Non-Exertional Heatstroke: A Case Report and Review of the Literature.
BACKGROUND Heatstroke (HS) is a life-threatening condition characterized by an elevation of the core body temperature above 40°C, central nervous system dysfunction, and possible multi-organ failure. HS can trigger systemic inflammation, disseminated intravascular coagulation (DIC), rhabdomyolysis, cerebral edema and seizures, pulmonary edema, heart dysfunctions, and renal and hepatic failure. CASE REPORT We report the case of a 41-year-old Romanian woman with a history of alcoholism who developed HS after arriving by bus in Verona, Italy in June 2016. The patient developed consecutive multi-organ dysfunction, including liver and renal failure, rhabdomyolysis, DIC, and arrhythmia. The patient was successfully treated with conservative measures. After 17 days, she recovered completely. CONCLUSIONS The exact mechanism of HS-related multiple organ dysfunction is not completely understood and its pathogenesis is complex. It involves inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Development of a model in which chronic alcohol abuse alters oxidative, inflammatory, and ER stress response could also be a conceivable solution to the positive prognosis of severe HS patients, in which liver failure has a prominent role.


A Neurocomputational Model of the Effect of Cognitive Load on Freezing of Gait in Parkinson's Disease.
Experimental data show that perceptual cues can either exacerbate or ameliorate freezing of gait (FOG) in Parkinson's Disease (PD). For example, simple visual stimuli like stripes on the floor can alleviate freezing whereas complex stimuli like narrow doorways can trigger it. We present a computational model of the cognitive and motor cortico-basal ganglia loops that explains the effects of sensory and cognitive processes on FOG. The model simulates strong causative factors of FOG including decision conflict (a disagreement of various sensory stimuli in their association with a response) and cognitive load (complexity of coupling a stimulus with downstream mechanisms that control gait execution). Specifically, the model simulates gait of PD patients (freezers and non-freezers) as they navigate a series of doorways while simultaneously responding to several Stroop word cues in a virtual reality setup. The model is based on an actor-critic architecture of Reinforcement Learning involving Utility-based decision making, where Utility is a weighted sum of Value and Risk functions. The model accounts for the following experimental data: (a) the increased foot-step latency seen in relation to high conflict cues, (b) the high number of motor arrests seen in PD freezers when faced with a complex cue compared to the simple cue, and (c) the effect of dopamine medication on these motor arrests. The freezing behavior arises as a result of addition of task parameters (doorways and cues) and not due to inherent differences in the subject group. The model predicts a differential role of risk sensitivity in PD freezers and non-freezers in the cognitive and motor loops. Additionally this first-of-its-kind model provides a plausible framework for understanding the influence of cognition on automatic motor actions in controls and Parkinson's Disease.


[Progressive subcortical arteriosclerotic encephalopathy (Binswanger's disease)].
A case of progressing subcortical arteriosclerotic encephalopathy (Binswanger's disease) in a female of 91 is described; the patient suffered from hypertension with cerebral crises for 40 years. The mechanism of vascular-cerebral insufficiency in the pathogenesis of multiple small foci of complete or incomplete necrosis in various parts of white matter of the cerebral hemisphere characteristic for this disease which is rarely described by pathologists is discussed.


Validity of wrist-worn consumer products to measure heart rate and energy expenditure.
The ability to monitor physical activity throughout the day and during various activities continues to improve with the development of wrist-worn monitors. However, the accuracy of wrist-worn monitors to measure both heart rate and energy expenditure during physical activity is still unclear. The purpose of this study was to determine the accuracy of several popular wrist-worn monitors at measuring heart rate and energy expenditure. Participants wore the TomTom Cardio, Microsoft Band and Fitbit Surge on randomly assigned locations on each wrist. The maximum number of monitors per wrist was two. The criteria used for heart rate and energy expenditure were a three-lead electrocardiogram and indirect calorimetry using a metabolic cart. Participants exercised on a treadmill at 3.2, 4.8, 6.4, 8 and 9.7 km/h for 3 minutes at each speed, with no rest between speeds. Heart rate and energy expenditure were manually recorded every minute throughout the protocol. Mean absolute percentage error for heart rate varied from 2.17 to 8.06% for the Fitbit Surge, from 1.01 to 7.49% for the TomTom Cardio and from 1.31 to 7.37% for the Microsoft Band. The mean absolute percentage error for energy expenditure varied from 25.4 to 61.8% for the Fitbit Surge, from 0.4 to 26.6% for the TomTom Cardio and from 1.8 to 9.4% for the Microsoft Band. Data from these devices may be useful in obtaining an estimate of heart rate for everyday activities and general exercise, but energy expenditure from these devices may be significantly over- or underestimated.


Case Report: Adrenocortical carcinoma in children-symptoms, diagnosis, and treatment.
Adrenocortical carcinomas are extremely rare in the paediatric population. Most of them are hormone-secretive lesions; therefore, they should be taken into consideration in a child with signs of precocious puberty and/or Cushing's syndrome symptoms. Nonetheless, differentiation from benign adrenal tumours is necessary. We report a rare case of adrenocortical carcinoma in a girl and a literature review using the PubMed database. A four-year-old girl presented with rapidly progressing precocious puberty and signs of Cushing's syndrome. Imaging of the abdomen revealed a large heterogeneous solid mass. Histopathologic evaluation confirmed adrenocortical carcinoma with high mitotic activity, atypical mitoses, pleomorphism, necrosis, and vascular invasion. After tumourectomy, a decrease of previously elevated hormonal blood parameters was observed. Genetic tests confirmed Li Fraumeni syndrome. Adrenocortical carcinoma should be suspected in children with premature pubarche and signs of Cushing's syndrome. Diagnosis must be based on clinical presentation, hormonal tests, imaging, and histopathological evaluation. Complete surgical resection of the tumour is the gold standard. Oncological treatment in children is not yet well-studied and should be individually considered, especially in advanced, inoperable carcinomas with metastases. Genetic investigations are useful for determining the prognosis in patients and their siblings.


The sperm-associated antigen 6 interactome and its role in spermatogenesis.
Mammalian SPAG6, the orthologue of Chlamydomonas reinhardtii PF16, is a component of the central apparatus of the '9 + 2' axoneme that controls ciliary/flagellar motility, including sperm motility. Recent studies revealed that SPAG6 has functions beyond its role in the central apparatus. Hence, we reexamined the role of SPAG6 in male fertility. In wild-type mice, SPAG6 was present in cytoplasmic vesicles in spermatocytes, the acrosome of round and elongating spermatids and the manchette of elongating spermatids. Spag6-deficient testes showed abnormal spermatogenesis, with abnormalities in male germ cell morphology consistent with the multi-compartment pattern of SPAG6 localization. The armadillo repeat domain of mouse SPAG6 was used as a bait in a yeast two-hybrid screen, and several proteins with diverse functions appeared multiple times, including Snapin, SPINK2 and COPS5. Snapin has a similar localization to SPAG6 in male germ cells, and SPINK2, a key protein in acrosome biogenesis, was dramatically reduced in Spag6-deficient mice which have defective acrosomes. SPAG16L, another SPAG6-binding partner, lost its localization to the manchette in Spag6-deficient mice. Our findings demonstrate that SPAG6 is a multi-functional protein that not only regulates sperm motility, but also plays roles in spermatogenesis in multiple cellular compartments involving multiple protein partners.


Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil.
In India, visceral leishmaniasis (VL) caused by Leishmania donovani has been successfully treated with miltefosine with a cure rate of > 90%. To assess the efficacy and safety of oral miltefosine against Brazilian VL, which is caused by Leishmania infantum, a phase II, open-label, dose-escalation study of oral miltefosine was conducted in children (aged 2-12 years) and adolescent-adults (aged 13-60 years). Definitive cure was assessed at a 6-month follow-up visit. The cure rate was only 42% (6 of 14 patients) with a recommended treatment of 28 days and 68% (19 of 28 patients) with an extended treatment of 42 days. The in vitro miltefosine susceptibility profile of intracellular amastigote stages of the pretreatment isolates, from cured and relapsed patients, showed a positive correlation with the clinical outcome. The IC50 mean (SEM) of eventual cures was 5.1 (0.4) µM, whereas that of eventual failures was 12.8 (1.9) µM (P = 0.0002). An IC50 above 8.0 µM predicts failure with 82% sensitivity and 100% specificity. The finding of L. infantum amastigotes resistant to miltefosine in isolates from patients who eventually failed treatment strongly suggests natural resistance to this drug, as miltefosine had never been used in Brazil before this trial was carried out.


School Nurse Staffing in Texas Alternative High Schools: A Mixed Methods Exploration.
School nurses represent cost-effective investments in students' health and educational success. Alternative high schools (AHSs) serve an understudied population of youth who are at risk for school dropout and face numerous social inequities, heightening their risk for poor health outcomes. In this two-phase explanatory sequential mixed methods study, we examined school nurse staffing in Texas AHSs. Findings suggest Texas AHSs face understaffing for familiar reasons common across districts (e.g., lack of funding), but also reveal potential deeper inequities. Quantitative findings indicate 71% of Texas AHSs have some form of nursing support, most often an on-call or part-time nurse. Qualitative findings support and enrich this finding with insights into the negative consequences of not having a full-time nurse, indiscriminate approaches to staffing AHSs, and how AHSs can be the only school in the district without a full-time nurse. Altogether, our findings reveal opportunities to better support AHSs with adequate nursing support.


FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction.
FKBP12-rapamycin associated protein (FRAP, also known as mTOR or RAFT) is the founding member of the phosphatidylinositol kinase-related kinase family and functions as a sensor of physiological signals that regulate cell growth. Signals integrated by FRAP include nutrients, cAMP levels, and osmotic stress, and cellular processes affected by FRAP include transcription, translation, and autophagy. The mechanisms underlying the integration of such diverse signals by FRAP are largely unknown. Recently, FRAP has been reported to be regulated by mitochondrial dysfunction and depletion of ATP levels. Here we show that exposure of cells to hyperosmotic conditions (and to glucose-deficient growth medium) results in rapid and reversible dissipation of the mitochondrial proton gradient. These results suggest that the ability of FRAP to mediate osmotic stress response (and glucose deprivation response) is by means of an intermediate mitochondrial dysfunction. We also show that in addition to cytosolic FRAP a large portion of FRAP associates with the mitochondrial outer membrane. The results support the existence of a stress-sensing module consisting of mitochondria and mitochondrial outer membrane-associated FRAP. This module allows the cell to integrate a variety of stress signals that affect mitochondrial function and regulate a growth checkpoint involving p70 S6 kinase.


Rimonabant and Cannabidiol Rewrite the Interactions between Breast Cancer Cells and Tumor Microenvironment.
The spread of breast cancer to distant sites is the major cause of death in breast cancer patients. Increasing evidence supports the role of the tumor microenvironment (TME) in breast cancers, and its pathologic assessment has become a diagnostic and therapeutic tool. In the TME, a bidirectional interplay between tumor and stromal cells occurs, both at the primary and metastatic site. Hundreds of molecules, including cytokines, chemokines, and growth factors, contribute to this fine interaction to promote tumor spreading. Here, we investigated the effects of Rimonabant and Cannabidiol, known for their antitumor activity, on reprogramming the breast TME. Both compounds directly affect the activity of several pathways involved in breast cancer progression. To mimic tumor-stroma interactions during breast-to-lung metastasis, we investigated the effect of the compounds on growth factor secretion from metastatic breast cancer cells and normal and activated lung fibroblasts. In this setting, we demonstrated the anti-metastatic potential of the two compounds, and the membrane array analyses highlighted their ability to alter the release of factors involved in the autocrine and paracrine regulation of tumor proliferation, angiogenesis, and immune reprogramming. The results enforce the antitumor potential of Rimonabant and Cannabidiol, providing a novel potential tool for breast cancer TME management.


Synergistic metabolism of salivary MUC5B in oral commensal bacteria during early biofilm formation.
Bacterial metabolism in oral biofilms is comprised of complex networks of nutritional chains and biochemical regulations. These processes involve both intraspecies and interspecies networks as well as interactions with components from host saliva, gingival crevicular fluid, and dietary intake. In a previous paper, a large salivary glycoprotein, mucin MUC5B, was suggested to promote a dental health-related phenotype in the oral type strain of Streptococcus gordonii DL1, by regulating bacterial adhesion and protein expression. In this study, nuclear magnetic resonance-based metabolomics was used to examine the effects on the metabolic output of monospecies compared to dual species early biofilms of two clinical strains of oral commensal bacteria, S. gordonii and Actinomyces naeslundii, in the presence of MUC5B. The presence of S. gordonii increased colonization of A. naeslundii on salivary MUC5B, and both commensals were able to utilize MUC5B as a sole nutrient source during early biofilm formation. The metabolomes suggested that the bacteria were able to release mucin carbohydrates from oligosaccharide side chains as well as amino acids from the protein core. Synergistic effects were also seen in the dual species biofilm metabolome compared to the monospecies, indicating that A. naeslundii and S. gordonii cooperated in the degradation of salivary MUC5B. A better understanding of bacterial interactions and salivary-mediated regulation of early dental biofilm activity is meaningful for understanding oral biofilm physiology and may contribute to the development of future prevention strategies for biofilm-induced oral disease.IMPORTANCEThe study of bacterial interactions and salivary-mediated regulation of early dental biofilm activity is of interest for understanding oral microbial adaptation to environmental cues and biofilm maturation. Findings in oral commensals can prove useful from the perspectives of both oral and systemic health of the host, as well as the understanding of general microbial biofilm physiology. The knowledge may provide a basis for the development of prognostic biomarkers, or development of new treatment strategies, related to oral health and disease and possibly also to other biofilm-induced conditions. The study is also an important step toward developing the methodology for similar studies in other species and/or growth conditions.


Psychedelics as a treatment for disorders of consciousness.
Based on its ability to increase brain complexity, a seemingly reliable index of conscious level, we propose testing the capacity of the classic psychedelic, psilocybin, to increase conscious awareness in patients with disorders of consciousness. We also confront the considerable ethical and practical challenges this proposal must address, if this hypothesis is to be directly assessed.


Computer software tool for heart rate variability (HRV), T-wave alternans (TWA) and heart rate turbulence (HRT) analysis from ECGs.
This paper presents a software package for quantitative evaluation of heart rate variability (HRV), heart rate turbulence (HRT), and T-wave alternans (TWA) from ECG recordings. The software has been developed for the purpose of scientific research rather than clinical diagnosis. The software is written in Matlab Mathematical Language. Procedures for evaluation of HRV, HRT and TWA were implemented. HRV analysis was carried out by applying statistical and spectral parametric and nonparametric methods. HRT parameters were derived using the Schmidt algorithm. TWA analysis was performed both in spectral and in time domain by applying Poincare mapping. A flexibility of choosing from a number of classical modelling approaches and their modifications was foreseen and implemented. The software underwent preliminary verification tests both on ECGs from the Physionet online ECG signal repository and recordings taken at the Department of Electrocardiology of the Medical University Hospital in Lodz. The result of the research is a program enabling simultaneous analysis of a number of parameters computed from ECG recordings with the use of the indicated analysis methods. The program offers options to preview the intermediate results and to alter the preprocessing steps. By offering the possibility to cross-validate the results of analyses obtained by several methods and to preview the intermediate analysis steps, the program can serve as a helpful aid for clinicians in comprehensive research studies. The software tool can also be utilized in training programs for students and medical personnel.


[Effect of elevated temperature on the persistence of measles virus vaccinal strain L-16 in a human cell culture].
The influence of high temperature (40 degrees C) on the virus carrier state and synthesis of virus-specific macromolecules in the HEp-2 cells--measles virus system was studied. The fluorescent antibody technique showed that cultivation at this high temperature led to changes in virus antigen morphology, a decrease in the number and then complete disappearance of the cells producing virus-specific antigen. Simultaneously, gradual cessation of synthesis of all kinds of virus-specific RNA was observed in chronically infected cells. The method of radioimmunoprecipitation showed the incubation at 40 degrees C to affect first of all the synthesis of virus nucleocapsid protein. The temperature-sensitive nature of synthesis of virus macromolecules may be explained by the existence of its mutations in the genome of the persisting virus.


A tale of two densities: active inference is enactive inference.
The aim of this article is to clarify how best to interpret some of the central constructs that underwrite the free-energy principle (FEP) - and its corollary, active inference - in theoretical neuroscience and biology: namely, the role that generative models and variational densities play in this theory. We argue that these constructs have been systematically misrepresented in the literature, because of the conflation between the FEP and active inference, on the one hand, and distinct (albeit closely related) Bayesian formulations, centred on the brain - variously known as predictive processing, predictive coding or the prediction error minimisation framework. More specifically, we examine two contrasting interpretations of these models: a structural representationalist interpretation and an enactive interpretation. We argue that the structural representationalist interpretation of generative and recognition models does not do justice to the role that these constructs play in active inference under the FEP. We propose an enactive interpretation of active inference - what might be called enactive inference. In active inference under the FEP, the generative and recognition models are best cast as realising inference and control - the self-organising, belief-guided selection of action policies - and do not have the properties ascribed by structural representationalists.


[Furanocoumarins contents and cytochrome P450 3A (CYP3A) inhibitory activities of various processed fruit peel products: outflow of 6',7'-Dihydroxybergamottin during processing treatment of peel].
Furanocoumarins (FCs) such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHBG) contained in grapefruits are known to be cytochrome P450 3A4 (CYP3A4) inhibitors. These are contained in larger quantity in peel than in pulp, and therefore, processed peel products possibly have strong CYP3A4 inhibitory activity. The CYP3A4 inhibitory potency of these processed peel products, however, remains to be elucidated. The FC content and CYP3A inhibitory activities of various processed fruit peel products were investigated. CYP3A inhibitory activities of crystallized grapefruit peel, grapefruit marmalade, lemon peel and bitter orange slice were close to that of 100% grapefruit juice, while the activities of yuzu slice, pomelo (buntan) marmalade and crystallized iyokan peel were very weak, 1/8-1/20 of 100% grapefruit juice. The maximum BG content was 5.6 µg/g in lemon peel. The maximum DHBG content was 7.2 µg/g in crystallized grapefruit peel, about 1/30 that of raw peel. Grapefruit marmalade and crystallized grapefruit peel contained similar amounts of FCs to 100% grapefruit juice, but FCs were not detected in pomelo (buntan) marmalade or crystallized iyokan peel. Good correlation (r=0.78) was observed between the FC contents of these peel products and those CYP3A inhibitory activities. Preparation of homemade grapefruit marmalade and crystallized peel revealed that considerably lower DHBG content in these products and lower CYP3A inhibitory activity than anticipated were attributable to outflow of DHBG to broth during boiling of the raw peel.


Negative Pressure-Temperature Slopes for Reactions Formign MgSiO3 Perovskite from Calorimetry.
A new and sensitive differential drop solution calorimetric technique was developed for very small samples. A single experiment using one 5.18-milligram sample of perovskite, synthesized at 25 gigapascals and 1873 Kelvin, gave 110.1 +/- 4.1 kilojoules per mole for the enthalpy of the ilmenite-pervoskite transition in MgSiO(3). The thermodynamics of the reaction of MgSiO(3) (ilmenite) to MgSiO(3) (perovskite) and of Mg(2)SiO(4) (spinel) to MgSiO(3) (pervoskite) and MgO (periclase) were assessed. Despite uncertainties in heat capacity and molar volume at high pressure and temperature, both reactions clearly have negative pressure-temperature slopes, -0.005 +/- 0.002 and -0.004 +/- 0.002 gigapascals per Kelvin, respectively. The latter may be insufficiently negative to preclude whole-mantle convection.


Generalized Joint Hypermobility Is Predictive of Hip Capsular Thickness.
The pathomechanics of hip microinstability are not clearly defined but are thought to involve anatomical abnormalities, repetitive forces across the hip, and ligamentous laxity. The purpose of this study was to explore the relationship between generalized joint hypermobility (GJH) and hip capsular thickness. The hypothesis was that GJH would be predictive of a thin hip capsule. Cross-sectional study; Level of evidence, 3. A prospective study was performed on 100 consecutive patients undergoing primary hip arthroscopy for the treatment of hip pain. A Beighton test score (BTS) was obtained prior to each procedure. The maximum score was 9, and a score of ≥4 was defined as hypermobile. Capsular thickness at the level of the anterior portal, corresponding to the location of the iliofemoral ligament, was measured arthroscopically using a calibrated probe. The presence of ligamentum teres (LT) pathology was also recorded. Fifty-five women and 45 men were included in the study. The mean age was 32 years (range, 18-45 years). The median hip capsule thickness was statistically greater in men than women (12.5 and 7.5 mm, respectively). The median BTS for men was 1 compared with 4 for women (P < .001). A statistically significant association was found between BTS and capsular thickness; a BTS of <4 is strongly predictive of having a capsular thickness of ≥10 mm, while a BTS ≥4 correlates with a capsular thickness of <10 mm. There was a statistically greater incidence of LT tears in patients with a capsular thickness of ≤7.5 mm and a BTS of ≥4 (P < .001). Measurement of the GJH is highly predictive of hip capsular thickness. A BTS of <4 correlates significantly with a capsular thickness of ≥10 mm, while a BTS ≥4 correlates significantly with a thickness of <10 mm.


Rapid Molecular Diagnostics to Inform Empiric Use of Ceftazidime/Avibactam and Ceftolozane/Tazobactam Against Pseudomonas aeruginosa: PRIMERS IV.
Overcoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa. In this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer β-lactam/β-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO). We found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA). The diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.


Grice arthrodesis in the treatment of valgus feet in children with myelomeningocele: a 12.8-year follow-up study.
Neurological deficit resulting in the lack of motor control in children with myelomeningocele often leads to a valgus position of the feet and ankles, usually in combination with planovalgus and pronation of the forefoot. The purpose of the study was to evaluate long-term patient satisfaction and clinical effects in ambulating children with lumbosacral myelomeningocele after having performed a Grice arthrodesis of a valgus unstable foot. The clinically most relevant radiographic measurements, such as the frontal and lateral talo-calcaneal angles, were used to evaluate the anatomical effects of the surgery, whereas the main research question was to reveal the patient satisfaction and usefulness of the procedure. The modified Grice-Green extraarticular subtalar arthrodesis was performed by the same surgeon on one standing and 22 walking patients (12 female) with lumbosacral myelomeningocele and valgus instability during the period 1985-1999. Twelve patients had bilateral surgery, giving a total of 35 operated feet. The patients attended a thorough check-up at a mean of 12.8 years (standard deviation [SD] +/- 3.2, range 7.7-20.2 years) after surgery. The mean age at surgery was 6.6 years (SD +/- 1.8) and at follow-up 19.4 years (SD +/- 3.8). Functional parameters, such as walking ability, pain and skin problems, and the need for braces and supportive orthopaedic shoes were noted at the follow-up interview. The parents were interviewed along with the patients in order to obtain all of the necessary information. Loaded radiographs in the lateral and frontal planes were taken of both feet and ankles pre-operatively and at follow-up, except for pre-operative radiographs in six patients that were not loaded and, thus, not included, except for the assessment of ankle valgus. Ankle valgus was assessed from lateral and frontal views of the ankle on a scale from grade 0 to grade 3 according to Malhotra. Frontal and lateral talo-calcaneal angles were measured for the assessment of subtalar varus or valgus. Lateral talo-first-metatarsal (Meary's) angles were measured to investigate the longitudinal arches of the feet. The mean lateral talo-calcaneal angle was reduced significantly (P < 001) from 55.1 degrees (SD +/- 8.9) to 38.8 degrees (SD +/- 8.1). The mean frontal talo-calcaneal angle was reduced from 24.7 degrees (SD +/- 9.7) pre-operatively to 16.6 degrees (SD +/- 6.3) at follow-up (P < 0.001). The mean lateral talo-first-metatarsal angle improved significantly from -16.1 degrees (SD +/- 24.7) pre-operatively to 0.9 degrees (SD +/- 15.1) at follow-up (P = 0.0015). The calcaneal pitch did not change significantly. In general, ankle valgus worsened during follow-up time, but not significantly (P = 0.113). The visual analogue scale (VAS) score of patient satisfaction improved significantly from 3.7 (SD +/- 1.7) prior to surgery to 7.2 (SD +/- 1.5) at follow-up (P < 0.005). Nineteen patients (83%) were satisfied with the surgery and would thus recommend the procedure. Based on the radiological findings and patient satisfaction, the patients participating in this study benefited from having had Grice arthrodeses performed on their valgus unstable feet. The results indicate good long-term correctional effect on valgus deformity after Grice arthrodesis, as the talo-calcaneal and talo-first-metatarsal angles improved significantly. A great majority of the patients were content with the surgery, and none claimed that any residual deformity was the cause for any reduced ability to ambulate.


Validity and reliability of the Spanish caregiver reaction assessment scale for caregivers of people with dementia.
Of the few instruments available to measure the important, positive aspects of caring, the Caregiver Reaction Assessment is regarded as the most suitable, but there is no validated Spanish version. The aim of this study was to translate the Caregiver Reaction Assessment into Spanish and assess its psychometric properties. The Caregiver Reaction Assessment was translated into Spanish and then back translated. Validation included construct validity, criterion validity and reliability: 287 interviews were conducted with informal caregivers of patients with dementia between November 2010 and April 2012. Principal component analysis confirmed the original instrument's five subscales. Criterion validity showed a moderate negative correlation between the impact on health and the EQ-5D (r = -.43), that is, a greater impact on health correlated with lower health-related quality of life. The Caregiver Reaction Assessment showed good internal consistency, with a Cronbach alpha of .804, and good temporal stability for the distinct subscales, with intraclass correlation coefficients varying from .683 to .729 (p < .001). The Caregiver Reaction Assessment is a reliable, valid instrument for the measurement of the reactions of informal caregivers of patients with dementia, with good psychometric properties.


[Use of phacolin in patients with allergic reaction to anti-cataract eye drops].
Allergic reaction to ++anti-cataract eye drops was confirmed in 11.1-34.8 percent of patients with these drops intolerance. Administration of phacolin in capsules to such patients helped eliminate the local allergic reactions. Phacolin had a reparative therapeutic effect in patients with metabolic involvement of the cornea (postherpetic, dystrophic, and other ones). None of the seventy-two patients treated with phacolin, twenty of them were treated with the drug for 2 to 5 years, complained of the drug intolerance.


Gastric mucosal pH and blood flow during weaning from mechanical ventilation in patients with chronic obstructive pulmonary disease.
To determine if gastric intramucosal pH changes during weaning from mechanical ventilation are related to gastric mucosal blood flow modifications, we studied 16 ventilator-supported patients with chronic obstructive pulmonary disease (COPD) who tolerated a 2-h trial of spontaneous breathing with pressure support ventilation and were successfully extubated and 11 patients with COPD who failed such a trial. Gastric mucosal perfusion was assessed using gastric intramucosal pH (pH(i)) by tonometry and laser-Doppler flowmetry. During the weaning attempt, the failure weaning group developed a rapid, shallow breathing pattern with acute respiratory acidosis. The pH(i) was lower and gastric intramucosal PCO(2) (PCO(2)im) was higher in the failure weaning group than in the successful weaning group (p < 0.05). No change in gastric intramucosal-arterial PCO(2) difference was observed and a linear correlation was found between arterial PCO(2) and PCO(2)im (r(2) = 0.70; p < 0.001). Cardiac index increased in the failure group (p < 0.05) and remained stable in the success group whereas gastric mucosal blood flow decreased in the failure group (H(120) (min): -22 +/- 11% from baseline; p < 0.05) and increased in the success group (H(120) (min): 85 +/- 27% from baseline; p < 0.05). We conclude that gastric intramucosal pH changes during a 2-h weaning trial are mainly due to arterial PCO(2) variations. Nevertheless, gastric mucosal blood flow changes do occur and differ according to the weaning success or failure.


Clinical review: Current scientific rationale for the use of somatostatin analogs and mTOR inhibitors in neuroendocrine tumor therapy.
Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR). The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy. The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which preferentially target subtype 2) and thus has a broader spectrum of activity. Everolimus is a rapamycin analog that inhibits mTOR, but it is more soluble than rapamycin and can be administered orally. mTOR is a protein kinase involved in many signaling pathways, primarily those initiated by tyrosine kinase receptors. Sustained mTOR activity leads to the induction of cell growth, proliferation, and cell survival. Everolimus therefore has obvious potential in cancer therapy. The combination of somatostatin analogs and everolimus in therapeutic trials offers a promising treatment option for neuroendocrine tumors.


Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease.
Inflammatory bowel disease (IBD) includes two entities, Crohn's disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient's quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependent disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn's disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunosuppressants is now advocated by some authors. The rational includes: (1) failure to modify IBD natural history of present therapeutic approach, (2) demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn's disease and ulcerative colitis, and (3) demonstration that early immunosuppression has a very positive impact on pediatric, recently diagnosed Crohn's disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab (SONIC Study), and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn's disease patients (AZTEC study).


Predicting Discontinuation of Pegylated Interferon as a Result of Lack of Efficacy in United States Veterans With Chronic Hepatitis C on Dual Therapy.
Many patients with chronic hepatitis C virus (HCV) being treated with pegylated interferon (peg-IFN) plus ribavirin (RBV) do not respond to therapy and do not clear the virus. Standard of care during the era of dual therapy was to discontinue the patient's therapy based on insufficient decreases in viral load after 12 and/or 24 weeks on therapy. We identified patient characteristics that were significant predictors of discontinuation as a result of lack of efficacy (LOE) in a national database of US veterans with genotypes 1 and 4. We identified US veterans who received care at Veterans Affairs medical centers in 2004-2009 and who had lab-confirmed HCV diagnoses and initiated therapy with peg-IFN plus RBV. Patients who discontinued therapy early were classified as either LOE or non-LOE discontinuers based on pharmacy refill patterns and laboratory response data. Predictors of LOE discontinuation were identified using univariate and multivariable Cox proportional hazards modeling. Of 321 238 HCV patients with an ICD-9 diagnosis code, 31 215 (9.7%) initiated dual therapy with peg-IFN plus RBV, and 10 333 (3.2%) met all inclusion criteria and were included in the analysis. Overall, 13.6% of the cohort was classified as LOE. Significant predictors of LOE discontinuation included treatment for drug abuse (hazard ratio [HR] = 2.18), age >65 years (HR = 1.75), antiretroviral therapy for HIV (HR = 1.48), black race (HR = 1.47), platelet count >100/mm3 (HR = 1.46), and drug therapy for insomnia (HR = 1.40). We identified risk factors for discontinuation caused by LOE. Future work should focus on determining whether these characteristics are also predictive of triple-therapy LOE discontinuations.


Excitatory deep transcranial magnetic stimulation with H-coil over the right homologous Broca's region improves naming in chronic post-stroke aphasia.
The role of the right hemisphere in poststroke aphasia recovery is still controversial and the effects of repetitive transcranial magnetic stimulation (rTMS) over the right homologous Broca's region have been seldom investigated. This study aimed to compare the effect of excitatory, inhibitory, and sham rTMS delivered with H-coil over the right inferior frontal gyrus in chronic aphasic patients. Five right-handed poststroke aphasic patients underwent a picture naming task before and immediately after each of 3 sessions of rTMS: excitatory (10 Hz), inhibitory (1 Hz), and sham rTMS, in random sequence and separated by at least 1 week. Only the excitatory 10-Hz stimulation was associated with a significant improvement in naming performance (P = .043) and was significantly more effective than 1-Hz rTMS (P = .043). A single session of excitatory deep brain rTMS over the right inferior frontal gyrus with H-coil significantly improves naming in right-handed chronic poststroke aphasic patients. This result is in line with the hypothesis of a positive, rather than detrimental, role of the right hemisphere in chronic aphasia due to a left-hemispheric stroke.


A low-power area-efficient 8 bit SAR ADC using dual capacitor arrays for neural microsystems.
We report an area-efficient 8bit SAR ADC using dual capacitor array banks for brain signal interface microsystems. The proposed ADC consumes 680nW and the total chip area is 0.035 mm(2). We reduced the area and power by a factor of eight when compared with conventional approaches. If we increase the resolution, the area and power reduction factor exponentially increases in our architecture (e.g., a factor of 16 for 10 bit resolution). The measured SNDR, SFDR, THD, and ENOB are 42.82 +/- 0.47 dB, 57.90 +/- 2.82dB, -53.58 +/- 2.15 dB, and 6.65 +/- 0.07 bits, respectively.


[Utilization of cluster analysis in evaluation of weather and geliophysical effects on patients with bronchial asthma].
Cluster analysis was used to grade the weather and solar activity factors by contribution to bronchial asthma exacerbation in patients. The analysis showed up clusters associating acute episodes of the disease of varying intensity with weather factors.


Well-differentiated neuroendocrine carcinoma of the lung: a case report.
Well-differentiated neuroendocrine carcinoma (WDNC) of the lower respiratory tract displays clinical and radiologic features intermediate between carcinoids and small cell carcinoma and shares some biologic characteristics with both. We describe a case of WDNC resistant to three different treatments. The patient, a 42-year-old woman, received 2 cycles of chemotherapy before coming to our observation, including cyclophosphamide, adriamycin and vincristine, with progression of disease. We administered r-alpha-2a interferon for 2 months, but the patient showed clinical progression. Therefore, streptozotocin associated with epirubicin was utilized, but the patient died of disease progression after 4 cycles and 10 months from the first treatment. The case of WDNC described in this report showed an unusual aggressive clinical course and was refractory to conventional and unconventional treatments. The proper management for WDNC is still unknown. However, according to literature data, the chemotherapeutic schemes employed for small cell lung cancer represent the first treatment choice for WDNC. Further studies are needed to help define treatment strategies according to the biology of the tumor.


Effect of Tacrolimus Time in Therapeutic Range on Postoperative Recurrence in Patients Undergoing Liver Transplantation for Liver Cancer.
Liver cancer is the second highest cause of cancer-related deaths worldwide. It is commonly treated with liver transplantation, where tacrolimus is typically used as an antirejection immunosuppressant. The purpose of this study was to evaluate the effect of tacrolimus time in therapeutic range (TTR) on liver cancer recurrence in liver transplant recipients and to compare the performance of TTRs calculated according to the target ranges recommended in published guidelines. A total of 84 patients who underwent liver transplantation for liver cancer were retrospectively included. Tacrolimus TTR was calculated using linear interpolation from the date of transplantation until recurrence or the last follow-up according to target ranges recommended in the Chinese guideline and international expert consensus. Twenty-four recipients developed liver cancer recurrence after liver transplantation. The CTTR (TTR calculated according to the Chinese guideline) for the recurrence group was significantly lower than that of the nonrecurrence group (26.39% vs. 50.27%, P < 0.001), whereas the ITTR (TTR calculated according to the international consensus) was not significantly different between the two groups (47.81% vs. 56.37%, P = 0.165). Multivariate survival analysis revealed that age, microvascular invasion, hepatocellular carcinoma, CTTR, and mean tacrolimus trough concentration were independent predictors of liver cancer recurrence after liver transplantation. TTR predicts liver cancer recurrence in liver transplant recipients. The range of tacrolimus concentrations recommended in the Chinese guideline was more beneficial than that recommended in the international consensus for Chinese patients undergoing liver transplantation for liver cancer.


Estimation of ELISA results using a parallel curve analysis.
We introduce a new method for the analysis of enzyme-linked immunosorbent assay (ELISA) data. The new method can use data near the asymptotes and does not give undue weight to responses on the flatter parts of the dose-response curve. We apply it to simulated data and to two real-world assays and show it is more accurate and more precise than the traditional interpolation method. In particular, the new method works much better for very low-concentration samples for which the traditional method is often unable to give a result.


Group patient visits for Parkinson disease: a randomized feasibility trial.
Group patient visits are medical appointments shared among patients with a common medical condition. This care delivery method has demonstrated benefits for individuals with chronic conditions but has not been evaluated for Parkinson disease (PD). We conducted a 12-month, randomized trial of group patient visits vs usual (one-on-one) care for patients with PD. Visits were led by one of 3 study physicians, included patients and caregivers, and lasted approximately 90 minutes. Those receiving group visits had 4 sessions over 12 months. The primary outcome measure was feasibility as measured by the ability to recruit participants and by the proportion of participants who completed the study. The primary efficacy outcome was quality of life as measured by the PD Questionnaire-39. Thirty patients and 27 caregivers enrolled in the study. Thirteen of the 15 patients randomized to group patient visits and 14 of the 15 randomized to usual care completed the study. Quality of life measured 12 months after baseline between the 2 groups was not different (25.9 points for group patient visits vs 26.0 points for usual care; p = 0.99). Group patient visits may be a feasible means of providing care to individuals with PD and may offer an alternative or complementary method of care delivery for some patients and physicians. This study provides Class II evidence that group patient visits did not improve quality of life for individuals with PD over a 1-year period.


Role of airway receptors in the breathing pattern of patients with chronic obstructive lung disease.
To determine whether airway receptors are responsible for the rapid, shallow breathing pattern seen in hypercapnic chronic obstructive lung disease, 10 patients underwent upper airway anaesthesia with inhaled lignocaine in a placebo controlled study. There was a significant reduction in breathing frequency after lignocaine (p less than 0.001) that was due to an increase in expiratory time (p less than 0.001). The inspiratory time remained unchanged, but tidal volume increased significantly (p less than 0.02). It is concluded that, while airway receptors may have a role in determining the frequency of breathing in chronic obstructive lung disease, other factors are responsible for the reduced inspiratory time.


Impaired oxidation of branched-chain amino acids in the medial thalamus of thiamine-deficient rats.
Thiamine, in its diphosphate form, is a required cofactor for enzymes of glucose metabolism and branched-chain alpha-ketoacid dehydrogenase (BCKDH). Although metabolic impairments in glucose metabolism have been found to occur in selectively vulnerable brain regions of the thiamine-deficient (TD) brain, the effects of thiamine deficiency on BCKDH have not been studied. BCKDH activity was assayed radiochemically in brain extracts of vulnerable (medial thalamus; MT) versus non-vulnerable (frontal cortex; FC) brain regions of rats made TD by administration of the central thiamine antagonist, pyrithiamine. A significant regional variation in BCKDH within the TD rat brain was noted, with a higher capacity for branched-chain amino acid oxidation in FC compared to MT: BCKDH activity was significantly reduced in MT of TD rats, resulting in selective accumulation of BCAAs in this brain region. Leucine concentrations were elevated over fivefold in the MT of symptomatic TD rats, compared with pair-fed control (PFC) rats. Impaired branched-chain ketoacid metabolism in rats may contribute to the neuronal dysfunction and ultimate thalamic neuronal cell death observed in thiamine deficiency.


Alignment in total knee arthroplasty.
Dissatisfaction following total knee arthroplasty is a well-documented phenomenon. Although many factors have been implicated, including modifiable and nonmodifiable patient factors, emphasis over the past decade has been on implant alignment and stability as both a cause of, and a solution to, this problem. Several alignment targets have evolved with a proliferation of techniques following the introduction of computer and robotic-assisted surgery. Mechanical alignment targets may achieve mechanically-sound alignment while ignoring the soft tissue envelope; kinematic alignment respects the soft tissue envelope while ignoring the mechanical environment. Functional alignment is proposed as a hybrid technique to allow mechanically-sound, soft tissue-friendly alignment targets to be identified and achieved. Cite this article: Bone Joint J 2020;102-B(3):276-279.


Degradation of atrazine by electrochemical advanced oxidation processes using a boron-doped diamond anode.
Solutions of 30 mg L(-1) of the herbicide atrazine have been degraded by environmentally friendly electrochemical advanced oxidation processes (EAOPs) such as anodic oxidation (AO), electro-Fenton (EF), and photoelectro-Fenton (PEF) using a small open and cylindrical cell with a boron-doped diamond (BDD) anode. AO has been carried out either with a stainless steel cathode or an O(2) diffusion cathode able to generate H(2)O(2). Hydroxyl radicals ((*)OH) formed at the BDD surface in all EAOPs and in the bulk from Fenton's reaction between added Fe(2+) and electrogenerated H(2)O(2) in EF and PEF are the main oxidants. All treatments yielded almost overall mineralization, although the rate for total organic carbon (TOC) removal is limited by the oxidation of persistent byproducts with (*)OH at the BDD surface. In AO, TOC abatement is enhanced by parallel electrochemical reduction of organics at the stainless steel cathode, while in PEF, it also increases from additional photolysis of intermediates by UVA light under the synergistic action of (*)OH in the bulk. The effect of current and pH on the degradative behavior of EAOPs has been examined to determine their optimum values. Atrazine decay always follows a pseudo-first-order reaction, being more rapidly destroyed from (*)OH in the bulk than at the BDD surface. Aromatic intermediates such as desethylatrazine, desethyldesisopropylatrazine, and cyanuric acid and short linear carboxylic acids such as formic, oxalic, and oxamic have been identified and quantified by reversed-phase and ion-exclusion HPLC, respectively. Released inorganic ions such as Cl(-), NO(3)(-), and NH(4)(+) have been followed by ionic chromatography.


Plasma chemistry reference values in hybrid falcons in relation to their species of origin.
Twenty-one blood chemistry parameters were determined in 127 peregrine falcons (Falco peregrinus), 79 gyr-peregrine hybrids and 166 gyr-saker hybrids. These parameters, together with those previously established in 53 gyr falcons (Falco rusticolus) and 234 saker falcons (Falco cherrug), were compared. There were statistically significant differences in 15 of the parameters between the saker and peregrine falcons; the saker and gyr falcons; the saker and gyr-saker hybrids; the peregrine and gyr falcons; and the peregrine and gyr-peregrine hybrids, but not between the gyr falcons and the gyr-saker falcon hybrids.


Beta-blocker therapy in patients with acute myocardial infarction: not all patients need it.
Most of the evidences for beneficial effects of beta-blockers in patients with acute myocardial infarction (AMI) were from the clinical studies published in the pre-reperfusion era when anti-platelet drugs, statins or inhibitors of renin-angiotensin-aldosterone system which are known to reduce cardiovascular mortality of patients with AMI were not introduced. In the reperfusion era, beta-blockers' benefit has not been clearly shown except in patients with reduced ejection fraction (EF; ≤40%). In the era of the early reperfusion therapy for AMI, a number of patients with mildly reduced EF (>40%, <50%) or preserved EF (≥50%) become increasing. However, because no randomized clinical trials are available until now, the benefit and the optimal duration of oral treatment with beta-blockers in patients with mildly reduced or preserved EF are questionable. Registry data have not showed the association of oral beta-blocker therapy with decreased mortality in survivors without heart failure or left ventricular systolic dysfunction after AMI. In the Korea Acute Myocardial Infarction Registry-National Institute of Health of in-hospital survivors after AMI, the benefit of beta-blocker therapy at discharge was shown in patients with reduced or mildly reduced EF, but not in those with preserved EF, which provides new information about beta-blocker therapy in patients without reduced EF. However, clinical practice can be changed when the results of appropriate randomized clinical trials are available. Ongoing clinical trials may help to answer the unresolved issues of beta-blocker therapy in patients with AMI.


Haematological and febrile response to Escherichia coli lipopolysaccharide in 12-week-old cockerels of genetically diverse layer lines fed diets with increasing L-arginine levels.
Due to its decisive function in the avian metabolic, endocrine and immune system L-arginine (Arg) is dietary indispensable for chickens. In 12-week-old cockerels of two high- and two low-performing purebred layer lines, the effects of increasing dietary Arg on the haematological and febrile response were studied over 48 h after single lipopolysaccharide (LPS) injection. The offered diets contained Arg equivalent to 70%, 100% and 200% of recommended supply. Pathophysiological alterations in weight gain, feed intake, body temperature and differential blood count were examined in comparison with their physiological initial values. Within the first 24 h after LPS injection, cockerels reduced feed intake and lost body weight subsequently. Thereby, low-performing genotypes lost body weight to a lesser extent than high-performing ones. The loss of body weight was further intensified by deficient dietary Arg. Within the following 24 h, cockerels recovered by improving feed intake and weight gain. Furthermore, LPS induced genotype-specific fever response: both brown genotypes showed initial hypothermia followed by longer lasting moderate hyperthermia, whereas the white genotypes exhibited biphasic hyperthermia. Fever response was accompanied by significant changes in differential blood counts. Characterized by lymphopenia and heterophilia, a severe leucopenia was observed from 4 to 8 h after LPS injection and replaced by a marked leucocytosis with longer lasting monocytosis up to 48 h after LPS injection. Under given pathophysiological conditions, deficiently Arg-supplied cockerels showed higher total leucocyte counts than adequately and excessively Arg-supplied cockerels. However, deficient and surplus dietary Arg tended to cause higher ratios between heterophils and lymphocytes. To conclude, present results confirmed that LPS induced numerous immunological changes in 12-week-old cockerels and emphasized that chicken's genotype is a source of variation to be considered for immunological studies. Deficient dietary Arg intensified acute changes in differential blood counts and weight gain during LPS-induced inflammation.


Target-controlled in situ formation of G-quadruplex DNAzyme for a sensitive visual assay of telomerase activity.
It is of great importance to achieve facile and reliable detection of telomerase because it is an important cancer biomarker. The complex components of cell extracts and ultra-low concentration of telomerase makes it more difficult to realize a simple and sensitive visual detection of telomerase activity. Herein, a facile and sensitive visual strategy was developed for the detection of telomerase based on the telomerase-controlled in situ formation of a G-quadruplex-hemin DNAzyme. To avoid the influence of the complex components of cell extracts, a telomerase substrate (TS) was immobilized onto the surface of magnetic beads (MBs) to form a MB/TS complex. MB/TS incubated with telomerase can add several TTAGGG repeat units to the 3' terminal of TS. After magnetic separation and washing, these G-rich elongated DNA folded into numerous G-quadruplex-hemin DNAzymes under the aid of K+ and hemin, which efficiently catalysed the TMB/H2O2 reaction. Magnetic separation basically eliminated the non-specific background interference from other cell extracts and redundant hemin. Taking full advantage of the in situ formation of multiple catalysts, the telomerase activity could be sensitively evaluated by a color change of the TMB/H2O2 solution. The telomerase activity down to 1 HeLa cell per μL and 0.5 HeLa cell per μL can be measured by the naked eye and UV-vis spectroscopy, respectively. Due to the magnetic separation and enrichment, the sensitivity was obviously improved compared with the previous colorimetric assay. Meanwhile, the telomerase activity of 5 HeLa cells per μL in human serum can be visually detected. Therefore, this study provides a facile, cost-effective and robust colorimetric assay for the visual detection of telomerase activity, which holds great potential in telomerase-based cancer clinical diagnostics.


Analysis of cumene (isopropylbenzene) degradation genes from Pseudomonas fluorescens IP01.
We obtained the DNA fragments encoding 2-hydroxy-6-oxo-7-methylocta-2,4-dienoic acid (HOMODA) hydrolase in the cumene (isopropylbenzene) degrader Pseudomonas fluorescens strain IP01 via PCR using two synthesized oligonucleotides corresponding to the conserved regions within known meta-cleavage compound hydrolases. Following colony hybridization using the amplified DNA as a probe, a 4.5-kb HindIII fragment was isolated from P. fluorescens IP01. After determining the nucleotide sequence of this fragment, three open reading frames (ORF11 [cumH], ORF12 [cumD], and ORF13) were identified. The deduced amino acid sequence of ORF12 showed homology with meta-cleavage compound hydrolases encoded by the tod, dmp, xyl, and bph operons. Although the product of ORF12 was found to exhibit HOMODA and 2-hydroxy-6-oxohepta-2,4-dienoic acid (HOHDA) hydrolase activities, it did not exhibit 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) hydrolase activity. The deduced amino acid sequence of ORF11 showed 40.4% homology with the sequence of todX in Pseudomonas putida F1 (Y. Wang, M. Ralings, D. T. Gibson, D. Labbé, H. Bergeron, R. Brousseau, and P. C. K. Lau, Mol. Gen. Genet. 246:570-579, 1995). The nucleotide sequence of ORF13 and its flanking region showed strong homology (91.0%) with IS52 from Pseudomonas savastanoi (Y. Yamada, P.-D. Lee, and T. Kosuge, Proc. Natl. Acad. Sci. USA 83:8263-8267, 1982). By characterization of cumH and cumD, the entire cum gene cluster from the cumene-degrader P. fluorescens IP01 (cumA1A2A3A4BCEGFHD) has been identified.


Challenge of Bovine Foot Skin Fibroblasts With Digital Dermatitis Treponemes Identifies Distinct Pathogenic Mechanisms.
Bovine digital dermatitis (BDD) is a common infectious disease of digital skin in cattle and an important cause of lameness worldwide, with limited treatment options. It is of increasing global concern for both animal welfare and food security, imposing a large economic burden on cattle farming industries each year. A polytreponemal etiology has been consistently identified, with three key phylogroups implicated globally: Treponema medium, Treponema phagedenis, and Treponema pedis. Pathogenic mechanisms which might enable targeted treatment/therapeutic development are poorly defined. This study used RNA sequencing to determine global differential mRNA expression in primary bovine foot skin fibroblasts following challenge with three representative BDD treponemes and a commensal treponeme, Treponema ruminis. A pro-inflammatory response was elicited by the BDD treponemes, mediated through IL-8/IL-17 signaling. Unexpectedly, the three BDD treponemes elicited distinct mechanisms of pathogenesis. T. phagedenis and T. pedis increased abundance of mRNA transcripts associated with apoptosis, while T. medium and T. pedis increased transcripts involved in actin rearrangement and loss of cell adhesion, likely promoting tissue invasion. The upregulation of antimicrobial peptide precursor, DEFB123, by T. phagedenis spirochaetes may present a microbial ecological advantage to all treponemes within BDD infected tissue, explaining their dominance within lesions. A commensal, T. ruminis, significantly dysregulated over three times the number of host mRNA transcripts compared to BDD treponemes, implying BDD treponemes, akin to the syphilis pathogen (Treponema pallidum), have evolved as "stealth pathogens" which avoid triggering substantial host immune/inflammatory responses to enable persistence and tissue invasion. Immunohistochemistry demonstrated increased IL-6, IL-8, RND1, and CFB protein expression in BDD lesions, confirming in vitro fibroblast observations and highlighting the system's value in modeling BDD pathogenesis. Several unique shared gene targets were identified, particularly RGS16, GRO1, MAFF, and ZC3H12A. The three key BDD Treponema phylogroups elicited both distinct and shared pathogenic mechanisms in bovine foot skin; upregulating inflammation whilst simultaneously suppressing adaptive immunity. The novel gene targets identified here should enable future vaccine/therapeutic approaches.


Inhibition of Pyramidal Neurons in the Basal Amygdala Promotes Fear Learning.
The basolateral amygdala complex, which contains the lateral (LA) and basal (BA) subnuclei, is a critical substrate of associative learning related to reward and aversive stimuli. Auditory fear conditioning studies in rodents have shown that the excitation of LA pyramidal neurons, driven by the inhibition of local GABAergic interneurons, is critical to fear memory formation. Studies examining the role of the BA in auditory fear conditioning, however, have yielded divergent outcomes. Here, we used a neuron-specific chemogenetic approach to manipulate the excitability of mouse BA neurons during auditory fear conditioning. We found that chemogenetic inhibition of BA GABA neurons, but not BA pyramidal neurons, impaired fear learning. Further, either chemogenetic stimulation of BA GABA neurons or chemogenetic inhibition of BA pyramidal neurons was sufficient to generate the formation of an association between a behavior and a neutral auditory cue. This chemogenetic memory required presentation of a discrete cue, and was not attributable to an effect of BA pyramidal neuron inhibition on general freezing behavior, locomotor activity, or anxiety. Collectively, these data suggest that BA GABA neuron activation and the subsequent inhibition of BA pyramidal neurons play important role in fear learning. Moreover, the roles of inhibitory signaling differ between the LA and BA, with excitation of pyramidal neurons promoting memory formation in the former, and inhibition of pyramidal neurons playing this role in the latter.


The effect of a new universal laser aiming device in C-arm fluoroscopy on the technician's accuracy.
This study aims to introduce a new low-cost universal laser aiming device (LAD) that can be used in existing C-arm fluoroscopy devices, independent of brand and model, and to determine whether this new universal LAD improves technician accuracy in locating the desired region at the midpoint of the fluoroscopic image. A low-priced universal LAD that is compatible with existing 12-inch C-arm fluoroscopy devices was designed. Eight radiology technicians with varied levels of experience in C-arm fluoroscopy participated in the study. A 12 mm cortical screw with a diameter of 3.5 mm was placed on proximal, diaphyseal, and distal points of femur, tibia, and humerus bones in the anteroposterior plane on L3 vertebrae and the left pubis arm in the pelvis bone model. Technicians were asked to align each screw in the image center 10 times from a distance of 30 cm in the anterolateral plane, first without the LAD and then with the LAD. The distance of the screw head to the center point was measured from the 3,520 images with the help of medical viewer software based on the X- and Y-axis. Each fluoroscopic image was divided into 48 equal parts and the length of a part was taken as one unit for distance measurements. The compliance between technicians without the LAD was 0.347 (95% confidence interval [CI]: 0.208-0.47, p=0.001) and with the LAD was 0.687 (95% CI: 0.621-0.741, p=0.001). The distance between the screw head and the center of the image without the LAD was 19.0±9.8 for technicians with more than 10 years of experience and 28.0±12.9 for those with less than 10 years of experience. This difference was statistically significant (p=0.001). When the LAD was used, the difference between the less experienced (3.1±1.5) and more experienced (3.3±2.0) technicians was statistically reduced, along with the distance (p=0.033). The use of the LAD with C-arm fluoroscopy appears to be successful in helping technicians capture the desired point in the center of the fluoroscopic image. The use of the LAD reduces the experience gap between technicians.


Periprosthetic fractures after total knee arthroplasties.
The management of periprosthetic fracture around the knee remains a challenging problem. The objective of this article was to review the general concepts, treatment algorithms, and the overall treatment outcomes of femoral and tibial periprosthetic fractures after total knee arthroplasty. This article aimed to highlight the deficiencies of the current classification systems that fail to provide a guideline for selection of appropriate treatment options. We proposed a new classification system for periprosthetic femoral fractures that takes into account the status of the prosthesis, the quality of distal bone stock, and the reducibility of the fracture. Type I fractures are those occurring in patients with good bone stock with the prosthesis being fixed and well positioned. Type IA fractures are either nondisplaced or easily reducible and can be treated conservatively. Type IB fractures are irreducible and require reduction and internal fixation. Type II fractures are defined as those occurring also in patients with good bone stock and being reducible, but either the components are loose or malpositioned. These fractures are treated by revision arthroplasty. Type III fractures are reducible or irreducible fractures that occur in patients with poor bone stock and in the vicinity of loose or malpositioned components. These fractures are treated by distal femoral replacement. Therapeutic study, level V (expert opinion). See Guidelines for Authors for a complete description of levels of evidence.


Micro-structure diffusion scalar measures from reduced MRI acquisitions.
In diffusion MRI, the Ensemble Average diffusion Propagator (EAP) provides relevant micro-structural information and meaningful descriptive maps of the white matter previously obscured by traditional techniques like Diffusion Tensor Imaging (DTI). The direct estimation of the EAP, however, requires a dense sampling of the Cartesian q-space involving a huge amount of samples (diffusion gradients) for proper reconstruction. A collection of more efficient techniques have been proposed in the last decade based on parametric representations of the EAP, but they still imply acquiring a large number of diffusion gradients with different b-values (shells). Paradoxically, this has come together with an effort to find scalar measures gathering all the q-space micro-structural information probed in one single index or set of indices. Among them, the return-to-origin (RTOP), return-to-plane (RTPP), and return-to-axis (RTAP) probabilities have rapidly gained popularity. In this work, we propose the so-called "Apparent Measures Using Reduced Acquisitions" (AMURA) aimed at computing scalar indices that can mimic the sensitivity of state of the art EAP-based measures to micro-structural changes. AMURA drastically reduces both the number of samples needed and the computational complexity of the estimation of diffusion properties by assuming the diffusion anisotropy is roughly independent from the radial direction. This simplification allows us to compute closed-form expressions from single-shell information, so that AMURA remains compatible with standard acquisition protocols commonly used even in clinical practice. Additionally, the analytical form of AMURA-based measures, as opposed to the iterative, non-linear reconstruction ubiquitous to full EAP techniques, turns the newly introduced apparent RTOP, RTPP, and RTAP both robust and efficient to compute.


Design, Synthesis and Biological Evaluation of Some Triazole Schiff's Base Derivatives as Potential Antitubercular Agents.
Tuberculosis (TB) is the second important cause of death worldwide caused by a bacterium called Mycobacterium tuberculosis. There is a need to find and develop new Anti-TB medications that are effective, inexpensive and suitable with human immunodeficiency virus and other anti-TB drugs used in many countries and mainly the developing countries where the disease is widespread. These drugs must be designed to shorten treatment time and to be active against resistant forms of the mycobacteria that will help to increase the patients compliance. A key compound which could be used as a lead to meet these requirements, is the thiolactomycin (TLM). This antibiotic which is naturally available has an ability to treat M. tuberculosis by inhibiting condensing enzymes called FAS II (mtFabH, KasA and KasB) which are related to biosynthesis of mycolic acid. Our main aims are to design and synthesize analogues of TLM as new lead molecules which could be a possible anti-TB candidate. To overcome the synthetic challenges associated with preparing the chiral TLM analogues; we synthesized and investigated a series of triazole analogues as inhibitors of KasA enzyme and the whole cell Mycobacteria. A series of twelve compounds were synthesized, purified and fully characterized using several spectroscopic techniques. Molecular modelling studies for our synthesised compounds were achieved by using a modelling program called AutoDock 4.2 utilising rigid docking. Our results indicate that analogues of TLM show a good activity as compared to TLM. The activity obtained for the synthesized compounds against Mycobacteria tuberculosis indicate that the synthesised compounds 1, 2, 6 and 9 are pharmacologically active as they restrained the growth of the Mycobacteria bacteria.


A critical review of the current conservative therapies for tennis elbow (lateral epicondylitis).
The pathogenesis, pathology, natural course, and in particular the treatment of lateral epicondylitis (tennis elbow) remains controversial. An extensive review of the scientific literature with respect to the conservative treatment of tennis elbow, revealed that acceptable epidemiological techniques of the prospective randomised control trials or case controlled studies are scarce. While administration of steroid compounds has traditionally been the mainstay of conservative treatment of tennis elbow, the high recurrence rate of side effects and structural tissue changes associated with steroid therapy, leaves this modality as the most controversial approach in the treatment of tennis elbow. In contrast, in some studies evidence in favour of a role for classical acupuncture, ultrasound and low level laser as effective therapeutic means in the treatment of tennis elbow has been provided. As these modalities have not been associated with any side effects, in view of the ease of application, low cost and good curative effects, their increased application has been suggested by some authors. This proposition, however, remains rather conjectural until it could be convincingly substantiated by future studies with appropriate epidemiological design.


Stable leaders pave the way for cooperation under time-dependent exploration rates.
The exploration of different behaviours is part of the adaptation repertoire of individuals to new environments. Here, we explore how the evolution of cooperative behaviour is affected by the interplay between exploration dynamics and social learning, in particular when individuals engage on prisoner's dilemma along the edges of a social network. We show that when the population undergoes a transition from strong to weak exploration rates a decline in the overall levels of cooperation is observed. However, if the rate of decay is lower in highly connected individuals (Leaders) than for the less connected individuals (Followers) then the population is able to achieve higher levels of cooperation. Finally, we show that minor differences in selection intensities (the degree of determinism in social learning) and individual exploration rates, can translate into major differences in the observed collective dynamics.


The gut microbiota-bile acid axis: A potential therapeutic target for liver fibrosis.
Liver fibrosis involves the proliferation and deposition of extracellular matrix on liver tissues owing to various etiologies (including viral, alcohol, immune, and metabolic factors), ultimately leading to structural and functional abnormalities in the liver. If not effectively treated, liver fibrosis, a pivotal stage in the path to chronic liver disease, can progress to cirrhosis and eventually liver cancer; unfortunately, no specific clinical treatment for liver fibrosis has been established to date. In liver fibrosis cases, both the gut microbiota and bile acid metabolism are disrupted. As metabolites of the gut microbiota, bile acids have been linked to the progression of liver fibrosis via various pathways, thus implying that the gut microbiota-bile acid axis might play a critical role in the progression of liver fibrosis and could be a target for its reversal. Therefore, in this review, we examined the involvement of the gut microbiota-bile acid axis in liver fibrosis progression to the end of discovering new targets for the prevention, diagnosis, and therapy of chronic liver diseases, including liver fibrosis.


Randomized controlled trial of KW-6356 monotherapy in patients with early untreated Parkinson's disease.
KW-6356 is a novel selective adenosine A2A receptor antagonist/inverse agonist. We evaluated the efficacy and safety of KW-6356 as monotherapy in patients with early, untreated Parkinson's disease (PD). This was a randomized, placebo-controlled, double-blind study conducted in Japan to investigate the efficacy and safety of once-daily KW-6356 (3 or 6 mg/day) orally administered as monotherapy for 12 weeks in patients with early PD (NCT02939391). The primary endpoint was the least squares means of change from baseline in the MDS-UPDRS Part III total score. Overall, 168 patients were randomized and treated (KW-6356 3 mg/day n = 55; 6 mg/day n = 58, placebo n = 55); Week 12 completion rates were >90% per group. LS mean [95% CI] changes from baseline to Week 12 in MDS-UPDRS Part III total scores were -5.37 [-7.25, -3.48] for 3 mg/day, -4.76 [-6.55, -2.96] for 6 mg/day and -3.14 [-4.97, -1.30] for placebo. Changes from baseline were larger for both KW-6356 groups than for the placebo group at all time points. Secondary endpoints supported the primary findings with larger changes in MDS-UPDRS Part II, Parts II + III, and Total scores in the KW-6356 groups than in the placebo group. Treatment was well-tolerated; the most common treatment-emergent adverse events with KW-6356 were constipation (n = 4 [7.3%] and n = 6 [10.3%] in the 3 and 6 mg/day groups, respectively) followed by nasopharyngitis (n = 4 [7.3%] and n = 5 [8.6%] in the 3 and 6 mg/day groups, respectively). KW-6356 monotherapy is well tolerated and more effective than placebo in patients with early, untreated PD.


Evaluation of oncofetal protein-related mRNA transport activity as a potential early cancer marker in dogs with malignant neoplasms.
A 55-kd protein with mRNA transport activity found in fetal rat liver cells and plasma from mice, rats, and human beings with malignant neoplasms has been designated oncofetal protein 55 (OFP55). Monoclonal antibody produced to rat OFP55 cross-reacts with human OFP55. Using this monoclonal antibody in a bioassay measuring mRNA transport stimulated by OFP55, we tested the plasma from 19 dogs with a variety of malignant neoplasms, including carcinomas, sarcomas, lymphomas, and melanomas, and compared the results with plasma from 20 clinically normal dogs without evidence of neoplasia. The mean mRNA transport activity from the group of dogs with malignant neoplasms was 0.43 +/- 0.28%/mg of protein. Mean transport activity from the group of control dogs was 0.04 +/- 0.02%/mg of protein. These means were significantly different (P < 0.0001). The degree of overlap between these 2 groups in their OFP55-related mRNA transport activity was minimal, and measurement of this protein appears to have potential for the early detection of malignant neoplasms in dogs.


[General Counsel for Administration of Public Hospitals in Paris: creation of a public health institution].
In 1801, Napoleon Bonaparte established the Conseil Général des Hospices de Paris, as the first centralized authority to manage all Parisian civilian hospitals. Through an examination of the debates and statements surrounding its creation, and its founding rules and regulations, its purpose will be shown to be twofold: to enforce the values of proper administration and morality, and to support certain medical advancements. The Conseil heralded the birth of a public health institution which would become, some 50 years later, the Assistance-Publique.


Iterative use of a priori exposure matrices to improve the characterization of chemical exposures in agricultural work studies.
To assess pesticide exposures of agricultural workers, a priori exposure matrices based on "circumstantial determinants" of pesticide use were incorporated into the questionnaire of a case-referent study. Circumstantial determinants (crops cultivated, their surface areas and crop infestations) were recalled more frequently than specific chemicals. After the matrices were applied, the proportion of missing values fell from 44 to 9% for specific chemicals, from 97 to 17% for the dose for each treatment, and from 80 to 16% for number of treatments per year in a random sample of 40 questionnaires. The number of workers changed from 19 to 30 for parathion use, from 4 to 10 for mancozeb use, and from 4 to 12 for DDT (dichlorodiphenyltrichloroethane) use when the matrix was applied. The matrix enabled exposure levels to be assigned in each case. Provided that the matrix used is valid, this approach could increase the efficiency of case-referent studies on agricultural exposure to chemicals.


User-centered development of a smartphone application (Fit2Thrive) to promote physical activity in breast cancer survivors.
Increased moderate and vigorous physical activity (MVPA) is associated with better health outcomes in breast cancer survivors; yet, most are insufficiently active. Smartphone applications (apps) to promote MVPA have high scalability potential, but few evidence-based apps exist. The purpose is to describe the testing and usability of Fit2Thrive, a MVPA promotion app for breast cancer survivors. A user-centered, iterative design process was utilized on three independent groups of participants. Two groups of breast cancer survivors (group 1 n = 8; group 2: n = 14) performed app usability field testing by interacting with the app for ≥3 days in a free-living environment. App refinements occurred following each field test. The Post-Study System Usability Questionnaire (PSSUQ) and the User Version Mobile Application Rating Scale (uMARS) assessed app usability and quality on a 7- and 5-point scale, respectively, and women provided qualitative written feedback. A third group (n = 15) rated potential app notification content. Quantitative data were analyzed using descriptive statistics. Qualitative data were analyzed using a directed content analysis. The PSSUQ app usability score (M1= 3.8; SD = 1.4 vs. M2= 3.2; SD = 1.1; lower scores are better) and uMARS app quality score (M1 = 3.4; SD = 1.3 vs. M2= 3.4; SD = 0.6; higher scores are better) appeared to improve in Field Test 2. Group 1 participants identified app "clunkiness," whereas group 2 participants identified issues with error messaging/functionality. Group 3 "liked" 53% of the self-monitoring, 71% of the entry reminder, 60% of the motivational, and 70% of the goal accomplishment notifications. Breast cancer survivors indicated that the Fit2Thrive app was acceptable and participants were able to use the app. Future work will test the efficacy of this app to increase MVPA.


Current implantable cardioverter-defibrillator programming in Europe: the results of the European Heart Rhythm Association survey.
The purpose of this European Heart Rhythm Association (EHRA) survey was to examine the current practice on the choice of implantable cardioverter-defibrillator (ICD) type, use of defibrillation testing, and ICD programming for detection and therapy of ventricular arrhythmias. In accordance with recent guidelines and the results of observational studies, the majority of EHRA research network centres reported a high utilization rate of dual-chamber ICDs in the presence of symptomatic and asymptomatic sinus node dysfunction, biventricular ICD in high-degree atrioventricular block and QRS duration <120 ms, and a limited use of defibrillation testing either in primary and secondary prevention settings. Activation of the long ventricular tachycardia (VT) detection window, slow VT zone, antitachycardia pacing before shock for slow and fast VT, and atrial tachyarrhythmia discrimination were considered useful in ICD programming for the majority of patients.


[Optimization of surgical strategy in trauma of the chest: correlation of thoracoscopy and thoracotomy].
The authors analyzed an experience with treatment of 4372 patients. Videothoracoscopy allowed the number of usual drainages of the pleural cavity to be reduced in closed trauma from 16.3% to 2.3%, in wounds--from 3.9% to 0.4%. Persistent hemo- and airstasis were obtained by coagulation of the vessels of the thoracic wall and lung, suturing lung wounds. The coagulated hemothorax was removed, diaphragm wounds were sutured, the pericardium wounds were revised, the character of intrathoracic lesions was reliably determined in 98% of cases. Conversion into thoracotomy was fulfilled in 91 (5.5%) patients. Thoracotomy was fulfilled in 344 (8%) patients with indications to operative interventions and severe condition and unstable hemodynamics. The number of thoracotomies and lethality in patients with penetrating wounds of the chest became 1.5-2 times less, was not considerably changed in closed traumas.


A review of the dynamics and severity of the pandemic A(H1N1) influenza virus on Réunion island, 2009.
On Reunion Island, in response to the threat of emergence of the pandemic influenza A(H1N1)2009 virus, we implemented enhanced influenza surveillance from May 2009 onwards in order to detect the introduction of pandemic H1N1 influenza and to monitor its spread and impact on public health. The first 2009 pandemic influenza A(H1N1) virus was identified in Réunion on July 5, 2009, in a traveller returning from Australia; seasonal influenza B virus activity had already been detected. By the end of July, a sustained community pandemic virus transmission had been established. Pandemic H1N1 influenza activity peaked during week 35 (24-30 August 2009), 4 weeks after the beginning of the epidemic. The epidemic ended on week 38 and had lasted 9 weeks. During these 9 weeks, an estimated 66 915 persons who consulted a physician could have been infected by the influenza A(H1N1)2009 virus, giving a cumulative attack rate for consultants of 8.26%. Taking into account the people who did not consult, the total number of infected persons reached 104 067, giving a cumulative attack rate for symptomatics of 12.85%. The crude fatality rate (CFR) for influenza A(H1N1)2009 and the CFR for acute respiratory infection was 0.7/10 000 cases. Our data show that influenza pandemic did not have a health impact on overall mortality on Réunion Island. These findings demonstrate the value of an integrated epidemiological, virological and hospital surveillance programme to monitor the scope of an epidemic, identify circulating strains and provide some guidance to public health control measures.


[Development and assessment of questionnaires].
This article describes the development and psychometric evaluation of self-report measurement instruments in (nursing) research. The aim of this study is to gain more insight into, and understanding of the use of such instruments. To be more specific, this paper deals with: (1) What is a self-report measurement instrument?; (2) How to develop such an instrument?; (3) What is its psychometric quality in terms of validity and reliability?; (4) How to analyze an instrument statistically?; (5) Which are the pros en cons of a self-report measurement instrument in general?; and (6) Where do we find examples of good measurement instruments? These six questions will be answered with the help of several practical research examples. The article concludes with a few suggestions for literature concerning existing measurement instruments and their psychometric qualities.


Uncertainty experiments support the roles of second-order mechanisms in spatial frequency and orientation discriminations.
Previous studies of spatial frequency and orientation discrimination [Vision Res. 32, 1885 (1992)] suggest the existence of two second-order cortical mechanisms: one that mediates spatial frequency discriminations and sums signals across orientations and one that mediates orientation discriminations and sums signals across spatial frequency bands. The existence of each mechanism is tested in an uncertainty experiment in which the observer does not know which of two hypothetically pooled signals deviates from the standard but must judge whether the deviation is an increment or a decrement. No uncertainty effect is expected if the signals are completely pooled. Observed effects are compared with this expectation and with both theoretical and empirical estimates of the effects expected if the signals are processed separately. Results support the existence of the first mechanism, but not its exclusive role in mediating spatial frequency judgments, and support the exclusive role of the second mechanism in mediating orientation judgments.


Upregulation of MicroRNA-15a Contributes to Pathogenesis of Abdominal Aortic Aneurysm (AAA) by Modulating the Expression of Cyclin-Dependent Kinase Inhibitor 2B (CDKN2B).
BACKGROUND The objective of the present study was to identify the association between miR-15a-5p and CDKN2B, and their roles in regulating the development of abdominal aortic aneurysm (AAA). MATERIAL AND METHODS We searched the miRNA database online (www.mirdb.org) and used a luciferase reporter assay system to study the regulatory relationship between miR-15a-5p and CDKN2B. We also conducted real-time PCR and Western blot analysis to study the mRNA and protein expression level of CDKN2B among different patient groups (participants with abdominal aortic aneurysm (AAA) and normal controls) or cells treated with scramble control, miR-15a-5p mimics, CDKN2B siRNA, and miR-15a-5p inhibitors. RESULTS We found that CDKN2B was a virtual target of miR-15a-5p with potential binding sites in the 3'UTR of CDKN2B (77-83 bp). We also showed that miR-15a-5p could bind to the CDKN2B 3'UTR, resulting in a significant decrease in luciferase activity compared with the scramble control. Furthermore, we found that the cells isolated from AAA participants showed an over-expression of miR-15a-5p compared to the normal controls, while the CDKN2B mRNA and protein expression level of the AAA group were much lower than the normal control group. Additionally, the expression of CDKN2B mRNA and the protein of the cells transfected with miR-15a-5p mimics and CDKN2B siRNA was downregulated, while the cells showed upregulated expression subsequent to transfection with miR-15a-5p inhibitors compared to the scramble control. CONCLUSIONS The data revealed a negative regulatory role of miR-15a-5p in the apoptosis of smooth muscle cells via targeting CDKN2B, and showed that miR-15a-5p could be a novel therapeutic target of AAA.


Association between platelet function and recurrent ischemic vascular events after TIA and minor stroke .
Platelet activation and aggregation play an important role in the pathological and physiological processes of recurrent ischemic vascular events in stroke patients. The purpose of this study is to determine the association between platelet function measured in the acute period and recurrent ischemic vascular events in patients with transient ischemic attack (TIA) or minor stroke. A total of 417 patients who were within the 24-hour period of clopidogrel-aspirin therapy after onset of a minor stroke or high-risk transient ischemic attack according to the Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were included in this study. The platelet aggregation ratio was detected using a method of continuous platelet counting; patients underwent CYP2C19 genotyping, and the baseline data were recorded. The patients underwent a 6-month follow-up period during which the recurrent ischemic vascular events were observed. Logistic regression analysis was performed to obtain the risk factors for recurrent ischemic vascular events. The number of patients with recurrent ischemic events who had an arachidonic acid-induced maximum platelet aggregation ratio (MAR-AA) (aspirin 100 mg) (31.85 ± 12.86 vs. 26.71 ± 12.44, p = 0.007) and adenosine diphosphate-induced maximum platelet aggregation ratio (MAR-ADP) after the administration of 75 mg clopidogrel for 12 ± 2 days (65.82 ± 10.72 vs. 53.10 ± 12.98, p < 0.001) was significantly higher compared with the no ischemic vascular event group. Multivariate logistic regression analyses showed that being a carrier of the CYP2C19 loss-of-function (LOF) allele (OR = 2.308, 95% CI: 1.087 ~ 4.901, p = 0.029) as well as the MAR-AA (aspirin 100 mg) (OR = 1.028, 95% CI: 1.006 ~ 1.052, p = 0.014) and MAR-ADP after the administration of 75 mg clopidogrel (OR = 1.067, 95% CI: 1.037 ~ 1.095, p < 0.001) were risk factors for ischemic vascular events. The MAR-ADP after the administration of 75 mg clopidogrel was significantly higher in patients who were carriers of the CYP2C19 (LOF) allele compared with non-carriers (57.53 ± 13.32 vs. 50.86 ± 12.55, p < 0.001), and no significant differences between the CYP2C19 LOF allele carriers and non-carriers in the MAR-ADP were detected after the administration of 300 mg clopidogrel (37.18 ± 11.36 vs. 35.86 ± 12.49, p = 0.264). Being a carrier of the CYP2C19 LOF allele has a significant influence on clopidogrel response. Platelet function is closely related to recurrent ischemic vascular events in acute minor stroke or TIA patients. .


[Electrographic reflection of vegetative protective and compensatory reactions in craniocerebral trauma].
The authors substantiate the assumption that the presence of high-amplitude superslow potential fluctuations in registration from the skin surface of the head is determined by destabilization of subcortical intercentral relationships which comprises inhibition of stem and activation of posterohypothalamic structures in craniocerebral trauma. The constant potential reacts only to the sharpest period of a severe craniocerebral trauma and reflects acute inflammatory and vascular phenomena on the cortical level in the first 24 hours; maintenance or appearance of increased positive values of the constant potential over one of the hemispheres suggests the presence of an intracranial hematoma above this hemisphere.


Pain ROADMAP: A Mobile Platform to Support Activity Pacing for Chronic Pain.
We present a mobile health platform for activity pacing referred to as Pain ROADMAP (rediscover occupation achieve & develop through a monitoring app for pain). Pain ROADMAP incorporates a mobile phone application and online portal that allows for remote monitoring, integration, and analysis of objective activity data, pain intensity ratings, medication intake and daily activity participation data. In this article this platform is presented and a summary of results obtained from a pilot study (n=20).


An analysis of silicone gel-filled breast implants: diagnosis and failure rates.
This retrospective review analyzed 180 women who underwent explantation of 357 silicone gel-filled breast implants from September of 1991 to January of 1995. Implant status, including shell integrity and implantation times, was determined at the time of explantation. The age range of the patients was 25 to 75 years, with a mean age of 47 years. The age of the implants ranged from 0.5 to 24 years, with a mean age of 10.5 years. Of the 292 implants with known and documented integrity status, there were 102 intact, 76 unruptured with signs of leakage, and 114 ruptured. The frequency of implant rupture significantly increased with implant age. The average age of rupture was 13.4 years. The average age of signs of leakage was 10.1 years. There were no significant differences in failure rates among the implant types of four manufacturers. Analysis of both mammography and magnetic resonance imaging (MRI) as diagnostic modalities for differentiating intact implants, implant leakage, and implant rupture was performed. Standard mammography was less reliable in diagnosing implant leakage or rupture (sensitivity, 55 percent; specificity, 69 percent) than MRI (sensitivity, 72 percent; specificity, 82 percent). In conclusion, implant rupture occurred at a significantly increasing rate with implant age (10 to 15 years). These findings were independent of implant type or manufacturer. Mammography alone is a below-average diagnostic tool for detecting leakage or rupture, whereas MRI is a more accurate modality.


A comparative clinical study of solid and granular porous hydroxylapatite implants in human periodontal osseous defects.
Solid and granular porous hydroxylapatite implants were compared in the surgical treatment of angular interproximal periodontal defects in 10 subjects. After completion of initial therapy, presurgical measurements of pocket depth, attachment level, gingival recession, gingival fluid and tooth mobility were recorded. Six months after the surgery the measurements were repeated. The use of both forms of porous hydroxylapatite resulted in reduction in pocket depth, and probeable attachment level gains as well as gingival recession and reduction of gingival fluid and tooth mobility. These changes were similar for both granular and solid forms of porous hydroxylapatite.


Psychiatric disorders related to polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The psychiatric disorders accompanying the clinical symptoms and hormonal abnormalities are important, but underestimated, aspects in PCOS. Obesity, hirsutism, acne, menstrual disturbances and infertility play important roles in lowering the quality of life in women with PCOS. Depression and anxiety are more often observed in patients with PCOS than in healthy women. Some authors consider that there is a relationship between valproic acid treatment of bipolar disease and PCOS. There have been reports that in women with PCOS anorexia nervosa, bulimia nervosa and other unspecified eating disorders are found more often than in the general population.


Introduction to Transitions in the Life Course of Autism and Other Developmental Disabilities.
The Health Care Transitions Research Network for Autism Spectrum Disorder and other Developmental Disabilities and the Life Course Research Network, both funded by the Maternal and Child Health Bureau, invited articles for this Supplement. Our goal in this Supplement is to highlight and explore developmental and transition-related challenges over the life course of individuals on the autism spectrum and other neurodevelopmental disabilities, discuss the clinical and practice implications of these issues, highlight gaps in knowledge, and identify directions for future research.