Clinician-friendly physical performance tests in athletes part 3: a systematic review of measurement properties and correlations to injury for tests in the upper extremity.
In parts 1 and 2 of this systematic review, the methodological quality as well as the quality of the measurement properties of physical performance tests (PPTs) of the lower extremity in athletes was assessed. In this study, part 3, PPTs of the upper extremity in athletes are examined. Database and hand searches were conducted to identify primary literature addressing the use of upper extremity PPTs in athletes. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist was used to critique the methodological quality of each paper. The Terwee Scale was used to analyse the quality of the measurement properties of each test. 11 articles that examined 6 PPTs were identified. The 6 PPTs were: closed kinetic chain upper extremity stability test (CKCUEST), seated shot put (2 hands), unilateral seated shot put, medicine ball throw, modified push-up test and 1-arm hop test. Best evidence synthesis provided moderate positive evidence for the CKCUEST and unilateral seated shot put. Limited positive evidence was available for the medicine ball throw and 1-arm hop test. There are a limited number of upper extremity PPTs used as part of musculoskeletal screening examinations, or as outcome measures in athletic populations. The CKCUEST and unilateral seated shot put are 2 promising PPTs based on moderate evidence. However, the utility of the PPTs in injured populations is unsubstantiated in literature and warrants further investigation.


Computer-aided detection of breast cancers using Haar-like features in automated 3D breast ultrasound.
Automated 3D breast ultrasound (ABUS) has gained interest in breast imaging. Especially for screening women with dense breasts, ABUS appears to be beneficial. However, since the amount of data generated is large, the risk of oversight errors is substantial. Computer aided detection (CADe) may be used as a second reader to prevent oversight errors. When CADe is used in this fashion, it is essential that small cancers are detected, while the number of false positive findings should remain acceptable. In this work, the authors improve their previously developed CADe system in the initial candidate detection stage. The authors use a large number of 2D Haar-like features to differentiate lesion structures from false positives. Using a cascade of GentleBoost classifiers that combines these features, a likelihood score, highly specific for small cancers, can be efficiently computed. The likelihood scores are added to the previously developed voxel features to improve detection. The method was tested in a dataset of 414 ABUS volumes with 211 cancers. Cancers had a mean size of 14.72 mm. Free-response receiver operating characteristic analysis was performed to evaluate the performance of the algorithm with and without using the aforementioned Haar-like feature likelihood scores. After the initial detection stage, the number of missed cancer was reduced by 18.8% after adding Haar-like feature likelihood scores. The proposed technique significantly improves our previously developed CADe system in the initial candidate detection stage.


When patients refuse COVID-19 testing, quarantine, and social distancing in inpatient psychiatry: clinical and ethical challenges.
The COVID-19 pandemic has introduced new ethical challenges in the care of patients with serious psychiatric illness who require inpatient treatment and who may have beeen exposed to COVID-19 or have mild to moderate COVID-19 but refuse testing and adherence to infection prevention protocols. Such situations increase the risk of infection to other patients and staff on psychiatric inpatient units. We discuss medical and ethical considerations for navigating this dilemma and offer a set of policy recommendations.


Pathogenesis of acute hepatopancreatic necrosis disease (AHPND) in shrimp.
Acute hepatopancreatic necrosis disease (AHPND), also called early mortality syndrome (EMS), is a recently emergent shrimp bacterial disease that has resulted in substantial economic losses since 2009. AHPND is known to be caused by strains of Vibrio parahaemolyticus that contain a unique virulence plasmid, but the pathology of the disease is still unclear. In this study, we show that AHPND-causing strains of V. parahaemolyticus secrete the plasmid-encoded binary toxin PirAB(vp) into the culture medium. We further determined that, after shrimp were challenged with AHPND-causing bacteria, the bacteria initially colonized the stomach, where they started to produce PirAB(vp) toxin. At the same early time point (6 hpi), PirB(vp) toxin, but not PirA(vp) toxin, was detected in the hepatopancreas, and the characteristic histopathological signs of AHPND, including sloughing of the epithelial cells of the hepatopancreatic tubules, were also seen. Although some previous studies have found that both components of the binary PirAB(vp) toxin are necessary to induce a toxic effect, our present results are consistent with other studies which have suggested that PirB(vp) alone may be sufficient to cause cellular damage. At later time points, the bacteria and PirA(vp) and PirB(vp) toxins were all detected in the hepatopancreas. We also show that Raman spectroscopy "Whole organism fingerprints" were unable to distinguish between AHPND-causing and non-AHPND causing strains. Lastly, by using minimum inhibitory concentrations, we found that both virulent and non-virulent V. parahaemolyticus strains were resistant to several antibiotics, suggesting that the use of antibiotics in shrimp culture should be more strictly regulated.


The financial burden of juvenile idiopathic arthritis: a Nova Scotia experience.
Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic illness. There is little published data on the financial burden of this illness. The primary objective of this study was to determine the annual costs borne by families of a child with JIA living in Nova Scotia (NS). All families in NS with a child followed in the Pediatric Rheumatology Clinic at the Izaak Walton Killam Health Centre (IWK) in 2009 were mailed a self-report questionnaire. The questionnaire evaluated disease related costs, gross household income and perceived financial burden. Dillman's method was used to optimize return rates. Descriptive statistics were used to summarize results. Spearman's correlation coefficient was used to assess the relationship of distance from the IWK and cost. The Mann-Whitney U test was used to compare median costs between groups. Of 172 possible respondents, we received 54 completed questionnaires and 11 blank questionnaires (overall response rate 31.4%). Approximately one third (35.9%) of parents rated the financial burden as moderate or large and 36% rated financial resources available as poor. The median annual total cost per patient was $619.50 CAD (range 0, $5535) which was a median 0.7% (range 0, 37%) of gross household incomes. The largest expense for families was visit related costs. There was not a significant relationship between total annual costs and distance from the IWK (rs = 0.18, P = 0.2). Families of a child with oligoarthritis had significantly lower costs than the families of a child with another subtype of JIA ($359.00 CAD vs. $877.00 CAD, P = 0.02). The costs associated with having a child with JIA in NS are on average modest, but may be considerable for some families. Oligoarticular JIA is associated with smaller costs. Many families perceive the burden to be at least moderate and the availability of financial resources to be poor. Supports should be targeted to those families most in need.


Hepatic encephalopathy as a complication of liver cirrhosis: an Asian perspective.
Hepatic encephalopathy is one of the most important clinical manifestations in decompensated liver cirrhosis. Accepted concepts regarding the pathophysiology of hepatic encephalopathy are that the endogenous neurotoxic substances, including ammonia: (i) escape from catabolism by the liver due both to the impaired function of the cirrhotic liver and also to the presence of portal systemic shunting; (ii) circulate at elevated concentrations in the systemic blood flow; (iii) reach the brain through the blood-brain barrier; and (iv) impair cerebral function leading to disturbances of consciousness. The majority of these toxic substances are produced in the intestine by the bacterial flora, and are absorbed into the portal venous flow. The epidemiology of liver cirrhosis depends particularly on its etiology, and shows a marked geographic difference worldwide between Western, and Asian countries. Hepatic encephalopathy developed at an annual rate of 8% in cirrhotics in Far Eastern studies. In Eastern and Far East countries, therapeutic options are similar to those in the western hemisphere, but pronounced application of dietary restriction, antimicrobial agents, disaccharides, shunt obliteration and branched chain amino acids is noted. In spite of improved therapeutic options for encephalopathy, the long-term survival is still low. Thus, hepatic encephalopathy remains a serious complication of liver cirrhosis. Establishment of truly effective prevention modalities and broader application of liver transplantation will help rescue patients suffering from this complication of liver cirrhosis in the near future.


Stability of carboplatin and oxaliplatin in their infusion solutions is due to self-association.
Carboplatin and oxaliplatin are commonly used platinum anticancer agents that are sold as ready-to-use aqueous infusion solutions with shelf lives of 2 and 3 years, respectively. The observed rate constants for the hydrolysis of these drugs, however, are too large to account for their long shelf lives. We here use electrospray-trap mass spectrometry to show that carboplatin and oxaliplatin are self-associated at concentrations in their ready-to-use infusion solutions (~27 mM and 13 mM, respectively) and, as expected, when the drug concentration is reduced to more physiologically relevant concentrations (100 μM and 5 μM, respectively) the association equilibrium is shifted in favor of the monomeric forms of these drugs. Using (1)H NMR we measure the intensity of the NH resonance of the two symmetry-equivalent NH(3) molecules of carboplatin, relative to the intensity of the γ-methylene CH resonance, as a function of total drug concentration. Then, by fitting the data to models of different molecularity, we show that the association complex is a dimer with a monomer-dimer association constant of K (M(-1)) = 391 ± 127. The work presented here shows that carboplatin and oxaliplatin mainly exist as association complexes in concentrated aqueous solution, a property that accounts for the long term stability of their ready-to-use infusion solutions, and that these association complexes may exist, to some extent, in the blood after injection.


CYCLOPS, a DNA-binding transcriptional activator, orchestrates symbiotic root nodule development.
Nuclear calcium oscillations are a hallmark of symbiotically stimulated plant root cells. Activation of the central nuclear decoder, calcium- and calmodulin-dependent kinase (CCaMK), triggers the entire symbiotic program including root nodule organogenesis, but the mechanism of signal transduction by CCaMK was unknown. We show that CYCLOPS, a direct phosphorylation substrate of CCaMK, is a DNA-binding transcriptional activator. Two phosphorylated serine residues within the N-terminal negative regulatory domain of CYCLOPS are necessary for its activity. CYCLOPS binds DNA in a sequence-specific and phosphorylation-dependent manner and transactivates the NODULE INCEPTION (NIN) gene. A phosphomimetic version of CYCLOPS was sufficient to trigger root nodule organogenesis in the absence of rhizobia and CCaMK. CYCLOPS thus induces a transcriptional activation cascade, in which NIN and a heterotrimeric NF-Y complex act in hierarchical succession to initiate symbiotic root nodule development.


Volcanism on Mercury: evidence from the first MESSENGER flyby.
The origin of plains on Mercury, whether by volcanic flooding or impact ejecta ponding, has been controversial since the Mariner 10 flybys (1974-75). High-resolution images (down to 150 meters per pixel) obtained during the first MESSENGER flyby show evidence for volcanic vents around the Caloris basin inner margin and demonstrate that plains were emplaced sequentially inside and adjacent to numerous large impact craters, to thicknesses in excess of several kilometers. Radial graben and a floor-fractured crater may indicate intrusive activity. These observations, coupled with additional evidence from color images and impact crater size-frequency distributions, support a volcanic origin for several regions of plains and substantiate the important role of volcanism in the geological history of Mercury.


Estimation of concentration ratio of indicator to pathogen-related gene in environmental water based on left-censored data.
A stochastic model for estimating the ratio between a fecal indicator and a pathogen based on left-censored data, which includes a substantially high number of non-detects, was constructed. River water samples were taken for 16 months at six points in a river watershed, and conventional fecal indicators (total coliforms and general Escherichia coli), genetic markers (Bacteroides spp.), and virulence genes (eaeA of enteropathogenic E. coli and ciaB of Campylobacter jejuni) were quantified. The quantification of general E. coli failed to predict the presence of the virulence gene from enteropathogenic E. coli, different from what happened with genetic markers (Total Bac and Human Bac). A Bayesian model that was adapted to left-censored data with a varying analytical quantification limit was applied to the quantitative data, and the posterior predictive distributions of the concentration ratio were predicted. When the sample size was 144, simulations conducted in this study suggested that 39 detects were enough to accurately estimate the distribution of the concentration ratio, when combined with a dataset with a positive rate higher than 99%. To evaluate the level of accuracy in the estimation, it is desirable to perform a simulation using an artificially generated left-censored dataset that has the identical number of non-detects as the actual data.


Analysis of photonic noise generated due to Kerr nonlinearity in silicon ring resonators.
The Kerr effect in silicon ring resonators (RRs) is widely used for switching and regeneration of optical communications signals. In addition, it has been shown to considerably limit the performance of refractive index sensors based on high quality-factor RRs. While the Kerr effect's impact on output signals of silicon RRs is well known, its influence on the properties of the output noise is yet to be explored. In this work, we analytically and numerically analyze the noise properties of Kerr effect in silicon RRs. We show that the input power, RR's bandwidth, and input optical signal to noise ratio (OSNR) have significant influence on the power and distribution of the output noise. We use the developed noise model to evaluate the RR's noise figure and output noise distribution for optical communications and sensing applications. These noise properties can be used for the design and performance evaluation of optical communications systems and sensors using silicon photonic RRs.


Prospective evaluation of the learning curve for ultrasound-guided peripheral intravenous catheter placement.
It is unclear how many ultrasound-guided peripheral intravenous catheters (USG PIVC) one must place to become proficient at the procedure. The objective of this study was to determine the learning curve associated with PIVC placement and determine how many attempts are required for non-physician learners to reach proficiency. This is a prospective observational study. Emergency department (ED) nurses and paramedics with competence in traditional PIVC placement underwent a USG PIVC placement training program. Their success or failure in placing USG PIVCs as part of patient care on ED patients with difficult IV access was monitored. Number of attempts (defined as one skin puncture) was recorded and success was defined as the ability to aspirate blood and flush saline. The probability of success over time was analyzed. Proficiency was defined a priori as 70% probability of success. Thirty-three providers with 1077 PIV access attempts on 796 patients over 1000 unique patient ED encounters were included in the study. Overall success rate for all providers was 88.24% (86.3%-90.2%). LOcally WEighted Scatter-plot Smoother (Lowess) smoothing and mixed effects logistic regression analysis both determined that a learner's probability of success would be greater than 70% after four USG PIVCs have been placed. Post hoc analysis for a more stringent 88% success rate resulted in 15 and 26 required attempts, respectively. After placement of four USG PIVCs, new learners of the procedure are capable of a greater than 70% success rate. A success rate of greater than 88% is achieved after 15 to 26 attempts.


The Association between Whole Grain Products Consumption and Successful Aging: A Combined Analysis of MEDIS and ATTICA Epidemiological Studies.
The quality of carbohydrates in the diet, including whole grains, matters greatly to health. There is emerging evidence supporting various protective effects from whole grain consumption against certain chronic diseases. However, being free of disease is not a requirement for healthy ageing, as many older adults have one or more health conditions but, when well controlled, have little influence on their wellbeing. The present study aimed to evaluate the association between whole grain consumption on successful aging, through an analysis of a sample of n = 3349, over-50-years-old men and women participating in the ATTICA and MEDIS population-based cross-sectional studies. Successful aging was evaluated using the validated successful aging index (SAI, range 0-10) comprising of health-related social, lifestyle and clinical components. High whole grain intake was positively associated with SAI as compared with low (b ± SE: 0.278 ± 0.091, p = 0.002), whereas no significant associations were observed between moderate whole grain consumption and SAI (p > 0.05). Increased whole grain intake has been associated with several health benefits, and, as is shown here, with higher successful aging levels. Therefore, consumption of whole grains should be encouraged, especially by replacing refined grains, without increasing total energy intake.


The relation of phase noise and luminance contrast to overt attention in complex visual stimuli.
Models of attention are typically based on difference maps in low-level features but neglect higher order stimulus structure. To what extent does higher order statistics affect human attention in natural stimuli? We recorded eye movements while observers viewed unmodified and modified images of natural scenes. Modifications included contrast modulations (resulting in changes to first- and second-order statistics), as well as the addition of noise to the Fourier phase (resulting in changes to higher order statistics). We have the following findings: (1) Subjects' interpretation of a stimulus as a "natural" depiction of an outdoor scene depends on higher order statistics in a highly nonlinear, categorical fashion. (2) Confirming previous findings, contrast is elevated at fixated locations for a variety of stimulus categories. In addition, we find that the size of this elevation depends on higher order statistics and reduces with increasing phase noise. (3) Global modulations of contrast bias eye position toward high contrasts, consistent with a linear effect of contrast on fixation probability. This bias is independent of phase noise. (4) Small patches of locally decreased contrast repel eye position less than large patches of the same aggregate area, irrespective of phase noise. Our findings provide evidence that deviations from surrounding statistics, rather than contrast per se, underlie the well-established relation of contrast to fixation.


Selection of memory clinic patients for CSF biomarker assessment can be restricted to a quarter of cases by using computerized decision support, without compromising diagnostic accuracy.
An accurate and timely diagnosis for Alzheimer's disease (AD) is important, both for care and research. The current diagnostic criteria allow the use of CSF biomarkers to provide pathophysiological support for the diagnosis of AD. How these criteria should be operationalized by clinicians is unclear. Tools that guide in selecting patients in which CSF biomarkers have clinical utility are needed. We evaluated computerized decision support to select patients for CSF biomarker determination. We included 535 subjects (139 controls, 286 Alzheimer's disease dementia, 82 frontotemporal dementia and 28 vascular dementia) from three clinical cohorts. Positive (AD like) and negative (normal) CSF biomarker profiles were simulated to estimate whether knowledge of CSF biomarkers would impact (confidence in) diagnosis. We applied these simulated CSF values and combined them with demographic, neuropsychology and MRI data to initiate CSF testing (computerized decision support approach). We compared proportion of CSF measurements and patients diagnosed with sufficient confidence (probability of correct class ≥0.80) based on an algorithm with scenarios without CSF (only neuropsychology, MRI and APOE), CSF according to the appropriate use criteria (AUC) and CSF for all patients. The computerized decision support approach recommended CSF testing in 140 (26%) patients, which yielded a diagnosis with sufficient confidence in 379 (71%) of all patients. This approach was more efficient than CSF in none (0% CSF, 308 (58%) diagnosed), CSF selected based on AUC (295 (55%) CSF, 350 (65%) diagnosed) or CSF in all (100% CSF, 348 (65%) diagnosed). We used a computerized decision support with simulated CSF results in controls and patients with different types of dementia. This approach can support clinicians in making a balanced decision in ordering additional biomarker testing. Computer-supported prediction restricts CSF testing to only 26% of cases, without compromising diagnostic accuracy.


The effect of alendronate on lipid profile of postmenopausal women with osteopenia and prediabetes: A randomized triple-blind clinical trial.
Prediabetes is a high-risk state for developing diabetes at an annual rate of 5%-10%. Early intervention can prevent further complications, including metabolic syndrome. Bisphosphonates are commonly used for osteoporotic postmenopausal women. The purpose of this study was to assess the effects of bisphosphonates on lipid profile including triglyceride (TG), total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) of prediabetic postmenopausal women with osteopenia. In this triple-blind randomized controlled trial, sixty prediabetic, postmenopausal women with sufficient Vitamin D and osteopenia, aged 45-60 years, were randomly enrolled in two groups of intervention (receiving 70-mg alendronate for 12 weeks [duration for maximum metabolic effect of bisphosphonates], n = 30) and control (receiving placebo, n = 30) according to a randomized block procedure of size 2 and 1:1 allocation ratio. The primary outcome of the study, the lipid profile, was evaluated before and after the interventions. The effect of the intervention was assessed using analysis of covariance. The lipid profiles showed no significant differences to the mean values at the baseline in both the groups (all P > 0.05). At the end of the study, the differences between the groups were not significant for 25(OH) D3 (mean difference: -11.09, 95% confidence interval: -32.43-10.25), T (4.19, -30.58-38.97), cholesterol (8.13, -13.07-29.33), LDL-cholesterol (5.07, -10.18-20.31), and HDL-cholesterol (-0.86, -6.04-4.31) when the baseline values and confounders were adjusted (all P > 0.05). No statistically significant difference was detected in the serum lipid profile of prediabetic postmenopausal women with osteopenia as a result of alendronate intervention. More studies with larger sample sizes and longer intervention periods are recommended.


Zinc supplementation for tinnitus.
Tinnitus is the perception of sound without external acoustic stimuli. Patients with severe tinnitus may have physical and psychological complaints and their tinnitus can cause deterioration in their quality of life. At present no specific therapy for tinnitus has been found to be satisfactory in all patients. In recent decades, a number of reports have suggested that oral zinc supplementation may be effective in the management of tinnitus. Since zinc has a role in cochlear physiology and in the synapses of the auditory system, there is a plausible mechanism of action for this treatment. To evaluate the effectiveness and safety of oral zinc supplementation in the management of patients with tinnitus. The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2016, Issue 6); PubMed; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 July 2016. Randomised controlled trials comparing zinc supplementation versus placebo in adults (18 years and over) with tinnitus. We used the standard methodological procedures recommended by Cochrane. Our primary outcome measures were improvement in tinnitus severity and disability, measured by a validated tinnitus-specific questionnaire, and adverse effects. Secondary outcomes were quality of life, change in socioeconomic impact associated with work, change in anxiety and depression disorders, change in psychoacoustic parameters, change in tinnitus loudness, change in overall severity of tinnitus and change in thresholds on pure tone audiometry. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. We included three trials involving a total of 209 participants. The studies were at moderate to high risk of bias. All included studies had differences in participant selection criteria, length of follow-up and outcome measurement, precluding a meta-analysis. The participants were all adults over 18 years with subjective tinnitus, but one study conducted in 2013 (n = 109) included only elderly patients. Improvement in tinnitus severity and disabilityOnly the study in elderly patients used a validated instrument (Tinnitus Handicap Questionnaire) for this primary outcome. The authors of this cross-over study did not report the results of the two phases separately and found no significant differences in the proportion of patients reporting tinnitus improvement at four months of follow-up: 5% (5/93) versus 2% (2/94) in the zinc and placebo groups, respectively (risk ratio (RR) 2.53, 95% confidence interval (CI) 0.50 to 12.70; very low-quality evidence).None of the included studies reported any significant adverse effects. Secondary outcomesFor the secondary outcome change in tinnitus loudness, one study reported no significant difference between the zinc and placebo groups after eight weeks: mean difference in tinnitus loudness -9.71 dB (95% CI -25.53 to 6.11; very low-quality evidence). Another study also measured tinnitus loudness but used a 0- to 100-point scale. The authors of this second study reported no significant difference between the zinc and placebo groups after four months: mean difference in tinnitus loudness rating scores 0.50 (95% CI -5.08 to 6.08; very low-quality evidence).Two studies used unvalidated instruments to assess tinnitus severity. One (with 50 participants) reported the severity of tinnitus using a non-validated scale (0 to 7 points) and found no significant difference in subjective tinnitus scores between the zinc and placebo groups at the end of eight weeks of follow-up (mean difference (MD) -1.41, 95% CI -2.97 to 0.15; very low-quality evidence). A third trial (n = 50) also evaluated the improvement of tinnitus using a non-validated instrument (a 0 to 10 scale: 10 = severe and unbearable tinnitus). In this study, after eight weeks there was no difference in the proportion of patients with improvement in their tinnitus, 8.7% (2/23) treated with zinc versus 8% (2/25) of those who received a placebo (RR 1.09, 95% CI 0.17 to 7.10, very low-quality evidence).None of the included studies reported any of our other secondary outcomes (quality of life, change in socioeconomic impact associated with work, change in anxiety and depression disorders, change in psychoacoustic parameters or change in thresholds on pure tone audiometry). We found no evidence that the use of oral zinc supplementation improves symptoms in adults with tinnitus.


Phosphorylation of DNA topoisomerase II in a human tumor cell line.
The phosphorylation of the nuclear enzyme DNA topoisomerase II was characterized from HeLa human cervical carcinoma cells labeled with 32Pi. Analysis of topoisomerase II immunoprecipitates from 32P-labeled HeLa cells indicated that phosphorylation of the enzyme occurred at serine residues. Incorporation of 32P into topoisomerase II was not due to other types of phosphomodifications such as poly(ADP-ribosylation) or covalent interactions of the enzyme with nucleic acids. The stability of topoisomerase II protein and topoisomerase II phosphorylation was also investigated in HeLa cells. Topoisomerase II protein was relatively stable, having a half-life of approximately 27 h. Phosphorylation of HeLa topoisomerase II was also remarkably stable with a T1/2 of 17 h.


The HMG I proteins: dynamic roles in gene activation, development, and tumorigenesis.
The high mobility group I, Y, and I-C proteins are low-molecular-weight, nonhistone chromosomal proteins that play a general role modulating gene expression during development and the immune response. Consistent with their role in early development, all three proteins are expressed at high levels during embryogenesis, and their expression is markedly diminished in differentiated cells. Exceptions to the general repression of these genes in adult tissues involve (1) A burst of synthesis of the HMG I protein during the immune response (during lymphocyte activation and preceding cytokine/adhesion molecule gene expression), (2) A constitutive expression of the HMG I and Y proteins in photoreceptor cells, and (3) Derepression of HMG I, Y, and often I-C expression in neoplastic cells. Work from several laboratories has now uncovered how these proteins participate in gene activation: (1) By altering the chromatin structure around an inducible gene-and thus influencing accessibility of the locus to regulatory proteins-(2) By facilitating the loading of transcription factors onto the promoters, and (3) By bridging adjacent transcription factors on a promoter via protein/protein interactions. Despite the similar structures and biochemical properties of the three proteins, the work has also provided clues to a division of labor between these proteins. HMG I and Y have demonstrable roles in enhanceosome formation, whereas HMG I-C has a specific role in adipogenesis. C-terminal truncations of HMG I-C and wild-type HMG Y appear to function in a manner analogous to oncogenes, as assessed by cellular transforation assays and transgenic mice. Future work should clearly define the similarities and differences in the biological roles of the three proteins, and should evolve to include attempts at pharmaceutical intervention in disease, based upon structural information concerning HMG I interactions with DNA and with regulatory proteins.


Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against beta-amyloid peptide-induced toxicity in SH-SY5Y cells.
Ginkgo biloba extract EGb761 has been shown to protect against beta-amyloid peptide (Abeta)-induced neurotoxicity but the specific mechanisms remain unclear. In the present study, effects of EGb761 and two of its constituents, quercetin and ginkgolide B, on the cytotoxic action of Abeta (1-42) were tested with human neuroblastoma SH-SY5Y cells. We found that EGb761 was able to block Abeta (1-42)-induced cell apoptosis, reactive oxygen species (ROS) accumulation, mitochondrial dysfunction and activation of c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling pathways. Both quercetin and ginkgolide B may be involved in the inhibitory effects of EGb761 on JNK, ERK1/2 and Akt signaling pathways. Ginkgolide B also helped to improve mitochondrial functions but quercetin failed to show this effect. Additional experiments suggest that, protective effects of EGb761 against Abeta toxicity may be associated with its antioxidant and platelet activating factor (PAF) antagonist activities. Quercetin but not ginkgolide B is one of the constituents responsible for the antioxidant action of EGb761. Both quercetin and ginkgolide B may be involved in the PAF antagonist activity of EGb761. Overall, actions of individual EGb761 components provide further insights into direct mechanisms underlying the neuroprotective effects of EGb761.


Beyond childhood: psychiatric comorbidities and social background of adults with Asperger syndrome.
Over the past few years, our knowledge about Asperger syndrome (AS) has increased enormously. Although it used to be a syndrome mainly encountered in childhood and adolescent psychiatry, it is now increasingly recognized in adult psychiatry. Nevertheless, little is known about psychiatric comorbidities and life course of adults with AS. The current study aimed to gain an insight into comorbidities and the development of the social situation of adults with AS. We investigated psychiatric comorbidities, psychiatric history, professional background, partnerships, and children in 50 adults with AS (34 men and 16 women) over a broad age range (20-62 years). Seventy percent of adults with AS had at least one psychiatric comorbiditiy. Most frequent comorbidities were depression and anxiety disorders. Obsessive-compulsive disorder and alcohol abuse/dependence were also observed. Many adults had previously been treated with psychopharmacological or psychotherapeutic interventions. Although most adults had a high-level school leaving certificate and had gone on to complete training/university studies, less than half were currently in employment. Fourteen adults were living in a partnership and 10 had children. Adults with AS often have psychiatric comorbidities, indicating lower levels of mental health. Additionally, they seem to have severe limitations concerning professional success, despite having a good school education. Their family situation is also impaired with regard to starting a family. These considerable limitations in the life of adults with AS may help to understand their specific problems, and emphasize the importance of developing specific treatments for improving their mental health and social integration.


Leisure Activities and Their Relationship With MRI Measures of Brain Structure, Functional Connectivity, and Cognition in the UK Biobank Cohort.
Introduction: This study aimed to evaluate whether engagement in leisure activities is linked to measures of brain structure, functional connectivity, and cognition in early old age. Methods: We examined data collected from 7,152 participants of the United Kingdom Biobank (UK Biobank) study. Weekly participation in six leisure activities was assessed twice and a cognitive battery and 3T MRI brain scan were administered at the second visit. Based on responses collected at two time points, individuals were split into one of four trajectory groups: (1) stable low engagement, (2) stable weekly engagement, (3) low to weekly engagement, and (4) weekly to low engagement. Results: Consistent weekly attendance at a sports club or gym was associated with connectivity of the sensorimotor functional network with the lateral visual (β = 0.12, 95%CI = [0.07, 0.18], FDR q = 2.48 × 10-3) and cerebellar (β = 0.12, 95%CI = [0.07, 0.18], FDR q = 1.23 × 10-4) networks. Visiting friends and family across the two timepoints was also associated with larger volumes of the occipital lobe (β = 0.15, 95%CI = [0.08, 0.21], FDR q = 0.03). Additionally, stable and weekly computer use was associated with global cognition (β = 0.62, 95%CI = [0.35, 0.89], FDR q = 1.16 × 10-4). No other associations were significant (FDR q > 0.05). Discussion: This study demonstrates that not all leisure activities contribute to cognitive health equally, nor is there one unifying neural signature across diverse leisure activities.


Hypoxia and senescence: the impact of oxygenation on tumor suppression.
Cellular senescence has emerged as a biological response to two major pathophysiological states of our being: cancer and aging. In the course of the transformation of a normal cell to a cancerous cell, senescence is frequently induced to suppress tumor development. In aged individuals, senescence is found in cells that have exhausted their replication potential. The similarity in these responses suggests that understanding how senescence is mediated can provide insight into both cancer and aging. One environmental factor that is implicated in both of these states is tissue hypoxia, which increases with aging and can inhibit senescence. Hypoxia is particularly important in normal physiology to maintain the stem cell niche; but at the same time, hypoxic inhibition of an essential tumor suppressor response can theoretically contribute to cancer initiation.


Differences between women and men in surgical treatment and case fatality rates for ruptured aortic abdominal aneurysm in England.
Differences between women and men in treatment and outcome after admission with a ruptured abdominal aortic aneurysm (AAA) in England were studied. Routinely collected data in Hospital Episode Statistics, linked to death records, for emergency admissions for ruptured AAA in England were analysed. The percentage of patients who underwent surgical repair was calculated, together with 30-day case fatality rates and age-adjusted odds ratios (ORs), comparing women with men. A total of 2463 women and 7615 men were admitted with a primary diagnosis of ruptured AAA (mean age 79.8 and 74.9 years respectively); 39.6 per cent of women and 66.4 per cent of men underwent surgical repair (OR 0.47 (95 per cent confidence interval 0.42 to 0.52)). Overall, 75.6 per cent of women and 61.7 per cent of men died within 30 days of admission (OR 1.36 (1.22 to 1.52)). The death rate for women and men who had surgery was similar (OR 1.01 (0.88 to 1.17)); when no operation was performed the mortality rate was higher in women, but not significantly so (OR 1.14 (0.91 to 1.42)). Women with a ruptured AAA were less likely to be treated surgically than men, and their overall mortality rate was higher. Lower rates of surgery in women than in men may contribute to the higher mortality in women, but other explanations are possible.


High-dimensional analysis of the murine myeloid cell system.
Advances in cell-fate mapping have revealed the complexity in phenotype, ontogeny and tissue distribution of the mammalian myeloid system. To capture this phenotypic diversity, we developed a 38-antibody panel for mass cytometry and used dimensionality reduction with machine learning-aided cluster analysis to build a composite of murine (mouse) myeloid cells in the steady state across lymphoid and nonlymphoid tissues. In addition to identifying all previously described myeloid populations, higher-order analysis allowed objective delineation of otherwise ambiguous subsets, including monocyte-macrophage intermediates and an array of granulocyte variants. Using mice that cannot sense granulocyte macrophage-colony stimulating factor GM-CSF (Csf2rb(-/-)), which have discrete alterations in myeloid development, we confirmed differences in barrier tissue dendritic cells, lung macrophages and eosinophils. The methodology further identified variations in the monocyte and innate lymphoid cell compartment that were unexpected, which confirmed that this approach is a powerful tool for unambiguous and unbiased characterization of the myeloid system.


Seroprevalence of Toxoplasma gondii infection among patients with non-schizophrenic neurodevelopmental disorders in Alexandria, Egypt.
Toxoplasma gondii is an opportunistic parasite with neurotropic characteristics that can mediate neurodevelopmental disorders, including mental, behavioral and personality aspects of their hosts. Therefore, the seroprevalence of anti-Toxoplasma antibodies has been studied in patients with different neurological disorders from different localities. On searching online databases, however, we could not find published studies on the seroprevalence of anti-Toxoplasma antibodies among patients with neurodevelopmental disorders in Egypt. Therefore, the present preliminary study was conducted to determine the serological profile of T. gondii infection among patients with non-schizophrenic neurodevelopmental disorders in Alexandria, Egypt. Data and blood samples were collected from 188 patients recruited for the study from four mental rehabilitation centers in the period from July 2014 to March 2015. The overall seropositivity rates of IgM and IgG among patients were 16.5% (31/188) and 50.0% (94/188), respectively. Of the studied patients' characteristics, only age was significantly associated with anti-Toxoplasma IgG seropositivity, with older patients being about twice more likely exposed to infection. However, no statistically significant association was found with IgM. In addition, seropositivity of anti-Toxoplasma IgG, but not IgM, was significantly associated with non-schizophrenic neurodevelopmental disorders; however, neither IgG nor IgM showed a significant association with cognitive impairment as indicated by the intelligence quotient scores.


Consensus & evidence-based INOSA Guidelines 2014 (first edition).
Obstructive sleep apnoea (OSA) and obstructive sleep apnoea syndrome (OSAS) are subsets of sleep-disordered breathing. Awareness about OSA and its consequences amongst the general public as well as the majority of primary care physcians across India is poor. This necessiated the development of the INdian initiative on Obstructive sleep apnoea (INOSA) guidelines under the auspices of Department of Health Research, Ministry of Health & Family Welfare, Government of India. OSA is the occurrence of an average five or more episodes of obstructive respiratory events per hour of sleep with either sleep related symptoms or co-morbidities or ≥ 15 such episodes without any sleep related symptoms or co-morbidities. OSAS is defined as OSA associated with daytime symptoms, most often excessive sleepiness. Patients undergoing routine health check-up with snoring, daytime sleepiness, obesity, hypertension, motor vehicular accidents and high risk cases should undergo a comprehensive sleep evaluation. Medical examiners evaluating drivers, air pilots, railway drivers and heavy machinery workers should be educated about OSA and should comprehensively evaluate applicants for OSA. Those suspected to have OSA on comprehensive sleep evaluation should be referred for a sleep study. Supervised overnight polysomnography (PSG) is the "gold standard" for evaluation of OSA. Positive airway pressure (PAP) therapy is the mainstay of treatment of OSA. Oral appliances are indicated for use in patients with mild to moderate OSA who prefer oral appliances to PAP, or who do not respond to PAP or who fail treatment attempts with PAP or behavioural measures. Surgical treatment is recommended in patients who have failed or are intolerant to PAP therapy.


Multiple Kernel Learning for Drug Discovery.
The support vector machine (SVM) methodology has become a popular and well-used component of present chemometric analysis. We assess a relatively recent development of the algorithm, multiple kernel learning (MKL), on published structure-property relationship (SPR) data. The MKL algorithm learns a weighting across multiple kernel-based representations of the data during supervised classifier creation and, thereby, may be used to describe the influence of distinct groups of structural descriptors upon a single structure-property classifier without explicitly omitting any of them. We observe a statistically significant performance improvement over a conventional, single kernel SVM on all three SPR data sets analysed. Furthermore, MKL output is observed to provide useful information regarding the relative influence of five distinct descriptor subsets present in each data set.


Establishing macroecological trait datasets: digitalization, extrapolation, and validation of diet preferences in terrestrial mammals worldwide.
Ecological trait data are essential for understanding the broad-scale distribution of biodiversity and its response to global change. For animals, diet represents a fundamental aspect of species' evolutionary adaptations, ecological and functional roles, and trophic interactions. However, the importance of diet for macroevolutionary and macroecological dynamics remains little explored, partly because of the lack of comprehensive trait datasets. We compiled and evaluated a comprehensive global dataset of diet preferences of mammals ("MammalDIET"). Diet information was digitized from two global and cladewide data sources and errors of data entry by multiple data recorders were assessed. We then developed a hierarchical extrapolation procedure to fill-in diet information for species with missing information. Missing data were extrapolated with information from other taxonomic levels (genus, other species within the same genus, or family) and this extrapolation was subsequently validated both internally (with a jack-knife approach applied to the compiled species-level diet data) and externally (using independent species-level diet information from a comprehensive continentwide data source). Finally, we grouped mammal species into trophic levels and dietary guilds, and their species richness as well as their proportion of total richness were mapped at a global scale for those diet categories with good validation results. The success rate of correctly digitizing data was 94%, indicating that the consistency in data entry among multiple recorders was high. Data sources provided species-level diet information for a total of 2033 species (38% of all 5364 terrestrial mammal species, based on the IUCN taxonomy). For the remaining 3331 species, diet information was mostly extrapolated from genus-level diet information (48% of all terrestrial mammal species), and only rarely from other species within the same genus (6%) or from family level (8%). Internal and external validation showed that: (1) extrapolations were most reliable for primary food items; (2) several diet categories ("Animal", "Mammal", "Invertebrate", "Plant", "Seed", "Fruit", and "Leaf") had high proportions of correctly predicted diet ranks; and (3) the potential of correctly extrapolating specific diet categories varied both within and among clades. Global maps of species richness and proportion showed congruence among trophic levels, but also substantial discrepancies between dietary guilds. MammalDIET provides a comprehensive, unique and freely available dataset on diet preferences for all terrestrial mammals worldwide. It enables broad-scale analyses for specific trophic levels and dietary guilds, and a first assessment of trait conservatism in mammalian diet preferences at a global scale. The digitalization, extrapolation and validation procedures could be transferable to other trait data and taxa.


Extinction of rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway.
Apoptosis is a normal physiological process which eliminates cells that do not receive adequate extracellular signals. One of the pathways signalling apoptosis is controlled by the small GTPases of the Rho family, also involved in cell proliferation, differentiation and motility. Another major apoptosis signalling pathway involves the p53 tumour suppressor which is activated by a variety of stress and mediates growth arrest or apoptosis in normal cells. We show here that upon detachment from the extracellular matrix, fibroblasts undergo rapid apoptosis that can be rescued by constitutive activation of Rac1 and Cdc42Hs GTPases. Conversely, inhibition of Rac1 and Cdc42Hs efficiently triggers apoptosis in adherent cells. Interestingly, apoptosis is not observed in p53-/- cells either cultured in suspension or inhibited for Rac1 and Cdc42Hs activity. Moreover, Rac1 and Cdc42Hs extinction in normal cells activates endogenous p53. Using specific inhibitors of MAPK pathways, we demonstrate that, in our experimental system, p38 signals survival, while ERK activity is required for apoptosis. Our data constitute the first demonstration that Rac1 and Cdc42Hs control pathways that require simultaneous signalling through MAPK ERK and p53 to induce apoptosis.


The impact of predictive cues and visual working memory on dynamic oculomotor selection.
Strategic use of advanced information about search display properties can benefit covert attentional selection. However, little work has investigated this benefit on overt selection. The present study examined how cued information impacts oculomotor selection over time and the role played by individual differences in visual working memory (VWM) capacity in utilizing such cues. Participants searched for a specific orientation target in a saccade localization search task. Prior to each trial, additional information regarding secondary display features (color singleton identity) was either provided by a word cue or not. The cue increased accuracy performance from the earliest saccadic responses. VWM capacity was measured via a change-detection task and results showed that individuals' VWM capacity scores were associated with cue impact, whereby participants with higher capacity derived an increased cue performance benefit. These findings suggest that strategic use of cue information to select and reject salient singletons can develop very early following display presentation and is related to an individual's VWM capacity. This research indicates that stimulus-driven and goal-directed processes are not simply additive in oculomotor selection, but instead exhibit a distinct and dynamic profile of interaction.


Binaural interaction in the auditory brainstem response: a normative study.
Binaural interaction can be investigated using auditory evoked potentials. A binaural interaction component can be derived from the auditory brainstem response (ABR-BIC) and is considered evidence for binaural interaction at the level of the brainstem. Although click ABR-BIC has been investigated thoroughly, data on 500 Hz tone-burst (TB) ABR-BICs are scarce. In this study, characteristics of click and 500 Hz TB ABR-BICs are described. Furthermore, reliability of both click and 500 Hz TB ABR-BIC are investigated. Eighteen normal hearing young adults (eight women, ten men) were included. ABRs were recorded in response to clicks and 500 Hz TBs. ABR-BICs were derived by subtracting the binaural response from the sum of the monaural responses measured in opposite ears. Good inter-rater reliability is obtained for both click and 500 Hz TB ABR-BICs. The most reliable peak in click ABR-BIC occurs at a mean latency of 6.06 ms (SD 0.354 ms). Reliable 500 Hz TB ABR-BIC are obtained with a mean latency of 9.47 ms (SD 0.678 ms). Amplitudes are larger for 500 Hz TB ABR-BIC than for clicks. The most reliable peak in click ABR-BIC occurs at the downslope of wave V. Five hundred Hertz TB ABR-BIC is characterized by a broad positivity occurring at the level of wave V. The ABR-BIC is a useful technique to investigate binaural interaction in certain populations. Examples are bilateral hearing aid users, bilateral cochlear implant users and bimodal listeners. The latter refers to the combination of unilateral cochlear implantation and contralateral residual hearing. The majority of these patients have residual hearing in the low frequencies. The current study suggests that 500 Hz TB ABR-BIC may be a suitable technique to assess binaural interaction in this specific population of cochlear implant users.


Persistence of Ebola virus after the end of widespread transmission in Liberia: an outbreak report.
Outbreak response efforts for the 2014-15 Ebola virus disease epidemic in west Africa brought widespread transmission to an end. However, subsequent clusters of infection have occurred in the region. An Ebola virus disease cluster in Liberia in November, 2015, that was identified after a 15-year-old boy tested positive for Ebola virus infection in Monrovia, raised the possibility of transmission from a persistently infected individual. Case investigations were done to ascertain previous contact with cases of Ebola virus disease or infection with Ebola virus. Molecular investigations on blood samples explored a potential linkage between Ebola virus isolated from cases in this November, 2015, cluster and epidemiologically linked cases from the 2014-15 west African outbreak, according to the national case database. The cluster investigated was the family of the index case (mother, father, three siblings). Ebola virus genomes assembled from two cases in the November, 2015, cluster, and an epidemiologically linked Ebola virus disease case in July, 2014, were phylogenetically related within the LB5 sublineage that circulated in Liberia starting around August, 2014. Partial genomes from two additional individuals, one from each cluster, were also consistent with placement in the LB5 sublineage. Sequencing data indicate infection with a lineage of the virus from a former transmission chain in the country. Based on serology and epidemiological and genomic data, the most plausible scenario is that a female case in the November, 2015, cluster survived Ebola virus disease in 2014, had viral persistence or recurrent disease, and transmitted the virus to three family members a year later. Investigation of the source of infection for the November, 2015, cluster provides evidence of Ebola virus persistence and highlights the risk for outbreaks after interruption of active transmission. These findings underscore the need for focused prevention efforts among survivors and sustained capacity to rapidly detect and respond to new Ebola virus disease cases to prevent recurrence of a widespread outbreak. US Centers for Disease Control and Prevention, Defense Threat Reduction Agency, and WHO.


Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor.
Basic and acidic fibroblast growth factors (FGF's) are potent mitogens for capillary endothelial cells in vitro, stimulate angiogenesis in vivo, and may participate in tissue repair. An oligonucleotide probe for bovine basic FGF was designed from the nucleotide sequence of the amino-terminal exon of bovine acidic FGF, taking into account the 55 percent amino acid sequence homology between the two factors. With this oligonucleotide probe, a full length complementary DNA for basic FGF was isolated from bovine pituitary. Basic FGF in bovine hypothalamus was shown to be encoded by a single 5.0-kilobase messenger RNA; in a human hepatoma cell line, both 4.6- and 2.2-kilobase basic FGF messenger RNA's were present. Both growth factors seem to be synthesized with short amino-terminal extensions that are not found on the isolated forms for which the amino acid sequences have been determined. Neither basic nor acidic FGF has a classic signal peptide.


Dual function of the hydration layer around an antifreeze protein revealed by atomistic molecular dynamics simulations.
Atomistic molecular dynamics simulations are used to investigate the mechanism by which the antifreeze protein from the spruce budworm, Choristoneura fumiferana, binds to ice. Comparison of structural and dynamic properties of the water around the three faces of the triangular prism-shaped protein in aqueous solution reveals that at low temperature the water structure is ordered and the dynamics slowed down around the ice-binding face of the protein, with a disordering effect observed around the other two faces. These results suggest a dual role for the solvation water around the protein. The preconfigured solvation shell around the ice-binding face is involved in the initial recognition and binding of the antifreeze protein to ice by lowering the barrier for binding and consolidation of the protein:ice interaction surface. Thus, the antifreeze protein can bind to the molecularly rough ice surface by becoming actively involved in the formation of its own binding site. Also, the disruption of water structure around the rest of the protein helps prevent the adsorbed protein becoming covered by further ice growth.


The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 convention.
In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.


Competency in electrocardiogram interpretation among internal medicine and emergency medicine residents.
Accurate interpretation of the electrocardiogram is critical, yet there are no evidence-based guidelines for assessing competency. Our study evaluated the ability of internal medicine residents and emergency medicine residents to interpret a variety of electrocardiograms. The 120 participants included 87 internal medicine residents and 33 emergency medicine residents at two hospitals. Participants reported their sex, training level, adequacy of training, career interest in cardiology, and estimated electrocardiogram proficiency. They then took a test containing 12 electrocardiograms and recorded their diagnosis and certainty. Two cardiologists independently established the correct diagnoses. Two blinded, independent graders scored each electrocardiogram (0 = incorrect, 1 = partially correct, 2 = correct). The median proficiency was 6 out of 10, total electrocardiogram score was 15 of 24, and certainty was 33 of 48. There was no significant difference in overall competency between emergency medicine and internal medicine residents (14.0 vs 15.0, P = 0.239). Internal medicine residents interested in a cardiology career scored higher than those not interested in a cardiology career (17.3 vs. 14.1, P = 0.003). When analyzing the most critical diagnoses, we found that the mean score for ventricular tachycardia was 1.6 of 2.0, for myocardial infarction was 1.3 of 2.0, and for complete heart block was 0.8 of 2.0. Over half of the participants felt their electrocardiogram training was inadequate. Despite improvement in interpretation with clinical experience, overall performance was low. Research is needed to find optimal methods to improve electrocardiogram competency.


Effect of orally administered potentized capsaicin and dihydrocapsaicin in humans: a homeopathic pathogenetic trial.
A homeopathic pathogenetic trial is a procedure to examine the disease-producing effect of any substance on humans. Capsaicin and dihydrocapsaicin are known as pain-producing agents. According to the homeopathic law of similars, any substance having the capacity to produce certain symptoms should also be able to treat them in return, when administered in small (potentized) dose. In a doubleblind, randomized placebo-controlled homeopathic pathogenetic trial with 22 volunteers, 15 received a combination of capsaicin and dihydrocapsaicin as a single remedy in 30c potency, while 7 received placebo. The volunteers' symptoms during 5 weeks were carefully noted as per protocol. The participants signed an informed consent, the study was approved by the ethics committee, and laboratory investigations were documented and safety measures adopted. A preparation of orally administered ultra-high diluted capsaicin and dihydrocapsaicin unveiled qualitatively and quantitatively distinct symptoms, comparable with effects of the crude substance. Compared to placebo, the homeopathic preparation produced significant symptoms in healthy human volunteers. These findings can subsequently be used therapeutically. The administration of potentized capsaicin and dihydrocapsaicin combination produced symptoms of pain (and others) in healthy volunteers. This preparation can be applied therapeutically following a basic homeopathic principle. Further research to confirm the assumptions is warranted.


Correlation Between Symptom Severity and Health-Related Life Quality of a Population With Gastroesophageal Reflux Disease.
Gastroesophageal reflux disease (GERD) is a chronic disease with a negative impact on the quality of life. The aim of this study was to investigate the reflux symptoms and the health-related quality of life in a population with GERD. Data from patients with GERD, according to the Montreal definition, were collected between January and December 2009. The enrolled patients were classified by different reflux symptoms according to the modified Chinese GERDQ. The general demographic data, the modified GERD impact scores and the SF-36 questionnaire scores of these groups of patients were analyzed. A total of 173 patients were enrolled, and the general data, endoscopic findings and lifestyle habits of the participants with different severity of heartburn or regurgitation were all similar. The patients with moderate severity of reflux symptoms had significant lower SF-36 scores than those with mild severity. The cases with advanced heartburn severity owned the lowest scores among all cases. The impact on the daily activity of each affected individual had a positive association with the stronger severity of reflux symptom. The life quality of a population with GERD achieved the meaningful declination in participants with the moderate severity of heartburn or regurgitation. The severity of the reflux symptoms had a greater impact on the normal daily activity of the patients with GERD. The cases with advanced severity of heartburn had the worst well-being.


The opportunistic effect of exosomes on Non-Hodgkin Lymphoma microenvironment modulation.
There has been a shift in the paradigm of Non-Hodgkin lymphomas, changing from the classical genetic aberration-based model to a more complex and dynamic model involving tumor microenvironment interactions. In this instance, exosomes have emerged as important mediators in intercellular communication by providing survival and proliferation signals, licensing immune evasion and acquisition of drug resistance. The capability to transfer molecular cargo made exosomes a focus of research to understand cancer pathogenesis and its progression pathways. Several studies identified exosomes transporting tumor-released components in peripheral blood and focused on understanding their clinical relevance in the diagnosis, prognostic and in monitoring cancer progression. Moreover, due to their biophysical properties and physiological function, exosomes have drawn attention as potential therapeutic target and drug delivery vehicles. This review will discuss the function of exosomes in Non-Hodgkin lymphomagenesis, highlight their potential as diagnosis and prognosis biomarkers, and as new therapeutic opportunities in lymphoma management.


Disaster modeling: medication resources required for disaster team response.
Responses to disasters involve many factors beyond personnel, such as medical and non-medical equipment and supplies. When disaster teams respond, they must do so with sufficient amounts of medicine and supplies to manage all of the patients expected for several days before re-supply. In order for this process to be efficient and expedient, accurate and advanced planning for supplies needed by disaster workers is necessary. These supplies must provide for general medical care and for hazard-specific problems. To develop a model that provides the framework for determining supply requirements for the National Disaster Medical System, Disaster Medical Assistance Teams, or other responding disaster teams in a civilian environment. A community hospital was modeled to determine patient characteristics when presenting to an emergency department (ED), including patient demographics and chief complaint, medications administered during the ED visit and prescribed at discharge, and laboratory tests ordered to assess disaster team supply requirements. Data were downloaded from a patient tracking software package and abstracted from various hospital data information systems. Data from the community hospital were compared with data published from two hurricane disasters by members of the National Disaster Medical System. To the extent possible, the model predicted the proportion of patient complaints and, therefore, the medicine and supplies needed for the management of these patients. This model offers a first step in preparing disaster medical teams for deployment.


Cardiac Monitoring During Adjuvant Trastuzumab-Based Chemotherapy Among Older Patients With Breast Cancer.
Patients treated with adjuvant trastuzumab require adequate cardiac monitoring. We describe the patterns of cardiac monitoring and evaluate factors associated with adequate monitoring in a large population-based study of older patients with breast cancer. Patients age 66 years or older with full Medicare coverage, diagnosed with stage I to III breast cancer between 2005 and 2009, and treated with adjuvant trastuzumab-based chemotherapy were identified in the SEER-Medicare and the Texas Cancer Registry-Medicare databases. The adequacy of cardiac monitoring was determined. Chemotherapy, trastuzumab use, cardiac monitoring, and comorbidities were identified by using International Classification of Diseases, 9th revision and Healthcare Common Procedure Coding System codes. Prescribing physician characteristics were also evaluated. Analyses included descriptive statistics and multilevel logistic regression models. In all, 2,203 patients were identified; median age was 72 years. Adequate monitoring was identified in only 36.0% of the patients (n = 793). In the multivariable model, factors associated with optimal cardiac monitoring included a more recent year of diagnosis (hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54), anthracycline use (HR, 1.39; 95% CI, 1.14 to 1.71), female prescribing physician (HR, 1.37; 95% CI, 1.10 to 1.70), and physician graduating after 1990 (HR, 1.66; 95% CI, 1.29 to 2.12). The presence of cardiac comorbidities was not a determinant for cardiac monitoring. Of the variance in the adequacy of cardiac monitoring, 15.3% was attributable to physician factors and 5.2% to measured patient factors. A large proportion of patients had suboptimal cardiac monitoring. Physician characteristics had more influence than measured patient-level factors in the adequacy of cardiac monitoring. Because trastuzumab-related cardiotoxicity is reversible, efforts to improve the adequacy of cardiac monitoring are needed, particularly in vulnerable populations.


Profile of the genes expressed in the human peripheral retina, macula, and retinal pigment epithelium determined through serial analysis of gene expression (SAGE).
We used the serial analysis of gene expression (SAGE) technique to catalogue and measure the relative levels of expression of the genes expressed in the human peripheral retina, macula, and retinal pigment epithelium (RPE) from one or both of two humans, aged 88 and 44 years. The cone photoreceptor contribution to all transcription in the retina was found to be similar in the macula versus the retinal periphery, whereas the rod contribution was greater in the periphery versus the macula. Genes encoding structural proteins for axons were found to be expressed at higher levels in the macula versus the retinal periphery, probably reflecting the large proportion of ganglion cells in the central retina. In comparison with the younger eye, the peripheral retina of the older eye had a substantially higher proportion of mRNAs from genes encoding proteins involved in iron metabolism or protection against oxidative damage and a substantially lower proportion of mRNAs from genes encoding proteins involved in rod phototransduction. These differences may reflect the difference in age between the two donors or merely interindividual variation. The RPE library had numerous previously unencountered tags, suggesting that this cell type has a large, idiosyncratic repertoire of expressed genes. Comparison of these libraries with 100 reported nonocular SAGE libraries revealed 89 retina-specific or enriched genes expressed at substantial levels, of which 14 are known to cause a retinal disease and 53 are RPE-specific genes. We expect that these libraries will serve as a resource for understanding the relative expression levels of genes in the retina and the RPE and for identifying additional disease genes.


Fat-soluble vitamins in advanced CKD/ESKD: a review.
Patients requiring dialysis often experience a significant decline in their nutritional status through a combination of chronic disease, reduced appetite, and dietary restrictions, which places them at risk for vitamin deficiencies. The concept of vitamin deficiency has evolved from obvious deficiency states to the subtle effects that suboptimal intake may have on chronic disease prevalence or progression. The purpose of this study was to summarize the current state of knowledge regarding the status of the fat-soluble vitamins (A, D, E, and K) in patients with chronic kidney disease receiving hemodialysis.


The pathogenetic influence of smoking on SARS-CoV-2 infection: Integrative transcriptome and regulomics analysis of lung epithelial cells.
Corona virus disease (COVID-19) has been emerged as pandemic infectious disease. The recent epidemiological data suggest that the smokers are more vulnerable to infection with COVID-19; however, the influence of smoking (SMK) on the COVID-19 infected patients and the mortality is not known yet. In this study, we aimed to discern the influence of SMK on COVID-19 infected patients utilizing the transcriptomics data of COVID-19 infected lung epithelial cells and transcriptomics data smoking matched with controls from lung epithelial cells. The bioinformatics based analysis revealed the molecular insights into the level of transcriptional changes and pathways which are important to identify the impact of smoking on COVID-19 infection and prevalence. We compared differentially expressed genes (DEGs) between COVID-19 and SMK and 59 DEGs were identified as consistently dysregulated at transcriptomics levels. The correlation network analyses were constructed for these common genes using WGCNA R package to see the relationship among these genes. Integration of DEGs with network analysis (protein-protein interaction) showed the presence of 9 hub proteins as key so called "candidate hub proteins" overlapped between COVID-19 patients and SMK. The Gene Ontology and pathways analysis demonstrated the enrichment of inflammatory pathway such as IL-17 signaling pathway, Interleukin-6 signaling, TNF signaling pathway and MAPK1/MAPK3 signaling pathways that might be the therapeutic targets in COVID-19 for smoking persons. The identified genes, pathways, hubs genes, and their regulators might be considered for establishment of key genes and drug targets for SMK and COVID-19.


Flow patterns in externally stented saphenous vein grafts and development of intimal hyperplasia.
Low and oscillatory wall shear stress promotes endothelial dysfunction and vascular disease. The aim of the study was to investigate the impact of an external stent on hemodynamic flow parameters in saphenous vein grafts (SVGs) and their correlation with the development of intimal hyperplasia. We performed post hoc computational fluid dynamics analysis of the randomized Venous External Support Trial, in which angiography and intravascular ultrasound data were available for 29 patients, 1 year after coronary artery bypass grafting. Each patient received 1 external stent, to either the right or left coronary territories; ≥ 1 patients with nonstented SVGs served as control(s). Diffuse flow patterns were assessed using mean values of various hemodynamic parameters, including time-averaged wall shear stress and oscillatory shear index (OSI). Focal flow disturbances were characterized using percentile analysis of each parameter. Angiography and intravascular ultrasound data were available for 53 and 43 SVGs, respectively. The stented versus nonstented SVG failure rates were significantly lower in the left territory (17.6% vs 27.5%; P = .02), and significantly higher in the right territory (46.2% vs 13.4%; P = .01). In both diffuse and focal flow-pattern analyses, OSI was significantly lower in the stented versus nonstented SVG group (P = .009 and P < .003, respectively), whereas no significant differences were observed in time-averaged wall shear stress values. High OSI values were correlated with the development of intimal hyperplasia (P = .01). External stenting affects SVG's hemodynamics 1 year after coronary artery bypass grafting and may mitigate the progression of intimal hyperplasia by reducing oscillatory shear stress.


The influence of anatomy app use on chiropractic students' learning outcomes: a randomised controlled trial.
Anatomy apps supplement traditional learning; however, it is unknown if their use can improve students' outcome. The present study examined whether the use of anatomy apps improved student performance on a neuroanatomy assessment. Second-year anatomy students, enrolled in a Bachelor of Science with Chiropractic Major program, were randomly allocated to experimental and control groups in July 2015. Students completed the Self-Directed Learning Readiness Scale (SDLRS). The experimental group had access to iPads with four anatomy apps for three weekly classes (1.5 h each). One week after the last class, students were assessed by an online 30-question neuroanatomy test. Linear regression was used to examine the association between test scores and app use, gender, previous anatomy unit score and SDLRS scores. Students' views on apps were collected by focus group discussion immediately after the test. Completed questionnaires were obtained from n = 25 control and n = 25 experimental students. There was no association between app use and neuroanatomy assessment score (B = 1.75, 95 % CI: -0.340-3.840, p = 0.099). Only previous anatomy unit score (B = 0.348, 95 % CI: 0.214-0.483, p < 0.001) affected neuroanatomy assessment scores. Students favored apps with clinical images and features including identification pins, sliding bars and rotatable 3D images. App use did not enhance learning outcomes in a second-year anatomy unit.


Bacterial cell division protein FtsZ is stable against degradation by AAA family protease FtsH in Escherichia coli cells.
We have found that FtsH protease of Escherichia coli could degrade E. coli cell division protein FtsZ in an ATP- and Zn(2+)-dependent manner in vitro and that the degradation did not show specificity for the N-terminus or C-terminus of FtsZ, like in the case of degradation of its conventional substrate sigma(32) protein. In continuation of these observations, in the present study, we examined whether FtsH would affect the stability and turnover of FtsZ in vivo. We found that FtsZ levels were not elevated in E. coli AR754 (ftsH1 ts) cells at nonpermissive temperature as compared to the levels in an FtsH-active isogenic AR753 strain. Neither did FtsH degrade ectopically expressed FtsZ in AR754 strain nor did ectopic expression of FtsH reduced FtsZ levels in E. coli AR5090 ftsH null strain (ftsH::kan, sfhC21). Pulse chase experiments in AR754 and AR5090 strains showed that there were no compensatory changes in FtsZ turnover, in case FtsZ degradation had occurred. Even under cell division arrested conditions, wherein FtsZ was not required, FtsH protease did not degrade unutilized FtsZ. These experiments demonstrate that either FtsH protease may not have a role in regulating the levels of FtsZ in vivo under the conditions tested or that some cellular component(s) might be stabilising FtsZ against FtsH protease.


A retrospective review of acupuncture use for the treatment of pain in sickle cell disease patients: descriptive analysis from a single institution.
This retrospective study describes the use of acupuncture for adult sickle cell patients in a single institution. We identified 47 sickle cell disease patients referred for acupuncture at the National Institutes of Health between January 2005 and September 2011. All patients were enrolled in a Study of the Natural History of sickle cell disease and signed consent. We reviewed patient demographics, location of acupuncture treatment sessions (inpatient vs. outpatient), number of sessions received, sites of pain, patient pain reporting, and the use of other complementary therapies. Of the 47 patients (60% women, median age 36 y) referred for acupuncture, 42 had homozygous SS disease (89%) and 5 had SC disease (11%). Over half of the patients (51%) reported >3 sites of pain. Only 24 patients (51%) underwent acupuncture treatment. Of those who elected not to receive acupuncture, a majority (87%) accepted some other forms of complementary therapies. Nine patients underwent only inpatient acupuncture for acute vaso-occlusive crisis. Eleven patients received only outpatient acupuncture treatment for chronic pain, and 4 patients received both inpatient and outpatient treatments. For the patients who received inpatient acupuncture treatment for acute vaso-occlusive crisis, there was a significant reduction of reported pain score immediately after acupuncture treatment with an average pain reduction of 2.1 points on the numeric pain scale (P<0.0001). Excluding the 2 outliers, 75% of patients (n=13) in the outpatient setting described their pain as improved compared with prior session. To our knowledge, this is the largest retrospective review of acupuncture use in the sickle cell population. This analysis describes the use of acupuncture and raises the possibility of its use as an adjuvant for pain management in this population. Future clinical trials are needed to evaluate acupuncture's efficacy and effectiveness for pain management in different treatment settings and for various types of pain etiologies among the sickle cell population.


Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study.
Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML). This analysis included 272 5-year AML survivors who participated in the Childhood Cancer Survivor Study (CCSS). All patients were diagnosed at age < or =21 years between the years 1970 and 1986, and none underwent stem cell transplantation. Rates of survival, relapse, and late outcomes were analyzed. The average follow-up was 20.5 years (range, 5-33 years). The overall survival rate was 97% at 10 years (95% confidence interval [95%CI], 94%-98%) and 94% at 20 years (95% CI, 90%-96%). Six survivors reported 8 recurrences. The cumulative incidence of recurrent AML was 6.6% at 10 years (95% CI, 3.7%-9.6%) and 8.6% at 20 years (95% CI, 5.1%-12.1%). Ten subsequent malignant neoplasms (SMN) were reported, including 4 with a history of radiation therapy, for a 20-year cumulative incidence of 1.7% (95% CI, 0.02%-3.4%). Six cardiac events were reported, for a 20-year cumulative incidence 4.7% (95% CI, 2.1%-7.3%). Half of the survivors reported a chronic medical condition and, compared with siblings, were at increased risk for severe or life-threatening chronic medical conditions (16% vs 5.8%; P < .001). Among those aged > or =25 years, the age-adjusted marriage rates were similar among survivors and the general United States population (57% for both) and lower compared with siblings (67%; P < .01). Survivors' college graduation rates were lower compared with siblings but higher than the general population (40% vs 52% vs 34%, respectively; P < .01). Employment rates were similar between survivors, siblings, and the general population (93%, 97.6%, and 95.8%, respectively). Long-term survival from childhood AML > or =5-years after diagnosis was favorable. Late-occurring medical events remained a concern with socioeconomic achievement lower than expected within the individual family unit, although it was not different from the general United States population.


Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection.
During acute and early HIV-1 infection (AEI), up to 60% of CD4(+) T cells in the lamina propria of the lower gastrointestinal (GI) tract are lost as early as 2-4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART) is well established. However, the extent of immune reconstitution in the GI tract is unknown. Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1-7 y of uninterrupted therapy). Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%-60% depletion of lamina propria lymphocytes despite 1-7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO+ HLA-DR+, returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4+ T cell depletion despite therapy. Rare HIV-1 RNA-expressing cells were detected by in situ hybridization. Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically silent over the short term, the long-term consequences of the persistence of this lesion may emerge as the HIV-1-infected population survives longer owing to the benefits of HAART.


Is it ACT yet? Real-world examples of evaluating the degree of implementation for assertive community treatment.
Despite growing interest in assessment of program implementation, little is known about the best way to evaluate whether a particular program has implemented the intended service to a level that is minimally acceptable to a funding source, such as a state mental health authority. Such is the case for assertive community treatment (ACT), an evidence-based practice being widely disseminated. Using an exploratory, actuarial approach to defining program standards, this study applies different statistical criteria for determining whether or not a program meets ACT standards using the 28-item Dartmouth Assertive Community Treatment Scale. The sample consists of 51 ACT programs, 25 intensive case management programs, and 11 brokered case management programs which were compared to identify levels of fidelity that discriminated between programs, but were still attainable by the majority of ACT programs. A grading system based on mean total score for a reduced set of 21 items appeared to be most attainable, but still discriminated ACT programs from other forms of case management. Implications for setting and evaluating ACT program standards are discussed.


A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment.
Synthetic cannabinoids (SCs) such as "Spice", "K2", etc. are widely available via the internet despite increasing legal restrictions. Currently, the prevalence of use is typically low in the general community (<1%) although it is higher among students and some niche groups subject to drug testing. Early evidence suggests that adverse outcomes associated with the use of SCs may be more prevalent and severe than those arising from cannabis consumption. To identify systematically the scientific reports of adverse events associated with the consumption of SCs in the medical literature and poison centre data. We searched online databases (Medline, PsycInfo, Embase, Google Scholar and Pubmed) and manually searched reference lists up to December 2014. To be eligible for inclusion, data had to be from hospital, emergency department, drug rehabilitation services or poison centre records of adverse events involving SCs and included both self-reported and/or analytically confirmed consumption. From 256 reports, we identified 106 eligible studies including 37 conference abstracts on about 4000 cases involving at least 26 deaths. Major complications include cardiovascular events (myocardial infarction, ischemic stroke and emboli), acute kidney injury (AKI), generalized tonic-clonic seizures, psychiatric presentations (including first episode psychosis, paranoia, self-harm/suicide ideation) and hyperemesis. However, most presentations were not serious, typically involved young males with tachycardia (≈ 37-77%), agitation (≈ 16-41%) and nausea (≈ 13-94%) requiring only symptomatic care with a length of stay of less than 8 hours. SCs most frequently result in tachycardia, agitation and nausea. These symptoms typically resolve with symptomatic care, including intravenous fluids, benzodiazepines and anti-emetics, and may not require inpatient care. Severe adverse events (stroke, seizure, myocardial infarction, rhabdomyolysis, AKI, psychosis and hyperemesis) and associated deaths manifest less commonly. Precise estimates of their incidence are difficult to calculate due to the lack of widely available, rapid laboratory confirmation, the variety of SC compounds and the unknown number of exposed individuals. Long-term consequences of SCs use are currently unknown.


Water used to moisten vegetables is a source of Escherichia coli and protozoan parasite contamination at markets in Hanoi, Vietnam.
The study was done to assess the level of fecal (Escherichia coli) and protozoan parasite (Cryptosporidium spp. and Giardia spp.) contamination in water used by traders to moisten vegetables at markets in Hanoi, Vietnam. A total of 200 splashing water samples from markets located within eight districts were analyzed for E. coli and Cryptosporidium spp. and Giardia spp. (oo)cysts. Giardia cysts were found in 17 splashing water samples and Cryptosporidium oocysts in nine samples, with median values of 20 cysts ml(-1) and 10 oocysts ml(-1), respectively. E. coli was found with a median concentration of 636 cfu ml(-1) and its occurrence was negatively correlated with the numbers of protozoan parasites. The splashing water was kept in buckets that were rarely cleaned and often used for handwashing. The finding of these pathogens in splashing water is likely to represent real food safety hazards.


Competitive selection from single domain antibody libraries allows isolation of high-affinity antihapten antibodies that are not favored in the llama immune response.
Single-domain antibodies (sdAbs) found in camelids lack a light chain, and their antigen-binding site sits completely in the heavy-chain variable domain (VHH). Their simplicity, thermostability, and ease in expression have made VHHs highly attractive. Although this has been successfully exploited for macromolecular antigens, their application to the detection of small molecules is still limited to a very few reports, mostly describing low-affinity VHHs. Using triclocarban (TCC) as a model hapten, we found that conventional antibodies, IgG1 fraction, reacted with free TCC with a higher relative affinity (IC(50) 51.0 ng/mL) than did the sdAbs (IgG2 and IgG3, 497 and 370 ng/mL, respectively). A VHH library was prepared, and by elution of phage with limiting concentrations of TCC and competitive selection of binders, we were able to isolate high-affinity clones, K(D) 0.98-1.37 nM (SPR), which allowed development of a competitive assay for TCC with an IC(50) = 3.5 ng/mL (11 nM). This represents a 100-fold improvement with regard to the performance of the sdAb serum fraction, and it is 100-fold better than the IC(50) attained with other antihapten VHHs reported thus far. Despite the modest overall antihapten sdAbs response in llamas, a small subpopulation of high-affinity VHHs is generated that can be isolated by careful design of the selection process.


Extended surgical staging for potentially resectable malignant pleural mesothelioma.
Extrapleural pneumonectomy for malignant pleural mesothelioma (MPM) is a high-risk procedure, and patients require careful preoperative staging to exclude advanced disease. Computed tomography, magnetic resonance imaging, and positron emission tomography are useful staging modalities, but do not reliably identify contralateral mediastinal involvement or transdiaphragmatic invasion. We evaluated the role of extended surgical staging procedures, which generally includes a combination of laparoscopy, peritoneal lavage, and mediastinoscopy, to more precisely stage patients with MPM. One hundred eighteen patients with MPM, deemed clinically and radiologically resectable, underwent extended surgical staging. Mediastinoscopy was performed in 111 patients, laparoscopy in 109 patients, and peritoneal lavage in 78 patients. Ten (9.2%) patients had gross evidence of transdiaphragmatic or peritoneal involvement. Peritoneal lavage was positive for metastatic MPM in 2 (2.6%) patients, neither of whom had obvious transdiaphragmatic invasion. Ipsilateral mediastinal nodes contained metastatic tumor in 10 of 62 (16.1%) patients. Contralateral nodes were positive in 4 of 111 (3.6%) patients. Of the patients who underwent biopsy of both ipsilateral and contralateral mediastinal nodes, and who had complete pathologic staging after extrapleural pneumonectomy (n = 46), 14 (30.4%) had N2-positive nodes. Only 5 of these patients were correctly identified by mediastinoscopy (sensitivity 36%, accuracy 80%). Extended surgical staging identified 16 (13.6%) patients who had contralateral nodal involvement, transdiaphragmatic invasion, or positive peritoneal cytology. Extended surgical staging defines an important subset of patients with unresectable MPM not identified by imaging. Because of the potential morbidity associated with extrapleural pneumonectomy, we advocate that extended surgical staging be performed in all patients with MPM before resection.


Changes in incidence, survival and mortality of prostate cancer in Europe and the United States in the PSA era: additional diagnoses and avoided deaths.
We describe changes in prostate cancer incidence, survival and mortality and the resulting impact in additional diagnoses and avoided deaths in European areas and the United States. Using data from 12 European cancer registries and the Surveillance, Epidemiology and End Results program, we describe changes in prostate cancer epidemiology between the beginning of the PSA era (USA: 1985-1989, Europe: 1990-1994) and 2002-2006 among patients aged 40-64, 65-74, and 75+. Additionally, we examine changes in yearly numbers of diagnoses and deaths and variation in male life expectancy. Incidence and survival, particularly among patients aged <75, increased dramatically, yet both remain (with few exceptions in incidence) lower in Europe than in the United States. Mortality reductions, ongoing since the mid/late 1990 s, were more consistent in the United States, had a distressingly small absolute impact among patients aged 40-64 and the largest absolute impact among those aged 75+. Overall ratios of additional diagnoses/avoided deaths varied between 3.6 and 27.6, suggesting large differences in the actual impact of prostate cancer incidence and mortality changes. Ten years of remaining life expectancy was reached between 68 and 76 years. Policies reflecting variation in population life expectancy, testing preferences, decision aids and guidelines for surveillance-based management are urgently needed.


Changes in testicular development, ultrasonographic and histological appearance of the testis in buck kids immunized against LHRH using recombinant LHRH fusion protein.
This study was designed to evaluate the effectiveness of recombinant Ovalbumin-LHRL (OL) immunization on changes in testicular size, histological appearance and testosterone production in buck kids. Thirty native buck kids at 18 weeks of age were divided into three groups, control (n = 10), immunization (n = 10) and castration (n = 10) groups. Immunized animals received OL protein generated by recombinant DNA technology. Ultrasonographic and histological examinations of the testes were performed. Animals were slaughtered at 44 weeks of age. Semen and epididymides were evaluated for the presence of sperm cells. Immunized animals generated anti-LHRH antibodies. Testosterone production, testicular and accessory glands development and sperm production were suppressed in the immunized animals (p < 0.01). Semineferous tubule diameters decreased (p < 0.01), basal membrane of the tubule was thickened and hyalinized in immunized kids. Immunization affected ultrasonographic appearance of the testes drastically. While testes of control animals gained their normal ultrasonographic appearance as the age increased, immunized animals had uniform hypoechogenic testicular structure as observed at 18 weeks of age until slaughter. Simultaneous histological and ultrasonographic evaluations indicated that the changes in testicular histology could partly be monitored via ultrasonographic imaging; nevertheless, it is difficult to claim that ultrasonographic image reflects the exact changes in such instances. In conclusion, these results indicate that recombinant OL fusion protein is effective in immunocastration in buck kids and has a potential to be used as an alternative to physical castration. Further researches should be conducted to help assessing reproductive status of testes from ultrasound images.


Transcriptional regulation of the fad regulon genes of Escherichia coli by ArcA.
ArcA is a global transcription factor required for optimal growth of Escherichia coli during anaerobic growth. In this study, the role of ArcA on the transcriptional regulatory subnetwork of the fad regulon was investigated. Gene expression profiles of deletion mutants (Delta arcA, Delta fadR and Delta arcA/Delta fadR) indicated that (i) ArcA is a major transcription factor for the transcriptional regulation of fatty acid metabolism in the absence of oxygen, and (ii) ArcA and FadR cooperatively regulate the fad regulon under anaerobic conditions. To determine the direct interaction between ArcA and the promoters of the fad regulon genes, chromatin immunoprecipitation (ChIP) analysis was performed. ChIP analysis suggested that ArcA directly binds to the promoter regions of the fad regulon genes in vivo. An ArcA-binding motif was identified from known binding sequences and predicted putative binding sites in the promoter regions of the fad regulon genes. These results indicate that ArcA directly represses the expression of fad regulon genes during anaerobic growth.


The perils of the imperfect expectation of the perfect baby.
Advances in modern medicine invite the assumption that medicine can control human biology. There is a perilous logic that leads from expectations of medicine's control over reproductive biology to the expectation of having a perfect baby. This article proposes that obstetricians should take a preventive ethics approach to the care of pregnant women with expectations for a perfect baby. We use Nathaniel Hawthorne's classic short story, "The Birthmark," to illustrate the perils of the logic of control and perfection through science and then identify possible contemporary sources of the expectation of the perfect baby. We propose that the informed consent process should be used as a preventive ethics tool throughout the course of pregnancy to educate pregnant women about the inherent errors of human reproduction, the highly variable clinical outcomes of these errors, the limited capacity of medicine to detect these errors, and the even more limited capacity to correct them.