Cognitive Reserve Assessment Scale in Health (CRASH): Its Validity and Reliability.
(1) Background: The cognitive reserve (CR) concept has not been precisely defined in severe mental disorders and has been estimated using heterogeneous methods. This study aims to investigate and develop the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH), an instrument designed to measure CR in people with severe mental illness; (2) Methods: 100 patients with severe mental illness (non-affective psychoses and affective disorders) and 66 healthy controls were included. The internal consistency and convergent validity of CRASH were assessed. Spearman's correlations coefficients were also performed to examine the relationship between CRASH and neuropsychological tests, psychosocial functioning, and clinical course; (3) Results: The internal consistency was high (Cronbach's alpha coefficient = 0.903). The CRASH global score had a large positive correlation with the Cognitive reserve questionnaire total score (r = 0.838, p < 0.001), demonstrating good convergent validity. The correlation coefficients between the CRASH total scores and clinical, functional, and neuropsychological performance were different between groups. In order to provide clinical interpretation, severity classification based on diagnosis (non-affective psychotic disorders, affective disorders, and healthy controls) have been created; (4) Conclusions: CRASH is the first CR measure developed specifically for patients with severe mental illness, facilitating reliable and valid measurement of this construct. The scale may aid in the stratification of patients and the implementation of personalized interventions.


Modified Fourier-Hankel method based on analysis of errors in Abel inversion using Fourier transform techniques.
Errors in discrete Abel inversion methods using Fourier transform techniques have been analyzed. The Fourier expansion method is very accurate but sensitive to noise. The Fourier-Hankel method has a significant systematic negative deviation, which increases with the radius; inversion error of the method can be reduced by adjusting the value of a factor. With a decrease of the factor both methods show a noise filtering property. Based on the analysis, a modified Fourier-Hankel method that is accurate, computationally efficient, and has the ability to filter noise in the inversion process is proposed for applying to experimental data.


Coal home heating and environmental tobacco smoke in relation to lower respiratory illness in Czech children, from birth to 3 years of age.
The objective of this study was to evaluate how indoor pollution from tobacco and home heating may adversely affect respiratory health in young children. A birth cohort was followed longitudinally for 3 years to determine incidence of lower respiratory illness (LRI). A total of 452 children born 1994-1996 in two districts in the Czech Republic participated. Indoor combustion exposures were home heating and cooking fuel, mother's smoking during pregnancy, and other adult smokers in the household. Diagnoses of LRI (primarily acute bronchitis) from birth to 3 years of age were abstracted from pediatric records. Questionnaires completed at delivery and at 3-year follow-up provided covariate information. LRI incidence rates were modeled with generalized linear models adjusting for repeated measures and for numerous potential confounders. LRI diagnoses occurred more frequently in children from homes heated by coal [vs. other energy sources or distant furnaces ; rate ratio (RR) = 1.45 ; 95% confidence interval (CI) , 1.07-1.97]. Maternal prenatal smoking and other adult smokers also increased LRI rates (respectively: RR = 1.48 ; 95% CI, 1.10-2.01 ; and RR = 1.29 ; 95% CI, 1.01-1.65) . Cooking fuels (primarily electricity, natural gas, or propane) were not associated with LRI incidence. For children never breast-fed, coal home heating and mother's smoking conferred substantially greater risks: RR = 2.77 (95% CI, 1.45-5.27) and RR = 2.52 (95% CI, 1.31-4.85) , respectively. Maternal smoking and coal home heating increased risk for LRI in the first 3 years of life, particularly in children not breast-fed. Few studies have described effects of coal heating fuel on children's health in a Western country. Breast-feeding may attenuate adverse effects of prenatal and childhood exposures to combustion products.


Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses.
Immunosenescence refers to age-related declines in the capacity to respond to infections such as influenza (flu). Caloric restriction represents a known strategy to slow many aging processes, including those involving the immune system. More recently, some changes in the microbiome have been described with aging, while the gut microbiome appears to influence responses to flu vaccination and infection. With these considerations in mind, we used a well-established mouse model of flu infection to explore the impact of flu infection, aging, and caloric restriction on the gut microbiome. Young, middle-aged, and aged caloric restricted (CR) and ad lib fed (AL) mice were examined after a sublethal flu infection. All mice lost 10-20% body weight and, as expected for these early time points, losses were similar at different ages and between diet groups. Cytokine and chemokine levels were also similar with the notable exception of IL-1α, which rose more than fivefold in aged AL mouse serum, while it remained unchanged in aged CR serum. Fecal microbiome phyla abundance profiles were similar in young, middle-aged, and aged AL mice at baseline and at 4 days post flu infection, while increases in Proteobacteria were evident at 7 days post flu infection in all three age groups. CR mice, compared to AL mice in each age group, had increased abundance of Proteobacteria and Verrucomicrobia at all time points. Interestingly, principal coordinate analysis determined that diet exerts a greater effect on the microbiome than age or flu infection. Percentage body weight loss correlated with the relative abundance of Proteobacteria regardless of age, suggesting flu pathogenicity is related to Proteobacteria abundance. Further, several microbial Operational Taxonomic Units from the Bacteroidetes phyla correlated with serum chemokine/cytokines regardless of both diet and age suggesting an interplay between flu-induced systemic inflammation and gut microbiota. These exploratory studies highlight the impact of caloric restriction on fecal microbiome in both young and aged animals, as well as the many complex relationships between flu responses and gut microbiota. Thus, these preliminary studies provide the necessary groundwork to examine how gut microbiota alterations may be leveraged to influence declining immune responses with aging.


Hamlet-Pattern-Based Automated COVID-19 and Influenza Detection Model Using Protein Sequences.
SARS-CoV-2 and Influenza-A can present similar symptoms. Computer-aided diagnosis can help facilitate screening for the two conditions, and may be especially relevant and useful in the current COVID-19 pandemic because seasonal Influenza-A infection can still occur. We have developed a novel text-based classification model for discriminating between the two conditions using protein sequences of varying lengths. We downloaded viral protein sequences of SARS-CoV-2 and Influenza-A with varying lengths (all 100 or greater) from the NCBI database and randomly selected 16,901 SARS-CoV-2 and 19,523 Influenza-A sequences to form a two-class study dataset. We used a new feature extraction function based on a unique pattern, HamletPat, generated from the text of Shakespeare's Hamlet, and a signum function to extract local binary pattern-like bits from overlapping fixed-length (27) blocks of the protein sequences. The bits were converted to decimal map signals from which histograms were extracted and concatenated to form a final feature vector of length 1280. The iterative Chi-square function selected the 340 most discriminative features to feed to an SVM with a Gaussian kernel for classification. The model attained 99.92% and 99.87% classification accuracy rates using hold-out (75:25 split ratio) and five-fold cross-validations, respectively. The excellent performance of the lightweight, handcrafted HamletPat-based classification model suggests that it can be a valuable tool for screening protein sequences to discriminate between SARS-CoV-2 and Influenza-A infections.


Psychiatric and psychological co-morbidity in patients with dermatologic disorders: epidemiology and management.
Psychiatric and psychological factors play an important role in at least 30% of dermatologic disorders. In many cases the impact of the skin disorder upon the quality of life is a stronger predictor of psychiatric morbidity than the clinical severity of the disorder as per physician ratings. Furthermore, in certain disorders such as acne and psoriasis, the psychiatric co-morbidity, which can be associated with psychiatric emergencies such as suicide, is an important measure of the overall disability experienced by the patient. The severity of depression and increased suicide risk are not always directly correlated with the clinical severity of the dermatologic disorder. Consideration of psychiatric and psychosocial factors is important both for the management, and for some aspects of secondary and tertiary prevention of a wide range of dermatologic disorders. It is useful to use a biopsychosocial model which takes into account the psychological (e.g. psychiatric comorbidity such as major depression and the impact of the skin disorder on the psychological aspects of quality of life) and social (e.g. impact upon social and occupational functioning) factors, in addition to the primary dermatologic factors, in the management of the patient. Some dermatology patients are likely to benefit from psychotherapeutic interventions and psychotropic agents for the management of the psychosocial comorbidity, in addition to the standard dermatologic therapies for their skin disorder.


Lateral heterojunctions within monolayer MoSe2-WSe2 semiconductors.
Heterojunctions between three-dimensional (3D) semiconductors with different bandgaps are the basis of modern light-emitting diodes, diode lasers and high-speed transistors. Creating analogous heterojunctions between different 2D semiconductors would enable band engineering within the 2D plane and open up new realms in materials science, device physics and engineering. Here we demonstrate that seamless high-quality in-plane heterojunctions can be grown between the 2D monolayer semiconductors MoSe2 and WSe2. The junctions, grown by lateral heteroepitaxy using physical vapour transport, are visible in an optical microscope and show enhanced photoluminescence. Atomically resolved transmission electron microscopy reveals that their structure is an undistorted honeycomb lattice in which substitution of one transition metal by another occurs across the interface. The growth of such lateral junctions will allow new device functionalities, such as in-plane transistors and diodes, to be integrated within a single atomically thin layer.


Quadriceps strengthening with the DAPRE technique: case studies with neurological implications.
The Daily Adjustable Progressive Resistive Exercise (DAPRE) technique was developed clinically in an effort to provide an objective means of increasing resistance concurrently with strength increases during knee rehabilitation subsequent to injury/surgery. The key to the DAPRE technique is that on the third and fourth sets of exercise the patient performs as many repetitions as possible. The number of repetitions performed during the third and fourth sets is used to determine the amount of weight that is added to (or sometimes removed from) the working weight for the next set and session, respectively. Consequently, patients exercise nearer their optimal capacity during each weight rehabilitation session, and their strength redevelopment occurs at a much faster rate. This report describes the quariceps muscle strength gains by 21 athletes who used the DAPRE technique following knee immobilization for a minimum of 3 wk. These patients averaged an increase of 4.3 +/- 2.2 (SD) kg X d-1 for a period of 6.4 +/- 2.2 d, as measured by a six repetitions maximum test. It seems unlikely that morphological changes were responsible for these strength increases. It is postulated that strength redevelopment following immobilization involves changes in neural pathways and/or overcoming possible neural inhibitors.


Are insecure-avoidant infants with extensive day-care experience less stressed by and more independent in the strange situation?
In order to test the hypothesis that elevated ratings of avoidance and classifications of insecure-avoidant attachments of infants with extensive infant day-care histories may be the result of the fact that children with routine experiences of separation are less stressed by, and more independent in, the Strange Situation than more traditionally reared infants, 2 groups of 12-month-old infants with insecure-avoidant attachments were compared on 2 behavioral indices in each reunion-with-mother episode of the Strange Situation. 9 infants experienced less than 20 hours per week of nonparental care in their first year, and 11 infants experienced 20 or more hours of care. Contrary to propositions advanced by Clarke-Stewart, Thompson, and others, insecure-avoidant infants with extensive nonparental care experience whimpered, fussed, and cried more and engaged in object play less in each reunion episode than their insecure-avoidant counterparts with less nonparental care experience. These results are discussed in terms of the recent controversy surrounding infant day-care in the United States.


Fatal outcome in classic Kaposi's sarcoma.
First described in 1872, Kaposi's sarcoma is defined as a rare multifocal tumor that originates in the endothelial cells and presents with cutaneous and extracutaneous manifestations. The classic form is most common in elderly men and progression is slow. This tumor responds well to chemotherapy and radiotherapy. This report describes a classic case of Kaposi's sarcoma in a woman with skin and visceral manifestations in whom the disease rapidly progressed to a fatal outcome.


Prevalence of inherited thrombophilia in patients with documented stent thrombosis.
Stent thrombosis (ST) is a multi-factorial process involving different mechanisms. The impact of inherited coagulation disorders in the genesis of ST has never been assessed. The aim of the present study was to evaluate the prevalence of G1691A Factor V Leiden mutation, G20210A Factor II (prothrombin) mutation and C677T homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism in patients with ST. The prevalence of the aforementioned gene variations was assessed in 127 patients: 50 admitted for ST and 77 previously treated with percutaneous coronary intervention not developing ST. A control cohort of 529 healthy volunteers was sampled from the same geographical area. Patients with ST were carriers of at least 1 gene variation in 28% of cases. The prevalence of G1691A Factor V Leiden mutation (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.04-10.5), G20210A Factor II mutation (OR=0.63; 95% CI: 0.12-3.28) and C677T MTHFR homozygous polymorphism (OR=1.13; 95% CI: 0.47-2.72) did not differ significantly among patients with or without ST. The logistic regression model did not show a significant association between gene variations and ST (OR=0.61; 95% CI: 0.24-1.60; P=0.32). A specific association between studied gene variations and ST has not been detected. The relatively high prevalence of at least 1 gene anomaly in such a rare subset of patients, and its consequences in term of secondary prevention therapy, suggests that screening for thrombophilia might be justifiable in cases of ST.


Design and assessment of a microfluidic network system for oxygen transport in engineered tissue.
Oxygen and nutrients cannot be delivered to cells residing in the interior of large-volume scaffolds via diffusion alone. Several efforts have been made to meet the metabolic needs of cells in a scaffold by constructing mass transport channels, particularly in the form of bifurcated networks. In contrast to progress in fabrication technologies, however, an approach to designing an optimal network based on experimental evaluation has not been actively reported. The main objective of this study was to establish a procedure for designing an effective microfluidic network system for a cell-seeded scaffold and to develop an experimental model to evaluate the design. We proposed a process to design a microfluidic network by combining an oxygen transport simulation with biomimetic principles governing biological vascular trees. The simulation was performed with the effective diffusion coefficient (D(e,s)), which was experimentally measured in our previous study. Porous scaffolds containing an embedded microfluidic network were fabricated using the lost mold shape-forming process and salt leaching method. The reliability of the procedure was demonstrated by experiments using the scaffolds. This approach established a practical basis for designing an effective microfluidic network in a cell-seeded scaffold.


The ecological validity of clinical tests of memory and attention in multiple sclerosis.
Ecological validity--the degree to which clinical tests of cognitive functioning predict functional impairment--has recently become an area of interest in neuropsychology. The current study used a sample of 31 cognitively and functionally impaired multiple sclerosis (MS) patients to determine if tests commonly used to assess memory and attentional functioning in MS are ecologically valid. Two methods of improving the ecological validity of cognitive testing were employed. Stepwise multiple regression analyses suggested that tests of memory and attention more analogous to everyday tasks are better predictors of functional impairment in MS than both standard clinical tests of memory and attention, and memory questionnaires completed by the patient or a significant other. Nonetheless, both standard clinical tests and more ecologically valid tests significantly predicted functional impairment. Importantly, they were not significantly correlated with one another, suggesting that the inclusion of both types of tests in evaluating MS patients is warranted.


Theoretical and Empirical Comparison of Big Data Image Processing with Apache Hadoop and Sun Grid Engine.
The field of big data is generally concerned with the scale of processing at which traditional computational paradigms break down. In medical imaging, traditional large scale processing uses a cluster computer that combines a group of workstation nodes into a functional unit that is controlled by a job scheduler. Typically, a shared-storage network file system (NFS) is used to host imaging data. However, data transfer from storage to processing nodes can saturate network bandwidth when data is frequently uploaded/retrieved from the NFS, e.g., "short" processing times and/or "large" datasets. Recently, an alternative approach using Hadoop and HBase was presented for medical imaging to enable co-location of data storage and computation while minimizing data transfer. The benefits of using such a framework must be formally evaluated against a traditional approach to characterize the point at which simply "large scale" processing transitions into "big data" and necessitates alternative computational frameworks. The proposed Hadoop system was implemented on a production lab-cluster alongside a standard Sun Grid Engine (SGE). Theoretical models for wall-clock time and resource time for both approaches are introduced and validated. To provide real example data, three T1 image archives were retrieved from a university secure, shared web database and used to empirically assess computational performance under three configurations of cluster hardware (using 72, 109, or 209 CPU cores) with differing job lengths. Empirical results match the theoretical models. Based on these data, a comparative analysis is presented for when the Hadoop framework will be relevant and non-relevant for medical imaging.


Enzyme I of the phosphotransferase system: induced-fit protonation of the reaction transition state by Cys-502.
Enzyme I (EI), the first component of the phosphoenolpyruvate (PEP):sugar phosphotransferase system (PTS), consists of an N-terminal domain with the phosphorylation site (His-189) and a C-terminal domain with the PEP binding site. Here we use C3-substituted PEP analogues as substrates and inhibitors and the EI(C502A) mutant to characterize structure-activity relationships of the PEP binding site. EI(C502A) is 10 000 times less active than wild-type EI [EI(wt)] with PEP as the substrate, whereas the two forms are equally active with ZClPEP. Cys-502 acts as an acid-base catalyst which stereospecifically protonates the pyruvoyl enolate at C3. The electron-withdrawing chlorine of ZClPEP can compensate for the lack of Cys-502, and in this case, the released 3-Cl-enolate is protonated nonstereospecifically. Several PEP analogues were assayed as inhibitors and as substrates. The respective K(I)/K(m) ratios vary between 3 and 40 for EI(wt), but they are constant and around unity for EI(C502A). EI(wt) with PEP as the substrate is inhibited by oxalate, whereas EI(C502A) with ZClPEP is not. The different behavior of EI(wt) and EI(C502A) toward the PEP analogues and oxalate suggests that the PEP binding site of EI(wt) exists in a "closed" and an "open" form. The open to closed transition is triggered by the interaction of the substrate with Cys-502. The closed conformation is sterically disfavored by C3-modified substrate analogues such as ZClPEP and ZMePEP. If site closure does not occur as with EI(C502A) and bulky substrates, the transition state is stabilized by electron dispersion to the electron-withdrawing substituent at C3.


Exercise-Induced Orgasm and Its Association with Sleep Orgasms and Orgasms During Partnered Sex: Findings From a U.S. Probability Survey.
Prior research has described women's experiences with exercise-induced orgasm (EIO). However, little is known about men's experiences with EIO, the population prevalence of EIO, or the association of EIO with other kinds of orgasm. Using U.S. probability survey data, the objectives of the present research were to: (1) describe the lifetime prevalence of exercise-induced orgasm (EIO) and sleep orgasm; (2) assess respondents' age at first experience of EIO as well as the type of exercise connected with their first EIO; (3) examine associations between lifetime EIO experience and orgasm at respondents' most recent partnered sexual event; and (4) examine associations between lifetime EIO experience and sleep orgasms. Data were from the 2014 National Survey of Sexual Health and Behavior (1012 men and 1083 women, ages 14 years and older). About 9% of respondents reported having ever experienced exercise-induced orgasm. More men than women reported having experienced orgasm during sleep at least once in their lifetime (66.3% men, 41.8% women). The mean age for women's first EIO was significantly older than men (22.8 years women, 16.8 years men). Respondents described a wide range of exercises as associated with their first EIO (i.e., climbing ropes, abdominal exercise, yoga). Lifetime EIO experience was associated with lifetime sleep orgasms but not with event-level orgasm during partnered sex. Implications related to understanding orgasm and recommendations for clinicians and sex educators are discussed.


Large-scale WGS of carbapenem-resistant Acinetobacter baumannii isolates reveals patterns of dissemination of ST clades associated with antibiotic resistance.
To describe the population genetics and antibiotic resistance gene distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates causing infections in three Mediterranean countries. Isolates were collected during the 2013-17 AIDA clinical trial in six hospitals in Israel, Greece and Italy. WGS, bioinformatic characterization and antibiotic resistance profiling were performed. In the 247 CRAB isolates characterized in this study, ST distribution varied by country: 29/31 (93.5%) Greek isolates, 34/41 (82.9%) Italian isolates and 70/175 (40.0%) Israeli isolates belonged to ST2. The identified ST2 isolates included eight distinct clades: 2C, 2D and 2H were significantly more common in Italy, while 2F was unique to Greece. The uncommon ST3 was not present among Greek isolates and constituted only 5/41 (12%) Italian isolates. On the other hand, it was much more common among Israeli isolates: 78/175 (44.6%) belonged to ST3. The vast majority of isolates, 240/247 (97.2%), were found to harbour acquired carbapenemases, primarily blaOXA-23. The chromosomal oxaAb (blaOXA-51-like) and ampC genes characteristic of this organism were also ubiquitous. Most (96.4%) ST3 isolates carried a broad-host-range plasmid IncP1α. The geographical differences in CRAB populations support the theory that clonal spread of CRAB leads to endemicity in hospitals and regions. The close association between antibiotic resistance genes and clades, and between plasmids and STs, suggest that de novo creation of MDR A. baumannii is rare. The clustering of antibiotic resistance genes and plasmids that is unique to each clade/ST, and nearly uniform within clades/STs, suggests that horizontal transmission is rare but crucial to the clade's/ST's success.


Tendon of Flexor Carpi Radialis in carpal tunnel: a radiologic and cadaveric study
Carpal tunnel is an important anatomical passage that carries the flexor tendons into the hand. As there is still no consensus about its contents among the anatomy textbooks, the main purpose of this study was to identify the relations of the flexor carpi radialis tendon in the carpal tunnel. This retrospective study was completed in April 2018 at authors' university's hospital. Seventy-four female and 44 male patients' wrists without any pathology were examined by using magnetic resonance images. The series of axial sections where the pisiform exist were evaluated by using T1 sequence and the structures in the carpal tunnel were identified. Results of this study showed that the tendon of the flexor carpi radialis was found above the flexor retinaculum within its own septal compartment in all patients. According to the results, tendon of flexor carpi radialis crosses the wrist region superficial to the carpal tunnel. Thus, tendon of flexor carpi radialis doesn't have any effect on the carpal tunnel syndrome. Further cadaveric studies would be useful for identifying the contents of the carpal tunnel and morphological organization of the wrist.


A Ru-Co hybrid material based on a molecular photosensitizer and a heterogeneous catalyst for light-driven water oxidation.
A novel approach to anchor a molecular photosensitizer onto a heterogeneous water oxidation catalyst via coordination bonds is presented. A photosensitizer (1) based on [Ru(bpy)3](2+) and decorated with two methylenediphosphonate (M2P) groups has been designed and synthesized for this purpose. The M2P groups in complex 1 allow for coordination of cobalt ions to afford a novel molecular-heterogeneous hybrid material P1. Scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) spectroscopy and X-ray photoelectron spectroscopy (XPS) were used to characterize P1 as an amorphous, non-uniform material that contains Ru and Co in a ratio of 1 : 2. A suspension of P1 in a buffered aqueous solution is active as a light-driven water oxidation catalyst in the presence of persulfate (S2O8(2-)) as electron acceptor. The yield of oxygen is higher when P1 is prepared in situ by mixing and illuminating 1 and Co(2+) in the presence of S2O8(2-). After oxygen evolution ceases, a second material P2 can be isolated from the reaction mixture. P2 is characterized by a lower Ru content than P1, and contains Co in a higher oxidation state. Interestingly, P2 as a freshly prepared suspension is also active for light-driven water oxidation. It is shown that 1 resides in the interior of P1 and P2, and is thus in a location where undesirable quenching pathways of the photo-excited state of 1 limit the oxygen production yields for both P1 and P2.


Postradical cystectomy delayed urethral recurrence: a rare presentation posing diagnostic dilemma.
The incidence of urethral recurrence after radical cystectomy is 1% to 8%, with most cases occurring within the first 2 years of surgery. Prophylactic urethrectomy is rarely performed nowadays due to no known survival benefit and increased morbidity due to the procedure. However, we encountered a rare case of delayed urethral recurrence presenting as recurrent urethral collection 4 years after radical cystectomy with ileal conduit diversion, posing a diagnostic dilemma.


Production of huitlacoche, Ustilago maydis: timing inoculation and controlling pollination.
Huitlacoche is the name given to young, fleshy, edible galls that form when ears of Zea mays are infected by Ustilago maydis. Huitlacoche is processed and sold fresh at markets in Mexico. Interest has increased recently in producing U. maydis as a specialty mushroom in the United States. Silk-channel inoculation methods developed to evaluate common smut resistance in maize can be used to produce huitlacoche commercially. This research assessed the effects of time of inoculation and preventing pollination on the severity of ear galls and yield of huitlacoche produced by inoculating silks with U. maydis. Yield of huitlacoche and severity of ear galls were closely related, as was evident from highly significant linear or curvilinear regressions. Severity and yield were greatest when ears were inoculated 4-8 d after the mid-silk growth stage. Ear galls were 5-15% more severe and yield of huitlacoche was 18-150% greater on ears that were not pollinated, compared to those that were pollinated. Maximum yield of huitlacoche was 131 g ear(-1) from unpollinated male-sterile field corn inoculated 6 d after the mid-silk growth stage and 92 g ear(-1) from detasseled sweet corn inoculated 6 d after mid-silk. About 25% of the total weight of ears consisted of marketable huitlacoche when yields were highest. Quality of huitlacoche was not affected by time of inoculation or pollination treatments, but quality of huitlacoche harvested 12-14 d after inoculation was unacceptable primarily due to lack of teliospores, which affected color and flavor.


Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.
Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.


K+ changes in the extracellular space of the spinal cord and their physiological role.
K+ accumulates in the intercellular space as a result of neuronal activity. The changes in extracellular K+ concentration, delta[K]e (estimated by K+-selective microelectrodes), depends on neuronal activity, on the density of discharging neurones and the removal of the accumulated K+ by diffusion, active transport and current flow through cells. In the mammalian as well as the amphibian spinal cord a single volley in a peripheral nerve increases [K]e by 0.2-0.5 mmol . 1-1, while tetanic stimulation (100 Hz) by 7-8 m-mol . 1-1, with a maximum in the lower dorsal horn. Increased [K]e was also found in lumbar segments when the somatosensory cortex of the cat and medulla of the frog were stimulated. In the frog spinal cord, the tactile stimulation of the hindlimb evoked delta[K]e by about 0.1 mumol . 1-1, nociceptive stimulation by 0.2-1.0 mmol . 1-1. Spontaneous delta[K]e and dorsal root potentials (DRPs) were observed at various intervals after stimulation, associated with the decay phase of delta[K]e. It was shown that primary afferent depolarization (PAD) consists of two components: the 'early' component (mediated by GABA and depressed by picrotoxin or bicuculline) and the 'late' K+ component (potentiated by picrotoxin and bicuculline). Even when increased [K]e produces PAD, this does not mean that it also results in presynaptic inhibition. It was found that the delta[K]e produced depolarization of motoneurones and neuroglia and there is every reason to believe that this also applies to the interneurones. Evidence is available that an increase of [K]e up to 6 mmol . 1-1 facilitates impulse transmission in the spinal cord while higher levels result in its inhibition.


Nasopharyngeal carriage of Streptococcus pneumoniae in healthy children: implications for the use of heptavalent pneumococcal conjugate vaccine.
We assessed the prevalence of Streptococcus pneumoniae serotypes in the nasopharynx of healthy children, antimicrobial susceptibility patterns, risk factors for carriage, and the coverage of heptavalent pneumococcal conjugate vaccine. In 2,799 healthy infants and children, the S. pneumoniae carrier rate was 8.6% (serotypes 3, 19F, 23F, 19A, 6B, and 14 were most common). Most pneumococci (69.4%) were resistant to one or more antimicrobial classes. The rate of penicillin resistance was low (9.1%); macrolide resistance was high (52.1%). Overall, 63.2% of the isolates belonged to strains covered by the heptavalent pneumococcal vaccine. This percentage was higher in children <2 years old (73.1%) and in those ages 2-5 years (68.9%). Sinusitis in the previous 3 months was the only risk factor for carrier status; acute otitis media was the only risk factor for the carriage of penicillin-resistant S. pneumoniae. Most isolated strains are covered by the heptavalent conjugate vaccine, especially in the first years of life, suggesting that its use could reduce the incidence of pneumococcal disease.


Agreement between erythrocyte sedimentation rate and C-reactive protein in hospital practice.
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are frequently prescribed jointly. The usefulness of this practice is uncertain. All patients with ESR and CRP measured at the same time in an academic tertiary hospital during a 1-year period were included. Concomitant measures of serum creatinine, hematocrit, and anti-Xa activity were recorded to study noninflammatory cause of increased ESR. Level of agreement between ESR and CRP was assessed with kappa coefficient, and their accuracy was determined in a medical chart review of 99 randomly selected patients with disagreement between both markers. Among 5777 patients, 35% and 58% had an elevated CRP and ESR, respectively. ESR and CRP were in agreement in 67% of patients (both elevated in 30%, both normal in 37%). A disagreement was observed in 33% (elevated ESR/normal CRP in 28%, normal ESR/elevated CRP in 5%). The kappa coefficient showed poor agreement (k=0.38) between both markers. Review of medical chart showed that 25 patients with elevated CRP and normal ESR had an active inflammatory disease (false-negative ESR). Conversely, 74 patients had elevated ESR and normal CRP-32% had resolving inflammatory disorders, 28% disclosed a variable interfering with the ESR measure (false-positive ESR), 32% had unexplained discrepancies, and 8% had an active inflammatory disease (false-negative CRP). In hospital practice, joint measurement of ESR and CRP is unwarranted. Because of slow variation and frequent confounding, ESR is frequently misleading in unselected patients. When an inflammatory disorder is suspected, priority should be given to CRP.


Neuroprotective Effect of Radix Trichosanthis Saponins on Subarachnoid Hemorrhage.
Redox homeostasis has been implicated in subarachnoid hemorrhage (SAH). As a result, antioxidants and/or free radical scavengers have become an important therapeutic modality. Considering that radix trichosanthis (RT) saponins exhibited strong antioxidant ability both in vivo and in vitro, the present study aimed to reveal whether the neuroprotective activities of RT saponins were mediated by p38/p53 signal pathway after SAH. An established SAH model was used and superoxide dismutase (SOD), malondialdehyde (MDA), induced nitric oxide synthase (iNOS), nitric oxide (NO), lactate dehydrogenase (LDH), p-p38, and p53 activation were detected after 48 h of SAH. The results showed that RT saponins inhibited iNOS expression to restore NO to basal level. Moreover, compared with Cu/Zn-SOD, RT saponins (2 mg/kg/d dosage) significantly increased Mn-SOD activity after SAH. Accompanied with lowered NO and elevated SOD, decreased p38 phosphorylation and p53 activities were observed, especially for RT saponins at 2 mg/kg/d dosage. In this setting, the neurological outcome was also improved with less neuronal cells damage after RT saponins pretreatment. Our findings demonstrated the beneficial effects of RT saponins in enhancing neuroprotective effects by deducing iNOS activity, normalizing SOD level, and inhibiting p-p38 and p53 expression, hence offering significant therapeutic implications for SAH.


4-Hydroxy-2(E)-nonenal enantiomers: (S)-selective inactivation of glyceraldehyde-3-phosphate dehydrogenase and detoxification by rat glutathione S-transferase A4-4.
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase was irreversibly and (S)-selectively inactivated by the enantiomers of racemic 4-hydroxy-2(E)-nonenal (HNE), a reactive product released from biomembranes by lipid peroxidation in cells. Rates of the enzyme inactivations were 1.7, 3.0, and 6.0 M(-1).s(-1) for (R)-, racemic and (S)-HNEs respectively. In rat liver cytosol the HNE was detoxified 2.5-fold more (S)-selectively by GSH conjugation and 2. 4-fold more (R)-selectively by NADH-dependent reduction mediated by alcohol dehydrogenase (ADH) than the opposite enantiomers. However, in the cytosol the GSH conjugation of (R)-HNE proceeded at a much higher rate than did its ADH-mediated reduction. The minor glutathione S-transferase (GST) isoform, A4-4, in the rat (r) liver had a major role in the cytosolic (S)-selective GSH conjugation. The catalytic efficiency, k(cat)/K(m), of purified rGSTA4-4 was 4-fold higher for (S)-HNE than for (R)-HNE; the K(m) was 3-fold higher for (R)-HNE than for (S)-HNE. (S)-HNE was preferentially detoxified to (R)-HNE by rGSTA4-4 when racemic HNE was used as a substrate.


Reduction of lesion-induced deficits in visual reversal learning following cross-modal training.
Two experiments examined the effects of postoperative auditory intensity training on serial brightness reversal learning of visual decorticate rats. In Experiment 1 rats learned an avoidance response cued by a high intensity light prior to visual decortication. Six days later the rats were given either avoidance training with an auditory intensity cue, additional training with the preoperative visual cue, or no training. The next day all rats began a series of 8 brightness discrimination reversals. The no-training lesion group failed the early reversals but reached criterion in later reversals. Lesion rats retrained with visual cues failed early reversals with the low intensity light cue but not reversals with the high intensity cue. In contrast, lesion rats given auditory training easily reached criterion in all reversals. Experiment 2 followed a similar training sequence except auditory training was given after the second reversal. All rats showed rapid acquisition of all visual reversals subsequent to auditory training. These data suggest that generalization of a learning set by cross-modal transfer training with an intact modality can reduce reversal learning deficits following brain damage more efficiently than comparable training with the damaged system.


Immunoradiometric assay of pS2 protein in breast cancer cytosols.
We studied the ELSA-pS2 immunoradiometric kit (CIS Bio International) for pS2 protein assay in breast cancer cytosols according to classic validation methods. In addition, we studied correlations between pS2, steroid receptors, and cathepsin-D assays. Repeatability (CV = 1.5% to 4.8%) and reproducibility (CV = 1.6% to 4.9%) were good. The results were linearly related to pS2 concentrations between 205 and 2200 ng/L; the detection limit was 40 ng/L. The accuracy of the assay was measured by assessing recovery; analytical recoveries were near 100% throughout the standard curve. The use of different compounds for cytosol preparation (Tris 10 mmol/L or phosphate 25 mmol/L, KCl 0.4 mol/L, bovine serum albumin 1 g/L) had no effect on pS2 results. pS2 was assayed in breast tumor cytosols from 197 postmenopausal and 92 premenopausal patients. The mean value was 24 micrograms/g of protein; the median and 25th and 75th percentiles were 6, 1, and 23 micrograms/g protein, respectively. We observed a relation between concentrations of pS2 and those of estrogen and progesterone receptors, but there was no relationship between the concentrations of pS2 and cathepsin-D.


Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures.
Ghrelin, which was identified from the rat stomach, is a potent stimulant for food intake. Several lines of evidence suggest that the orexigenic action of ghrelin is mediated via the neuropeptide Y (NPY) neurons in the arcuate nucleus, although the detailed mechanisms by which ghrelin stimulates NPY neurons are not clear. In this study, we examined the gene regulation of NPY and agouti-related peptide (AGRP), another orexigenic peptide synthesized in the NPY neurons, in the arcuate nucleus by ghrelin in hypothalamic organotypic cultures. Incubation of the hypothalamic explants with ghrelin significantly increased NPY and AGRP mRNA expression in the presence, but not absence, of dexamethasone. Glucocorticoids were also necessary for ghrelin action in vivo because an intracerebroventricular injection of ghrelin significantly increased NPY and AGRP mRNA expression in the arcuate nucleus only in sham-operated, but not in adrenalectomized rats. The stimulatory effects of ghrelin on gene expression were not blocked by a sodium channel blocker tetrodotoxin in the organotypic cultures. Ghrelin also increased NPY heteronuclear (hn) RNA expression, the first transcript that has been used as an indicator for gene transcription. The stimulatory effects of ghrelin on NPY gene expression were abolished in the presence of cycloheximide, which blocks translation, suggesting that de novo protein synthesis is required for ghrelin action. These data suggest that ghrelin stimulates NPY and AGRP gene expression independently of action potentials only in the presence of glucocorticoids. Furthermore, our data demonstrate stimulatory action of ghrelin on NPY gene transcription, which requires de novo protein synthesis.


Tuberculosis incidence correlates with sunshine: an ecological 28-year time series study.
Birmingham is the largest UK city after London, and central Birmingham has an annual tuberculosis incidence of 80 per 100,000. We examined seasonality and sunlight as drivers of tuberculosis incidence. Hours of sunshine are seasonal, sunshine exposure is necessary for the production of vitamin D by the body and vitamin D plays a role in the host response to tuberculosis. We performed an ecological study that examined tuberculosis incidence in Birmingham from Dec 1981 to Nov 2009, using publicly-available data from statutory tuberculosis notifications, and related this to the seasons and hours of sunshine (UK Meteorological Office data) using unmeasured component models. There were 9,739 tuberculosis cases over the study period. There was strong evidence for seasonality, with notifications being 24.1% higher in summer than winter (p<0.001). Winter dips in sunshine correlated with peaks in tuberculosis incidence six months later (4.7% increase in incidence for each 100 hours decrease in sunshine, p<0.001). A potential mechanism for these associations includes decreased vitamin D levels with consequent impaired host defence arising from reduced sunshine exposure in winter. This is the longest time series of any published study and our use of statutory notifications means this data is essentially complete. We cannot, however, exclude the possibility that another factor closely correlated with the seasons, other than sunshine, is responsible. Furthermore, exposure to sunlight depends not only on total hours of sunshine but also on multiple individual factors. Our results should therefore be considered hypothesis-generating. Confirmation of a potential causal relationship between winter vitamin D deficiency and summer peaks in tuberculosis incidence would require a randomized-controlled trial of the effect of vitamin D supplementation on future tuberculosis incidence.


Polyelectrolyte multilayers impart healability to highly electrically conductive films.
Healable, electrically conductive films are fabricated by depositing Ag nanowires on water-enabled healable polyelectrolyte multilayers. The easily achieved healability of the polyelectrolyte multilayers is successfully imparted to the Ag nanowire layer. These films conveniently restore electrical conductivity lost as a result of damage by cuts several tens of micrometers wide when water is dropped on the cuts.


Cost-effectiveness of antibiotic prophylaxis in elective cesarean section.
The proportion of pregnant women delivered by cesarean section has increased steadily during the past three decades. The risk of infection is 10-fold augmented after elective cesarean section compared to vaginal delivery. Antibiotic prophylaxis may reduce endometritis by 62% and superficial wound infection by 38% after elective cesarean section. International guidelines recommend antibiotic prophylaxis in elective cesarean section, but this procedure is not routinely followed in Sweden. Studies of costs of antibiotic prophylaxis in cesarean section show conflicting results and are based on substantially different incidence of postoperative infections. No study of costs of antibiotic prophylaxis in elective cesarean section in a Swedish or Nordic context has been pursued. The aim of this study was to investigate if antibiotic prophylaxis is cost-reducing in elective cesarean section in Örebro County, Sweden. All women undergoing elective cesarean in the Region Örebro County health care system during 2011-2012 were eligible for inclusion. Postoperative infections and risk factors for infections were registered. A hypothetical situation in which all participants had received antibiotic prophylaxis was compared to the actual situation, in which none of them had received antibiotic prophylaxis. The reduction in the risk of postoperative infections resulting from antibiotic prophylaxis was based on a meta-analysis. Costs for in-patient care of postoperative infections were extracted from the accounting system, and costs for out-patient care were calculated according to standard costs. Costs for antibiotic prophylaxis were calculated and compared with the cost reduction that would be implied by the introduction of such prophylaxis. The incidences of deep and superficial surgical site infection were 3.5% and 1.3% respectively. Introduction of antibiotic prophylaxis would reduce health care costs by 31 Euro per cesarean section performed (95% credible interval 4-58 Euro). The probability of cost-saving was 99%. Antibiotic prophylaxis in elective cesarean section is cost-reducing in this health care setting. Our results indicate that the introduction of antibiotic prophylaxis in elective cesarean section can also be cost-saving in low infection rate settings.Trial registration Ethical approval was given by the Regional Ethical Review Board in Uppsala (registration number 2013/484).


Validation of a prognostic calculator for prediction of early vesicoureteral reflux resolution in children.
Treatment of vesicoureteral reflux with observation or surgery is based on a number of clinical variables. We developed a prognostic calculator to predict spontaneous resolution using a computational model. External validation of the computational model is crucial for wide application in clinical practice. We reviewed the records of 82 Japanese children with primary vesicoureteral reflux with resolution status known at 2 years after diagnosis. Clinical data were input into the online prognostic calculator. Prognostic accuracy, positive predictive value and negative predictive value were calculated by comparing the predicted and actual clinical results. Clinical parameters were compared to determine the characteristics of cases in which the computational model failed to predict the reflux outcome. The 2-year resolution rate was 49% (40 of 82 patients). Of the cases 42 (51%) were predicted to resolve and 40 (49%) not to resolve by the prognostic calculator. Overall accuracy of the prognostic calculator was 80.5%, with the prediction accurate in 66 patients and inaccurate in 16. Sensitivity for spontaneous resolution was 82.5% and specificity was 78.6%. Positive predictive value was 78.6% and negative predictive value was 82.5%. The ROC for this calculator was 0.793. Mean age in the 16 cases that were inaccurately predicted (4.96 years) was significantly higher than in the 66 that were accurately predicted (3.00, p <0.05). The prognostic calculator was 80.5% accurate at predicting reflux resolution and was more accurate in younger children. This calculator can be widely applied for many patients with reflux.


The brain microenvironment preferentially enhances the radioresistance of CD133(+) glioblastoma stem-like cells.
Brain tumor xenografts initiated from glioblastoma (GBM) CD133(+) tumor stem-like cells (TSCs) are composed of TSC and non-TSC subpopulations, simulating the phenotypic heterogeneity of GBMs in situ. Given that the discrepancies between the radiosensitivity of GBM cells in vitro and the treatment response of patients suggest a role for the microenvironment in GBM radioresistance, we compared the response of TSCs and non-TSCs irradiated under in vitro and orthotopic conditions. As a measure of radioresponse determined at the individual cell level, γH2AX and 53BP1 foci were quantified in CD133(+) cells and their differentiated (CD133(-)) progeny. Under in vitro conditions, no difference was detected between CD133(+) and CD133(-) cells in foci induction or dispersal after irradiation. However, irradiation of orthotopic xenografts initiated from TSCs resulted in the induction of fewer γH2AX and 53BP1 foci in CD133(+) cells compared to their CD133(-) counterparts within the same tumor. Xenograft irradiation resulted in a tumor growth delay of approximately 7 days with a corresponding increase in the percentage of CD133(+) cells at 7 days after radiation, which persisted to the onset of neurologic symptoms. These results suggest that, although the radioresponse of TSCs and non-TSCs does not differ under in vitro growth conditions, CD133(+) cells are relatively radioresistant under intracerebral growth conditions. Whereas these findings are consistent with the suspected role for TSCs as a determinant of GBM radioresistance, these data also illustrate the dependence of the cellular radioresistance on the brain microenvironment.


Merging terminologies.
A terminology is a systematic, authoritative collection of concept names, or terms, in some domain. No single terminology names all the important concepts in biomedicine. One approach to creating a more comprehensive biomedical terminology is to merge existing biomedical terminologies, as the UMLS( Metathesaurus( has done for the last six years. Because existing terminologies may overlap--for example, one terminology may name a concept also named by another terminologyQthe terminologies in the Metathesaurus must be merged. Some terminologies suggest merges through their structure or content e.g., they suggest synonyms or connections to other terminologies; other merges can be suggested by algorithm. Regardless, all merges in the Metathesaurus must be approved by a human editor with appropriate domain knowledge. By the time Meta-U96 is released early in 1996, one prototype and seven released versions of the Metathesaurus will have been produced by a sequence of four qualitatively different methods, named for the way in which they merge terms: #1 "Term Rewrite Rules, #2 "Transitive Closure on Facts," #3 "Fact-at-a-Time Concept Merging," and #4 "Action-at-a-Time Object Processing." The development of each method has been constrained by the annual Metathesaurus release schedule. The first two methods made the best use of limited computational resources, and the last two make better use of human editing resources.


Obesity continues to increase in the majority of the population in mid-Sweden-a 12-year follow-up.
The aim was to investigate trends in the prevalence of obesity by age and level of education in the general population in mid-Sweden from year 2000 to 2012. A postal questionnaire was sent to a random population sample aged 25-74 years in years 2000, 2004, 2008 and 2012. The overall response rates were 67%, 65%, 60% and 53%, respectively, and the study included 29 017, 27 385, 25 910 and 24 152 respondents, respectively. Obesity (BMI ≥ 30 kg/m(2)) was based on self-reported weight and height. The age-standardized prevalence of obesity increased from 13% to 17% in women and from 12% to 17% in men between 2000 and 2012. Obesity increased in all age groups from 2000 to 2008 and continued to increase among the middle aged (45-64 years) between 2008 and 2012. The socioeconomic gradient in obesity changed during the study period since the absolute increase in obesity was steepest at the middle educational level. In 2012, the prevalence of obesity was almost twice as high at both middle and low educational levels compared with high educational level. The 'true' prevalence of adult obesity, corrected for self-reported weight and height, was around 20% in 2012 for both men and women. In the majority, among the middle-aged and those with secondary education, the prevalence of obesity continued to increase even between 2008 and 2012.


Case report: solid-pseudopapillary tumour of the pancreas associated with dorsal agenesis.
Solid-pseudopapillary tumour of the pancreas is a rare benign or low-grade malignant epithelial tumour; its association with pancreatic dorsal agenesis has been reported only once before. We present the radiological and histological findings of a case of pancreatic solid-pseudopapillary tumour associated with total pancreatic dorsal agenesis. A 49-year-old woman presented with abdominal pain radiating to the back for several months. Radiological findings showed absence of the dorsal pancreas and an 8 cm x 6 cm diameter tumour arising from the head of the pancreas. She underwent successful complete resection of the tumour. Histopathology revealed a diagnosis of solid-pseudopapillary tumour.


HIV-Tat Induces the Nrf2/ARE Pathway through NMDA Receptor-Elicited Spermine Oxidase Activation in Human Neuroblastoma Cells.
Previously, we reported that HIV-Tat elicits spermine oxidase (SMO) activity upregulation through NMDA receptor (NMDAR) stimulation in human SH-SY5Y neuroblastoma cells, thus increasing ROS generation, which in turn leads to GSH depletion, oxidative stress, and reduced cell viability. In several cell types, ROS can trigger an antioxidant cell response through the transcriptional induction of oxidative stress-responsive genes regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2). Here, we demonstrate that Tat induces both antioxidant gene expression and Nrf2 activation in SH-SY5Y cells, mediated by SMO activity. Furthermore, NMDAR is involved in Tat-induced Nrf2 activation. These findings suggest that the NMDAR/SMO/Nrf2 pathway is an important target for protection against HIV-associated neurocognitive disorders.


Progress of the study of rho-kinase and future perspective of the inhibitor.
Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that the Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in VSMC proliferation, cell migration, and gene expression. Two isoforms of Rho-kinase encoded by two different genes have been identified: ROCK1 and ROCK2. These isoforms are ubiquitously expressed, but with preferential expression of ROCK2 in the brain and skeletal muscle. The expression of Rho-kinase itself is mediated by the protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At the cellular level, Rho-kinase mediates VSMC contraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. Rho-kinase also upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, while it downregulates endothelial nitric oxide synthase and inhibits insulin signaling. Rho-kinase activity regulates major morphogenetic events during embryonic development through cell migration, differentiation, and axis formation. In animal and clinical studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and ischemia/reperfusion injury. Fasudil, a selective Rho-kinase inhibitor developed in Japan, is effective for the treatment of a wide range of cardiovascular diseases, with reasonable safety. Thus Rho-kinase is an important therapeutic target in cardiovascular medicine. This review summarizes the recent progress in the study of Rho-kinase and addresses future perspectives of Rho-kinase inhibitors.


First molecular survey and identification of Anaplasma spp. in white yaks (Bos grunniens) in China.
Anaplasmosis is caused by a group of obligate intracellular bacteria in the genus Anaplasma, which are transmitted by ticks and infect humans, domestic animals and wildlife. This study was conducted to determine the prevalence and molecular characterization of Anaplasma spp. in semi-wild white yaks sampled in Tianzhu Tibetan Autonomous County, northwest China. Out of 332 samples tested, 35 (10·9%) were positive for Anaplasma spp. The positive rates were 6·2% (20/322) and 5·3% (17/322) for Anaplasma bovis and Anaplasma phagocytophilum in white yaks, respectively. None of the sample was positive for Anaplasma marginale. Two (0·6%) samples were simultaneously positive to A. bovis and A. phagocytophilum. Sequence analysis of the 16S rRNA gene revealed two genotypes (ApG1 and ApG2) of A. phagocytophilum and two sequence types (ST1 and ST2) of A. bovis in white yaks. This study is the first to document the presence of Anaplasma in white yaks. Our findings extend the host range for Anaplasma species and provide more valuable information for the control and management of anaplasmosis in white yaks.


Chemical and enzymatic N-glycan release comparison for N-glycan profiling of monoclonal antibodies expressed in plants.
Plants synthesize N-glycans containing the antigenic sugars alpha(1,3)-fucose and beta(1,2)-xylose. Therefore it is important to monitor these N-glycans in monoclonal antibodies produced in plants (plantibodies). We evaluated several techniques to characterize the N-glycosylation of a plantibody produced in tobacco plants with and without the KDEL tetrapeptide endoplasmic reticulum retention signal which should inhibit or drastically reduce the addition of alpha(1,3)-fucose and beta(1,2)-xylose. Ammonium hydroxide/carbonate-based chemical deglycosylation and PNGase A enzymatic release were investigated giving similar 2-aminobenzamide-labeled N-glycan HPLC profiles. The chemical release does not generate peptides which is convenient for MS analysis of unlabeled pool but its main drawback is that it induces degradation of alpha1,3-fucosylated N-glycan reducing terminal sugar. Three analytical methods for N-glycan characterization were evaluated: (i) MALDI-MS of glycopeptides from tryptic digestion; (ii) negative-ion ESI-MS/MS of released N-glycans; (iii) normal-phase HPLC of fluorescently labeled glycans in combination with exoglycosidase sequencing. The MS methods identified the major glycans, but the HPLC method was best for identification and relative quantitation of N-glycans. Negative-mode ESI-MS/MS permitted also the correct identification of the linkage position of the fucose residue linked to the inner core N-acteylglucosamine (GlcNAc) in complex N-glycans.


Cognitive-behavioral therapy to promote smoking cessation among African American smokers: a randomized clinical trial.
The health consequences of tobacco smoking disproportionately affect African Americans, but research on whether efficacious interventions can be generalized to this population is limited. This study examined the efficacy of group-based cognitive-behavioral therapy (CBT) for smoking cessation among African Americans. Participants (N = 154; 65% female, M = 44 years old, mean cigarettes/day = 13) were randomly assigned to either (a) group CBT or (b) group general health education (GHE). Participants in both conditions received 6 sessions of counseling and 8 weeks of transdermal nicotine patches. The primary outcome variable was 7-day point prevalence abstinence (ppa), assessed at the end of counseling (2 weeks) and at 3- and 6-month follow-ups. Secondary outcomes included 24-hr ppa and 28-day continuous abstinence (assessed at 3 and 6 months). Intent-to-treat analyses demonstrated the hypothesized effects, such that 7-day ppa was significantly greater in the CBT than the GHE condition at the end of counseling (51% vs. 27%), at 3 months (34% vs. 20%), and at 6 months (31% vs. 14%). Results of a generalized linear mixed model demonstrated a significant effect of CBT versus GHE on 7-day ppa (odds ratio = 2.57, 95% CI [1.40, 4.71] and also an effect of time (p < .002). The Condition x Time interaction was not significant. Similar patterns of results emerged for 24-hour ppa and 28-day continuous abstinence. Results from per protocol analyses (i.e., participants who completed all aspects of the study) corroborate the intent-to-treat findings. These results demonstrate that intensive, group CBT smoking cessation interventions are efficacious among African American smokers.


Doctors, managers and politicians.
Doctors and politicians have rarely seen eye to eye on what a health service should provide and how it should be managed. The introduction of general management in 1984, while initially successful, created new fault-lines between doctors, managers and politicians that were compounded by a succession of NHS reorganisations. These changes brought politics too close to front-line management, highlighted the incompatibility of managerially determined targets with the essence of professional practice, and have led to the development of a management agenda disconnected from healthcare. Remedies are suggested here that reflect the particular roles and contributions of each group that could restore a sense of shared purpose in the running of the NHS.


Giant cell arteritis: a review.
Giant cell arteritis is the most common vasculitis in Caucasians. Acute visual loss in one or both eyes is by far the most feared and irreversible complication of giant cell arteritis. This article reviews recent guidelines on early recognition of systemic, cranial, and ophthalmic manifestations, and current management and diagnostic strategies and advances in imaging. We share our experience of the fast track pathway and imaging in associated disorders, such as large-vessel vasculitis.


Noncoding RNAs and immune checkpoints-clinical implications as cancer therapeutics.
A major mechanism of tumor development and progression is silencing of the patient's immune response to cancer-specific antigens. Defects in the so-called cancer immunity cycle may occur at any stage of tumor development. Within the tumor microenvironment, aberrant expression of immune checkpoint molecules with activating or inhibitory effects on T lymphocytes induces immune tolerance and cellular immune escape. Targeting immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and its ligand PD-L1 with specific antibodies has proven to be a major advance in the treatment of several types of cancer. Another way to therapeutically influence the tumor microenvironment is by modulating the levels of microRNAs (miRNAs), small noncoding RNAs that shuttle bidirectionally between malignant and tumor microenvironmental cells. These small RNA transcripts have two features: (a) their expression is quite specific to distinct tumors, and (b) they are involved in early regulation of immune responses. Consequently, miRNAs may be ideal molecules for use in cancer therapy. Many miRNAs are aberrantly expressed in human cancer cells, opening new opportunities for cancer therapy, but the exact functions of these miRNAs and their interactions with immune checkpoint molecules have yet to be investigated. This review summarizes recently reported findings about miRNAs as modulators of immune checkpoint molecules and their potential application as cancer therapeutics in clinical practice.


Combined CXC chemokine and interleukin-12 gene transfer enhances antitumor immunity.
It has been shown that intratumor administration of an adenovirus vector expressing IL-12 produces a potent T cell-mediated response that leads to significant tumor regression in a murine breast cancer model. IP-10 and MIG are CXC chemokines that recruit mononuclear cells in vivo. In addition to their chemotactic roles, IP-10 and MIG inhibit angiogenesis. We tested whether the addition of IP-10 or MIG may both enhance the antitumor immune response of IL-12 through T cell recruitment and inhibit tumor growth through angiostasis. Adenovirus vectors expressing IP-10 or MIG and/or IL-12 were administered intratumorally in a murine model of mammary adenocarcinoma and fibrosarcoma. Administration of IP-10 or MIG in combination with IL-12 resulted in considerable tumor regression and increased survival time of tumor-bearing animals as compared with IP-10, MIG, IL-12 alone or control-treated animals, with the IP-10 IL-12 combination being most effective. These results suggest augmenting the antitumor immune response and inhibiting tumor angiogenesis with adenoviral vectors expressing IP-10 in combination with IL-12 is a novel way to enhance tumor regression.


Prolyl 4-hydroxylase from Volvox carteri. A low-Mr enzyme antigenically related to the alpha subunit of the vertebrate enzyme.
Prolyl 4-hydroxylase was isolated in a highly purified form from a multi-cellular green alga, Volvox carteri, by a procedure consisting of ion-exchange chromatography and affinity chromatography on poly(L-hydroxyproline) coupled to Sepharose. Two other affinity-column procedures were also developed, one involving 3,4-dihydroxyphenylacetate and the other 3,4-dihydroxyphenylpropionate linked to Sepharose. The Km values of the Volvox enzyme for the co-substrates and the peptide substrate, as well as the inhibition constants for selected 2-oxoglutarate analogues, were similar to those of the enzyme from Chlamydomonas reinhardii, except that the Km for 2-oxoglutarate with the Volvox enzyme was 6-fold greater. The temperature optimum of the Volvox enzyme was also 10 degrees C higher. The apparent Mr of the Volvox enzyme by gel filtration was about 40,000, being similar to that reported for the Chlamydomonas enzyme but markedly lower than that of the vertebrate enzymes. A similar apparent Mr of about 40,000 was also found for prolyl 4-hydroxylase from the green alga Enteromorpha intestinalis, whereas the enzyme from various vascular plants gave an apparent Mr greater than 300,000. SDS/polyacrylamide-gel electrophoresis demonstrated in the highly purified Volvox enzyme the presence of a major protein band doublet with a Mr of about 65,000 and a minor doublet of Mr about 55,000-57,000. A polyclonal antiserum, prepared against the Mr-65,000 doublet, stained in immunoblotting the Mr-65,000 doublet as well as the alpha subunit, but not the beta subunit, of the vertebrate prolyl 4-hydroxylase. An antiserum against the beta subunit of the vertebrate enzyme stained in immunoblotting a Mr-50,000 polypeptide in a partially purified Volvox enzyme preparation, but did not stain either the Mr-65,000 or the Mr-55,000-57,000 doublet of the highly purified enzyme. The data thus suggest that the active Volvox carteri prolyl 4-hydroxylase is an enzyme monomer antigenically related to the alpha subunit of the vertebrate enzyme.


Assessing the Effectiveness of Strategies in US Birth Cohort Screening for Hepatitis C Infection.
Chronic hepatitis C infection in the USA is a highly morbid condition and current guidelines recommend one-time screening among the birth cohort (1945-1965). Understanding strategies to optimize screening can help inform future hepatitis C virus (HCV) screening guidelines. A focused literature search was performed using PubMed and manual abstract review from major hepatology conferences over the past 2 years. The search strategy involved using Medical Subject Headings terms for hepatitis C, screening, birth cohort, baby boomers, and 1945-1965. The review was limited to data from the USA. A total of 327 articles were identified and 36 abstracts were included, with studies published between 2012-2019. Strategies including clinician education, electronic medical record alerts, reflex HCV RNA testing, point-of-care testing, multisite (outpatient, inpatient, emergency department, endoscopy suite) initiatives, direct patient solicitation, and utilization of non-physician providers have increased HCV screening rates. However, broad implementation remains less than optimal. Barriers include lack of patient acceptance to screening and engagement in the HCV care cascade. The Veterans Affairs Healthcare System has achieved higher birth cohort screening rates through an integrated approach requiring high-level engagement by leadership and institutional commitment. Multiple strategies for increasing birth cohort screening have been successful, but overall rates of HCV screening remain low. These strategies can inform public health efforts to implement emerging national recommendations for expansion of HCV screening to all U.S. adults age 18 or older.


IL-6 induces long-term protective immunity against a lethal challenge of influenza virus.
The coadministration of cytokines can modulate immunity in DNA based viral vaccines. In order to determine the effects of various cytokines on long-term protection against the influenza virus, mice were intramuscularly coinoculated with plasmids that encoded either the granulocyte-macrophage colony-stimulating factor (GMCSF), interleukin-4 (IL-4), interleukin-12 (IL-12), or the interleukin-6 (IL-6) gene, in the presence of two plasmids that encoded the nucleoprotein (NP) and the hemagglutinin (HA) gene of the influenza A virus. The coadministration of IL-4, IL-6 and IL-12 transiently enhanced antibody responses against influenza virus in early time points (4 to 7 week post immunization) after post inoculation. The expression of GMCSF gene resulted in the sustained elevation of antibody responses for at least 20 weeks post inoculation. However, NP-specific CTL responses decreased in these animals. Mice that received either the IL-12 or the IL-6 gene had enhanced NP-specific CTL responses. Remarkably, the coadministration of the IL-6 gene completely protected mice from a lethal challenge with influenza virus. Conversely, mice that received the IL-4 gene appeared to be more susceptible to lethal challenge than mice that were inoculated with the NP and the HA genes alone. These results demonstrate that the use of cytokines as molecular adjuvants when coadministered in influenza DNA vaccination must be specific. Our data also demonstrates that the coadministration of IL-6 should be considered to enhance the efficacy of influenza DNA vaccines.


Intermediate nerve conduction velocities define X-linked Charcot-Marie-Tooth neuropathy families.
Three genetic loci for the Charcot-Marie-Tooth (CMT) syndromes with slow motor nerve conduction velocities (hereditary motor and sensory neuropathy: HMSN type I) have been mapped to chromosomes 1 (CMT1B), 17 (CMT1A), and the X chromosome (CMTX). The clinical features of these three CMT subgroups are similar. To determine whether any clinical features distinguish CMTX families, the range of clinical findings and motor nerve conduction velocities were examined in two large CMTX families, the range of clinical findings and motor nerve conduction velocities were examined in two large CMTX families with CMTX proven by linkage to X-chromosome markers. CMTX males had more wasting and weakness than CMTX females or individuals with CMT1A. Patellar reflexes were more often retained in CMTX. Motor nerve conduction velocities were faster than in CMT1A. Intermediate-range median nerve conduction velocities were present in CMTX females (45 +/- 9 m/sec; range, 26 to 61 m/sec). These velocities were significantly faster than those for CMT1A females (22 +/- 8 m/sec, p < 0.0001). Median nerve conduction velocities in CMTX males (31 +/- 6 m/sec) were significantly slower than in CMTX females and faster than in CMT1A males (20 +/- 6 m/sec, p < 0.0001). The combination of slow conduction velocities in affected males (< 40 m/sec) and intermediate-range median motor conduction velocity results (> 40 m/sec) in affected or obligate carrier females is a useful distinguishing feature to separate CMTX from CMT1A, as intermediate conduction velocities are not present in autosomal-dominant dominant CMT1A families. This feature defines possible CMTX families for linkage studies. Families with no male-to-male inheritance of the syndrome, slow motor nerve conductions in affected males, and normal or intermediate-range conduction velocities in carrier females should be considered to be X-linked CMT families.


Disordered eating in male athletes: a meta-analysis.
We examined the propensity for male athletes to exhibit symptoms of disordered eating. Using meta-analytic techniques, we examined overall effect size, individual effect sizes for specific sport types, standard of athletic competition and diagnostic tools from 31 studies. When all studies were considered as a homogeneous group, male athletes did not have symptoms of disordered eating that were significantly different from non-athletic controls. However, significant moderator effects emerged for sport type and measurement: (a) wrestling reported a greater incidence of disordered eating; and (b) studies that reported data from the Eating Attitudes Test yielded a significantly greater incidence of disordered eating in male athletes compared to non-athletes. Although some sports seem to present a higher risk of disordered eating compared to others, the effects are weak and heterogeneous. We make suggestions for the development of the research area, which has been severely hampered by the diagnostic tools that have been available for the study of men.


Three-dimensional assessment of facial development in children with unilateral cleft lip with and without alveolar cleft.
Children with cleft lip or cleft lip and alveolus represent a minor group in the cleft population. The aim of this study was to analyze the faces of these children. In a prospective, cross-sectional study, 344 healthy children and 30 children with cleft lip or cleft lip and alveolus were scanned three-dimensionally at the age of 0 to 6 years. Twenty-one standard anthropometric landmarks were identified, and the images were superimposed. Growth curves for normal facial development were calculated. The facial morphology of cleft children was compared with that of unaffected children.Facial morphology and growth in the transverse direction of the examined patients appeared broadened in all levels. Especially the nasal landmarks indicated a widening of the nose. The landmarks ac l, sbal l, sbal r, c l, sn l, and ls l differed significantly from unaffected children. In the sagittal and vertical dimensions, there was no significant difference compared with unaffected children.Our study demonstrates that surgical and orthodontic treatment can restore the vertical and sagittal dimensions of the face in children with cleft lip with and without alveolar clefts; however, the transverse dimension-especially the nose-remains too broad.


Adapterama I: universal stubs and primers for 384 unique dual-indexed or 147,456 combinatorially-indexed Illumina libraries (iTru & iNext).
Massively parallel DNA sequencing offers many benefits, but major inhibitory cost factors include: (1) start-up (i.e., purchasing initial reagents and equipment); (2) buy-in (i.e., getting the smallest possible amount of data from a run); and (3) sample preparation. Reducing sample preparation costs is commonly addressed, but start-up and buy-in costs are rarely addressed. We present dual-indexing systems to address all three of these issues. By breaking the library construction process into universal, re-usable, combinatorial components, we reduce all costs, while increasing the number of samples and the variety of library types that can be combined within runs. We accomplish this by extending the Illumina TruSeq dual-indexing approach to 768 (384 + 384) indexed primers that produce 384 unique dual-indexes or 147,456 (384 × 384) unique combinations. We maintain eight nucleotide indexes, with many that are compatible with Illumina index sequences. We synthesized these indexing primers, purifying them with only standard desalting and placing small aliquots in replicate plates. In qPCR validation tests, 206 of 208 primers tested passed (99% success). We then created hundreds of libraries in various scenarios. Our approach reduces start-up and per-sample costs by requiring only one universal adapter that works with indexed PCR primers to uniquely identify samples. Our approach reduces buy-in costs because: (1) relatively few oligonucleotides are needed to produce a large number of indexed libraries; and (2) the large number of possible primers allows researchers to use unique primer sets for different projects, which facilitates pooling of samples during sequencing. Our libraries make use of standard Illumina sequencing primers and index sequence length and are demultiplexed with standard Illumina software, thereby minimizing customization headaches. In subsequent Adapterama papers, we use these same primers with different adapter stubs to construct amplicon and restriction-site associated DNA libraries, but their use can be expanded to any type of library sequenced on Illumina platforms.


Liability of the mentally ill and their insurers in negligence and other civil actions.
Although familiar with the insanity defense, psychiatrists know little about the liability of mentally ill persons in civil actions or the secondary liability of their insurers. Generally the mentally ill are responsible civilly for their actions regardless of mental state except where the law requires specific intent and the illness negates such intent. Psychiatrists and other mental health workers may thus have grounds for suit against patients who injure them. While insurance coverage may exclude intentional acts, insurers may be civilly liable, even for blatant criminal acts. The author reviews the relevant laws and presents illustrative case examples.


Users' and providers' perspectives on technological procedures for 'normal' childbirth in a public maternity hospital in Salvador, Brazil.
To reveal the effect of cultural practices on the way in which normal birth is conducted in a public hospital in Brazil. This article about a public maternity hospital in Salvador, Brazil, compares the points of view of providers and users on four technological normal childbirth procedures: trichotomy, episiotomy, oxytocin infusion, and epidural analgesia. Fieldwork carried out from 2002 to 2003 combined qualitative and quantitative methods. Institutional practices make childbirth unnecessarily difficult for women. Nonetheless, most women accept the conditions because the medical procedures make sense according to their cultural understandings. Service providers support the use of such procedures, although doctors are aware that they contradict recommendations found in scientific medical literature. This article argues that from the perspective of both providers and users, the technological procedures are infused with a culturally specific set of meanings and values. Policymakers must address the cultural understandings of both users and health care professionals in order to improve maternal healthcare in public hospitals in Brazil.


How do extraverts process jokes? An event-related potential study on humor processing.
Extraverts and introverts show different preferences for humor regarding different humor types. However, few studies focused on the neurological underpinnings of the connection between extraversion and the stage-wise cognitive model of humor processing. To investigate the influence of extraversion on different sub-stages of humor processing, electroencephalography (EEG) data was collected when participants read and rated jokes and non-jokes. The event-related potential (ERP) data showed a smaller N400 (300-500 ms) but a larger late positive potential (500-900 ms) for jokes than non-jokes, which may reflect lexical association and integrative interpretation in joke processing. The more extraverted group had a larger P2 (200-300 ms) and a smaller N400 than the less extraverted group in response to all the stimuli, which may indicate their different allocation of attentional and cognitive resources to external stimulation. Additionally, the regression analyses showed that the late positivity effects of jokes were positively correlated with the extraversion level. The results could imply extraverts' controlled processes of cognitive resource allocation for jokes, and suggest the same groups' attentiveness and motivation for reward stimuli (i.e., jokes). Importantly, our ERP data could support extraverts' increased exploration for verbal humor from a better temporal aspect for the first time.


[Pituitary gonadotropin releasing hormone (GnRH) and breast cancer].
Peptide and steroidal hormones, growth promoting factors and other trophic factors are all involved in the regulation of tumoral growth. Hormonal therapy of breast cancer includes a medical treatment and surgical as well, such as oophorectomy and hypophysectomy. The hormone-dependent cancer like breast cancer, is treated with anti-estrogenic substances, but with the arrival of analogues of gonadotropins releasing (a-GnRH) hormone; these neuropeptides may have an important role in the treatment of breast cancer, due to the few side effects.


Supramolecular GAG-like Self-Assembled Glycopeptide Nanofibers Induce Chondrogenesis and Cartilage Regeneration.
Glycosaminoglycans (GAGs) and glycoproteins are vital components of the extracellular matrix, directing cell proliferation, differentiation, and migration and tissue homeostasis. Here, we demonstrate supramolecular GAG-like glycopeptide nanofibers mimicking bioactive functions of natural hyaluronic acid molecules. Self-assembly of the glycopeptide amphiphile molecules enable organization of glucose residues in close proximity on a nanoscale structure forming a supramolecular GAG-like system. Our in vitro culture results indicated that the glycopeptide nanofibers are recognized through CD44 receptors, and promote chondrogenic differentiation of mesenchymal stem cells. We analyzed the bioactivity of GAG-like glycopeptide nanofibers in chondrogenic differentiation and injury models because hyaluronic acid is a major component of articular cartilage. Capacity of glycopeptide nanofibers on in vivo cartilage regeneration was demonstrated in microfracture treated osteochondral defect healing. The glycopeptide nanofibers act as a cell-instructive synthetic counterpart of hyaluronic acid, and they can be used in stem cell-based cartilage regeneration therapies.


Distinct lipid effects on tBid and Bim activation of membrane permeabilization by pro-apoptotic Bax.
After exposure to stressful stimuli, apoptotic signals can be relayed to mitochondria by pro-apoptotic activator proteins, tBid (truncated Bid/p15) and Bim (Bcl-2 interacting mediator), which activate Bax (Bcl-2 associated X protein) and or Bak (Bcl-2 antagonist/killer) to induce mitochondrial outer membrane (MOM) permeabilization (MOMP). These protein-protein and protein-membrane interactions are critical for apoptosis regulation, since MOMP irreversibly leads to cell death. Whereas the distinct roles of tBid and Bim as sensors of different types of stress are well recognized, it is not known whether the molecular mechanisms whereby they initiate MOMP are the same. In the present study, we compare membrane permeabilization by Bax activated by either cBid [cleaved Bid (p7 and p15)] or Bim and we examine the role of membrane lipids in the recruitment and activation of these three Bcl-2 (B-cell lymphoma 2) pro-apoptotic proteins. We employ fluorescently-labelled proteins and liposomes to quantify the effects of specific lipids on each of the well-characterized steps in Bax-mediated membrane permeabilization. We show that high levels of cholesterol in the membrane inhibit permeabilization by categorically identifying the recruitment of Bax by the activators and Bax insertion in the membrane as the steps being hindered by cholesterol. Furthermore, we show that binding of both cBid and Bim to membranes is facilitated by electrostatic interactions with anionic phospholipids. However, whereas Bim does not require any particular anionic lipids, the conformational change in tBid depends on cardiolipin (CL). This suggests that CL can activate tBid in a similar manner to Mtch2 (mitochondrial carrier homologue 2). Thus, lipids modify multiple aspects of Bax-mediated membrane permeabilization.


Plasmodium knowlesi in pig-tailed macaques: a potential new model for malaria vaccine research.
Plasmodium knowlesi is an established experimental model for basic and pre-clinical malaria vaccine research. Historically, rhesus macaques have been the most common host for malaria vaccine studies with P. knowlesi parasites. However, rhesus are not natural hosts for P. knowlesi, and there is interest in identifying alternative hosts for vaccine research. The study team previously reported that pig-tailed macaques (PTM), a natural host for P. knowlesi, could be challenged with cryopreserved P. knowlesi sporozoites (PkSPZ), with time to blood stage infection equivalent to in rhesus. Here, additional exploratory studies were performed to evaluate PTM as potential hosts for malaria vaccine studies. The aim was to further characterize the parasitological and veterinary health outcomes after PkSPZ challenge in this macaque species. Malaria-naïve PTM were intravenously challenged with 2.5 × 103 PkSPZ and monitored for blood stage infection by Plasmodium 18S rRNA RT-PCR and thin blood smears. Disease signs were evaluated by daily observations, complete blood counts, serum chemistry tests, and veterinary examinations. After anti-malarial drug treatment, a subset of animals was re-challenged and monitored as above. Whole blood gene expression analysis was performed on selected animals to assess host response to infection. In naïve animals, the kinetics of P. knowlesi blood stage replication was reproducible, with parasite burden rising linearly during an initial acute phase of infection from 6 to 11 days post-challenge, before plateauing and transitioning into a chronic low-grade infection. After re-challenge, infections were again reproducible, but with lower blood stage parasite densities. Clinical signs of disease were absent or mild and anti-malarial treatment was not needed until the pre-defined study day. Whole blood gene expression analysis identified immunological changes associated with acute and chronic phases of infection, and further differences between initial challenge versus re-challenge. The ability to challenge PTM with PkSPZ and achieve reliable blood stage infections indicate this model has significant potential for malaria vaccine studies. Blood stage P. knowlesi infection in PTM is characterized by low parasite burdens and a benign disease course, in contrast with the virulent P. knowlesi disease course commonly reported in rhesus macaques. These findings identify new opportunities for malaria vaccine research using this natural host-parasite combination.


Regulatory mechanisms of eosinophil adhesion to and transmigration across endothelial cells by alpha4 and beta2 integrins.
To participate in allergic airway inflammation, it is necessary for blood eosinophils (Eos) to adhere to and migrate across pulmonary vascular endothelial cells (EC). Accumulating evidence has established that Eos adhesion molecules, such as alpha4 and beta2 integrins, play central roles in these processes. We have reported that Eos spontaneously adhere to recombinant human (rh)-VCAM-1, while adhesion to rh-ICAM-1 requires a second stimulus such as GM-CSF. Furthermore, our study employing human pulmonary microvascular endothelial cells (HPMEC) revealed that although the alpha4 integrin/VCAM-1 pathway is crucial for the firm adhesion of Eos, subsequent transendothelial migration occurred dependent on the beta2 integrin/ICAM-1 pathway. We also discuss secretagogues that would affect Eos recruitment to the airways via regulation of alpha4 and beta2 integrins.


Dl-3-n-butylphthalide induced anaphylactic shock: a case report.
Dl-3-n-butylphthalide (DL-NBP) has good neuroprotective function and is safe for use in patients with acute ischaemic stroke. DL-NBP induced anaphylactic shock is rarely reported. Here we describe the case of a 75-year-old woman who received an injection of DL-NBP (25 mg/100 mL intravenously guttae, twice daily) for acute ischaemic stroke. Approximately 5 min after the DL-NBP injection was administered, the patient developed a decrease in blood pressure and an increase in heart rate along with skin pruritus, mottlement of the lower limbs, discomfort, and the desire to defecate, following which DL-NBP was discontinued immediately. The patient recovered with antiallergic therapy and could tolerate further treatment. We emphasise that the increased use of DL-NBP in recent year raises the importance of attention to potential allergies in clinical use, especially in patients with a history of allergies to multiple drugs.


Predictors of objective sleep tendency in the general population.
Daytime sleepiness is a pervasive problem that is associated with a significant public-health burden. Although self-reported measures of daytime sleepiness may be useful in identifying at-risk individuals, there is significant controversy because there are no population-based data relating subjective and objective measures of daytime sleep tendency. The aims of this study were to examine the associations between the Multiple Sleep Latency Test (MSLT), an objective measure of daytime sleep tendency, and self-reported information on the Epworth Sleepiness Scale (ESS) and nighttime sleep duration in the general population. Cross-sectional study. Population-based sample of 261 women and 371 men, mean age of 50.8 years, enrolled in the Wisconsin Sleep Cohort Study. MSLT, ESS, and self-reported sleep duration prior to the MSLT. Using survival analysis to model the time to sleep onset during the MSLT, we found that individuals with an intermediate (6-11) and high (> or = 12) ESS score had a 30% and 69% increase in risk for sleep onset during the MSLT, respectively, compared to individuals with a low ESS score (< or = 5). A dose-response relationship between self-reported duration of nighttime sleep and objective sleep tendency was also observed. Compared to individuals reporting more than 7.50 hours of sleep (highest tertile), individuals reporting 6.75 to 7.50 hours and less than 6.75 hours (lowest tertile) had a 27% and 73% increase in risk for sleep onset during the MSLT, respectively. Subjective reports of daytime sleep tendency on the ESS and the duration of nighttime sleep are associated with the results of the MSLT in the general population.


Ayurpharmacoepidemiology en Route to Safeguarding Safety and Efficacy of Ayurvedic Drugs in Global Outlook.
Ayurpharmacoepidemiology is a new field developed by synergy of the fields of clinical pharmacology, epidemiology, and ayurveda. It will use the effects of ayurvedic medicinal products on large populations to describe and analyze the practices, evaluate the safety and efficacy, and carry out medicoeconomic evaluations. Good pharmacoepidemiology practices in ayurveda is projected to assist with issues of ayurpharmacoepidemiologic research. The embraced good pharmacoepidemiology practices guideline in this viewpoint will be able to provide valuable evidence about the health effects of ayurvedic herbs/drugs and consider different fields like pharmacovigilance, pharmacoeconomics, and drug discovery with ayurvedic reverse pharmacology approach, also pass out significant data for further basic sciences study in ayurveda biology, ayurgenomics, ayurnutrigenomics, and systems biology. Several unanswered questions about ayurvedic drug use and informed interventions or policies that can be addressed by informatics database, which will eventually demonstrate the credibility and rationality of ayurceuticals in the future.


Perception-action and the Müller-Lyer illusion: amplitude or endpoint bias?
Over the past decade there has been a great deal of controversy regarding the relative impact of visual illusions on cognitive judgments and the control of goal-directed action. We report the results of two experiments indicating that perceptual biases associated with the Müller-Lyer illusion involve a misjudgment of amplitude/extent while aiming biases involve error in the specification of a movement endpoint. This dissociation of perception and action is consistent with some aspects of Milner and Goodale's two visual system model, but not others.


Enhanced transmission mediated by guided resonances in metallic gratings coated with dielectric layers.
Transmission properties of metallic gratings coated symmetrically with a dielectric layer on both sides are studied theoretically. For subwavelength narrow slits, besides cavity resonances in slits and surface plasmon-polaritons, a new kind of mechanisms for enhanced transmission in coated metallic gratings, namely, guided resonances in the dielectric coating layers, is found. Transmission peaks mediated by guided resonances are found to be much sharper than those mediated by cavity or surface plasmon-polariton resonances.


Angioid Streaks in Types I and II Congenital Dyserythropoietic Anaemia (CDA).
Background. Angioid streaks (AS) are visible irregular breaks in Bruch's membrane, extending radially from the optic nerve head and with overlaying atrophic retinal pigment epithelium. In 50 % of patients, AS are associated with Pseudoxanthoma elasticum, Ehlers-Danlos syndrome, sickle cell anaemia or Paget's disease. In 50 % of patients, AS are idiopathic. Congenital Dyserythropoietic Anaemia (CDA) is a rare, inherited disorder of ineffective erythropoiesis with morphologically abnormal erythroblasts. CDA was first recognised as a separate entity in 1968 and classified into three main groups. CDA demographics have identified 614 known families and > 700 cases worldwide. A few case reports of AS in CDA I and III have been published, but there is no report of AS in CDA II, the most frequent of the CDAs, as well no follow-up. History and Signs. 8 eyes of 4 CDA patients were examined. The CDA I patients were a 46 year old man and a 52 year old woman. They were first seen in 2009 and followed up for 9 and 11 months, respectively. The 2 female CDA II patients were seen in 2010 and were aged 35 and 42 years at first presentation. Vision, Amsler grid, optical coherence tomography (OCT), fundus pictures and fluorescent angiography were performed. Blood was drawn for neutrophil elastase determination (ELA2). Therapy and Outcome. All patients showed bilateral AS. Mean best corrected visual acuity was 20/20 without metamorphopsia and with normal OCT. During the follow-up period, no progression occurred. No choroidal neovascularisation (CNV) was detected. ELA2 serum levels were normal. Conclusions. This is the first report of AS in CDA II and the first follow-up in CDA I. No evidence of progression was seen within this period of time. Longer follow-up is needed to detect whether AS progresses. All patients with AS should be seen by an ophthalmologist on a regular basis. The risk of CNV is given. Therapy is possible and the outcome is best if the CNV is recognised and treated early.


Adenomatoid tumor of the adrenal gland.
An adenomatoid tumor of the adrenal gland is presented. The tumor was discovered in a patient with hypertension and was clinically mistaken for a pheochromocytoma. This is the first reported case, to my knowledge, of an adenomatoid tumor within the adrenal gland, with the exception of one previous article in which the lesion was mistaken for a lymphangioma. This case illustrates that adenomatoid tumors can rarely occur in extragenital locations, even in regions presumably devoid of mesothelial cells.