HDL dysfunction is a hallmark of ESRD. In this study, we compared HDL composition and metrics of HDL functionality in patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) with those in healthy controls. We detected a marked suppression of several metrics of HDL functionality in patients on HD or PD. Compositional analysis revealed that HDL from both dialysis groups shifted toward a more proinflammatory phenotype with profound alterations in the lipid moiety and protein composition. With regard to function, cholesterol efflux and anti-inflammatory and antiapoptotic functions seemed to be more severely suppressed in patients on HD, whereas HDL-associated paraoxonase activity was lowest in patients on PD. Quantification of enzyme activities involved in HDL metabolism suggested that HDL particle maturation and remodeling are altered in patients on HD or PD. In summary, our study provides mechanistic insights into the formation of dysfunctional HDL in patients with ESRD who are on HD or PD.


Bone sarcomas: Overview of management, with a focus on surgical treatment considerations.
Outcomes for patients with bone sarcomas have improved dramatically over the past 40 years, and most bone sarcomas today are treated with surgery and chemotherapy. The most common clinical findings in patients with bone sarcomas are pain and an enlarging bone mass, although pain is not generally a good indicator of malignancy. In general, any patient with a bone mass with indeterminate imaging findings should be referred to an orthopedic oncologist. Bone sarcomas are diagnosed after a biopsy, which is best performed by the surgeon who will be doing the curative resection. Postresection reconstruction of the affected limb is generally done with an allograft-prosthetic composite or a modular metallic prosthetic joint replacement device. Post-therapy follow-up at frequent and regular intervals is critical to assess for recurrence and lung metastasis.