Combined strategies for effective cancer immunotherapy with a novel anti-CD47 monoclonal antibody.
CD47 is a widely expressed cell-surface protein that regulates phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, signal regulatory protein (SIRP)-α, which in turn inhibits phagocytosis. Several targeted CD47 therapeutic antibodies have been investigated clinically; however, how to improve its therapeutic efficacy remains unclear. Herein, we developed a CD47 blocking antibody, named IBI188, that could specifically block the CD47-SIRP-α axis, which transduces the "don't eat me" signal to macrophages. In vitro phagocytosis assays demonstrated the pro-phagocytosis ability of IBI188. Furthermore, several in vivo models were chosen to evaluate the anti-tumor efficacy of IBI188. IBI188 treatment upregulated cell movement- and inflammation-related genes in macrophages. Synergism was observed when combined with an anti-CD20 therapeutic antibody, whose function depends on antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). CD47 expression was evaluated following azacytidine (AZA) treatment, a standard-of-care for patients with multiple myeloma; enhanced anti-tumor efficacy was observed in the combination group in AML xenograft models. Notably, IBI188 treatment increased vascular endothelial growth factor-A (VEGF-A) levels in a solid tumor model, and combined treatment with an anti-VEGF-A antibody and IBI188 resulted in an enhanced anti-tumor effect. These data indicate that IBI188 is a therapeutic anti-CD47 antibody with anti-tumor potency, which can be enhanced when used in combination with standard-of-care drugs for cancer treatment.


Resistance of SARS-CoV-2 variants to neutralization by convalescent plasma from early COVID-19 outbreak in Singapore.
The rapid spreading of SARS-CoV-2 variants B.1.1.7 originated from the United Kingdom and B.1.351 from South Africa has contributed to the second wave of COVID-19 cases in the respective countries and also around the world. In this study, we employed advanced biochemical and virological methodologies to evaluate the impact of Spike mutations of these strains on the degree of protection afforded by humoral immune responses following natural infection of the ancestral SARS-CoV-2 strain during the early stages of the outbreak. We found that antibody-mediated neutralization activity was partially reduced for B.1.1.7 variant and significantly attenuated for the B.1.351 strain. We also found that mutations outside the receptor-binding domain (RBD) can strongly influence antibody binding and neutralization, cautioning the use of solely RBD mutations in evaluating vaccine efficacy. These findings highlight an urgent need to develop new SARS-CoV-2 vaccines that are not based exclusively on the ancestral SARS-CoV-2 Spike gene sequence.


Purification, crystallization, and preliminary X-ray diffraction analysis of rat kidney annexin V, a calcium-dependent phospholipid-binding protein.
We have purified annexin V, a monomeric 35-kDa protein, from rat kidney using calcium-dependent phospholipid chromatography. The identity of annexin V was confirmed by immunoblot analysis using monospecific anti-annexin V antibody. Large single crystals of annexin V in the presence of calcium have been grown from ammonium sulfate under a variety of conditions, with an optimum pH range of 7.5-8.0. The crystals diffract to at least 2.2 A Bragg spacing and are stable to x-rays. Preliminary crystallographic analysis reveals the space group to be R3, with hexagonal cell dimensions of a = b = 156.8 A and c = 36.9 A, and there is one molecule/asymmetric unit.


Integrating the digital twin concept into the evaluation of reconfigurable manufacturing systems (RMS): literature review and research trend.
With the rapid advent of new information technologies (Big Data analytics, cyber-physical systems, such as IoT, cloud computing and artificial intelligence), digital twins are being used more and more in smart manufacturing. Despite the fact that their use in industry has attracted the attention of many practitioners and researchers, there is still a need for an integrated and comprehensive digital twin framework for reconfigurable manufacturing systems. To close this research gap, we present evidence from a systematic literature review, including 76 papers from high-quality journals. This paper presents the current research trends on evaluation and the digital twin in reconfigurable manufacturing systems, highlighting application areas and key methodologies and tools. The originality of this paper lies in its proposal of interesting avenues for future research on the integration of the digital twin in the evaluation of RMS. The benefits of digital twins are multiple such as evaluation of current and future capabilities of an RMS during its life cycle, early discovery of system performance deficiencies and production optimization. The idea is to implement a digital twin that links the virtual and physical environments. Finally, important issues and emerging trends in the literature are highlighted to encourage researchers and practitioners to develop studies in this area that are strongly related to the Industry 4.0 environment.


Applicability of small endomyocardial biopsies for evaluation of high energy phosphates and glycogen in the heart.
To evaluate variability of biochemical determination of energy stores in endomyocardial biopsies, we compared myocardial contents of high energy phosphates and glycogen in endomyocardial and transmural myocardial biopsies from 12 75-kg pigs before, during, and after cardioplegia. Before cardioplegia, comparable amounts of adenine nucleotides and glycogen were found in left and right ventricular endomyocardial and left ventricular transmural biopsies. Phosphocreatine levels were lower in endomyocardial than in transmural biopsies. Significant correlations were observed between endomyocardial and transmural adenine nucleotide and glycogen contents but not phosphocreatine content. During cardioplegia, myocardial ATP and phosphocreatine contents increased and glycogen concentration tended to decrease. During reperfusion, ATP and glycogen levels decreased, whereas phosphocreatine levels increased remarkably. Transmural changes in left ventricular adenine nucleotide and glycogen levels were reflected in endomyocardial biopsies but those in phosphocreatine were not. By increasing the number of endomyocardial biopsies from one to three, within-subject variance was reduced from 33-47% to 14-23% of total variance whereas four or more biopsies only added minor further reduction in variability. In conclusion, endomyocardial biopsies yield representative estimates of the average myocardial content of adenine nucleotides and glycogen but not of phosphocreatine in the normal heart. Endomyocardial biopsies offer a sensitive estimate of the changes in myocardial adenine nucleotides and glycogen induced by cardioplegia and reperfusion. However, metabolite content in endomyocardial biopsies shows a high variability. Three or more endomyocardial biopsies are necessary to reduce variability to acceptable levels.


Inborn Error of STAT2-Dependent IFN-I Immunity in a Patient Presented with Hemophagocytic Lymphohistiocytosis and Multisystem Inflammatory Syndrome in Children.
Human inborn errors of immunity (IEI) affecting the type I interferon (IFN-I) induction pathway have been associated with predisposition to severe viral infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome that has been increasingly associated with inborn errors of IFN-I-mediated innate immunity. Here is reported a novel case of complete deficiency of STAT2 in a 3-year-old child that presented with typical features of HLH after mumps, measles, and rubella vaccination at the age of 12 months. Due to the life-threatening risk of viral infection, she received SARS-CoV-2 mRNA vaccination. Unfortunately, she developed multisystem inflammatory syndrome in children (MIS-C) after SARS-CoV-2 infection, 4 months after the last dose. Functional studies showed an impaired IFN-I-induced response and a defective IFNα expression at later stages of STAT2 pathway induction. These results suggest a possible more complex mechanism for hyperinflammatory reactions in this type of patients involving a possible defect in the IFN-I production. Understanding the cellular and molecular links between IFN-I-induced signaling and hyperinflammatory syndromes can be critical for the diagnosis and tailored management of these patients with predisposition to severe viral infection.


Anthropogenically sourced low concentration PAHS: In situ bioavailability to juvenile Pacific salmon.
Gill 7-ethoxyresorufin O-deethylase (EROD) activity of juvenile Chinook salmon caged in Auke Lake, AK was used as a biomarker of polycyclic aromatic hydrocarbon (PAH) exposure. Biomarker measurements in conjunction with a comprehensive sampling program that included grab water and sediment samples, and passive sampling devices were used to determine PAH concentrations, source(s), bioavailability, and resulting biological response. PAHs were detected at all lake locations except the reference site upstream of anthropogenic activity. Water samples were the best predictor of a biological response and EROD activity correlated to corresponding parts per trillion water pyrene concentrations (r(2)=0.9662; p=0.0004). Sediment samples yielded the clearest indication of PAH sources and amalgamated contaminant magnitude, and passive samplers served as accumulators of retrospective aqueous conditions. Results suggest that salmon stocks are being exposed to chronic low-concentrations of anthropogenically sourced PAHs during sensitive life-stages, which may be in part a contributor to their declining numbers.


"She's Not Ready to Give Up Yet!": When a Family Member Overrides the Patient's Medical Decisions.
Autonomy, which gives individuals the right to make informed decisions about their medical treatment, is a central principle in Western bioethics. However, we often encounter patients for whom a family member seems to dominate medical decision-making, to the extent that clinicians become concerned that the patient is subject to excessive pressure or even coercion. In this article, we describe one such case and how we assess a decision-making process that involves family influence. This entails acknowledging that many individuals weigh their family members' preferences and/or well-being heavily in making medical decisions, and family norms for decision-making differ. A family member who tells their loved one "You can't give up now" is typically not ursurping the patient's liberty to make a different decision. However, there are some family influences which may be autonomy-limiting, including credible threats, or in situations of abuse. Aside from these scenarios, our role is not to alter a couple's long-standing dynamics and decision-making processes. However, for the patient who wants to assert herself, we can set the stage in a family meeting and amplify her voice. We must also attend to the emotional level of family members' statements. "I won't let you give up" might be more a statement of grief rather than a true reflection of their values or intent. Supporting the family member's coping may help to bring together what initially seem to be divergent goals. Exploring these decision-making dynamics is key to providing good palliative care.


Cyclic nucleotide phosphodiesterase-4 inhibitors: a promising therapeutic approach to premature birth?
Pharmacological interventions in preterm labour attempt to target various protagonists involved in the signalling pathway leading to myometrial contractions. None of these interventions has clearly demonstrated any real clinical benefit, and some are associated with severe maternal and fetal side effects. The original study now reported has disclosed a new potential target, myometrial phosphodiesterase-4 (PDE4), for tocolysis. The PDE4 family specifically hydrolyses cAMP, a major intracellular second messenger implicated in the mechanisms governing smooth muscle motility. One particular isoform, PDE4B2, is overexpressed in the human myometrium at the end of pregnancy, and we observed a change of the myorelaxant properties of selective PDE4 inhibitors at this time. Signalling factors involved in labour at term or in infection-induced preterm labour, such as PGE2 or IL-1beta, are also able to induce PDE4B2 expression by way of a cAMP-dependent pathway. This feedback loop explains, at least in part, the process of desensitisation to relaxant agents that occurs at the end of pregnancy. In addition, PDE4 inhibitors block the production of LPS-induced inflammatory cytokines by myometrial explants. Thus, a combination of myorelaxant and anti-inflammatory properties make the PDE4 inhibitors particularly attractive as a target for the prevention of threatened infection-induced preterm delivery and its consequences for the premature infant.


Validation of the McGill Quality of Life Questionnaire in home hospice settings in Israel.
Given that the meaning and significance of 'quality of life' can differ among language and cultural groups, it is incumbent upon researchers to assess whether the tool they have chosen is appropriate to the population under study. This study aimed to test the reliability and validity of the McGill Quality of Life Questionnaire (MQOL) translated into Hebrew for use with palliative care patients in Israel. In this, as in previous studies, the 16 questions of the tool clustered into four domains (physical, psychological, existential well-being and support), although the distribution of items among them differed somewhat. The existential well-being and psychological domains had an independent effect on the overall quality of life of patients in Israel, as in other countries. It seems that this tool produces similar responses in metastatic cancer patients around the world, and hence can be used to compare palliative care services in different countries.


Detection of neuron specific enolase concentrations in cerebrospinal fluid from patients with neurological disorders by means of a sensitive enzyme immunoassay.
An enzyme linked immunosorbent assay (ELISA) for the detection of neuron specific enolase (NSE) in cerebrospinal fluid (CSF) was developed. The sensitivity of the ELISA was less than 1 microgram/ml. This sensitivity is comparable with radioimmunoassays which have the disadvantage that radiolabelled products are used. The developed assay was used to measure cerebrospinal fluid neuron specific enolase (CSF-NSE) levels in 1178 patients with neurological disorders to establish its potential usefulness and clinical application. CSF-NSE levels in this group of patients were independent of sex and no correlation with age was found. CSF-NSE was significantly increased in Creutzfeldt-Jacob disease, meningeal hemorrhage, thrombosis, Guillain-Barré syndrome and in schizophrenia.


Psychosocial work factors affecting mental health of young workers: a systematic review.
For the general working population, robust evidence exists for associations between psychosocial work exposures and mental health. As this relationship is less clear for young workers, this systematic review aims at providing an overview of the evidence concerning psychosocial work factors affecting mental health of young workers. The electronic databases used were PubMed, Web of Science, and PsycINFO and were last searched in October 2021. The eligible outcomes included depression-, stress-, burnout- and anxiety-related complaints, and fatigue, excluding clinical diagnoses and suicide-related outcomes. Only studies with workers aged 35 years or younger were included, which reported at least one association between a psychosocial work factor as exposure and a mental health complaint as outcome. Studies had to be in English, German or Dutch. Risk of bias was assessed using an instrument from the National Heart, Lung, and Blood Institute. Data synthesis was conducted using GRADE. In total 17 studies were included in this systematic review, including data from 35,600 young workers in total. Across these studies 86 exposure-outcome associations were reported. Nine exposure-outcome associations could be synthesised. The application of the GRADE framework led to one "low" assessment for the association between psychosocial job quality and mental health. The certainty of evidence for the other eight associations in the synthesis was very low. The current systematic review disclosed a high degree of uncertainty of the evidence due to conceptually fuzzy outcomes and exposures as well as large heterogeneity between studies.


Brugia malayi: microfilarial polyunsaturated fatty acid composition and synthesis.
The polyunsaturated fatty acid composition of Brugia malayi microfilariae was analyzed by gas chromatography and compared to that of sera from B. malayi-infected jirds. The essential fatty acid, linoleic acid (18:2 omega 6), was the most abundant fatty acid present in both microfilarial total lipids and phospholipids as well as in jird sera. In contrast, arachidonic acid (20:4 omega 6), as well as the 18:3 omega 6, 20:2 omega 6, and 20:3 omega 6 intermediates that are formed in the enzymatic conversion of linoleic acid to arachidonic acid, were proportionally more abundant in microfilariae than in jird sera. To assess the capacity of microfilariae to transform linoleic acid into arachidonic acid, B. malayi microfilariae were incubated with [14C]linoleic acid. Microfilarial lipids were extracted and resolved by high-pressure liquid chromatography and thin-layer chromatography. A portion of [14C]linoleic acid incorporated by microfilariae was converted to [14C]arachidonic acid. Thus, microfilariae can not only incorporate exogenous arachidonic acid, as previously demonstrated, but can also synthesize arachidonic acid from exogenous linoleic acid. The capacity of microfilariae to utilize specific host polyunsaturated fatty acids raises the possibility that intravascular filarial parasites may synthesize eicosanoid metabolites of arachidonic acid that could mediate filarial-host cell interactions.


Cross-frequency and inter-regional phase synchronization in explicit transitive inference.
Explicit logical reasoning, like transitive inference, is a hallmark of human intelligence. This study investigated cortical oscillations and their interactions in transitive inference with EEG. Participants viewed premises describing abstract relations among items. They accurately recalled the relationship between old pairs of items, effectively inferred the relationship between new pairs of items, and discriminated between true and false relationships for new pairs. First, theta (4-7 Hz) and alpha oscillations (8-15 Hz) had distinct functional roles. Frontal theta oscillations distinguished between new and old pairs, reflecting the inference of new information. Parietal alpha oscillations changed with serial position and symbolic distance of the pairs, representing the underlying relational structure. Frontal alpha oscillations distinguished between true and false pairs, linking the new information with the underlying relational structure. Second, theta and alpha oscillations interacted through cross-frequency and inter-regional phase synchronization. Frontal theta-alpha 1:2 phase locking appeared to coordinate spectrally diverse neural activity, enhanced for new versus old pairs and true versus false pairs. Alpha-band frontal-parietal phase coherence appeared to coordinate anatomically distributed neural activity, enhanced for new versus old pairs and false versus true pairs. It suggests that cross-frequency and inter-regional phase synchronization among theta and alpha oscillations supports human transitive inference.


A 28-year trend of infective endocarditis associated with congenital heart diseases: a single institute experience.
Infective endocarditis (IE) is still one of the major complications of congenital heart disease and, therefore, prevention has always been an important issue. But there has been no large scale investigation of IE in Japan. Clinical and microbiological features in 183 patients with congenital heart diseases complicated with infective endocarditis (IE), which were treated in our institute in the last 28 years, were reviewed. During the period, the age distribution of the patients shifted to an older age; 80% were older than 15 years in the latest 7 year period. In the underlying diseases more complex conditions increased, such as the post Rastelli operation. Dental or oral diseases were the major preceding events and Streptococcus was the major pathogen throughout the study periods in the data. The result indicates the importance of continuing education for the prevention of IE and oral hygiene especially in adult patients with a risk for IE.


[Necrotizing fasciitis as the first manifestation of tuberculosis in a immunocompromised patient].
Disseminated tuberculosis is a process that mainly affects immunocompromised hosts. Its initial appearance as necrotising fasciitis is exceptional especially if it is not associated to a bone disorder. The diagnosis of this rare complication requires a high degree of suspicion and the evidence of Mycobacterium tuberculosis in the muscular tissue, since the symptoms may mimic the underlying illness itself, for this reason the most sensitive method for demonstrating tuberculous infection is a muscular biopsy. Here we present the case of a patient who was receiving immunosuppressant therapy for nephrotic syndrome by minimal lesion glomerulonephritis and who developed this rare complication, where diagnosis was made by muscular biopsy. So we do a review of similar case reports in the literature.


Visual mapping of body image disturbance in anorexia nervosa reveals objective markers of illness severity.
Body image disturbance (BID) is a core feature of eating disorders, for which there are few objective markers. We examined the feasibility of a novel digital tool, "Somatomap", to index BID related to anorexia nervosa (AN) severity. Fifty-five AN inpatients and 55 healthy comparisons (HC) outlined their body concerns on a 2-Dimensional avatar. Next, they indicated sizes/shapes of body parts for their current and ideal body using sliders on a 3-Dimensional avatar. Physical measurements of corresponding body parts, in cm, were collected for reference. We evaluated regional differences in BID using proportional z-scores to generate statistical body maps, and multivariate analysis of covariance to assess perceptual discrepancies for current body, ideal body, and body dissatisfaction. The AN group demonstrated greater regional perceptual inaccuracy for their current body than HC, greater discrepancies between their current and ideal body, and higher body dissatisfaction than HCs. AN body concerns localized disproportionately to the chest and lower abdomen. The number of body concerns and perceptual inaccuracy for individual body parts was strongly associated with Eating Disorder Examination Questionnaire (Global EDE-Q) scores across both groups. Somatomap demonstrated feasibility to capture multidimensional aspects of BID. Several implicit measures were significantly associated with illness severity, suggesting potential utility for identifying objective BID markers.


Local BCG failures in superficial bladder cancer. A multivariate analysis of risk factors influencing survival.
Of 221 patients with superficial bladder cancers treated with intravesical BCG, BCG therapy failed locally within the bladder or prostate in 41 patients. A multivariate analysis was done using data on these local failures to identify clinical variables influencing survival. Patients presenting with T1 tumors which relapsed initially in the prostate were at highest risk of dying of bladder cancer. Cystectomy is justified in such patients. Others with noninvasive local refractory disease can be managed by continued conservative therapy.


Different action mechanisms of low- and high-level quercetin in the brains of adult zebrafish (Danio rerio).
Quercetin is reported to be beneficial to or pose hazards to the health of animals, the inconsistence remains to be recognized and debated. This work was conducted to understand the neuroprotective or neurotoxic properties of quercetin, and investigate the different action mechanisms between low- and high-level quercetin. Therefore, we evaluated brain oxidative stress and monoamine neurotransmitters in adult zebrafish (Danio rerio) after exposure to 1 and 1000 μg/L quercetin. In addition, the brain transcriptional profiles were analyzed to identify genes and pathways that were differentially regulated in the brains. The results of oxidative stress and neurotransmitters suggest that low-level quercetin might be beneficial to nervous system, while high-level quercetin might exert detrimental effects. Furthermore, transcriptional profiles also suggested different toxic mechanisms occurred between low- and high-level quercetin. At 1 μg/L quercetin, enrichment analysis of differently expressed genes (DEGs) revealed that the fanconi anemia pathway might be an important mechanism in neuroprotective effects. At 1000 μg/L quercetin, the up-regulated DEGs were enriched in many Gene Ontology (GO) terms related to neuronal synapses, indicating potential neuroprotective effects; however, enrichment of up-regulated DEGs in GO terms of response to stimulus and the MAPK signaling pathway was also found, which indicated increases of stress. Notably, at 1000 μg/L quercetin, the down-regulated DEGs were enriched in several GO terms related to the proteostasis and the proteasome pathway, indicating impairment of proteasome functions which was involved in neurodegenerative diseases. Moreover, several hub genes involved in the pathology of neurodegenerative diseases were identified by Protein-protein interaction analysis at 1000 μg/L quercetin. Thus, high-level quercetin might pose potential risk inducing neurodegenerative diseases, which should receive more attention in the future. Additionally, our findings may provide awareness to society and researchers about toxicity possibilities of phytochemicals on wildlife and human.


Mitochondria-targeted photoacoustic probe for imaging of hydrogen peroxide in inflamed mouse model.
In this chapter, we gave a brief introduction of hydrogen peroxide (H2O2) and its existing analytical methods and described the need of mitochondria-targeted photoacoustic (PA) probe for H2O2 detection in vivo. Then we provided the detailed protocols for the design and characterization of a mitochondria-targeted PA probe (TPP-HCy-BOH) to visualize H2O2in vivo, which was developed in our previous work. Compared to control probe without mitochondria-targeted ability (HCy-BOH), TPP-HCy-BOH could efficiently accumulate in mitochondria and activate its PA signals toward overproduced H2O2 in inflamed mouse model with higher PA sensitivity.


Sensory Experience in Development Balances Excitation and Inhibition to Stabilize Frequency Tuning in Central Auditory Neurons.
The balance between excitation and inhibition is critical in shaping receptive field tuning properties in sensory neurons and, ultimately, in determining how sensory cues are extracted, transformed and interpreted by brain circuits. New findings suggest that developmentally-regulated, experience-dependent changes in intracortical inhibitory networks are key to defining receptive field tuning properties of auditory cortical neurons.


Immunogenicity and safety of the meningococcal B recombinant (4CMenB) vaccine in allogeneic hematopoietic cell transplantation recipients.
Despite a high risk of invasive meningococcal (Men) disease, there is no published data on any MenB vaccine after hematopoietic cell transplantation (HCT). We investigated the immunogenicity and safety of the 4CMenB recombinant vaccine (Bexsero) in adult HCT recipients. Patients were eligible from 6 months post-HCT to receive 2 4CMenB doses at 2-month intervals. Sera were collected at baseline, 1 month after the second dose, and 12 months after enrolment. The serum bactericidal activity (SBA) using human complement (hSBA) was assessed against fHbp, NadA, PorAP1.4, and NHBA antigens. The vaccine response was defined by one criterion for one vaccine antigen: (1) in patients with a hSBA titer <4 at baseline: a titer ≥4; (2) in patients with a hSBA titer ≥4 at baseline: at least a 4 time increase. Forty (40) patients were included at a median of 2.14 (0.57-13.03) years posttransplant. At baseline, most patients (32/40, 80%) had hSBA titers <4 for all vaccine antigens. After 2 vaccine doses, the proportion of patients with a titer ≥4 was significantly increased for fHbp (23/40, 57.5%), NadA (25/40, 62.5%), and PorA (31/40, 77.5%) but not for NHBA for which only 6 of 40 (15%) patients responded. Of patients, 36 out of 0 (90%) were responders to ≥1 antigen. However, 9 months later, only 23 out of 37 (62.2%) patients were still seroprotected. No severe adverse event was observed. The response rate of 90% for ≥1 vaccine antigen and our safety data supports the 4CMenB vaccination of HCT recipients from 6 months after transplant with 2 doses.


Recurrent tuberculous cerebellar abscess: A case study and review of the literature.
Tuberculous cerebellar abscess is a rare form of extra-pulmonary tuberculosis. The outcome is often favorable with well-managed treatment; however, they can continue to develop. We share in this article our experience on the management of this rare pathologie. A 10-year-old boy with a medical history of tuberculous meningitis after 3 months of tuberculosis treatment. He presented to the hospital with acute obstructive hydrocephalus due to a large tuberculous cerebellar abscess. A puncture of the abscess was initially performed, followed by placement of a ventriculoperiotoneal shunt, which resulted in some clinical improvement. However, the child subsequently presented with neurological deterioration due to the massive enlargement of the tuberculous abscess despite adequate antituberculosis chemotherapy. The initiation of corticosteroid therapy associated with a readjustment of the dose of anti-tuberculosis drugs and a repeated puncture ultimately led to clinical improvement. Tuberculous brain abscess is an extra-pulmonary location of tuberculosis rarely seen in immunocompetent children. The treatment consists of surgery associated with antituberculosis chemotherapy and rigorous clinico-radiological monitoring. Recurrence is possible despite well-conducted treatment. Additional corticosteroid therapy is necessary with readjustment of the anti-tuberculosis treatment for an effective cure. Rarely, the tuberculous abscess of the cerebellum continues to evolve despite proper treatment. This pattern does not necessarily mean treatment failure. Close clinical and imaging monitoring is crucial in the management of these cases.


Hendecad repeat in segment 2A and linker L2 of intermediate filament chains implies the possibility of a right-handed coiled-coil structure.
The conformation adopted by intermediate filament chains (IF) has been described in terms of a central rod domain with four, alpha-helical, left-handed coiled-coil segments (1A, 1B, 2A, and 2B) joined by linkers (L1, L12, and L2, respectively). The rod domain is terminated at its N- and C-terminal ends by "globular" head and tail domains, respectively. This analysis, initially undertaken about 20-25 years ago, was based on the recognition of an underlying heptad substructure in the sequence of the rod domain, the presence of which can be directly associated with an alpha-helical coiled-coil structure. In this work, a hendecad sequence motif that is closely related to the heptad repeat but which is nonetheless significantly different from it has been recognized in the primary structure of segments 2A and linker L2. This motif, which is 11 residues long and structurally equivalent to a true heptad plus another heptad with an inclusive stutter, is consistent with the chains adopting a continuous right-handed coiled-coil structure with a long-period pitch length. It is therefore predicted that segment 2 as a whole may have a coiled-coil conformation with both right-handed (2A+L2) and left-handed (2B) regions. The changeover in handedness would be expected to occur at the C-terminal end of linker L2 and N-terminal end of segment 2B.


Prevalence of usage of hearing aids and its association with cognitive impairment in Japanese community-dwelling elders with hearing loss.
Hearing loss is a risk factor for cognitive impairment, and the use of a hearing aid (HA) may prevent cognitive decline alongside hearing loss. We aimed to elucidate the prevalence of self-reported HA usage in Japanese community-dwelling elders with hearing loss, and the effect of hearing and HA on cognitive impairment. A total of 1193 participants, who had audiometric defined hearing loss and were aged 60 years or over, had their cumulative 3260 observations followed up for 10 years from a large cohort of a Japanese study. Association between hearing (pure-tone average threshold level at 500, 1000, 2000, and 4000 Hz from the better hearing ear: PTABHE) and HA usage with cognitive impairment (total score of Mini-Mental State Estimation was under 27 or diagnosed as dementia) was analyzed using generalized estimating equations. The HA usage rate of the 1193 community-dwelling elders with hearing loss was 6% during the first involvement. The majority (59.2%) of HA users always used an HA. HA usage rate was 0.7% for the mild hearing loss group and 32.4% for the moderate or greater hearing loss group in the latest participating wave. PTABHE was significantly associated with cognitive impairment (odds ratio for every 10 dB 1.36; 95% CI 1.21-1.53, p<0.0001) after adjusting for age, sex, education, depressed mood, smoking status, alcohol intake, income, activity, obesity, histories of hypertension, dyslipidemia, ischemic heart disease, diabetes, stroke, ear disease, and occupational noise exposure. PTABHE was also significantly associated with cognitive impairment in the mild hearing loss group (odds ratio for every 10 dB 1.34; 95% CI 1.05-1.72, p = 0.020) and moderate hearing loss group (odds ratio for every 10 dB 1.82; 95% CI 1.27-2.61, p = 0.001). HA use showed a significant suppressive effect on cognitive impairment in those with moderate hearing loss who always use an HA (odds ratio 0.54; 95% CI 0.30-1.00, p = 0.049). The prevalence of HA usage among Japanese community-dwelling elders with hearing loss is consistent, at around 10%. The hearing level remained a primary risk factor for cognitive impairment among elders with hearing loss after adjusting for several confounding factors. Regular HA use may have a protective effect on cognitive impairment in those with moderate hearing loss.


Electronic Retinal Prostheses.
Retinal prostheses are a promising means for restoring sight to patients blinded by photoreceptor atrophy. They introduce visual information by electrical stimulation of the surviving inner retinal neurons. Subretinal implants target the graded-response secondary neurons, primarily the bipolar cells, which then transfer the information to the ganglion cells via the retinal neural network. Therefore, many features of natural retinal signal processing can be preserved in this approach if the inner retinal network is retained. Epiretinal implants stimulate primarily the ganglion cells, and hence should encode the visual information in spiking patterns, which, ideally, should match the target cell types. Currently, subretinal arrays are being developed primarily for restoration of central vision in patients impaired by age-related macular degeneration (AMD), while epiretinal implants-for patients blinded by retinitis pigmentosa, where the inner retina is less preserved. This review describes the concepts and technologies, preclinical characterization of prosthetic vision and clinical outcomes, and provides a glimpse into future developments.


Risk Factors Related to Superior Facet Joint Violation During Lumbar Percutaneous Pedicle Screw Placement in Minimally Invasive Transforaminal Lumbar Interbody Fusion (MIS-TLIF).
To investigate the incidence of superior facet joint violation (FJV) during percutaneous pedicle screw placement in minimally invasive transforaminal lumbar interbody fusion, and assess the possible risk factors for FJV. An analysis of 91 patients with lumbar degenerative diseases treated with percutaneous pedicle screw placement via minimally invasive transforaminal lumbar interbody fusion from 2012 to 2018 was performed. Superior FJV was evaluated and graded by 3-dimensional lumbar computed tomography reconstruction. Analysis of possible risk factors included general condition of patients, anatomical characteristics of facet joint (FJ; axial, sagittal, and coronal diameters of FJ, facet angle, lumbar lordosis angle, lumbar lordosis index, and depth of lamina), and surgical factors (pedicle screw angle, screw-superior FJ distance, cranial angle, proximal rod length, and rod contouring). The overall violation rate of superior FJ was 34.07% (62/182), and high-grade violation rate was 16.06% (27/182). The logistic regression analysis revealed that body mass index ≥30 kg/m2 and pedicle screw placement at L5 were independent risk factors of FJV. Anatomical factors showed that the incidence of FJV was significantly increased when axial, sagittal, and coronal diameters of FJ were all ≥12 mm or FA was ≥40°. Surgical factors showed that the FJV group had a smaller pedicle screw angle and screw-superior FJ distance compared with the non-FJV group (P < 0.05). Body mass index ≥30 kg/m2 and pedicle screw placement at L5 were independent risk factors of superior FJV. FJV was more likely to occur in hypertrophic FJ (axial, sagittal, and coronal diameters ≥12 mm) or coronal orientation (FA ≥40°).


Neutral desorption extractive electrospray ionization mass spectrometry for fast screening sunscreen agents in cream cosmetic products.
High throughput analysis of sunscreen agents present in cream cosmetic has been demonstrated, typically 2 samples per minute, using neutral desorption extractive electrospray ionization mass spectrometry (ND-EESI-MS) without sample pretreatment. For the targeted compounds such as 4-Aminobenzoic acid and oxybenzone, ND-EESI-MS method provided linear signal responses in the range of 1-100 ppb. Limits of detection (LOD) of the method were estimated at sub-ppb levels for the analytes tested. Reasonable relative standard deviation (RSD=8.4-16.0%) was obtained as a result of 10 independent measurements for commercial cosmetics samples spiked with each individual sunscreen agents at 1-10 ppb. Acceptable recoveries were achieved in the range of 87-116% for direct analysis of commercial cream cosmetic samples. The experimental data demonstrate that ND-EESI-MS is a useful tool for high throughput screening of sunscreen agents in highly viscous cream cosmetic products, with the capability to obtain quantitative information of the analytes.


Percutaneous screw fixation of acetabular fractures with 2D fluoroscopy-based computerized navigation.
The treatment of displaced acetabular fractures with formal open reduction and internal fixation has gained general acceptance. However, extensile exposure can lead to complications. Two-dimensional fluoroscopy-based computerized navigation for placement of percutaneous screw across non-displaced acetabular fractures has attracted interest by making use of stored patient-specific imaging data to provide real-time guidance in multiple image planes during implant placement. The purpose of the present study was to document early treatment results and complications associated with this new technique and evaluate its clinical application to displaced acetabular fractures amenable to closed or limited open reduction. Eighteen adult patients with 12 non-displaced and 8 displaced acetabular fractures were treated with percutaneous screw fixation under the guidance of a fluoroscopy-based navigation system. There were 14 men and four women with a mean age of 42.1 years (range 19-54 years). According to the AO and Orthopaedic Trauma Association Classification, there were nine 62-A3, five 62-B1, three 62-B2, and three 62-B3. The mean follow-up was 21 months (range 12-28 months). The mean time from injury to surgery was 4 days (range 2-7 days). A total of 30 acetabular screws were inserted, including 21 anterior column screws and 9 posterior column screws. The average operation time was 24.6 min (range 16-47 min) from the image acquisition to wound closure. The average fluoroscopic time was 28.4 s (range 11-58 s). Compared to the final position of the screw, the average deviated distance of wire tip was 2.5 mm (range 1.1-3.6 mm) and the average trajectory difference was 2.45 degrees (range 1.5 degrees -4.6 degrees ). Maximal gap displacement averaged 10 mm (range 2-22 mm) preoperatively and 3 mm (range 0-5 mm) postoperatively; while maximal step displacement averaged 4 mm (range 1-10 mm) preoperatively and 2 mm (range 0-4 mm) postoperatively. One patient sustained a transient femoral nerve palsy and resolved 2 months after the operation. No superficial or deep infection occurred. Using the rating system of D'Aubigne and Postel, 13 patients had excellent results, 4 patients had good results, and 1 patient had a fair result. Percutaneous screw fixation of acetabular fractures with 2D fluoroscopy-based navigation could be applied not only to non-displaced fractures but also to displaced fractures amenable to closed or limited open reduction.


[Effect of meteorologic and solar factors on the psychophysiologic responses of healthy subjects and patients with vascular lesions of the brain].
Study of the time-course of psychophysiological parameters in relation to the effect of meteoheliofactors revealed a significant correlation of the studied processes in all the examinees. The most sensitive to such an effect was higher nervous activity. The atmospheric pressure exerted the most pronounced influence on the parameters. There were two major (positive and negative) and the intermediate (inert) types of responses. Reactions of some patients either preceded or occurred some time after exposure to meteoheliofactors.


Relationship of adiponectin to endogenous GH pulse secretion parameters in response to stimulation with a growth hormone releasing factor.
Obesity is associated with both reduced growth hormone (GH) and adiponectin. However, the relationship between adiponectin and parameters of endogenous GH secretion remains unknown. The aim of this study was to determine the relationship between total and high molecular weight (HMW) adiponectin and parameters of endogenous pulsatile GH secretion and the effects of tesamorelin, a synthetic GH releasing hormone (GHRH(1-44)), on total and HMW adiponectin. A 2-week interventional study with tesamorelin was conducted at an academic medical center in 13 men with BMI 20-35 kg/m(2). Overnight frequent blood sampling and measurement of total and HMW adiponectin at baseline and after treatment were performed to assess the effects of augmenting endogenous pulsatile GH secretion. Total, but not HMW, adiponectin was positively associated with log(10)Peak GH area (r=+0.73; P=0.005), basal GH secretion (r=+0.67; P=0.01), and total GH production (r=+0.57; P=0.04), but was not associated with the number of secretion events (P=0.85). Two-week treatment with tesamorelin increased endogenous GH release and IGF-1, but neither total (change -0.16±0.64; P=0.40), nor HMW (change +0.03±0.70; P=0.87) adiponectin changed significantly with treatment. Sub-analyses in overweight and obese men yielded similar results. Our study demonstrates a strong relationship between specific parameters of endogenous GH pulsatility and adiponectin. However, short-term augmentation of GH pulsatility over 2-weeks does not change adiponectin. Therefore, the relationship between GH and adiponectin is most likely mediated by specific covariates related to adiposity or other factors.


Cuffless blood pressure estimation using chaotic features of photoplethysmograms and parallel convolutional neural network.
As a nonlinear framework in dynamical system analysis, chaotic approaches are mainly applied to evolve the complexity of biological systems. Due to the chaotic nature of the cardiovascular systems, the nonlinear features can intuitively provide a reliable framework in blood pressure (BP) estimation. Cuffless BP estimation is usually carried out by establishing deep neural network models estimating the BP values through machine-learned features of photoplethysmogram (PPG) signals. In this study, a novel parallel deep architecture is proposed to handle the machine-learned and chaotic features of PPG signals in estimating the actual BP values. The chaotic handcrafted features were the signal properties associated with the Poincare sections in the phase space and the recurrence plot-based measures called recurrence quantification analysis (RQA). Moreover, the measures quantifying the nonlinear properties of the temporal sequences such as correlation dimension, fractal dimension, Lyapunov exponent, and entropy-based quantities were also employed. The parallel architecture not only embedded the chaotic nature of PPG signals but also provided a facility to include the pseudo-periodic variations of PPGs by utilizing a concatenating layer. Our framework was examined on the public dataset, namely, Multi-Parameter Intelligent in Intensive Care II contained the recording of PPG, ECG and arterial blood pressure. The performance of the employed handcrafted features in distinguishing between the levels of BP values was investigated based on Spearman's statistics. In addition, our proposed scheme is evaluated in terms of Pearson's correlation coefficient (R), root mean square error (RMSE), and mean absolute error (MAE). The best performance was achieved when the employed handcrafted features accompanied by PPG sequences were applied to the parallel deep network. In particular, the values of R, RMSE, and MAE were obtained 0.9529, 2.76 mmHg, and 1.73 mmHg for diastolic BP, and 0.9444, 6.18 mmHg, and 3.8 mmHg for systolic BP, respectively. Moreover, based on the requirements of the standards set by the British Hypertension Society (BHS), the proposed scheme achieved a grade of A. Our proposed scheme outperformed the state-of-the-art BP estimation methods. In addition, the results confirmed that the concatenation of the PPG-related machine-learned and nonlinear handcrafted features can be properly applied in continuous BP monitoring.


Identification and characterization of key haem pathway genes associated with the synthesis of porphyrin in Pacific oyster (Crassostrea gigas).
Molluscs exhibit diverse shell colors. The molecular regulation of shell coloration is however not well understood. To investigate the connection of shell coloration with pigment synthesis, we analyzed the distribution of porphyrins, a widespread group of pigments in nature, in four Pacific oyster strains of different shell colors including black, orange, golden, and white. The porphyrin distribution was analyzed in oyster mantles and shells by fluorescence imaging and UV spectrophotometer. The results showed that red fluorescence emitted by porphyrins under the UV light was detected only on the nacre of the orange-shell strain and mantles of orange, black and white-shell strains. Extracts from newly deposit shell, nacre and mantle tissue from orange-shell specimens showed peaks in UV-vis spectra that are characteristic of porphyrins, but these were not observed for the other shell-color strains. In addition, genes of the haem synthetic pathway were isolated and characterized. Phylogenetic analysis of CgALAS, CgALAD, CgPBGD, CgUROS, and CgUROD provide further evidence for a conserved genetic pathway of haem synthesis during evolution. Differential expression of the haem genes expressed in mantle tissues support these findings and are consistent with porphyrins being produced by the orange strain only. Tissue in situ hybridization demonstrated the expression of these candidate genes at the outer fold of C. gigas mantles where shell is deposited. Our studies provide a better understanding of shell pigmentation in C. gigas and candidate genes for future mechanistic analysis of shell color formation in molluscs.


Predicting Sequence Features, Function, and Structure of Proteins Using MESSA.
MEta-Server for protein Sequence Analysis (MESSA) is a tool that facilitates widespread protein sequence analysis by gathering structural (local sequence properties and three-dimensional structure) and functional (annotations from SWISS-PROT, Gene Ontology terms, and enzyme classification) predictions for a query protein of interest. MESSA uses multiple well-established tools to offer consensus-based predictions on important aspects of protein sequence analysis. Being freely available for noncommercial users and with a user-friendly interface, MESSA serves as an umbrella platform that overcomes the absence of a comprehensive tool for predictive protein analysis. This article reveals how to access MESSA via the Web and shows how to input a protein sequence to analyze using the MESSA web server. It also includes a detailed explanation of the output from MESSA to aid in better interpretation of results. © 2019 by John Wiley & Sons, Inc.


A case of extreme hyponatremia without neurologic symptoms.
Our case report highlights that profound hyponatremia with sodium level 101 mmol/L could have no CNS symptoms, and drugs and endocrine disorders are relatively common causes and should be considered in the differential diagnosis of hyponatremia. Standard dose trimethoprim-sulfamethoxazole-induced hyponatremia is rare but still worth close attention in clinical practice.


Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats.
To assess the involvement of the AGE-specific receptor (AGER, also known as RAGE) axis and nuclear factor kappa-B (NFKB, also known as NF-kappaB) activation in the development of lacrimal gland and tear film dysfunction in diabetes, the present study evaluated: (1) lacrimal gland and tear film alterations in diabetic rats; and (2) the expression of AGE, AGER and NFKB in ocular tissues of normoglycaemic and diabetic rats. Diabetes was induced in male Wistar rats with intravenous streptozotocin. Tear secretion parameters were measured and NFKB expression was evaluated in lacrimal glands of control and diabetic rats by western blot. Immunohistochemistry with confocal microscopy was used to assess AGE, AGER and NFKB expression in lacrimal glands of both groups. Lacrimal gland weight and tear film volume were lower in diabetic than in control rats (p=0.01 and 0.02, respectively). IL1B and TNF concentrations in tears were higher in diabetic than in control rats (p=0.007 and 0.02, respectively). NFKB protein was identified in rat cornea, conjunctiva and lacrimal glands. AGE, AGER and NFKB expression were greater in lacrimal glands of diabetic than in those of control rats. Diabetes induces significant alterations in rat lacrimal gland structure and secretion. The higher expression of AGE, AGER and NFKB in lacrimal glands of diabetic rats suggests that these factors are involved in signalling and in subsequent inflammatory alterations related to dry eye in diabetes mellitus.


A study of suicides of older people in Sydney.
Reports based on studies of coroner's files show that suicides in old age are commonly related to depression, but that in a majority of cases disability or ill-health is also a major factor. The aim of this study was to try to understand more clearly the precipitant causes of suicide in an older population. An Australian metropolitan coroner's office provided data concerning suicides in 1994-1998 of persons aged over 65 years. Of 210 elderly people who killed themselves, 160 (76%) were clearly depressed, including a majority of the 24% deemed to have understandable reasons for suicide. Physical ill-health or disability was the major factor leading to suicide in 34% and appeared to contribute to suicidal ideation in another 24% of those who died; they had usually not been seen by psychiatrists. Because depression is often treatable, even when associated with depressing circumstances, there is potential for further reduction of old age suicide rates by recognising and appropriately responding to symptoms of depression and distress.


[Preliminary observations on the clinical use of calcitonin. Treatment and postoperative prevention of pancreatitis].
Calcitonin was administered to 4 patients presenting with acute pancreatitis as well as to 6 patients presenting with postoperative pancreatitis. Prophylactic administration was performed in 3 cases consecutive to pancreatic interventions. Following calcitonin all patients showed considerable improvement of clinical course. Although 8 patients recuperated completely 2 patients died from independent complications. After prophylactic administration of calcitonin the postoperative course was uncomplicated without demonstrable increase in serum amylase. It is emphasized that only early case histories are reported; their verification will depend upon the results of a controlled survey presently being performed.


Amniotic fluid arborization in the diagnosis of previable preterm premature rupture of membranes.
To determine the accuracy of using amniotic fluid arborization to diagnose preterm premature rupture of membranes (PPROM) in the second trimester using specimens collected from the vaginal pool. Women presenting for pregnancy termination between 14 and 22 weeks' gestation were enrolled. At the time of termination, amniotic fluid samples were collected directly from the amniotic sac and from the vaginal pool, air dried and examined for arborization. Arborization was detected in 51/59 (86.4%) samples collected from the amniotic sac and 41/59 (69.5%) samples collected from the vaginal pool. The sensitivity and specificity in detecting arborization in fluid collected by swabbing the vagina was 0.69 and 0.98, respectively (positive predictive value 0.98%, negative predictive value 0.76). While the presence of arborization in samples collected from the vaginal pool is predictive of PPROM in the second trimester, the absence of arborization should not rule out the diagnosis if there is strong clinical suspicion.


Comparison of survival by allocation to medical therapy, surgery, or heart transplantation for ischemic advanced heart failure.
To ascertain survival of ischemic advanced heart failure patients by treatment allocation, we examined the outcome of transplant assessment patients allocated to medical therapy, high-risk conventional surgery, or transplantation. Patients were identified from the Papworth transplant database and excluded if primary etiology was not ischemic. Grouping was undertaken according to treatment allocation at initial assessment, and analysis was performed by intention to treat. Survival was computed from the time of assessment and Cox regression used to stratify patients according risk with the Heart Failure Survival Score. From May 1993 to September 2001, a total of 755 patients were admitted for transplant assessment, with 348 (46.1%) identified as having heart failure of ischemic origin. Variables required for calculation of the Heart Failure Survival Score was available in 273 patients (78.4%), and 20 patients (7.3%) were lost to follow-up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery, and 132 (52.2%) to transplantation. The relative risk (95% confidence limit) of death compared with medical therapy was 0.62 (0.28, 1.40) for surgery and 0.38 (0.24, 0.61) for transplantation in medium- to high-risk patients. For low-risk patients, the relative risks for death compared with medical therapy were 1.87 (0.63, 5.60) for surgery and 1.97 (0.79, 4.96) for transplantation. Transplantation improved survival of medium- and high-risk patients compared with medical therapy. In the low-risk group, this was not evident. However, repeated assessment of risk is required because the hazard for death rises steadily after the third year in these patients.


Panacea or diagnosis? Imaginaries of innovation and the 'MIT model' in three political cultures.
Innovation studies continue to struggle with an apparent disconnect between innovation's supposedly universal dynamics and a sense that policy frameworks and associated instruments of innovation are often ineffectual or even harmful when transported across regions or countries. Using a cross-country comparative analysis of three implementations of the 'MIT model' of innovation in the UK, Portugal and Singapore, we show how key features in the design, implementation and performance of the model cannot be explained as mere variations on an identical solution to the same underlying problem. We draw on the concept of sociotechnical imaginaries to show how implementations of the 'same' innovation model - and with it the notion of 'innovation' itself - are co-produced with locally specific diagnoses of a societal deficiency and equally specific understandings of acceptable remedies. Our analysis thus flips the conventional notion of 'best-practice transfer' on its head: Instead of asking 'how well' an innovation model has been implemented, we analyze the differences among the three importations to reveal the idiosyncratic ways in which each country imagines the purpose of innovation. We replace the notion of innovation as a 'panacea' - a universal fix for all social woes - with that of innovation-as-diagnosis in which a particular 'cure' is 'prescribed' for a 'diagnosed' societal 'pathology,' which may in turn trigger 'reactions' within the receiving body. This approach offers new possibilities for theorizing how and where culture matters in innovation policy. It suggests that the 'successes' and 'failures' of innovation models are not a matter of how well societies are able to implement a sound, universal model, but more about how effectively they articulate their imaginaries of innovation and tailor their strategies accordingly.


A system for measurement of prosthetic eye movements using a magnetic search coil technique.
We describe the use of a magnetic search coil technique for measuring the movement of prosthetic eyes. The technique allows for accurate comparison of implant designs and surgical techniques.


Design of dispersant for highly concentrated one-dimensional Nb2Se9 inorganic molecular chains from bulk crystal.
We determined the optimum dispersant to separate bulk Nb2Se9 material into 1D chain units. The Nb2Se9, which had a negative zeta potential (-43.3 mV), showed acidic characteristics and strongly bonded with the amine head of octadecyl amine through a charge transfer (from the amine to Se atoms) reaction. The steric hindrance of the octadecyl tail resulted in excellent dispersion of Nb2Se9 (down to nanometre-sized mono-chains).


Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: direct and stereoselective synthesis of (E)-allylic alcohols.
A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.


Ischemia-modified albumin as a biochemical marker in children with neuroblastoma and soft tissue sarcomas.
In this study, the levels of ischemia-modified albumin (IMA) in pediatric oncology patients with soft tissue sarcomas (STSs) and neuroblastoma (NB) were analyzed. To date, there have been no studies concerning IMA in these groups of patients. Ninety-nine children with STSs and NB were analyzed from 2006 to 2009, and 30 healthy children were also enrolled in the study. IMA levels were measured throughout treatment in all patients. The levels of IMA in all cancer patients (mean 116.8±39.3 U/ml), in patients with STSs (mean 119.8±27.5 U/ml), and in patients with NB (mean 114.6±36.6 U/ml) were significantly higher than in the control patients (mean 87.3±38.3 U/ml; P=0.0013, 0.0066, and 0.0164, respectively). IMA levels increased before and during the treatment compared with levels in the controls. The determination of IMA levels in pediatric oncology patients with poor prognoses from STSs and NB may play an important role in predicting response to therapy and overall outcome.


Enantioselective para-Claisen Rearrangement for the Synthesis of Illicium-Derived Prenylated Phenylpropanoids.
The development of the first enantioselective para-Claisen rearrangement has been achieved. Using a chiral aluminum Lewis acid, illicinole is rearranged to give (-)-illicinone A (er 87:13), which can then be converted into more complex Illicium-derived prenylated phenylpropanoids. The absolute configurations of the natural products (+)-cycloillicinone and (-)-illicarborene A have been determined, and our results cast doubt on the enantiopurity of the natural samples.


Activation of 45Ca2+ influx and 22Na+/H+ exchange by epidermal growth factor and vanadate in A431 cells is independent of phosphatidylinositol turnover and is inhibited by phorbol ester and diacylglycerol.
Both epidermal growth factor (EGF) and vanadate can activate 45Ca2+ influx into A431 epidermal carcinoma cells, without a detectable lag period possibly via a voltage-independent calcium channel. 22Na+/H+ exchange and 45Ca2+ uptake are mutually independent. Neither EGF nor vanadate induce any significant change in the steady-state levels of [1,3-3H]glycerol-labeled diacylglycerol, myo-[2-3H]inositol-labeled inositol trisphosphate or in 32P-labeled polyphosphoinositides or phosphatidic acid over the first 10 min of treatment, suggesting that the EGF receptor is not directly coupled to phosphatidylinositol turnover and that the two ion fluxes are not induced via a kinase C-dependent pathway. An increase in turnover of polyphosphoinositides can be detected in EGF-stimulated cells by nonequilibrium labeling with [32P]phosphate, but the increase shows a lag of about 1 min under the conditions used to detect 45Ca2+ influx. Chelation of free Ca2+ decreases but does not abolish the EGF-stimulated turnover. Preincubation with tetradecanoylphorbol acetate or 1-oleoyl-2-acetylglycerol inhibits the increase in 45Ca2+ uptake by both EGF and vanadate. Tetradecanoylphorbol acetate alone does not alter the basal rate of influx when added together with 45Ca2+. Surprisingly, the activation by vanadate and its inhibition by phorbol 12-myristate 13-acetate are unaffected by down-regulation of the EGF receptors through prior incubation with growth factor. Therefore, in A431 cells the activation of Na+/H+ exchange and Ca2+ influx appear to be independent of phosphatidylinositol turnover, and the EGF receptor does not itself function as a Ca2+ channel. Vanadate apparently activates influx through a mechanism distinct from or distal to the EGF receptor.


Penile prosthesis infections.
In this retrospective review we looked at infection rates and risk factors in penile prosthesis recipients. Computer registry records of patients implanted with three-piece inflatable prostheses from April 1986 to March 1999 were reviewed. Bacteriological culture report data were obtained from the medical records. There were 491 three-piece inflatable penile prosthesis recipients with follow-up ranging from 1 to 168 months (mean 83). All patients were implanted more than 1 y ago. There were 10 infections in 491 recipients (2.0%). In 285 primary prosthesis recipients there were seven infections (2.5%). In 206 secondary prosthesis recipients there were three infections (1.5%). Seven infections occurred in 354 non-diabetics (2.0%) and three infections occurred in 137 diabetics (2.2%). None of these differences were statistically significant. Explants for infection were performed in 8 weeks or less following implantation in eight patients. In two patients explants occurred at 17 and 26 months following implantation. Cultures from the periprosthetic space grew E. coli (four), Proteus mirabilis (two), Staph. aureus (two), and bacteroides (two). Infections occurred in 2.0% of three-piece inflatable penile prosthesis recipients. There were no statistically significant differences in infection rates between first time and repeat prosthesis recipients and between diabetic and non-diabetic recipients. Eight of the 10 infections occurred 8 weeks or less following implantation.


Hydrogensquarates of 3-nicotinoyl and 3-isonicotinoyl coumarin--crystal structures and spectroscopic elucidation.
Two novel hydrogensquarates of 3-nicotinoyl (1) and 3-isonicotinoyl (2) coumarin have been synthesized and their structures and properties elucidated spectroscopically and structurally, using single crystal X-ray diffraction, linear-polarized solid-state IR-spectroscopy, UV-spectroscopy and negative ESI MS. Quantum chemical calculations were used to obtain the electronic structure, vibrational data and electronic spectra. The IR-spectroscopic elucidation is carried out by a comparison with the characteristics of corresponding neutral 3-nicotinoyl and 3-isonicotinoyl coumarins.


Bacterial survival strategies in sludge alkaline fermentation for volatile fatty acids production: Study on the physiological properties, temporal evolution and spatial distribution of bacterial community.
This study investigated the dynamics of ATP synthase activity, phospholipid fatty acid (PLFA) profile, and temporal evolution and spatial distribution of bacterial community to analyze bacterial survival strategies in sludge alkaline fermentation (SAF) for volatile fatty acids (VFAs) production. The results revealed a significant increase in ATP synthase activity at pH 9 and 10 (p < 0.05), which could contribute to proton entry into cells and benefit bacterial survival. PLFA analysis indicated that the unsaturated fatty acids content increased with the increase of pH. Firmicutes were the dominant microorganisms in the running stage of the pH 10 reactor (35.81-62.34%) and might have been the key microbes that influenced VFAs production. Further analysis of the spatial distribution of microbial community suggested that Firmicutes mainly lived inside flocs during SAF. These findings provide an understanding for bacterial survival strategies in SAF, which could help to develop methods to further improve VFAs yield.


Effective dose evaluation for BNCT treatment in the epithermal neutron beam at THOR.
This paper aims to evaluate the effective dose as well as equivalent doses of several organs of an adult hermaphrodite mathematical phantom according to the definition of ICRP Publication 60 for BNCT treatments of brain tumors in the epithermal neutron beam at THOR. The MCNP5 Monte Carlo code was used for the calculation of the average absorbed dose of each organ. The effective doses for a typical brain tumor treatment with a tumor treatment dose of 20 Gy-eq were evaluated to be 0.59 and 0.35 Sv for the LLAT and TOP irradiation geometries, respectively. In addition to the stochastic effect, it was found that it is also likely to produce deterministic effects, such as cataracts and depression of haematopoiesis.


Metabolomics Study of the Hepatoprotective Effects and Mechanism of Aqueous Extract of Dendrobium nobile Lindl. on Alcoholic Liver Injury in Rats.
Dendrobium nobile Lindl. (DNL) is effective for the treatment of alcoholic liver disease (ALD), but the underly mechanism is still unclear. This research aimed to investigate the effects and mechanism of the aqueous extract of Dendrobium nobile Lindl (AEDNL) in ALD rats based on a metabolomics approach. In this study, 18 Sprague-Dawley male rats were randomly divided into control, model, and AEDNL groups (n=six). Rats in the AEDNL group were given AEDNL (152 mg/kg) intragastric administration from the first day for 30 consecutive days. From day 15 to day 30, model and AEDNL groups were given 30% ethanol (10 ml/kg) after 4 h of daily administration. Then, serum and liver samples were collected for biochemical analysis, histopathological examination, and Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UPLC-Q-TOF/MS) determination for metabolomic analysis. Compared with the model group, the liver/body weight index and serum levels of TC, LDL-C, and TBIL in the AEDNL group were significantly decreased. Hepatocyte cord arrangement, hepatocyte balloon, and fat vacuolization were significantly improved in the AEDNL group. Metabolism profiles were changed in the model and AEDNL groups. Seven and two common differential metabolites (Guanosine3',5'-cyclic monophosphate, and Glutaric acid) were found in serum and liver, respectively. In addition, the hepatoprotective effect of AEDNL on ALD was related to steroid hormone biosynthesis, riboflavin metabolism, and glycerophospholipid metabolism. The research could provide novel evidence of the protective effects of AEDNL on ALD.


Detrimental effect of propranolol in patients with coronary arterial spasm countered by combination with diltiazem.
This study determines, with quantitative variables, if propranolol is detrimental in patients with documented coronary arterial spasm and if this drug can be used in combination with calcium antagonists. Eleven patients with documented coronary spasm were entered prospectively in a study with 4 phases of 2 days each: (1) control, (2) diltiazem or propranolol (mean 225 +/- 75 mg/day), (3) propranolol or diltiazem (360 mg/day), (4) propranolol and diltiazem. The effects of the drugs were assessed by the detection of ischemic electrocardiographic episodes (24-hour electrocardiographic monitoring) and provocative tests with ergonovine. During the period of treatment with propranolol, the number and the duration of attacks increased and provocative tests had positive results in all patients. Diltiazem completely abolished spontaneous episodes, but 6 of 11 patients remained sensitive to the administration of ergonovine. The association of the 2 drugs led to a disappearance of ischemic episodes. In conclusion, propranolol is ineffective in patients with coronary artery spasm. It can be used in combination with diltiazem, but without any advantage over diltiazem alone.


The effect of cognitive impairment on the predictive value of multimorbidity for the increase in disability in the oldest old: the Leiden 85-plus Study.
prevention of disability is an important aim of healthcare for older persons. Selection of persons at risk is a first crucial step in this process. this study investigates the predictive value of multimorbidity for the development of disability in the general population of very old people and the role of cognitive impairment in this association. the Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up. general population of the city of Leiden, the Netherlands. population based sample of 594 participants aged 85 years. disability in activities of daily living (ADL) was measured annually for 5 years with the Groningen Activity Restriction Scale (range 9-36, 9 = optimal). Multimorbidity is defined as the presence of two or more chronic diseases at age 85 years. Cognitive function was measured at baseline with the mini-mental state examination (MMSE). at baseline participants with multimorbidity had higher ADL disability scores compared with those without [median 11 inter-quartile range (IQR 9-16) versus 9 (IQR 9-13) ADL points, Mann-Whitney U test P < 0.001]. Stratified into four MMSE groups, ADL disability increased over time in all groups, even in participants without multimorbidity (P trend <0.001). Multimorbidity predicted accelerated increase in ADL disability in participants with MMSE of 28-30 points (n = 205, 0.67 points/year, P < 0.001), but not in participants with lower MMSE scores (all P > 0.100). the predictive value of multimorbidity for the increase in ADL disability varies with cognitive function in very old people. In very old people with good cognitive function, multimorbidity predicts accelerated increase in ADL disability. This relation is absent in very old people with cognitive impairment.


Hospitals play hardball. DMC, others are telling governments they can choose between giving them more money or accepting cutbacks.
Hospitals are applying the same gritty, hard-nosed negotiating tactics they used with commercial payers to a new target: local government. For example, Detroit Medical Center has announced major cuts unless city, county and state governments pledge to boost funding. DMC Chairman Dick Gabrys, left, says the system means business.


Gastrodin combined with rhynchophylline inhibits cerebral ischaemia-induced inflammasome activation via upregulating miR-21-5p and miR-331-5p.
The protective effects of gastrodin and rhynchophylline in ischaemic injury have been reported. However, the underlying mechanism and the effect of the combination of these two drugs in ischaemic injury remain unclear. Herein, we aimed to explore the effects of the combination of gastrodin and rhynchophylline on ischaemia-induced inflammasome activation as well as the underlying mechanism. Middle cerebral artery occlusion (MCAO) mice and oxygen glucose deprivation (OGD)-treated BV2 cells were used as in vivo and in vitro models of ischaemia, respectively. Cerebral injury was determined by TTC staining, H&E staining and neurological deficit scores. The effects of the combination of gastrodin and rhynchophylline on inflammasome activation were measured by the MTT assay, Western blotting and ELISA. The expression of miR-21-5p and miR-331-5p was measured by qRT-PCR. The potential binding between miR-21-5p and TXNIP and between miR-331-5p and TRAF6 was analysed with Targetscan and a luciferase assay. MCAO-induced tissue infarction, neurological deficits, inflammasome activation, and downregulation of miR-21-5p and miR-331-5p were all mitigated by the combination of gastrodin and rhynchophylline. In OGD-treated BV2 cells, the combination of gastrodin and rhynchophylline also alleviated inflammasome activation and restored the expression of miR-21-5p and miR-331-5p. TXNIP and TRAF6 were confirmed to be targets of miR-21-5p and miR-331-5p, respectively. Moreover, OGD-induced inflammasome activation was attenuated by the overexpression of either miR-331-5p or miR-21-5p and was further attenuated by the overexpression of both. Finally, we demonstrated that a miR-21-5p inhibitor and/or a miR-331-5p inhibitor counteracted the protective effects of gastrodin and/or rhynchophylline. The combination of gastrodin and rhynchophylline exerts neuroprotective effects by preventing ischaemia-induced inflammasome activation via upregulating miR-21-5p and miR-331-5p.


Bi- or multiparametric MRI in a sequential screening program for prostate cancer with PSA followed by MRI? Results from the Göteborg prostate cancer screening 2 trial.
The PIRADS Steering Committee has called for "higher quality data before making evidence-based recommendations on MRI without contrast enhancement as an initial diagnostic work up," however, recognizing biparametric (bp) MRI as a reasonable option in a low-risk setting such as screening. With bpMRI, more men can undergo MRI at a lower cost and they can be spared the invasiveness of intravenous access. The aim of this study was to assess cancer detection in bpMRI vs mpMRI in sequential screening for prostate cancer (PCa). Within the ongoing Göteborg PCa screening 2 trial, we assessed cancer detection in 551 consecutive participants undergoing prostate MRI. In the same session, readers first assessed bpMRI and then mpMRI. Four targeted biopsies were performed for lesions scored PIRADS 3-5 with bpMRI and/or mpMRI. Cancer was detected in 84/551 cases (15.2%; 95% CI: 12.4-18.4) with mpMRI and in 83/551 cases (15.1%; 95% CI: 12.3-18.2%) with bpMRI. The relative risk (RR) for cancer detection with bpMRI compared to mpMRI was 0.99 (95% one-sided CI: > 94.8); bpMRI was non-inferior to mpMRI (10% non-inferiority margin). bpMRI resulted in fewer false positives, 45/128 (35.2%), compared to mpMRI, 52/136 (38.2%), RR = 0.92; 95% CI: 0.84-0.98. Of 8 lesions scored positive only with mpMRI, 7 were false positives. The PPV for MRI and targeted biopsy was 83/128 (64.8%) for bpMRI and 84/136 (61.8%) for mpMRI, RR = 1.05, 95% CI: 1.01-1.10. In a PSA-screened population, bpMRI was non-inferior to mpMRI for cancer detection and resulted in fewer false positives. • In screening for prostate cancer with PSA followed by MRI, biparametric MRI allows radiologists to detect an almost similar number of prostate cancers and score fewer false positive lesions compared to multiparametric MRI. • In a screening program, high sensitivity should be weighed against cost and risks for healthy men; a large number of men can be saved the exposure of gadolinium contrast medium by adopting biparametric MRI and at the same time allowing for a higher turnover in the MRI room.


Regulatory T cells induce transplant immune tolerance.
Organ transplantation is the preferred treatment option for end-stage organ failure. Although immunosuppressants are effective for preventing the occurrence of acute rejection, they also cause a series of side effects in transplant recipients. To improve the quality of patient survival, a new therapeutic strategy that has fewer side effects than current immunosuppressive regimens and can induce allograft immune tolerance and effectively prevent transplant rejection is needed. In this context, regulatory T cells (Tregs) are considered to be promising research targets. With the increasing understanding of the immunomodulatory role of Tregs, the use of Treg-based cellular therapies has shifted from prevention/treatment of autoimmune diseases to clinical trials for organ transplantation. This review describes the phenotype and in vitro expansion of Tregs and the mechanisms by which they exert immunomodulatory effects in transplantation immunity, highlights recent clinical trial data on Treg-based cellular therapies in transplantation, and describes future directions and limitations.


The NH2- and COOH-terminal amino acid sequence of nuclear protein A24.
The NH2- and COOH-terminal sequence of nuclear portein A24 has been determined by automatic Edman degradation and carboxypeptidase A and B digestion. Protein A24 is of interest because it is composed in part of histone 2A (Goldknofp, I.L., and Busch, H., (1975) Biochem, Biophys. Res. Commun. 65, 951-960). The sequence of the first 37 NH2-terminal residues is: Met-Gln-Ile-Phe-Val-Lys-Thr-Leu-Thr-Gly-Lys-Thr-Ile-Thr-Leu-Glu-Val-Glu-Pro-Ser-Asp-Thr-Ile-Glu-Asn-Val-Lys-Ala-Lys-Ile-Gln-Asp-Lys-Glu-Gly-Ile-Pro- This sequence is not homologous to any known histone sequence. It contains regions of internal homology (italics). The COOH-terminal amino acid sequence is the same as that of histone 2A, naely: -His-His-Lys-Ala-Lys-Gly-Lys-COOH.


Anatomic pathology of hepatocellular carcinoma: impact on prognosis and response to therapy.
A better understanding of signaling pathways in HCC pathogenesis has led to targeted therapies against HCC. Identification of liver cancer stem cell markers and their related pathways is one of the most important goals of liver cancer research. New therapies should ideally target cancer stem cells and not normal stem/progenitor cells, because the latter are very important in regeneration and repair. Individualized HCC therapy will require better definition of patient subgroups that benefit most or should be protected from therapy failure and unwanted side effects. Tumor tissue acquisition should be mandatory, reversing the practice that was established years ago when targeted HCC therapy was but a pipe dream.


Interval between onset of symptoms and diagnosis of medulloblastoma in children: distribution and determinants in a population-based study.
Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis.


Perceiving numerosity does not cause automatic shifts of spatial attention.
It is debated whether the representation of numbers is endowed with a directional-spatial component so that perceiving small-magnitude numbers triggers leftward shifts of attention and perceiving large-magnitude numbers rightward shifts. Contrary to initial findings, recent investigations have demonstrated that centrally presented small-magnitude and large-magnitude Arabic numbers do not cause leftward and rightward shifts of attention, respectively. Here we verified whether perceiving small or large non-symbolic numerosities (i.e., clouds of dots) drives attention to the left or the right side of space, respectively. In experiment 1, participants were presented with central small (1, 2) vs large-numerosity (8, 9) clouds of dots followed by an imperative target in the left or right side of space. In experiment 2, a central cloud of dots (i.e., five dots) was followed by the simultaneous presentation of two identical dot-clouds, one on the left and one on the right side of space. Lateral clouds were both lower (1, 2) or higher in numerosity (8, 9) than the central cloud. After a variable delay, one of the two lateral clouds turned red and participants had to signal the colour change through a unimanual response. We found that (a) in Experiment 1, the small vs large numerosity of the central cloud of dots did not speed up the detection of left vs right targets, respectively, (b) in Experiment 2, the detection of colour change was not faster in the left side of space when lateral clouds were smaller in numerosity than the central reference and in the right side when clouds were larger in numerosity. These findings show that perceiving non-symbolic numerosity does not cause automatic shifts of spatial attention and suggests no inherent association between the representation of numerosity and that of directional space.


Prevalence of driving with blood drug concentrations above proposed new legal limits in Norway: estimations based on drug concentrations in oral fluid.
To estimate the prevalence of driving with blood drug concentrations above the recently proposed Norwegian legal limits for drugged driving in random traffic. The results from a roadside survey of 10,816 drivers was used as basis for the estimation, and the most prevalent drugs were included. Three approaches were used to estimate the prevalence of drug concentrations above the proposed legal limits in blood based on drug concentrations in oral fluid: comparison with drug concentrations observed in oral fluid and blood in pharmacokinetic studies, estimating the prevalence of drug concentrations in blood by calculating the prevalence of drug concentrations in oral fluid that were larger than the limit in blood multiplied with mean oral fluid/blood ratios, and a mathematical simulation mimicking the relationship between drug concentration distributions in blood and oral fluid for populations of drug users. In total, alcohol or drugs were detected in 5.7% of the samples of oral fluid from drivers in normal traffic; 3.8% (n=410) were positive for the drugs that we included in the assessment. The estimation of drug concentrations in blood suggested that about 1.5% had concentrations above the proposed legal limits in blood for the studied drugs, which is about 40% of those who were positive for the drugs in oral fluid. The estimated prevalence of driving with concentrations of psychoactive drugs in blood above the proposed legal limits was for illegal drugs 0.4% and for medicinal drugs 1.1%. These may be regarded as minimum estimates as some drugs were not included in the assessment. These prevalences are higher than the prevalence of driving with blood alcohol concentrations above the legal limit of 0.2g/kg in Norway.


Purification and sequence of a novel ovine adrenal medullary peptide and its precursor.
A 24 amino acid polypeptide that does not originate from (pre)proenkephalin has been isolated from ovine adrenal chromaffin granules. Its sequence is: Arg-Leu-Pro-Gly-Glu-Leu-Arg-Asn-Tyr-Leu-Asp-Tyr-Gly-Glu-Glu-Val-Gly-Glu- Glu-Ala -Ala-Arg-Gly-Val. This peptide is generated from a precursor molecule that has also been purified and partially sequenced. The proteolytic cleavage occurs at a triple Arg site. A search of the available protein sequence data banks shows very little homology to any known protein.


Using spoken attributions to classify abusive families.
Despite claims that beliefs held by abusive parents are important indicators of family functioning, few studies have explored the relationship between patterns of beliefs and severity of abuse. This study applies findings from marital research that demonstrate that maladaptive attributional patterns predict the level of distress experienced in adult relationships. It examines spoken attributions produced by 18 families during diagnostic therapy sessions following serious abuse of a child. Attributions were identified from transcripts and coded using a standard system. Patterns of attributions, defined on the basis of previous work, successfully predicted classification of families by therapists as Good, Uncertain, and Poor, in terms of prognosis for rehabilitation. Using this classification to test hypotheses based on attributional style, group differences were found. In families rated Good, parents were more likely to attribute more control to self than child for negative outcomes. They were also more likely to nominate themselves as causing negative events. Case accounts of families from each category are presented to illustrate how attributional analysis can contribute to an understanding of the individual nature of child abuse.


Antimutator activity during mitosis by a meiotic mutant of yeast.
Diploids homozygous for the mutation spo7-1 do not exhibit net premeiotic DNA synthesis at 34 degrees C and are defective in commitment to recombination following exposure to sporulation medium. The spo7-1 mutation confers antimutator activity during mitosis at 34 degrees C, indicating that the SPO7 gene product is involved in both mitotic and premeiotic DNA metabolism. Strains bearing spo7-1 are slightly more sensitive to killing by ultraviolet light than the wild type but are proficient in UV induced mutation and mitotic intragenic recombination. The mitotic antimutator activity of spo7-1 is directed against a class of forward mutations known to occur more frequently during mitosis than meiosis.


Injustice Without Evidence: The Unique Role of Conspiracy Theories in Social Justice Research.
Conspiracy theories are widespread and have a profound impact on society. The present contribution proposes that conspiracy theories are explanatory narratives that necessarily contain justice judgments, as they include attributions of blame and accusations of unethical or criminal conduct. Conspiratorial narratives also are mental simulations, however, and may elicit genuine feelings of injustice also without evidence of actual malpractice. Indeed, conspiracy theories sometimes describe unfair events that are unlikely to have occurred, unethical authorities that might not actually exist, and so on. Here I propose two complementary processes that stimulate belief in evidence-free conspiracy theories: (1) Existential threats instigate biased mental processing and motivated reasoning, that jointly promote an alternative perception of reality; and (2) group allegiances shape how people perceive, interpret, and remember facts to highlight the immoral qualities of competing outgroups. Due to these processes, conspiracy theories elicit a set of distinct reactions such as poor health choices and rejection of science. Moreover, evidence-free conspiracy theories require interventions beyond traditional approaches to install justice principles, such as debunking falsehoods and reducing polarized intergroup distinctions. I conclude that the scientific study of conspiracy theories is part of, and has a unique place in, social justice research.


Changes in gait and balance parameters in elderly subjects attending an 8-week supervised Pilates programme.
Falls in the elderly have important clinical and economic costs and interventions that may reduce the risk of such problems are potentially important. Although evidence exists for a range of exercise interventions, few have looked at a Pilates-based intervention in a supervised community-based setting and none have specifically measured gait parameters as an outcome. This observational study investigated gait parameters including inter-stride variability (ISV) and postural sway in a group (n = 9) of elderly (age range, 60-76) subjects attending a weekly Pilates class over eight weeks. The results suggest that significant improvement in walking speed (0.14 m/s (95% CI: 0.06-0.21)), step cycle (0.07 m (95% CI: 0.01-0.14)) and length (0.10 m (95% CI: 0.05-0.15)) and a composite ambulation index (6.5% (95% CI: 1.85-11.26)) were seen post the intervention, while coefficients of variation decreased around 15%. In addition both anterior-posterior sway decreased along with a improvement in a fall risk index (FRI). Inter-stride variability on the other hand did not change. The results of this study suggest that a short Pilates program may have the potential to improve gait and sway parameters, including those associated with fall risk.


Histogenesis of adenomatous polyps in the human large intestine.
Detailed histologic analyses have been performed in 75, minute, colorectal polyps from familial polyposis patients. All polyps were composed of typical adenomatous tissue, with, in addition, some normal-looking glands still to be found among the neoplastic elements. Bifurcating glands were not observed, and branching patterns were present in 27% of the polyps only. In 86% of the lesions, the number of gland openings along the polyp surface was larger than the number of gland bases observed along the muscularis mucosae. This difference increased with polyp size (r = 0.9043). Those data, together with previous radioautographic observations, suggest that formation of new adenomatous glands mainly results from an infolding of the surface epithelium between normal, preexisting glands. This mechanism sharply contrasts with villous polyps in which papillary projections arise upwards from the mucosal surface.


Pharmacokinetic interaction between tacrolimus and diltiazem: dose-response relationship in kidney and liver transplant recipients.
To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and tacrolimus in kidney and liver transplant recipients. Nonrandomised seven-period stepwise pharmacokinetic study. Stable kidney (n = 2) and liver (n = 2) transplant recipients maintained on oral tacrolimus twice daily but not taking diltiazem. Patients were treated with seven incremental dosages of diltiazem (0 to 180 mg/day) at > or = 2-weekly intervals. At the end of each interval, 13 blood samples were taken over a 24-hour period to allow determination of morning (AUC(12)), evening (AUC(12-24)) and 24-hour (AUC(24)) areas under the concentration-time curve for tacrolimus, as well as AUC(24) for diltiazem and three of its metabolites. There was considerable interpatient variability in tacrolimus-sparing effect. In the two kidney transplant recipients, an increase in tacrolimus AUC(24) occurred following the 20 mg/day dosage of diltiazem (26 and 67%). The maximum increase in tacrolimus AUC(24) occurred at the maximum diltiazem dosage used (180 mg/day), when the increase was 48 and 177%. In the two liver transplant recipients, an increase in tacrolimus AUC(24) did not occur until a higher diltiazem dosage (60 to 120 mg/day) was given. The increase at the maximum diltiazem dosages used (120 mg/day in one and 180 mg/day in the other) was also lower (18 and 22%) than that exhibited by the kidney transplant recipients. The increase in tacrolimus AUC(12) was similar to the increase in AUC(12-24) when diltiazem was given in the morning only (dosages < or = 60 mg/day). Hence, diltiazem affects blood tacrolimus concentrations for longer than would be predicted from the half-life of diltiazem in plasma. The mean tacrolimus-sparing effect of diltiazem was similar in magnitude to the cyclosporin-sparing effect previously reported. Whether the lesser tacrolimus-sparing effect with diltiazem seen in the liver transplant recipients was due to functional differences in the transplanted liver is not known, but it was not due to lower plasma diltiazem concentrations. Diltiazem makes a logical tacrolimus-sparing agent because of the potential financial savings and therapeutic benefits. Because of interpatient variability, the sparing effect should be demonstrated in each patient and not merely assumed.


Highly permselective uric acid detection using kidney cell membrane-functionalized enzymatic biosensors.
Abnormal blood uric acid (UA) levels can lead to its crystallization in the joints, consequently resulting in gout. Accurate detection of UA in the blood is imperative for the early diagnosis of gout. However, electrochemical UA biosensors are vulnerable to antioxidants in the blood, limiting accurate UA detection. To address this issue, we focused on the function of uric acid transporter 1 (URAT1), which is selectively permeable to UA. URAT1 is abundant in the kidney cell membrane (KCM). To apply URAT1 to a sensor, we developed a KCM-coated UA biosensor (called the KCM sensor) that could selectively detect UA through URAT1. The KCM coating in the fabricated KCM sensor was verified via scanning electron microscopy, atomic force microscopy, and confocal microscopy. The KCM sensor enabled the detection of UA in the range of 0-1000 μM, with a limit of detection of 8.5 μM, suggesting that it allows the diagnosis of the early stages of gout. On the other hand, the UA permeability of the KCM sensor was significantly reduced in the presence of a URAT1 inhibitor, implying that URAT1 is a key factor for UA detection. The selectivity of the KCM sensor was demonstrated by measuring the amount for UA in the presence of various antioxidants. Finally, the KCM sensor was capable of measuring UA in human serum and was reproducible with 0.5-1.6% deviation. The UA permeability and selectivity of the KCM sensor were maintained even after 3 weeks of storage.


Periodicity and synchronization in blood-stage malaria infection.
Malaria fever is highly periodic and is associated with the parasite replication cycles in red blood cells. The existence of periodicity in malaria infection demonstrates that parasite replication in different red blood cells is synchronized. In this article, rigorous mathematical analysis of an age-structured human malaria model of infected red blood cells (Rouzine and McKenzie, Proc Natl Acad Sci USA 100:3473-3478, 2003) is provided and the synchronization of Plasmodium falciparum erythrocytic stages is investigated. By using the replication rate as the bifurcation parameter, the existence of Hopf bifurcation in the age-structured malaria infection model is obtained. Numerical simulations indicate that synchronization with regular periodic oscillations (of period 48 h) occurs when the replication rate increases. Therefore, Kwiatkowski and Nowak's observation (Proc Natl Acad Sci USA 88:5111-5113, 1991) that synchronization could be generated at modest replication rates is confirmed.


Absence of sex differences in size of the genital ducts of the rat prior to embryonic day 15.5-16.0.
Sexual dimorphisms of the rat brain are generally believed to be brought about by the presence of testosterone during a critical period starting at embryonic day (ED) 17/18. In contrast, sex differences of diencephalic and mesencephalic dopaminergic neurons were observed to develop in cell cultures raised from ED 14 rat brains. This was interpreted as evidence indicating that sexual differentiation of certain neural systems may occur independently of gonadal hormones. To substantiate this claim, it was felt necessary to examine the rat embryo for clues to a possible existence of sex differences in hormonal environment prior to ED 17. Morphometry was applied to compare the development of male and female Wolffian and Müllerian ducts, both primary targets of hormones secreted from the male gonad. Diameters of serially cross-sectioned Wolffian and Müllerian ducts were measured in rats of ED 15.0 to ED 16.5. Females had thicker Müllerian ducts from ED 15.5 on. The first step of differentiation in males was the widening of the lumen and a slight increase of the outer diameter of the Wolffian duct at ED 16.0. The size differences of both ducts were most obvious in the vicinity of the lower half of the gonad. Except in Wolffian ducts of ED 16.5, sex differences were absent in the caudal parts of the ducts. It appears that gonadal androgen and Müllerian inhibiting substance do not affect the development of their classical target organs prior to ED 16.0 and ED 15.5, respectively. Furthermore, the first effects are paracrine in nature. There is no evidence for sex differences in systemic androgen environment until ED 16.5.(ABSTRACT TRUNCATED AT 250 WORDS)