Effect of 17 beta-estradiol on pituitary cAMP binding and responses to DBcAMP.
Effects of 17 beta-estradiol (E2) on adenosine 3',5'-cyclic monophosphate (cAMP) binding and luteinizing hormone (LH) and prolactin (PRL) responses to N6-O-2'-dibutyryl cAMP (DBcAMP) were examined in pituitary monolayer cultures prepared from female rats. Incubation with 8 mM DBcAMP for 4 h significantly (P less than 0.05) increased both LH and PRL release into medium by two- to threefold. E2 pretreatment augmented the DBcAMP-induced LH release but not PRL release to 160% of the non-E2-treated controls. However, the cellular and total accumulation of both LH and PRL were significantly increased in cultures pretreated with E2. The effect of E2 was time dependent, and the maximal effect was observed after 3 days of treatment. Furthermore, E2 treatment significantly increased cAMP-binding activities to 254% of the non-E2-treated controls. The time course of the E2 effect on cAMP-binding activities closely resembled the time course of the E2 effect on LH and PRL accumulation as well as the DBcAMP-induced LH release. These results suggest that the priming effect of E2 on pituitary LH and PRL responses to DBcAMP is associated with increased hormone synthesis and cAMP binding stimulated by E2 pretreatment.


Putaminal magnetic resonance imaging features at various magnetic field strengths in multiple system atrophy.
We delineated the effects of magnetic field strength on signal intensities to facilitate the specific findings of multiple system atrophy (MSA). Fifteen patients with probable MSA were imaged by 0.35T fast spin-echo (FSE), 1.5T FSE, and 3.0T FSE using a consistent protocol, testing all field strengths on the same day. Sixty patients with probable Parkinson's disease (PD) also underwent imaging. Moderate or marked hyperintensity at the dorsolateral outer putaminal margin, hyperintensity of the putaminal body, hypointensity relative to the globus pallidus at the dorsolateral putaminal margin, and infratentorial signal changes were evaluated as specific findings for MSA. As the field strength increased, the occurrence of hyperintensity both at the dorsolateral outer putaminal margin and of the putaminal body decreased, while the occurrence of hypointensity at the dorsolateral putaminal margin increased in MSA. The occurrence of uniform mild hyperintensity of the outer putaminal margin was evident in 7% at 0.35T, 40% at 1.5T, and 47% at 3.0T in MSA and in 5% at 0.35T, 60% at 1.5T, and 75% at 3.0T in PD. However, no PD patients showed hyperintensity at the dorsolateral outer putaminal margin and that of the putaminal body. Putaminal magnetic resonance imaging (MRI) findings in MSA were altered considerably by magnetic field strength. The severity and distribution of signal changes are important for assessing putaminal MRI findings in MSA.


Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use.
The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.


Blood pressure, body mass index and risk of cardiovascular disease in Chinese men and women.
It is still uncertain whether increased blood pressure (BP) has a stronger effect on the risk of cardiovascular disease (CVD) in lean persons than in obese persons. We tested it using a data set collected from a large cohort of Chinese adults. Systolic and diastolic BP, body mass index (BMI) and other variables were measured in 169,871 Chinese men and women > or = 40 years of age in 1991 using standard protocols. Follow-up evaluation was conducted in 1999-2000, with a response rate of 93.4%. Data were analyzed with Cox proportional hazards models. After adjusted for age, sex, cigarette smoking, alcohol consumption, high school education, physical inactivity, geographic region, and urbanization, we found that the effects of systolic or diastolic BP on risk of CVD generally increased with the increasing BMI levels (underweight, normal, overweight, and obese). For example, hazard ratios (HRs) and 95% confidence interval (CI) per 1- standard deviation (SD) increase in systolic BP within corresponding BMI levels were 1.27(1.21-1.33), 1.45(1.41-1.48), 1.52 (1.45-1.59) and 1.63 (1.51-1.76), respectively. Statistically significant interactions (P < 0.0001) were observed between systolic BP, diastolic BP and BMI in relation to CVD. In baseline hypertensive participants we found both obese men and women had higher risk of CVD than normal-weight persons. The multivariate-adjusted HRs(95%CI) were 1.23(1.03-1.47) and 1.20(1.02-1.40), respectively. Our study suggests that the magnitude of the association between BP and CVD generally increase with increasing BMI. Hypertension should not be regarded as a less serious risk factor in obese than in lean or normal-weight persons in Chinese adults.


An Automated Two-step Pipeline for Aggressive Prostate Lesion Detection from Multi-parametric MR Sequence.
A substantial percentage of prostate cancer cases are overdiagnosed and overtreated due to the challenge in deter- mining aggressiveness. Multi-parametric MR is a powerful imaging technique to capture distinct characteristics of prostate lesions that are informative for aggressiveness assessment. However, manual interpretation requires a high level of expertise, is time-consuming, and significant inter-observer variation exists for radiologists. We propose a completely automated approach to assessing pixel-level aggressiveness of prostate cancer in multi-parametric MRI. Our model efficiently combines traditional computer vision and deep learning algorithms, to remove reliance on manual features, prostate segmentation, and prior lesion detection and identified optimal combinations of MR pulse sequences for assessment. Using ADC and DWI, our proposed model achieves ROC-AUC of 0.86 and ROC-AUC of 0.88 for the diagnosis of aggressive and non-aggressive prostate lesions, respectively. In performing pixel-level clas- sification, our model's classifications are easily interpretable and allow clinicians to infer localized analyses of the lesion.


Genetic modification of the heart: transgenic modification of cardiac lipid and carbohydrate utilization.
Many recent advances in cardiovascular research have been made possible by the use of transgenic technology. This review will discuss a number of mouse models where transgenic technology has been utilized to alter expression of genes involved in cardiac uptake and metabolism of either lipid or carbohydrate. Particular attention will be paid to the proteins which regulate (1) carbohydrate and lipid transport into cardiomyocytes and (2) the subsequent metabolic process which occur within the cytosol. These steps are important in determining substrate availability for mitochondrial oxidative metabolism. The heart relies predominantly on fatty acids as its major fuel supply, while glucose and lactate provide a small percentage. Under certain conditions, this balance becomes altered such that the heart relies more on glucose, as seen in pathological hypertrophy or may rely almost solely on fatty acids, as observed in cardiac tissue of animal models of diabetes. Initially this switch in metabolic substrate provides adequate energy to maintain normal cardiac function however with time diastolic dysfunction and cardiac failure often occur associated with depletion in high-energy phosphates. The creation of transgenic mice with altered expression of genes involved in carbohydrate and lipid metabolism have provided a unique insight into the fine balance which exits in the mouse heart to maintain energy status and cardiac function. The models discussed in this review define both transport and cytosolic metabolism of lipid and carbohydrate as key cellular processes in the regulation of cardiac function and the pathogenesis of cardiac disease.


D2O as a substitute for 3H2O, as a reference indicator in liver multiple-indicator dilution studies.
The hepatic space of distribution and the processes underlying uptake of tracer substrate may be appraised by the multiple-indicator dilution technique after simultaneous injection of noneliminated vascular (51Cr-labeled red blood cells), extracellular 125I-labeled albumin and [14C]sucrose (or [58Co]EDTA) as high- and low-molecular-weight interstitial references, respectively], and cellular (3H2O or [14C]urea) indicators, together with the tracer-labeled substrate. The use of 3H2O or [14C]urea, with [14C]- or [3H]sucrose, however, precludes the simultaneous introduction and analysis of the behavior of 3H- and 14C-labeled substrate and metabolite. An assay for the quantitation of D2O in plasma by Fourier transform infrared spectrometry was therefore developed such that D2O could be used in lieu of 3H2O in multiple-indicator dilution studies in the blood-perfused rat liver. In experiments performed with an injection dose containing 51Cr-labeled red blood cells, 125I-labeled albumin, [14C]sucrose, 3H2O, and D2O, D2O was found to behave virtually identical to 3H2O in blood and liver; the accessible cellular water spaces were 0.625 and 0.621 ml/g liver for 3H2O and D2O, respectively, and the corresponding ratios of the sum of the cellular water plus the interstitial water space to the sinusoidal water space were 3.87 and 3.89. D2O was found to be an ideal substitute and is much superior to [14C]urea, which exhibits a small red blood cell carriage effect and which is slightly less dispersed than 3H2O.


Clinical guidance for radioiodine refractory differentiated thyroid cancer.
Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.


Machine Learning Model for Computer-Aided Depression Screening among Young Adults Using Wireless EEG Headset.
Depression is a disorder that if not treated can hamper the quality of life. EEG has shown great promise in detecting depressed individuals from depression control individuals. It overcomes the limitations of traditional questionnaire-based methods. In this study, a machine learning-based method for detecting depression among young adults using EEG data recorded by the wireless headset is proposed. For this reason, EEG data has been recorded using an Emotiv Epoc+ headset. A total of 32 young adults participated and the PHQ9 screening tool was used to identify depressed participants. Features such as skewness, kurtosis, variance, Hjorth parameters, Shannon entropy, and Log energy entropy from 1 to 5 sec data filtered at different band frequencies were applied to KNN and SVM classifiers with different kernels. At AB band (8-30 Hz) frequency, 98.43 ± 0.15% accuracy was achieved by extracting Hjorth parameters, Shannon entropy, and Log energy entropy from 5 sec samples with a 5-fold CV using a KNN classifier. And with the same features and classifier overall accuracy = 98.10 ± 0.11, NPV = 0.977, precision = 0.984, sensitivity = 0.984, specificity = 0.976, and F1 score = 0.984 was achieved after splitting the data to 70/30 ratio for training and testing with 5-fold CV. From the findings, it can be concluded that EEG data from an Emotiv headset can be used to detect depression with the proposed method.


A framework for classifying patient safety practices: results from an expert consensus process.
Development of a coherent literature evaluating patient safety practices has been hampered by the lack of an underlying conceptual framework. The authors describe issues and choices in describing and classifying diverse patient safety practices (PSPs). The authors developed a framework to classify PSPs by identifying and synthesising existing conceptual frameworks, evaluating the draft framework by asking a group of experts to use it to classify a diverse set of PSPs and revising the framework through an expert-panel consensus process. The 11 classification dimensions in the framework include: regulatory versus voluntary; setting; feasibility; individual activity versus organisational change; temporal (one-time vs repeated/long-term); pervasive versus targeted; common versus rare events; PSP maturity; degree of controversy/conflicting evidence; degree of behavioural change required for implementation; and sensitivity to context. This framework offers a way to classify and compare PSPs, and thereby to interpret the patient-safety literature. Further research is needed to develop understanding of these dimensions, how they evolve as the patient safety field matures, and their relative utilities in describing, evaluating and implementing PSPs.


Low-intensity LED therapy (λ 640 ± 20 nm) on saphenectomy healing in patients who underwent coronary artery bypass graft: a randomized, double-blind study.
Myocardial revascularization surgery (CABG) is the most appropriate treatment for coronary artery disease. Currently, the great challenge is to reduce postoperative complications, such as wound infections, dehiscence, pain, and patients' quality of life. The saphenectomy is the target of complications in 10% of cases, which can cause greater morbidity, time, and cost of hospitalization. Studies show that low-intensity laser or light-emitted diode (LED) therapy promotes positive biomodulation of the tissue repair process, culminating in a lower incidence of dehiscence, pain reduction, and improvement in quality of life. The objective of the present study was to evaluate clinically the saphenous tissue repair after LED therapy. Forty subjects of both genders who underwent CABG with extracorporeal circulation were randomly divided into two groups: the placebo (PG) and experimental (EG). The experimental group underwent low-intensity LED therapy (λ 640 ± 20 nm, 6 J/cm2) on saphenectomy. The tissue repair was analyzed by digital photogrammetry on the first and fifth postoperative day. The border closure was blindly evaluated by three researchers. The hematoma and hyperemia area was quantitatively analyzed using ImageJ© software. The results showed that in the experimental group, there were less bleeding points and no dehiscence in saphenectomy, as compared to the placebo group. There was also a smaller area of hematoma and hyperemia in the experimental group (p < 0.0009). These data lead to the conclusion that the type of phototherapy protocol employed can assist in tissue repair.


Media Coverage, Forecasted Posttraumatic Stress Symptoms, and Psychological Responses Before and After an Approaching Hurricane.
Exposure to disaster-related media coverage is associated with negative mental health outcomes. However, risk factors that render individuals vulnerable to this exposure are unknown. Hurricane-associated media exposure was expected to explain the association between forecasted posttraumatic stress (PTS) and adjustment after the hurricane. To examine forecasted PTS responses and media coverage as risk factors for negative mental health outcomes in the context of media coverage of an approaching disaster (Hurricane Irma). In a representative probability community sample of 1637 adults from Florida, respondents completed 2 online surveys: the first during the 60 hours before Hurricane Irma's landfall (wave 1; September 8-11, 2017) and the second approximately 1 month later (wave 2; October 12-29, 2017). Poststratification weights were applied to facilitate population-based inferences. Data were analyzed from October 19 through 31, 2018. Posttraumatic stress responses, psychological distress, functional impairment, and worry about future events. The wave 1 survey included 1637 participants (57.0% response rate); 1478 participants were retained at the wave 2 follow-up (90.3% retention) (weighted proportion of women, 62.2%; mean [SD] age, 59.1 [15.2] years). The final weighted sample closely approximated US Census benchmarks for the state of Florida. Data analyses using structural equation modeling revealed that exposure to media coverage of the hurricane (β = 0.21; 95% CI, 0.11-0.31; P < .001) and forecasted PTS (β = 0.44; 95% CI, 0.35-0.52; P < .001) were significantly associated with adjustment after the hurricane. In addition, a significant indirect path from forecasted PTS to adjustment after the storm occurred through exposure to hurricane-related media coverage (β = 0.07; 95% CI, 0.05-0.08; P < .001). Covariates included demographics, mental health diagnoses before the storm, perceived evacuation zone status, and degree of hurricane exposure. Results of this study provide a more thorough understanding of how psychological factors before hurricanes are associated with adjustment after hurricanes via media consumption. The findings may also demonstrate the importance of considering prestorm psychological factors when assessing poststorm outcomes, with implications for the media and public health efforts.


Enhanced wavelength sensitivity of the self-collimation superprism effect in photonic crystals via slow light.
We demonstrate that the wavelength sensitivity of a self-collimation superprism in photonic crystals (PhCs) can be greatly improved via slow light. With the help of a saddle point Van Hove singularity, we present an approach to obtain such a wavelength-sensitive self-collimation superprism. Our superprism not only has extremely high wavelength sensitivity, but also can suppress beam divergence, irregular beam generation, and wavelength channel dropout, overcoming the limitations of traditional PhC-based superprisms. Based on our superprism, a high-performance compact demultiplexer is also proposed.


Excessive daytime sleepiness in psychiatric disorders: Prevalence, correlates and clinical significance.
This study examined the prevalence of excessive daytime sleepiness, as measured by the Epworth Sleepiness Scale (ESS), in a cohort of adult psychiatric patients. A total of 300 psychiatric outpatients and an additional 300 healthy controls completed the ESS. Excessive sleepiness was defined by a score of > or =10. The prevalence of excessive daytime sleepiness was higher in the psychiatric group (34%) than the control group (27%), and the mean ESS score was also significantly higher in the psychiatric group. The prevalence of excessive sleepiness was higher for female psychiatric patients, but this pattern was not found in the control group. Surprisingly, there was no difference in ESS score between patients taking antipsychotic medication and those not taking antipsychotic medication. The data suggest that excessive daytime sleepiness is a significant issue in general adult psychiatry, but this must be interpreted against a relatively high prevalence in the normal population.


Will neurobiology influence psychoanalysis?
Neurobiologic research has begun to elucidate brain mechanisms of affective states and behavioral patterns. Discussions of anxiety and sexual identity demonstrate how these researches lead the psychoanalyst to broader views of behaviors that were previously considered entirely psychological in origin. While introspection and extrospection are distinct realms of investigation and conceptualization, they share common boundaries and areas of interpenetration. Psychoanalytic theory is challenged to accord with newer findings in biology and to provide important questions for further research. Neurobiologic advances will continue a centuries-old process of confining the realm of psyche, but there is no danger that mind will disappear.


[Characteristics of nuclear DNA of a Lepidoptera, the great wax moth Galleria mellonella, using reassociation kinetics].
Reassociation kinetics of great wax moth--Galleria mellonella nuclear DNA short fragments was studied within the C0t values of 0.02 and 10(4). The least squares analysis of the experimental curve obtained revealed two components with C0t1/2 = 0.72 and C0t1/2 = 750 appropriately. The fraction of the component with C0t1/2 = 0.72 in the genome of great wax moth is 22% and that of the other one is 61%. There is also a rapid component which renatured at the C0t values less then 0,02. The fraction of this component in the genome is 17%. The great wax moth genome size determined kinetically is 4,83 X 10(8) base pairs. It was shown that the efficiency of DNA molecules network formation can qualify the genome studied as being a short or a long period of interspersion. On the basis that 80-90% of great wax moth DNA molecules participated in network formation which is inherent to the short period interspersion genomes, it was concluded that the great wax moth genome is of the Xenopus-like type.


Association analysis of genes of the IL19 cluster and their receptors in vitiligo patients.
The aim of the present study was to explore whether the genes encoding interleukin (IL) 19, IL-20, IL-24 and 2 chains of the IL-20 receptor type I (IL-20-RI), IL-20RA and IL-20RB, located on chromosomes 1q32, 6q22–23 and 3q22, respectively, are associated with vitiligo. The study involved 76 patients with vitiligo and 236 unrelated healthy volunteers. Genomic DNA was extracted from the whole blood and the frequencies of 20 single nucleotide polymorphisms were analysed by tetraprimer amplification refractory mutation system polymerase chain reaction. The minor allele of IL19 rs2243188 was significantly increased in vitiligo patients compared to controls (53.3 vs. 28.6%, adjusted p < 0.0001). The haplotype analysis revealed associations of 2 IL19/IL20 extended haplotypes (AACGTAA and ACCGTAA) and 2 IL20RB haplotypes (AGTA and AGGA) with vitiligo, remaining significant after correction for multiple testing. The A-to-C exchange at position IL19 rs2243188 leads to the loss of a nuclear receptor subfamily 2 factor binding site that is thought to influence mouse hippocampal development and neuronal differentiation. The third position of the IL20RB haplotypes is taken by rs747842 that induces the loss of the interferon regulatory factor 4 binding site that has an important role in the regulation of innate and adaptive immunity and in the signalling of pigmentation as well. In conclusion, the present study describes first-time associations between polymorphisms of genes of the IL19 cluster and their receptors and vitiligo, indicative of the part of IL19 and its receptor gene IL20RB in disease pathogenesis.


Illusions and delusions: relating experimentally-induced false memories to anomalous experiences and ideas.
The salience hypothesis of psychosis rests on a simple but profound observation that subtle alterations in the way that we perceive and experience stimuli have important consequences for how important these stimuli become for us, how much they draw our attention, how they embed themselves in our memory and, ultimately, how they shape our beliefs. We put forward the idea that a classical memory illusion - the Deese-Roediger-McDermott (DRM) effect - offers a useful way of exploring processes related to such aberrant belief formation. The illusion occurs when, as a consequence of its relationship to previous stimuli, a stimulus that has not previously been presented is falsely remembered. Such illusory familiarity is thought to be generated by the surprising fluency with which the stimulus is processed. In this respect, the illusion relates directly to the salience hypothesis and may share common cognitive underpinnings with aberrations of perception and attribution that are found in psychosis. In this paper, we explore the theoretical importance of this experimentally-induced illusion in relation to the salience model of psychosis. We present data showing that, in healthy volunteers, the illusion relates directly to self reported anomalies of experience and magical thinking. We discuss this finding in terms of the salience hypothesis and of a broader Bayesian framework of perception and cognition which emphasizes the salience both of predictable and unpredictable experiences.


Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge.
The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.


Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion.
Pediatric-onset systemic lupus erythematosus arises in humans and mice lacking the endonuclease Dnase1L3. When Dnase1L3 is absent, DNA from circulating apoptotic bodies is not cleared, leading to anti-DNA antibody production. Compared to early anti-DNA and anti-chromatin responses, other autoantibody responses and general immune activation in Dnase1L3-/- mice are greatly delayed. We investigated the possibility that immune activation, specifically inflammasome activation, is regulated by Dnase1L3. Here, we report that Dnase1L3 inhibition blocked both NLR family, pyrin domain containing 3 (NLRP3) and NLRC4 inflammasome-mediated release of high-mobility group box 1 protein and IL-1β. In contrast to IL-1β release, Dnase1L3 inhibition only mildly impaired NLRP3-dependent pyroptosis, as measured by propidium iodide uptake or LDH release. Mechanistically, we found that Dnase1L3 was needed to promote apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) nuclear export and speck formation. Our results demonstrate that Dnase1L3 inhibition separates cytokine secretion from pyroptosis by targeting ASC. These findings suggest that Dnase1L3 is necessary for cytokine secretion following inflammasome activation.


Inhibition of experimental metastasis and cell adhesion of B16F1 melanoma cells by inhibitors of protein kinase C.
Phorbol esters which activate protein kinase C (PKC) have been shown to enhance experimental lung metastasis. Therefore, it was reasoned that inhibitors of PKC might also modulate metastasis. We have investigated this possibility using a PKC inhibitor, MDL 27,032 [4-propyl-5(4-pyridinyl)-2(3H)-oxazolone], as well as staurosporine and H-7. Treatment of B16F1 murine melanoma cells with MDL 27,032 for 24 h in culture and subsequent i.v. injection of the cells into mice resulted in greater than 90% inhibition of lung metastasis. Inhibition of metastasis was time dependent, with 90% of maximum inhibition occurring by 8 h of incubation. The 50% inhibitory concentration (IC50) for inhibition of metastasis with MDL 27,032 was 7 microM, a value similar to that for the inhibition of B16F1 membrane-associated PKC (IC50 = 13 microM) but not cytosolic PKC (IC50 = 54 microM). B16F1 cells treated with MDL 27,032 for 24 h were less adherent than untreated cells to extracellular matrix/basement membrane proteins. Adhesion to fibrinogen and collagen IV was inhibited (IC50 = 6 microM and 48 microM, respectively) by MDL 27,032, whereas adherence to laminin and fibronectin was not affected, indicating that the drug affects specific adhesion molecules. MDL 27,032-treated cells were also found to be less adherent than untreated cells to human umbilical vein endothelial cells. The phosphorylation of an 80-kDa B16F1 cell plasma membrane protein was stimulated under conditions known to stimulate PKC activity, and MDL 27,032 inhibited this phosphorylation in a dose-dependent manner. MDL 27,032 was more potent than H-7 for the inhibition of metastasis but was significantly less potent than staurosporine. These results support the hypothesis that there is a critical role for PKC-mediated phosphorylation of cell surface adhesion receptors in metastasis.


SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.
Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through activating transcription factor 2 (ATF2) to the cyclic adenosine monophosphate (AMP) response element (CRE) in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more than the other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.


Modulation of excitatory synaptic coupling facilitates synchronization and complex dynamics in a biophysical model of neuronal dynamics.
In this paper, complex dynamical synchronization in a non-linear model of a neural system is studied, and the computational significance of the behaviours is explored. The local neural dynamics is determined by voltage- and ligand-gated ion channels and feedback between densely interconnected excitatory and inhibitory neurons. A mesoscopic array of local networks is modelled by introducing coupling between the local networks via weak excitatory-to-excitatory connectivity. It is shown that with modulation of this long-range synaptic coupling, the system undergoes a transition from independent oscillations to stable chaotic synchronization. Between these states exists a 'weakly' stable state associated with complex, intermittent behaviour in the temporal domain and clusters of synchronous regions in the spatial domain. The paper concludes with a discussion of the putative relevance of such processes in the brain, including the role of neuromodulatory systems and the mechanisms underlying sensory perception, adaptation, computation and complexity.


Congenital glaucoma and retinal dysplasia.
The differential diagnosis of leukocoria (pseudoglioma) in the neonate includes multiple conditions, including malformations with retinal dysplasia as a component. Typically bilateral, retinal dysplasia is characteristically seen in microphthalmic eyes. Certain chromosomal defects have been described. The case reported herein presented in the first month of life with an enlarged eye, elevated intraocular pressure, prominent iris vasculature, and leukocoria. Family history was positive in one respect: this is the second child of a Viet Nam veteran exposed to Agent Orange. The first child, from a different mother, also had birth defects. Other than his left eye, the child is completely normal. Ultrasonography showed posterior vitreous opacities of indeterminate configuration. CT scan suggested a posterior intraocular mass. Histologically, the principal features were an anomalous, largely unformed corneoscleral angle, intraocular hemorrhage, and retinal dysplasia. Light microscopic studies were performed. The corneoscleral angle revealed an anteriorly inserted iris with an absence of trabecular meshwork and Schlemm's canal. This case is considered unique on the basis of the association of retinal dysplasia with congenital glaucoma and larger-than-normal eye. The significance of reported paternal exposure to Agent Orange in this instance is unknown.


A facile method for high-throughput screening of drug-eluting coatings in droplet microarrays based on ultrasonic spray deposition.
Coating modification such as drug-eluting coating is one of the most important approaches for the functionalization of biomedical devices. However, the throughputs are limited in conventional coating methods and the concept of miniaturization is rarely fulfilled. A droplet microarray (DMA), as a unique high-throughput platform, can avoid cross-contamination and reduce the consumption of materials which is inherently suitable for coating research yet is difficult to apply with coating materials via traditional methods. Here, we bring up a facile method based on ultrasonic spray deposition to integrate coating materials into a DMA. Several common polymer materials were selected to fabricate a DMA, and the obtained DMA showed the ability to anchor water droplets and form specific patterns. Coating arrays with a typical sandwich structure were also prepared for the high-throughput screening of drug-eluting coatings to demonstrate the potential of the platform in coating research. This developed method is efficient and compatible and enriches the choices of materials that can be applied in DMAs.


Mycobacterium abscessus chest wall and pulmonary infection in a cystic fibrosis lung transplant recipient.
Mycobacterial infections are increasingly recognized in cystic fibrosis (CF) patients before transplant; however, knowledge about the clinical significance or spectrum of infections observed with mycobacterial infections in lung transplant recipients is still evolving. Herein, we report a case of infection with Mycobacterium abscessus in a CF lung transplant recipient. Despite aggressive treatment before and peri-operatively with anti-mycobacterial therapy, the patient developed skin and soft tissue infection of the incision and of bilateral breast implants, eventually leading to disseminated pulmonary infection and death. This report highlights the potential for M abscessus to cause post-transplant disease in CF patients undergoing lung transplant, despite peri-operative anti-mycobacterial therapy. Thus, pre-transplant colonization with M abscessus should be viewed as a strong relative, if not absolute, contraindication to lung transplantation. The combination of the virulent pre-transplant pathogen M abscessus and foreign bodies in the chest likely acted synergistically to contribute to the unfortunate outcome in this patient.


Suicide in Canadian veterans living in Ontario: a retrospective cohort study linking routinely collected data.
To compare the risk of death by suicide in male veterans with age-matched civilians. Retrospective cohort study linking provincial administrative databases between 1990 and 2013 with follow-up complete until death or December 31, 2015. Population-based study in Ontario, Canada. Ex-serving Canadian Armed Forces and Royal Canadian Mounted Police veterans living in Ontario who registered for provincial health insurance were included. A civilian comparator group was matched 4:1 on age and sex. Death by suicide was classified using standard cause of death diagnosis codes from a provincial registry of mandatory data collected from death certificates. Fine and Gray sub-distribution hazards regression compared the risk of death by suicide between veterans and civilians. Analyses were adjusted for age, residential region, income, rurality and major physical comorbidities. 20 397 male veterans released to Ontario between 1990 and 2013 and 81 559 age-sex matched civilians were included. 4.2% of veterans died during the study time frame, compared with 6.5% of the civilian cohort. Death by suicide was rare in both cohorts, accounting for 4.6% and 3.6% of veteran and civilian deaths, respectively. After adjustment for confounders, veterans had an 18% lower risk of dying from causes other than suicide (HR 0.82, 95% CI 0.76 to 0.89) and a similar risk of dying by suicide (HR 1.01, 95% CI 0.71 to 1.43), compared with civilians. Deaths by suicide were rare in male veterans residing in Ontario. Our findings demonstrate that veterans had a similar risk of suicide-related mortality as an age-matched civilian population. A better understanding of effective suicide prevention as well as clarifying pathways to seeking and receiving mental health supports and services are important areas for future consideration.


Fractionation of social brain circuits in autism spectrum disorders.
Autism spectrum disorders are developmental disorders characterized by impairments in social and communication abilities and repetitive behaviours. Converging neuroscientific evidence has suggested that the neuropathology of autism spectrum disorders is widely distributed, involving impaired connectivity throughout the brain. Here, we evaluate the hypothesis that decreased connectivity in high-functioning adolescents with an autism spectrum disorder relative to typically developing adolescents is concentrated within domain-specific circuits that are specialized for social processing. Using a novel whole-brain connectivity approach in functional magnetic resonance imaging, we found that not only are decreases in connectivity most pronounced between regions of the social brain but also they are selective to connections between limbic-related brain regions involved in affective aspects of social processing from other parts of the social brain that support language and sensorimotor processes. This selective pattern was independently obtained for correlations with measures of social symptom severity, implying a fractionation of the social brain in autism spectrum disorders at the level of whole circuits.


The therapy of Cushing's disease in adults and children: an update.
Cushing's disease (CD) is a rare endocrine disorder resulting from excessive production of adrenocorticotrophin hormone by a pituitary adenoma. The consequent hypercortisolaemia gives rise to characteristic features of the disease and its morbidities. Treatments aim to restore normal cortisol levels, provide long-term control of the disease and the tumour, and the improvement of patient well-being. The first line of treatment remains transsphenoidal surgery with remission rates of 65-90% in CD secondary to a pituitary microadenoma. Second-line treatment includes repeat surgery, radiotherapy, medical therapy, and bilateral adrenalectomy. The success rate of radiotherapy ranges from 46% to 74% and is probably independent of the mode of delivery of the radiation, but may take several years to become effective. Medical therapy is useful in acutely unwell patients or while awaiting radiotherapy to become effective. The most often-used medical agents include metyrapone and ketoconazole, which inhibit steroidogenesis; less often, centrally-acting drugs or a glucocorticoid receptor blocker are used, but experience with them is more limited. Bilateral adrenalectomy remains an important treatment option to control unresponsive severe hypercortisolism, particularly in patients with severe CD.The management of childhood CD does not differ from adult disease, with transsphenoidal surgery as successful as in adults but radiotherapy is more rapid in onset. Regardless of the age of the patient, Cushing's disease remains a challenge to the physician and requires a multidisciplinary approach to achieve the most desirable outcome.


Biochemical studies on the sulphated glycosaminoglycan fraction of skin fibroblasts cultured from a patient with the Hurler syndrome.
1. The metabolism of the sulphated glycosaminoglycan fraction in cultured skin fibroblasts derived from a patient with the Hurler syndrome and from a normal subject was studied. Two labelled precursors, Na(2) (35)SO(4) and d-[2-(3)H]glucose, were used and their intracellular fates during uptake and ;chase' periods were assessed after separation of sulphated glycosaminoglycans from hyaluronic acid. After 4 or 8h of exposure to culture medium containing both labels, [(35)S]sulphate incorporation into the sulphated glycosaminoglycan fraction was twofold greater in Hurler-syndrome cells than in normal cells. At the same time, the rate of incorporation of [(3)H]glucose into the sulphated glycosaminoglycan fraction was approximately the same for both cell types. Consequently, an increased (35)S/(3)H ratio (nmol of [(35)S]sulphate incorporated/nmol of [(3)H]glucose incorporated) was observed for Hurler-syndrome cells compared with normal cells. 2. The results of ;chase' experiments revealed that although the expected loss and relative retention of labelled sulphate occurred in the sulphated glycosaminoglycan fraction of normal and Hurler-syndrome cells, both cell types retained all of their radioactivity derived from [(3)H]glucose. 3. After 34h exposure to a ;corrective-factor' preparation from urine, the sulphated glycosaminoglycan content (as hexosamine and [(35)S]sulphate) of the Hurler-syndrome cells approached normal values. At the same time, there was an increase in specific radioactivity of ;corrected' Hurler-syndrome cells.


Evidence for TRPA1 involvement in central neural mechanisms in a rat model of dry eye.
Dry eye (DE) disease is commonly associated with ocular surface inflammation, an unstable tear film and symptoms of irritation. However, little is known about the role of central neural mechanisms in DE. This study used a model for persistent aqueous tear deficiency, exorbital gland removal, to assess the effects of mustard oil (MO), a transient receptor potential ankyrin (TRPA1) agonist, on eyeblink and eyewipe behavior and Fos-like immunoreactivity (Fos-LI) in the trigeminal brainstem of male rats. Spontaneous tear secretion was reduced by about 50% and spontaneous eyeblinks were increased more than 100% in DE rats compared to sham rats. MO (0.02-0.2%) caused dose-related increases in eyeblink and forelimb eyewipe behavior in DE and sham rats. Exorbital gland removal alone was sufficient to increase Fos-LI at the ventrolateral pole of trigeminal interpolaris/caudalis (Vi/Vc) transition region, but not at more caudal regions of the trigeminal brainstem. Under barbiturate anesthesia ocular surface application of MO (2-20%) produced Fos-LI in the Vi/Vc transition, in the mid-portions of Vc and in the trigeminal caudalis/upper cervical spinal cord (Vc/C1) region that was significantly greater in DE rats than in sham controls. MO caused an increase in Fos-LI ipsilaterally in superficial laminae at the mid-Vc and Vc/C1 regions in a dose-dependent manner. Smaller, but significant, increases in Fos-LI also were seen in the contralateral Vc/C1 region in DE rats. TRPA1 protein levels in trigeminal ganglia from DE rats ipsilateral and contralateral to gland removal were similar. Persistent tear reduction enhanced the behavioral and trigeminal brainstem neural responses to ocular surface stimulation by MO. These results suggested that TRPA1 mechanisms play a significant role in the sensitization of ocular-responsive trigeminal brainstem neurons in this model for tear deficient DE.


Genes and gene polymorphisms associated with periodontal disease.
The scientific literature during the last ten years has seen an exponential increase in the number of reports claiming links for genetic polymorphisms with a variety of medical diseases, particularly chronic immune and inflammatory conditions. Recently, periodontal research has contributed to this growth area. This new research has coincided with an increased understanding of the genome which, in turn, has permitted the functional interrelationships of gene products with each other and with environmental agents to be understood. As a result of this knowledge explosion, it is evident that there is a genetic basis for most diseases, including periodontitis. This realization has fostered the idea that if we can understand the genetic basis of diseases, genetic tests to assess disease risk and to develop etiology-based treatments will soon be reality. Consequently, there has been great interest in identifying allelic variants of genes that can be used to assess disease risk for periodontal diseases. Reports of genetic polymorphisms associated with periodontal disease are increasing, but the limitations of such studies are not widely appreciated. While there have been dramatic successes in the identification of mutations responsible for rare genetic conditions, few genetic polymorphisms reported for complex genetic diseases have been demonstrated to be clinically valid, and fewer have been shown to have clinical utility. Although geneticists warn clinicians on the over-enthusiastic use and interpretation of their studies, there continues to be a disparity between the geneticists and the clinicians in the emphasis placed on genes and genetic polymorphism associations. This review critically reviews genetic associations claimed for periodontal disease. It reveals that, despite major advances in the awareness of genetic risk factors for periodontal disease (with the exception of periodontitis associated with certain monogenetic conditions), we are still some way from determining the genetic basis of both aggressive and chronic periodontitis. We have, however, gained considerable insight into the hereditary pattern for aggressive periodontitis. Related to our understanding that it is autosomal-dominant with reduced penetrance comes a major clinically relevant insight into the risk assessment and screening for this disease, in that we appreciate that parents, offspring, and siblings of patients affected with aggressive periodontitis have a 50% risk of this disease also. Nevertheless, we must exercise caution and proper scientific method in the pursuit of clinically valid and useful genetic diagnostic tests for chronic and aggressive periodontitis. We must plan our research using plausible biological arguments and carefully avoid the numerous bias and misinterpretation pitfalls inherent in researching genetic associations with disease.


Innovation for universal health coverage in Bangladesh: a call to action.
A post-Millennium Development Goals agenda for health in Bangladesh should be defined to encourage a second generation of health-system innovations under the clarion call of universal health coverage. This agenda should draw on the experience of the first generation of innovations that underlie the country's impressive health achievements and creatively address future health challenges. Central to the reform process will be the development of a multipronged strategic approach that: responds to existing demands in a way that assures affordable, equitable, high-quality health care from a pluralistic health system; anticipates health-care needs in a period of rapid health and social transition; and addresses underlying structural issues that otherwise might hamper progress. A pragmatic reform agenda for achieving universal health coverage in Bangladesh should include development of a long-term national human resources policy and action plan, establishment of a national insurance system, building of an interoperable electronic health information system, investment to strengthen the capacity of the Ministry of Health and Family Welfare, and creation of a supraministerial council on health. Greater political, financial, and technical investment to implement this reform agenda offers the prospect of a stronger, more resilient, sustainable, and equitable health system.


Hemostatic Balance in Severe Trauma.
Acute coagulopathy is prevalent in adult and pediatric trauma patients and is associated with increased morbidity and mortality. While reasonable hypotheses have been created to explain the underlying perturbations of adult trauma coagulopathy (i.e., tissue factor-related increase in thrombin generation, protein C activation, hypoperfusion, and hyperfibrinolysis), only a small number of studies have been performed to prove whether these mechanisms can likewise be detected in pediatric trauma patients. In addition, severe hypofibrinogenemia (<100 mg/dL) is a frequent finding in pediatric trauma patients (>20%). Although the probability of life-threatening coagulopathy is low with minor to moderate injury, it is present in almost all patients with an injury severity score >25, hypotension, hypothermia, and acidosis. As these multifactorial changes in hemostasis cannot be adequately and rapidly measured using standard laboratory testing, the use of viscoelastic measurements has been established in adult trauma management, but prospective studies in children are urgently needed. Apart from diagnostic challenges, several studies have focused on the impact of blood product ratios on the treatment of massively bleeding pediatric trauma patients. The majority of these studies were unable to show improved survival by using higher plasma to red blood cell ratios or higher platelet to red blood cells ratios, but there are no published randomized trials to definitively answer this question. A goal-directed transfusion protocol using viscoelastic tests together with early substitution with an antifibrinolytic and fibrinogen replacement is a promising alternative to traditional ratio-based interventions. Another crucial factor in treating trauma-induced coagulopathy is the early detection of hypofibrinogenemia, a common condition in massively transfused patients. Early treatment of hypofibrinogenemia is associated with improved morbidity and mortality in adults, but needs to be further studied in future pediatric trials. Pediatric trauma patients are not only threatened by coagulopathy-related bleeding but are also at higher risk for venous thromboembolism. Pediatric trauma patients with brain injury, central venous catheters, immobilization, or surgical procedures are at highest risk for developing a deep venous thrombosis. There are no specific pediatric guidelines established to prevent venous thromboembolism in children suffering from traumatic injury.


The specificity and Kd at physiological ionic strength of an ATP-binding site on cytochrome c suit it to a regulatory role.
Cytochrome c binds ATP with marked specificity at a site that contains the evolutionarily invariant residue Arg-91. The binding of ATP to this site was studied using equilibrium gel filtration, equilibrium dialysis and affinity chromatography. At physiological ionic strength the affinity is such that the major change in occupancy coincides with the normal cellular ATP concentration range, and the degree of saturation is proportional to the ratio of [ATP]/[ADP]. The specificity of binding at this site is more a function of the degree of phosphorylation of the nucleotide, than of the nature of the nucleoside moiety. Thus under physiological conditions the degree of occupancy of this site is proportional to the energy state of the cell, providing a means for the regulation of the respiratory chain which is sensitive to cytoplasmic ATP levels.


A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes.
Susceptibility to murine and human insulin-dependent diabetes mellitus correlates strongly with major histocompatibility complex (MHC) class II I-A or HLA-DQ alleles that lack an aspartic acid at position beta57. I-Ag7 lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse. The crystal structure of I-Ag7 was determined at 2.6 angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65. I-Ag7 has a substantially wider peptide-binding groove around beta57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of Asp(beta57) leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T cell receptor.


[Asbestos-induced malignant mesothelioma of the tunica vaginalis testis].
Since 1977 the diffuse malignant mesothelioma of the pleura and peritoneum caused by asbestos represents one of the most often compensated occupational cancers in Germany. Because of the probability of an asbestos-related etiology, it is considered as a "signal tumour", mainly indicating exposure to asbestos dust at the workplace. Two cases of histologically confirmed rare malignant mesothelioma of the tunica vaginalis testis are presented. Previous exposure to asbestos at the workplace is to be considered as a causal factor in both tumors. If cases of mesothelioma occur the criteria for indicating an occupational disease (No. 4105 of the German Law of Occupational Diseases, BKV) are fulfilled.


First-principle calculation of Chern number in gyrotropic photonic crystals.
As an important figure of merit for characterizing the quantized collective behaviors of the wavefunction, Chern number is the topological invariant of quantum Hall insulators. Chern number also identifies the topological properties of the photonic topological insulators (PTIs), thus it is of crucial importance in PTI design. In this paper, we develop a first principle computatioal method for the Chern number of 2D gyrotropic photonic crystals (PCs), starting from the Maxwell's equations. Firstly, we solve the Hermitian generalized eigenvalue equation reformulated from the Maxwell's equations by using the full-wave finite-difference frequency-domain (FDFD) method. Then the Chern number is obtained by calculating the integral of Berry curvature over the first Brillouin zone. Numerical examples of both transverse-electric (TE) and transverse-magnetic (TM) modes are demonstrated, where convergent Chern numbers can be obtained using rather coarse grids, thus validating the efficiency and accuracy of the proposed method.


Cardiovascular effects of peritoneal insufflation of carbon dioxide for laparoscopy.
We have investigated, in 13 artificially ventilated and anaesthetized patients, the cardiovascular effects of peritoneal insufflation of carbon dioxide preparatory to laparoscopy. Stepwise increases of intra-abdominal pressure up to a maximum of 25 cm H(2)O were accompanied by increases of airway pressure, intrathoracic pressure, central venous pressure, and femoral venous pressure and by signs of cardiovascular stimulation with mild tachycardia and hypertension. End-tidal carbon dioxide tension rose only slightly. The anaesthetic technique used provided good surgical conditions; our results suggest that it does not impose undue strain on the homoeostatic ability of the patient's cardiovascular system.


Trisacryl gelatin microspheres for therapeutic embolization, II: preliminary clinical evaluation in tumors and arteriovenous malformations.
To evaluate an embolic agent that is precisely calibrated, perfectly spherical in shape, and soft but nonresorbable for use in the embolization of vascular disease of the head, neck, and spine in humans. We used supple, hydrophilic, and calibrated trisacryl gelatin microspheres 200, 400, 600, 800 and 1000 microns in diameter for superselective embolization in 105 patients (27 tumors, 14 facial arteriovenous malformations [AVMs], 37 spinal cord AVMs, 21 cerebral AVMs, and 6 miscellaneous diseases). We used particles in 200 to 600 microns in diameter for tumors and for facial AVMs, particles 400 to 600 microns in diameter for spinal cord AVMs, and particles over 1000 micros in diameter for cerebral AVMs. Delivery of the embolic material was easy: microspheres did not aggregate and catheters did not become obstructed by particles. It was possible to control the embolization through precise accounting of the amount of microspheres and matching of the particle size to the size of the pathologic vascular network. The microspheres are easy to use and allow precise control of the embolization procedure. Their physical characteristics make them a safe embolic agent.


Infection with Mycobacterium avium subsp. paratuberculosis results in rapid interleukin-1β release and macrophage transepithelial migration.
Pathogen processing by the intestinal epithelium involves a dynamic innate immune response initiated by pathogen-epithelial cell cross talk. Interactions between epithelium and Mycobacterium avium subsp. paratuberculosis have not been intensively studied, and it is currently unknown how the bacterium-epithelial cell cross talk contributes to the course of infection. We hypothesized that M. avium subsp. paratuberculosis harnesses host responses to recruit macrophages to the site of infection to ensure its survival and dissemination. We investigated macrophage recruitment in response to M. avium subsp. paratuberculosis using a MAC-T bovine macrophage coculture system. We show that M. avium subsp. paratuberculosis infection led to phagosome acidification within bovine epithelial (MAC-T) cells as early as 10 min, which resulted in upregulation of interleukin-1β (IL-1β) at transcript and protein levels. Within 10 min of infection, macrophages were recruited to the apical side of MAC-T cells. Inhibition of phagosome acidification or IL-1β abrogated this response, while MCP-1/CCL-2 blocking had no effect. IL-1β processing was dependent upon Ca(2+) uptake from the extracellular medium and intracellular Ca(2+) oscillations, as determined by EGTA and BAPTA-AM [1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester)] treatments. Thus, M. avium subsp. paratuberculosis is an opportunist that takes advantage of extracellular Ca(2+)-dependent phagosome acidification and IL-1β processing in order to efficiently transverse the epithelium and enter its niche--the macrophage.


Associations of diet quality with health-related quality of life in older Australian men and women.
This study investigated associations between diet quality measures and quality of life two years later. Adults 55-65 years participating in the Wellbeing, Eating and Exercise for a Long Life (WELL) study in Victoria, Australia (n = 1150 men and n = 1307 women) completed a postal survey including a 111-item food frequency questionnaire in 2010. Diet quality in 2010 was assessed via the dietary guideline index (DGI), recommended food score (RFS) and Mediterranean diet score (MDS). The RAND 36-item survey assessed health-related quality of life in 2012. Associations were assessed using logistic regression adjusted for covariates. In men, DGI and RFS were associated with better reported energy (OR = 1.79, CI: 1.25, 2.55 and OR = 1.56, CI: 1.11, 2.19 respectively), and DGI was additionally associated with better general health (OR = 1.54, 95% CI: 1.08, 2.20), and overall mental component summary scale (OR = 1.51, CI: 1.07, 2.15) in the fully adjusted model. In women, associations between two indices of diet quality (DGI, RFS) physical function (OR = 1.66, CI: 1.19, 2.31 and OR = 1.70, CI: 1.21, 2.37 respectively) and general health (OR = 1.83, CI: 1.32, 2.54 and OR = 1.54, CI: 1.11, 2.14 respectively) were observed. DGI was also associated with overall physical component summary score (OR = 1.56, CI: 1.12, 2.17). Additional associations between emotional wellbeing and DGI (OR = 1.40, CI: 1.01, 1.93) and RFS (OR = 1.44, CI: 1.04, 1.99), and MDS and energy (OR = 1.53, CI: 1.11, 2.10) were observed in the fully adjusted model, in women only. Older adults with better quality diets report better health-related quality of life, with additional associations with emotional wellbeing observed in women.


Transplantation of Human Cortically-Specified Neuroepithelial Progenitor Cells Leads to Improved Functional Outcomes in a Mouse Model of Stroke.
Stroke is a leading cause of death and long-term disability worldwide. Current therapeutic options are limited in terms of their time for implementation and efficacy in promoting recovery. Cell transplantation has been shown to have promise in several animal models however significant challenges remain, including the optimal source of cells to promote neural repair. Here, we report on the use of a population of human ESC derived, cortically specified, neuroepithelial precursor cells (cNEPs) that are neurally restricted in their lineage potential. CNEPs have the potential to give rise to mature neural cell types following transplantation, including neurons, astrocytes and oligodendrocytes. With a view towards translation, we sought to determine whether this human cell source was effective in promoting improved functional outcomes following stroke. Undifferentiated cNEPs were transplanted in a pre-clinical endothelin-1 (ET-1) model of ischemic motor cortical stroke in immunocompromised SCID-beige mice and cellular and functional outcomes were assessed. We demonstrate that cNEP transplantation in the acute phase (4 days post-stroke) improves motor function as early as 20 days post-stroke, compared to stroke-injured, non-transplanted mice. At the time of recovery, a small fraction (<6%) of the transplanted cNEPs are observed within the stroke injury site. The surviving cells expressed the immature neuronal marker, doublecortin, with no differentiation into mature neural phenotypes. At longer survival times (40 days), the majority of recovered, transplanted mice had a complete absence of surviving cNEPS. Hence, human cNEPs grafted at early times post-stroke support the observed functional recovery following ET-1 stroke but their persistence is not required, thereby supporting a by-stander effect rather than cell replacement.


Leukocytoclastic vasculitis due to ruxolitinib treatment: A rare adverse effect.
Primary myelofibrosis (PMF) is characterized by myeloid cell proliferation and prominent bone marrow fibrosis. Ruxolitinib, a selective inhibitor of JAK 1 and 2, significantly reduces constitutional symptoms and spleen size compared with placebo, and has significant clinical benefits in patients with myelofibrosis. The most common haematological side effects are thrombocytopenia and anaemia, and the most common non-haematological side effects are grade 1-2 diarrhoea and pyrexia. Leukocytoclastic vasculitis is small vessel vasculitis, characterized histopathologically by immune complex-mediated vasculitis of the dermal capillaries and venules in the lower extremities, which can be seen as palpable purpura. Although the cause is 50% idiopathic, the aetiology of leukocytoclastic vasculitis can be collected under many headings. The case is here presented of a patient with PMF who developed leukocytoclastic vasculitis after ruxolitinib treatment. Ruxolitinib was discontinued as the lesions were thought to be drug-related and all skin lesions disappeared approximately 2 months after termination of the drug. When the ruxolitinib treatment was restarted at the same dose (2 × 15 mg), the skin lesions recurred. The drug dose was reduced to 1 × 15 mg, and the rashes disappeared. Currently, the patient has no active complaints and is being followed up with ruxolitinib 1 × 15 mg without any complications. To the best of our knowledge, leukocytoclastic vasculitis due to ruxolitinib is extremely uncommon. This case report can be considered to contribute to the literature of this rare event.


Immunotoxicity of silver nanoparticles in an intravenous 28-day repeated-dose toxicity study in rats.
Nanosilver is used in a variety of medical and consumer products because of its antibacterial activity. This wide application results in an increased human exposure. Knowledge on the systemic toxicity of nanosilver is, however, relatively scarce. In a previous study, the systemic toxicity of 20 nm silver nanoparticles (Ag-NP) was studied in a 28-day repeated-dose toxicity study in rats. Ag-NP were intravenously administered with a maximum dose of 6 mg/kg body weight (bw)/day. Several immune parameters were affected: reduced thymus weight, increased spleen weight and spleen cell number, a strongly reduced NK cell activity, and reduced IFN-γ production were observed. Prompted by these affected immune parameters, we wished to assess exposure effects on the functional immune system. Therefore, in the present study the T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) was measured in a similar 28-day intravenous repeated-dose toxicity study. In addition, a range of immunological parameters was measured. Data obtained using the benchmark dose (BMD) approach were analyzed by fitting dose-response models to the parameters measured. A reduction in KLH-specific IgG was seen, with a lowest 5% lower confidence bound of the BMD (BMDL) of 0.40 mg/kg bw/day. This suggests that Ag-NP induce suppression of the functional immune system. Other parameters sensitive to Ag-NP exposure were in line with our previous study: a reduced thymus weight with a BMDL of 0.76 mg/kg bw/day, and an increased spleen weight, spleen cell number, and spleen cell subsets, with BMDLs between 0.36 and 1.11 mg/kg bw/day. Because the effects on the spleen are not reflected by increased KLH-specific IgG, they, however, do not suggest immune stimulation. Intravenous Ag-NP administration in a 28-day repeated-dose toxicity study induces suppression of the functional immune system. This finding underscores the importance to study the TDAR to evaluate immunotoxicity and not to rely solely on measuring immune cell subsets.


National malaria vector control policy: an analysis of the decision to scale-up larviciding in Nigeria.
New vector control tools are needed to combat insecticide resistance and reduce malaria transmission. The World Health Organization (WHO) endorses larviciding as a supplementary vector control intervention using larvicides recommended by the WHO Pesticides Evaluation Scheme (WHOPES). The decision to scale-up larviciding in Nigeria provided an opportunity to investigate the factors influencing policy adoption and assess the role that actors and evidence play in the policymaking process, in order to draw lessons that help accelerate the uptake of new methods for vector control. A retrospective policy analysis was carried out using in-depth interviews with national level policy stakeholders to establish normative national vector control policy or strategy decision-making processes and compare these with the process that led to the decision to scale-up larviciding. The interviews were transcribed, then coded and analyzed using NVivo10. Data were coded according to pre-defined themes from an analytical policy framework developed a priori. Stakeholders reported that the larviciding decision-making process deviated from the normative vector control decision-making process. National malaria policy is normally strongly influenced by WHO recommendations, but the potential of larviciding to contribute to national economic development objectives through larvicide production in Nigeria was cited as a key factor shaping the decision. The larviciding decision involved a restricted range of policy actors, and notably excluded actors that usually play advisory, consultative and evidence generation roles. Powerful actors limited the access of some actors to the policy processes and content. This may have limited the influence of scientific evidence in this policy decision. This study demonstrates that national vector control policy change can be facilitated by linking malaria control objectives to wider socioeconomic considerations and through engaging powerful policy champions to drive policy change and thereby accelerate access to new vector control tools.


Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency.
Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.


Gentamicin and tobramycin penetration into burn eschar. Pharmacokinetics and microbiological effects.
This study was designed to determine whether intravenously administered gentamicin sulfate and tobramycin sulfate penetrate into the eschar of patients with severe burns. In addition, each antibiotic's pharmacokinetics in serum and the effect on eschar microbiology were determined. Twenty patients with suspected burn wound sepsis received either gentamicin or tobramycin. The microbiology of the baseline eschar was determined and repeated on days 2, 4, and 7. All patients had measurable aminoglycoside tissue concentrations, and elimination from serum was not unusually rapid. Thirteen patients had baseline eschar cultures positive for Pseudomonas aeruginosa or Serratia marcescens; eight patients were initially bacteremic. Pseudomonas aeruginosa strains were sensitive to both antibiotics and usually declined in concentration with time or were eliminated; the more drug-resistant isolates of S marcescens persisted or caused super-infection and bacteremia. Aminoglycoside antibiotics penetrate into burn eschar and appear to have a substantial effect on eschar microbiology.


Inflammation and oxidant-stress in beta-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial.
We assessed whether oxidant-stress and inflammation in beta-thalassemia could be controlled by the novel oral iron chelator deferasirox as effectively as by deferoxamine. Forty-nine subjects were enrolled from seven sites and studied at baseline, and after 1, 6, and 12 months of therapy. Malondialdehyde, protein carbonyls, vitamins E and C, total non-transferrin bound iron, transferrin saturation, C-reactive protein, cytokines, serum ferritin concentration and liver iron concentration were measured. Liver iron concentration and ferritin declined significantly in both treatment groups during the study. This paralleled a significant decline in the oxidative-stress marker malondialdehyde (deferasirox -22%/year, deferoxamine -28%/year, average decline p=0.006). The rates of decline did not differ between treatment groups. Malondialdehyde was higher in both treatment groups than in a group of 30 non-thalassemic controls (p < 0.001). The inflammatory marker high-sensitivity C-reactive protein decreased significantly only in the group receiving deferasirox (deferasirox -51%/year, deferoxamine +8.5%/year, p = 0.02). This result was confounded by a chance difference in the level of high-sensitivity C-reactive protein between the two groups at baseline, but analyses controlling for this difference suggested an equally large treatment effect. Iron chelation therapy with deferoxamine or with deferasirox was equally effective in decreasing iron burden and malondialdehyde. The possible differential effect of the two chelators on inflammation warrants further investigation.


Effect of early shearing during gestation on the productive and reproductive behavior of female sheep offspring in their first 18 months of age.
The research has shown the interesting contributions of shearing in mid-gestation on the performance of lambs from birth to weaning. Other studies have reported that shearing at early pregnancy influences the development of the placenta and lamb live weight at birth. However, there was a lack of information on the effect of early-prepartum shearing on the behavior of the offspring from weaning onward. This study evaluated the effect of shearing ewes at 50 days of gestation on the growth, reproductive behavior and response to a gastrointestinal parasite challenge in the female offspring from weaning to 18 months old. Fifty-seven Polwarth female lambs were used, 22 being singles and 35 twins born to ewes either shorn at 50 days of pregnancy (PS, n = 23) or shorn at 62 days postpartum (U, control, n = 34) resulting in four subgroups: single lambs born to PS ewes (n = 8), born to U ewes (n = 14), twin lambs born to PS ewes (n = 15) or born to U ewes (n = 20). All progeny were managed together under improved pasture with a minimum forage allowance of 6% live weight on dry basis. Body weight, body condition score and fecal eggs count were recorded every 14 days from weaning to 18 months of age. Concentrations of progesterone were measured weekly (from 4 to 10 months of age and from 14 to 18 months of age) to establish the onset of puberty. Ovulation rate at an induced and a natural heat (545 ± 1.0 and 562 ± 1.0 day old) was recorded. Prepartum shearing did not affect the age at puberty or the ovulation rate of female offspring, but those born as singles were more precocious ( P = 0.03) and heavier ( P = 0.02) at puberty than twin born lambs. Both the average value of parasite egg count ( P = 0.0 7) and the Famacha index ( P = 0.02) for the entire study period were lower in lambs born to prepartum shorn ewes than those born to postpartum shorn ewes. In conclusion, shearing at 50 days of gestation did not affect the growth or the reproductive behavior of female offspring. However, female lambs born from ewe shorn during gestation showed a better response to the parasitic challenge, and further research is required to confirm this.


Tolerance of the optic apparatus in single-fraction irradiation using stereotactic radiosurgery: evaluation in 100 patients with craniopharyngioma.
To determine the limiting dose to the optic apparatus in single-fraction irradiation in patients with craniopharyngioma treated with gamma knife radiosurgery (GKRS). One hundred patients with 109 craniopharyngiomas treated with GKRS were evaluated with a median follow-up period of 68 months. Tumor volume varied from 0.1 to 36.0 (median, 3.3) cm. Marginal doses varied from 10 to 18 (median, 11.4) Gy. Maximum dose to any part of the optic apparatus varied from 2 to 18 (median, 10) Gy. The actuarial 5- and 10-year overall rates of survival of tumor progression after GKRS were 93% and 88%, respectively. Similarly, the actuarial 5- and 10-year progression-free survival rates were 62% and 52%, respectively. Among 94 patients in whom visual function was evaluable after GKRS, only 3 patients developed radiation-induced optic neuropathy, indicating an overall Kaplan-Meier radiation-induced optic neuropathy rate of 5%. Of these patients, 2 received 15 Gy or greater to the optic apparatus. Another patient who received 8 Gy or less had undergone previous fractionated radiation therapy with a biologically effective dose of 60 Gy. The optic apparatus seems to be more tolerant of irradiation than previously thought. Careful dose planning is essential, particularly in patients who underwent prior external beam radiation therapy.


Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model.
Local thrombosis of the frontal cortex (Fr1 and Fr3 fields), caused by combination of the intravenous photosensitive dye Rose Bengal administration with focused high-intensity illumination of the frontal bone, was shown to provoke a pronounced deficit in step-through passive avoidance performance in rats without concomitant motor disturbances. N-Phenylacetyl-L-prolylglycine ethyl ester (GVS-111) administered intravenously at a dose of 0.5 mg/kg/day, for the first time 1 h after ischaemic lesion and then for 9 post-operative days, with the last administration 15 min before testing, attenuated the deficit. This treatment significantly diminished the volume of the infarcted area. Thus, post-ischaemic injection of GVS-111 demonstrated both cognition-restoring and neuroprotective properties. The cognition-restoring effect is probably based on an increase in neocortical and hippocampal neuronal plasticity. Neuroprotective effects of GVS-111 combine antioxidant activity with the ability to attenuate glutamate-provoked neurotoxicity and block voltage-gated ionic channels, i.e. the compound mitigates the main metabolic shifts involved in pathogenesis of brain ischaemia.


Thyrotropin-releasing hormone and thyroid hormone interactions on thyrotropin secretion in the rat: lack of inhibiting effects of small doses of triiodo-L-thyronine in the hypothyroid rat.
Rats were thyroidectomized (T) and injected once daily with thyroxine (T4) or triiodothyronine (T3) ip; circulating thyrotropin (TSH) levels and TSH response to 100 ng of thyrotropin releasing hormone (TRH) iv, were measured in different groups of rats at several intervals after the last dose of T4 or T3. It was found that T rats on 1.8 mug T4 or 0.4 mug T3/100 g BW/day, response to TRH decreased after the injection of the hormone, maximum suppressive effect being found about 7-8 h after T4, or 4 h after T3. The response increased as T4 or T3 levels reached a nadir, in agreement with present views on TRH, T4, and T3 interactions at the pituitary level. The degree of TSH response to TRH appears as a sensitive parameter of T4 or T3 activity in this experimental model. However, in T rats on 0.2 mug T3/100 g BW/day, TSH response to TRH did not decrease, but actually increased, after the daily injection of T3. These animals appeared to be in a state of continuous thyroid hormone deficiency. The same 0.2 mug T3 dose effectively suppresses the elevated basal TSH levels of these animals. It is also capable of decreasing TSH response to 100 ng TRH in animals under more "euthyroid" conditions. These results in the T rats on 0.2 mug T3 are not easily fitted into the relatively simple model frequently described to explain TRH-T3 interactions and TSH secretion.


Neuroimaging and neurodevelopmental outcome of premature infants.
Preterm birth is associated with variable degrees of brain injury and adverse neurodevelopmental outcomes. Neuroimaging has been investigated as a predictor of outcome in this population. Head ultrasound allows for rapid bedside evaluation of the neonatal brain for early intraventricular hemorrhage surveillance and later detection of periventricular leukomalacia. Computed tomography can provide excellent views for bones, hemorrhage, extra-axial space, and the ventricles but is rarely used for prognostic purposes. Magnetic resonance imaging allows for high-resolution images of brain structures, differentiation of white and gray matter, visualization of the brain stem and posterior fossa, and getting additional physiological information with specialized sequences. Though controversial, the use of magnetic resonance imaging, at term equivalent, as a predictor of later outcome in preterm infants has been increasing and has been advocated by some as a standard practice. In this article, we review and contrast the use of these various imaging modalities in predicting neurodevelopmental outcome of premature infants.


The in situ physiology of "Nostocoida limicola" II, a filamentous bacterial morphotype in bulking activated sludge, using fluorescence in situ hybridization and microautoradiography.
The in situ physiology of the actinobacterial bulking and foaming filamentous bacterium "Nostocoida limicola" II was studied by fluorescence in situ hybridization/microautoradiography. Substrate assimilation patterns of pure cultures of this bacterium were different to those seen in activated sludge biomass samples. There was no evidence to suggest that "N. limicola" II preferred hydrophobic substrates, but evidence was produced to support the view that it is metabolically active under anaerobic conditions in activated sludge.


Coherent scattering and the assessment of mineral concentration in trabecular bone.
The number of 103.2 keV (153Sm) gamma-rays scattered coherently and incoherently from the os calcis of three cadaver feet has been measured using a high purity Ge detector. The ratio of the intensities of coherent to incoherent scattered photons is dependent on elemental composition while the number scattered incoherently is dependent on density. The results indicate that techniques for the assessment of mineral status in the skeleton may be based on either of these measurements and each will exhibit a similar sensitivity to a given biological change. It is shown that a method based entirely on the detection of coherently scattered photons will be more sensitive to changes in mineral composition than either of the above. Such a system is proposed and optimised with respect to incident beam energy and scattering angle. For a dose of 4 mSV, coherent intensity measurements with a precision of 3% are anticipated.


Children's views on the experience of a visual examination and intra-oral photographs to detect dental caries in epidemiological studies.
To elicit children's views on the established visual examination method used for the epidemiological surveillance of dental caries and an experimental intra-oral photographic examination method. Focus group interviews were conducted with 5-year-olds (with the aid of a puppet) and 10/11-year-olds (without puppet) after experiencing both methods. Ten focus groups were conducted in each cohort. The children's views on the methods related to the acceptability of their experience. The key factors affecting acceptability and preferences related to the combined effects of contextual factors prior to the examination and experiences during the examination. These included communication and children's expectations. These factors influenced the examination experience along with their feelings about the environment and the tactile sensation from instruments in the mouth. Most children preferred the experimental photographic method as a means of caries detection over the traditional visual examination. They also wanted feedback on their oral health and more communication on what was happening during the examination. CONCLUSION Appropriate communication, attention to the examination environment and handling of instruments can enhance the dental examination experience for children in the school setting. The children's preferences indicated that generally, the intra-oral camera was well received as a means of caries detection for epidemiological studies within the school setting. These results may have implications for seeking ethical approval and conducting epidemiological studies on children in the future.


First-principles study on the elastic, electronic and optical properties of all-inorganic halide perovskite solid solutions of CsPb(Br1-x Cl x )3 within the virtual crystal approximation.
All-inorganic halide perovskites have drawn significant attention for optoelectronic applications such as solar cells and light-emitting diodes due to their excellent optoelectronic properties and high stabilities. In this work, we report a systematic study on the material properties of all-inorganic bromide and chloride perovskite solid solutions, CsPb(Br1-x Cl x )3, varying the Cl content x from 0 to 1 with an interval of 0.1 by applying the first-principles method within the virtual crystal approximation. The lattice constants of the cubic phase are shown to follow the linear function of mixing ratio x, verifying that Vegard's law is satisfied and the pseudopotentials of the virtual atoms are reliable. We calculate the band structures with the HSE06 hybrid functional with and without spin-orbit coupling, yielding band gaps in good agreement with experimental results, and find that the band gap increases along the quadratic function of the Cl content x. With increasing Cl content x, the elastic constants and moduli increase linearly, the effective mass of the electron and hole increase, while mobilities decrease linearly, the static dielectric constant decreases linearly, and exciton binding energy increases quadratically. We calculate the photo-absorption coefficients and reflectivity, predicting the absorption peaks shift to the ultraviolet region from bromide to chloride.


An estimate of the cost of burnout on early retirement and reduction in clinical hours of practicing physicians in Canada.
Interest in the impact of burnout on physicians has been growing because of the possible burden this may have on health care systems. The objective of this study is to estimate the cost of burnout on early retirement and reduction in clinical hours of practicing physicians in Canada. Using an economic model, the costs related to early retirement and reduction in clinical hours of physicians were compared for those who were experiencing burnout against a scenario in which they did not experience burnout. The January 2012 Canadian Medical Association Masterfile was used to determine the number of practicing physicians. Transition probabilities were estimated using 2007-2008 Canadian Physician Health Survey and 2007 National Physician Survey data. Adjustments were also applied to outcome estimates based on ratio of actual to planned retirement and reduction in clinical hours. The total cost of burnout for all physicians practicing in Canada is estimated to be $213.1 million ($185.2 million due to early retirement and $27.9 million due to reduced clinical hours). Family physicians accounted for 58.8% of the burnout costs, followed by surgeons for 24.6% and other specialists for 16.6%. The cost of burnout associated with early retirement and reduction in clinical hours is substantial and a significant proportion of practicing physicians experience symptoms of burnout. As health systems struggle with human resource shortages and expanding waiting times, this estimate sheds light on the extent to which the burden could be potentially decreased through prevention and promotion activities to address burnout among physicians.


Gut microbiota defined epigenomes of Alzheimer's and Parkinson's diseases reveal novel targets for therapy.
The origins of Alzheimer's disease (AD) and Parkinson's disease (PD) involve genetic mutations, epigenetic changes, neurotoxin exposure and gut microbiota dysregulation. The gut microbiota's dynamic composition and its metabolites influence intestinal and blood-brain barrier integrity, contributing to AD and PD development. This review explores protein misfolding, aggregation and epigenetic links in AD and PD pathogenesis. It also highlights the role of a leaky gut and the microbiota-gut-brain axis in promoting these diseases through inflammation-induced epigenetic alterations. In addition, we investigate the potential of diet, probiotics and microbiota transplantation for preventing and treating AD and PD via epigenetic modifications, along with a discussion related to current challenges and future considerations. These approaches offer promise for translating research findings into practical clinical applications.


Structural elucidation of the N- and O-glycans of human apolipoprotein(a): role of o-glycans in conferring protease resistance.
Apolipoprotein(a) (apo(a)) is a multikringle domain glycoprotein that exists covalently linked to apolipoprotein B100 of low density lipoprotein, to form the lipoprotein(a) (Lp(a)) particle, or as proteolytic fragments. Elevated plasma concentrations of apo(a) and its fragments may promote atherosclerosis, but the underlying mechanisms are incompletely understood. The factors influencing apo(a) proteolysis are also uncertain. Here we have used exoglycosidase digestion and mass spectrometry to sequence the Asn (N)-linked and Ser/Thr (O)-linked oligosaccharides of human apo(a). We also assessed the potential role of apo(a) O-glycans in protecting thermolysin-sensitive regions of the polypeptide. Apo(a) contained two major N-glycans that accounted for 17% of the total oligosaccharide structures. The N-glycans were complex biantennary structures present in either a mono- or disialylated state. The O-glycans were mostly (80%) represented by the monosialylated core type 1 structure, NeuNAcalpha2-3Galbeta1-3GalNAc, with smaller amounts of disialylated and non-sialylated O-glycans also detected. Removal of apo(a) O-glycans by sialidase and O-glycosidase treatment dramatically increased the sensitivity of the polypeptide to thermolysin digestion. These studies provide the first direct sequencing data for apo(a) glycans and indicate a novel function for apo(a) O-glycans that is potentially related to the atherogenicity of Lp(a).


Modulation of cholesterol in midlife affords cognitive advantage during ageing - a role for altered redox balance.
General practitioners, geriatricians, neurologists and health care professionals all over the world will be facing by 2040 the diagnostic, therapeutic and socioeconomic challenges of over 80 million people with dementia. Dementia is one of the most common diseases in the elderly which drastically affects daily life and everyday personal activities, is often associated with behavioural symptoms, personality change and numerous clinical complications and increases the risk for urinary incontinence, hip fracture, and - most markedly - the dependence on nursing care. The costs of care for patients with dementia are therefore immense. Serum cholesterol levels above 6.5 mmol/L are known to be associated with an increased RR of 1.5 and 2.1 to develop Alzheimer's disease, the most common form of dementia, and a reduction of serum cholesterol in midlife is associated with a lowered dementia risk. The aim of this work is to critically discuss some of the main results reported recently in the literature in this respect and to provide the pathophysiological rationale for the control of dyslipidemia in the prevention of dementia onset and progression.


Differential Elevation of Inflammation and CD4+ T Cell Activation in Kenyan Female Sex Workers and Non-Sex Workers Using Depot-Medroxyprogesterone Acetate.
Depot Medroxyprogesterone (DMPA) is one of the most widely used contraceptives in Sub-Saharan Africa where HIV incidence is high. We explored the effect of DMPA on the activation of HIV cellular targets and inflammation as a possible mechanism of increased HIV risk with DMPA use. Since sex work is known to affect the immune system, this study aimed to understand the effect of DMPA on the immune system among sex workers and non-sex worker women. Twenty-seven DMPA-using HIV seronegative female sex workers (FSW) and 30 DMPA-using HIV seronegative non-sex worker (SW) women were enrolled in the study. Twenty-four FSWs and 30 non-sex workers who were not using any hormonal contraception (no HC) were recruited as controls. Blood and cervico-vaginal samples were collected from all participants and assayed for T cell activation and proinflammatory cytokines. Among no HC users, sex workers had lower expression of CD38 and CD69 on blood-derived CD4+ T cells along with lower CD4+CCR5+ cells frequency in the endocervix. Plasma MCP-1, TNFα and IL-17 also had reduced expression in FSW not using HC. Non-sex workers using DMPA had elevated proportions of blood-derived CD4+CD38+, CD4+CD69+ and CD4+HLA-DR+ T cells relative to non-sex workers who were not taking any HC. DMPA-using non-sex workers also had an increased level of plasma interferon gamma (IFN-γ), monokine induced by interferon-γ (MIG) and sCD40L, alongside higher proportion of CD4+CD38+ and CD4+CD69+ T cells at the cervix compared to non-sex workers no-HC controls., Finally, non-sex workers and FSWs using DMPA had similar levels of genital and peripheral CD4+ T cell activation and inflammation. DMPA increased inflammation and expression of activation markers on potential HIV target cells in non-sex workers. These data show that DMPA is a strong immune modulator and its use counteracts the decreased immune activation associated with sex work. These findings suggest that inflammation and increased HIV target cells in blood and at the genital tract may be mechanisms by which DMPA increases susceptibility to HIV.


Severe ipsilateral carotid stenosis and middle cerebral artery disease in lacunar ischaemic stroke: innocent bystanders?
Lacunar infarcts are thought to be mostly due to intracranial small vessel disease. Therefore, when a stroke patient with a relevant lacunar infarct does have severe ipsilateral internal carotid artery (ICA) or middle cerebral artery (MCA) disease, it is unclear whether the arterial disease is causative or coincidental. If causative, we would expect ICA/MCA disease to be more severe on the symptomatic side than on the asymptomatic side. Therefore, our aim was to compare the severity of ipsilateral with contralateral ICA and MCA disease in patients with lacunar ischaemic stroke. We studied 259 inpatients and outpatients with a recent lacunar ischaemic stroke and no other prior stroke. We used carotid Duplex ultrasound and transcranial Doppler (TCD) ultrasound to identify ICA and MCA disease, and compared our results with previously published data. In our study, there was no difference between the severity of ipsilateral and contralateral ICA stenosis within individuals (median difference 0%, Wilcoxon paired data p=0.24, comparing severity of ipsilateral and contralateral stenosis). The overall prevalence of severe ipsilateral stenosis was 5%, and the prevalence of severe contralateral stenosis was 4% (OR 1.6, 95% CI 0.6, 4.8). There was no difference in the prevalence of ipsilateral and contralateral MCA disease. A systematic review of the other available studies strengthened this conclusion. Carotid stenosis in patients with a lacunar ischaemic stroke may be coincidental. Further studies are required to elucidate the causes of lacunar stroke, and to evaluate the role of carotid endarterectomy.