Controllable construction of half-sandwich octanuclear complexes based on pyridyl-substituted ligands with conjugated centers.
Functional metal bis(1,3,5-triazapentadienato) units [M(tap)2] (M = NiII/PdII) and pyrene groups were introduced as central units of three tetradentate tetrapyridyl-substituted ligands, with which seven half-sandwich organometallic complexes were controllably synthesized. The multi-centered hybrid products constructed from the two [M(tap)2] units revealed delocalized π-bonding environments. The products were characterized by proton NMR and IR spectroscopy, elemental analyses and electrospray ionization (ESI) mass spectrometry. The molecular structures of four of the products were determined by X-ray diffraction analysis, revealing their octanuclear structures.


Active Subdivision Surfaces for the Semiautomatic Segmentation of Biomedical Volumes.
We present a new family of active surfaces for the semiautomatic segmentation of volumetric objects in 3D biomedical images. We represent our deformable model by a subdivision surface encoded by a small set of control points and generated through a geometric refinement process. The subdivision operator confers important properties to the surface such as smoothness, reproduction of desirable shapes and interpolation of the control points. We deform the subdivision surface through the minimization of suitable gradient-based and region-based energy terms that we have designed for that purpose. In addition, we provide an easy way to combine these energies with convolutional neural networks. Our active subdivision surface satisfies the property of multiresolution, which allows us to adopt a coarse-to-fine optimization strategy. This speeds up the computations and decreases its dependence on initialization compared to singleresolution active surfaces. Performance evaluations on both synthetic and real biomedical data show that our active subdivision surface is robust in the presence of noise and outperforms current state-of-the-art methods. In addition, we provide a software that gives full control over the active subdivision surface via an intuitive manipulation of the control points.


DNA methylation of the Trip10 promoter accelerates mesenchymal stem cell lineage determination.
Epigenetic regulation of gene expression by DNA methylation and histone modification controls cell fate during development and homeostasis in adulthood. Aberrant epigenetic modifications may lead to abnormal development, even diseases. We have found that Trip10 (thyroid hormone receptor interactor 10), an adaptor protein involved in diverse functions, is epigenetically regulated during lineage-specific induction of human bone marrow-derived mesenchymal stem cells (MSCs). To determine whether DNA methylation-induced gene silencing is sufficient to restrict cell fate changes, we applied an invitro method to specifically methylate the promoter of Trip10. Our hypothesis was that the methylation status of the Trip10 promoter in MSCs alters the differentiation preference of MSCs. Transfection of in vitro-methylated Trip10 promoter DNA into MSCs resulted in progressive accumulation of cytosine methylation at the endogenous Trip10 promoter, reduced Trip10 expression, and accelerated MSC-to-neuron and MSC-to-osteocyte differentiation. A two-component EGFP reporter gene system was established to confirm the level of transcriptional silencing and visualize the targeted DNA methylation. EGFP expression induced in the reporter system by targeted Trip10 methylation was reversed by adding 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, confirming that the suppressed Trip10 expression and disrupted MSC differentiation resulted from the in vitro-introduced methylations in the Trip10 promoter. With this targeted DNA methylation and reporter system, we are able to monitor the progression of locus-specific DNA methylation in vivo and correlate such changes with potential functional changes. Using this approach, we have established a new role for Trip10, showing that the level of Trip10 expression is associated with the maintenance and differentiation of MSCs.


Moral tensions and obligations of occupational therapy practitioners providing home care.
Home care has been valued as a relevant context for the provision of occupational therapy since the inception of the field. The setting provides rich opportunities to restore meaningfulness in living for clients whose lives have been disrupted by illness or untoward events. Additionally the home care setting allows practitioners to exercise professional commitments and to meet ethical obligations congruent with the field of occupational therapy. Nevertheless, the home care arena is not exempt from the pressures that pervade the health care industry. To thrive in the provision of home care, occupational therapy practitioners must prepare themselves to deal with the philosophic, economic, and moral challenges inherent in the setting. This article explores the moral obligations of occupational therapy practitioners who provide home care. More specifically, it addresses obligations to self, to patients, to caregivers, to society, to the profession, to fellow health care providers, and to agencies and payers. Ethical principles associated with each are highlighted, and issues are raised. Home care practitioners who are attuned to the moral commitments imbedded in occupational therapy philosophy will most likely incorporate these tenets into their clinical decisions.


Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2).
Post-translational S-palmitoylation directs the trafficking and membrane localization of hundreds of cellular proteins, often involving a coordinated palmitoylation cycle that requires both protein acyl transferases (PATs) and acyl protein thioesterases (APTs) to actively redistribute S-palmitoylated proteins toward different cellular membrane compartments. This process is necessary for the trafficking and oncogenic signaling of S-palmitoylated Ras isoforms, and potentially many peripheral membrane proteins. The depalmitoylating enzymes APT1 and APT2 are separately conserved in all vertebrates, suggesting unique functional roles for each enzyme. The recent discovery of the APT isoform-selective inhibitors ML348 and ML349 has opened new possibilities to probe the function of each enzyme, yet it remains unclear how each inhibitor achieves orthogonal inhibition. Herein, we report the high-resolution structure of human APT2 in complex with ML349 (1.64 Å), as well as the complementary structure of human APT1 bound to ML348 (1.55 Å). Although the overall peptide backbone structures are nearly identical, each inhibitor adopts a distinct conformation within each active site. In APT1, the trifluoromethyl group of ML348 is positioned above the catalytic triad, but in APT2, the sulfonyl group of ML349 forms hydrogen bonds with active site resident waters to indirectly engage the catalytic triad and oxyanion hole. Reciprocal mutagenesis and activity profiling revealed several differing residues surrounding the active site that serve as critical gatekeepers for isoform accessibility and dynamics. Structural and biochemical analysis suggests the inhibitors occupy a putative acyl-binding region, establishing the mechanism for isoform-specific inhibition, hydrolysis of acyl substrates, and structural orthogonality important for future probe development.


Vitronectin: a migration and wound healing factor for human corneal epithelial cells.
The stratified squamous epithelial covering of the cornea provides one of the first physical and immunological lines of defense. A breach in its integrity results in a wound healing response that resolves quickly. However, under certain conditions-for example, when migrating cells are unable to adhere to the basement membrane-healing may be delayed. The aim of this study was to determine whether vitronectin (VN) promotes corneal epithelial wound healing. Primary human corneolimbal epithelial cells and the human corneal epithelial cell (HCEC) line were cultured and monitored to determine the rate of epithelial recovery after injury. Human corneas were placed in organ culture and the epithelium debrided. Therapeutic contact lenses (CLs) soaked in saline or coated in a solution of recombinant human VN were applied and the epithelium assessed histologically after 7 days. Vitronectin (5 μg/mL) significantly enhanced the wound closure rate in cultured HCECs as well as in primary human corneal epithelial cells. Wound recovery was significantly blocked with a cyclic arginine-glycine-aspartate (RGD) peptide (10 μg/mL), a neutralizing antibody to VN (25 μg/mL) as well as after transiently silencing β5-integrin. Wound closure was not related to the effect of VN on cell proliferation. Finally, incubating epithelial-debrided human corneas with CLs loaded in VN resulted in effective re-epithelialization of the injured surface. Vitronectin is a key extracellular matrix protein that expedites corneal epithelial wound recovery in vitro and ex vivo. Delivery of VN on therapeutic CLs may be an effective and efficient way to treat patients with persistent epithelial defects of the ocular surface.


Ab Initio Evaluation of Henry Coefficients Using Importance Sampling.
We present a new algorithm that allows for an efficient evaluation of the Henry coefficient of a guest molecule inside a porous material, which permits to use ab initio energy calculations. The Widom insertion method, which is currently used to compute these Henry coefficients, typically requires millions of energy evaluations. Our new methodology reduces this number by more than 1 order of magnitude, enabling the use of an ab initio potential energy surface. The methodology we propose is reminiscent of the well-known importance sampling technique which is frequently used in Monte Carlo integrations. First, a conventional Widom insertion simulation is performed using a force field. In the second step, the Widom results are used to select a limited number of configurations and only for these configurations the ab initio evaluation of the energy is required. Finally, by appropriately reweighting the latter energies, an accurate estimation of the ab initio Henry coefficient is possible at a moderate computational cost. We apply our methodology to the adsorption of CO2 in Mg-MOF-74, a prototypical case where interactions of a polar guest molecule with unsaturated metal sites dominate the adsorption mechanism. In this case generic force fields such as UFF or Dreiding are inappropriate and the use of ab initio methods is indispensable. In a second case study, we compute Henry coefficients of methane in UiO-66 using different levels of theory. We pay particular attention to the influence of the dispersion corrections and the role of many-body effects. For the final example, we qualitatively investigate adsorption features for a series of functionalized UiO-66 frameworks. Overall the cases we present show that accurate computations of Henry coefficients is extremely challenging, as different levels of theory provide strongly varying results. At the same time ab initio calculations have added value compared to force fields, as they provide a physically more sound description of the adsorption mechanism and in some cases clearly improve correspondence with experiment.


Dual-polarization mode-locked Nd:YAG laser.
A mode-locked solid-state laser containing a birefringent element is shown to emit synchronously two frequency combs associated to the two polarization eigenstates of the cavity. An analytical model predicts the polarization evolution of the pulse train, which is determined by the adjustable intracavity birefringence. Experiments realized with a Nd:YAG laser passively mode locked by a semiconductor saturable absorber mirror are in perfect agreement with the model. Locking between the two combs arises for particular values of their frequency difference, e.g., half the repetition rate, and the pulse train polarization sequence is then governed by the relative overall phase offset of the two combs.


A low-cost, reliable, high-throughput system for rodent behavioral phenotyping in a home cage environment.
Inexpensive, high-throughput, low maintenance systems for precise temporal and spatial measurement of mouse home cage behavior (including movement, feeding, and drinking) are required to evaluate products from large scale pharmaceutical design and genetic lesion programs. These measurements are also required to interpret results from more focused behavioral assays. We describe the design and validation of a highly-scalable, reliable mouse home cage behavioral monitoring system modeled on a previously described, one-of-a-kind system. Mouse position was determined by solving static equilibrium equations describing the force and torques acting on the system strain gauges; feeding events were detected by a photobeam across the food hopper, and drinking events were detected by a capacitive lick sensor. Validation studies show excellent agreement between mouse position and drinking events measured by the system compared with video-based observation--a gold standard in neuroscience.


Is there a relationship between impaired median nerve excursion and carpal tunnel syndrome? A systematic review.
Systematic review. It is accepted that the etiology of carpal tunnel syndrome (CTS) is multifactorial. One of the most commonly accepted etiologic factors for CTS is compromise of the kinematic behavior and excursion of the median nerve. The objective of this systematic review was to establish if there is a relationship between impaired median nerve excursion and CTS. A systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, was conducted. Studies were sought where in vivo median nerve excursion was compared between people with CTS to an appropriate control group. Quality appraisal for each study was conducted using the Newcastle-Ottawa Scale by 2 independent evaluators. Ten case-control studies using ultrasound imaging to quantify median nerve excursion were included. All studies were rated as of "moderate" methodologic quality having scored 6 or 7 (of 9 stars) for the Newcastle-Ottawa Scale. Seven of the 10 studies concluded that median nerve excursion was reduced in a CTS population when compared with controls. The literature suggests that median nerve excursion is reduced in people with CTS when compared with healthy controls. 3a.


Associations between tinnitus and glaucoma suggest a common mechanism: A clinical and population-based study.
The purpose of this study was to determine if there is an association between tinnitus and glaucoma. We tested this by first completing a clinic-based cross-sectional questionnaire study in which we sent a series of tinnitus-related questions to glaucoma patients and healthy subjects, and then followed up with a large population-based cross-sectional study in which glaucoma and tinnitus were also assessed by questionnaire. For the clinical study, we received 209 responses from glaucoma patients and 109 responses from healthy subjects (primarily the spouses of the patients). For the population-based study, we evaluated 79,866 participants. Logistic regression models were used to test the relationship between glaucoma and tinnitus; the clinical study analysis was adjusted for age, gender, BMI, hypertension, and diabetes and the population-based study was adjusted for these same variables with the addition of socioeconomic status and subjective hearing loss. For the clinical study, glaucoma patients had an 85% increase in odds for tinnitus (adjusted OR 1.85, 95% CI 1.10 to 3.05). The effect did not depend on pretreatment intraocular pressure, and the associated symptoms were not pulsatile in nature. For the population-based study, glaucoma patients had a 19% increase in odds for tinnitus (adjusted OR 1.19, 95% CI 1.02 to 1.40). Overall, our results suggest that those with glaucoma are more likely to have tinnitus than those without glaucoma. These results provide hypotheses for a mechanism involved in both tinnitus and glaucoma. One possible mechanism could be vascular dysregulation due to impairment of nitric oxide production.


Treatment of fatigue in multiple sclerosis: a systematic review of the literature.
Fatigue is common in people with multiple sclerosis (MS) and symptoms of fatigue are often reported as the most debilitating symptoms of the disease. However, there are few reports of interventions for fatigue in MS. A systematic review of published literature examining pharmacological and psychosocial/psychological interventions for fatigue in MS was conducted. The search and review strategy undertaken used the Centre for Reviews and Dissemination guidelines. Papers were reviewed by two independent reviewers. Of 81 studies short-listed for inclusion, 15 studies were included, of which 10 were studies of pharmacological therapy and five were studies of psychosocial/psychological interventions. Of the pharmacological studies, two were rated as of moderate-to-high quality, three of moderate quality, two of moderate-to-low quality and three of low quality. Of the psychosocial/psychological studies, three were rated as of moderate quality and two of moderate-to-low quality. None of the studies reviewed reached the highest level of quality according to pre-agreed criteria. Regardless of level of quality, effectiveness of both pharmacological and psychosocial/psychological interventions was modest at best and often absent. Accordingly, there is little evidence-based advice that can be offered to people with MS to help manage their fatigue.


Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.
Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.


Evaluation of parathyroid hormone bound to a synthetic matrix for guided bone regeneration around dental implants: a histomorphometric study in dogs.
A polyethylene glycol (PEG)-based hydrogel matrix covalently bound to a 35-amino acid peptide of parathyroid hormone cystein-PTH 1-34 (cys-PTH 1-34) was shown to enhance bone regeneration around implants. The aim of this study is to test if the addition of an integrin-receptor-binding arginine-glycine-aspartic acid (RGD)-containing peptide at early healing time points improves the performance of the PEG matrix supplemented with cys-PTH 1-34 (PTH) when applied in acute defects around implants at early healing time points (2 and 4 weeks). Six dogs received 48 implants. Each side of the mandible was randomly assigned for implantation at day 0 or 2 weeks. A circumferential critical-size defect was created at each site before implantation. Sites were randomly assigned to one of four groups: 1) PEG alone (PEG group), 2) PEG plus RGD (PEG/RGD group), 3) PEG plus PTH (PEG/PTH group), and 4) PEG plus RGD plus PTH (PEG/RGD/PTH group). Dogs were sacrificed 2 weeks after the second surgery, and specimens were obtained for histologic analysis. For the statistical analysis, mixed linear regression with repeated measurements was used, and a Dunnett-Hsu adjustment was made for multiple comparisons. At 2 weeks, the percentages of new bone formation within the defect were 12.43% for the PEG group, 15.95% for the PEG/RGD group, 15.32% for the PEG/PTH group, and 16.60% for the PEG/RGD/PTH group. At 4 weeks, the percentages of new bone formation within the defect were 30.01% for the PEG group, 27.90% for the PEG/RGD group, 29.89% for the PEG/PTH group, and 27.58% for the PEG/RGD/PTH group. A marginally significant difference (PEG/RGD/PTH group versus PEG group; P = 0.055) was found at 2 weeks but not at 4 weeks. The highest percentage of bone-to-implant contact (BIC) in the defect site at 2 weeks was observed for the PEG/RGD group (8.57%). The BIC after 4 weeks of healing ranged from 11.54% (PEG/RGD/PTH group) to 16.61% (PEG group). No statistically significant differences were observed in BIC. The effect of binding PTH covalently to a synthetic, RGD-modified PEG hydrogel marginally significantly improved bone formation at 2 weeks of healing compared to the use of PEG alone. Bone regeneration within the defects increased in all groups at week 4 of healing without statistically significant differences.


Assessment of groundwater vulnerability in the coastal region of Oman using DRASTIC index method in GIS environment.
A study was carried out to develop a vulnerability map for Barka region in the North Batina of Oman using DRASTIC vulnerability index method in GIS environment. DRASTIC layers were created using data from published reports and the seven DRASTIC layers were processed by the ArcGIS geographic information system. Finally, DRASTIC maps were created for 1995 and 2004 to understand the long-term changes in the vulnerability index. DRASTIC vulnerability maps were evaluated using groundwater quality data such as chemical and biological parameters. DRASTIC vulnerability maps of 1995 and 2004 indicate that the northern part of Barka is more vulnerable to pollution than southern part and the central part of Barka also shows high relative vulnerability which is mostly related to the high conductivity values. Moreover, the changes in water level due to high abstraction rate of groundwater reflect in the vulnerability maps and low vulnerability area is increased in the southern part during 2004 compared to 1995. Moreover, regional distribution maps of nitrate, chloride and total and fecal coliforms are well correlated with DRASTIC vulnerability maps. In contrast to this, even though DRASTIC method predicted the central part of the study region is highly vulnerable, both chemical and biological parameters show lower concentrations in this region compared to coastal belt, which is mainly due to agricultural and urban development. In Barka, urban development and agricultural activities are very high in coastal region compared to southern and central part of the study area. Hence, this study concluded that DRASTIC method is also applicable in coastal region having ubiquitous contamination sources.


Predicting Adolescent Electronic Cigarette Use: Differences by Never, Ever, and Current Users.
Rising rates of adolescent electronic cigarette (ECIG) use is concerning because it can lead to adverse health outcomes and increased risk behavior. There are known predictors of ever versus never ECIG use, but less are known about risk factors for ever versus current use of ECIGs. Problem behavior theory (PBT) was used to evaluate possible risk factors for different ECIG use status. Participants were 573 high school students who completed questionnaires measuring ECIG use, as well as constructs within the Social Environment, Perceived Environment, Personality, and Behavior domains of PBT. Multinomial logistic regression was used to evaluate how predictor variables differentiated between participants who reported (a) never use, (b) ever ECIG use, or (c) current ECIG use. Adolescents were more likely to endorse ever ECIG use than never use if they reported peer ECIG use, perceived more benefits and fewer costs (e.g., health) of ECIG use, higher extraversion, alcohol and cigarette use (never vs. ever vs. past 30 days), or attended a school with a higher percentage of socioeconomically disadvantaged students. Adolescents were more likely to report current ECIG use than ever ECIG use if they perceived fewer costs of ECIG use or used cannabis in their lifetime (yes/no). PBT variables differentiated between ever ECIG use and never ECIG use. However, these variables did not differentiate between ever and current ECIG use. Identifying unique risk factors for current versus ever ECIG use is important to understanding persistent ECIG use and subsequent targeted prevention and intervention programs.


A Multiple Correspondence Analysis of Patterns of CBD Use in Hemp and Marijuana Users.
Background: With the passing of the 2018 Agriculture Improvement Act that legalized hemp-derived products, i.e., cannabidiol (CBD), the use of CBD has increased exponentially. To date, the few studies that have characterized individuals who use CBD suggest that co-use of CBD and tetrahydrocannabinol (THC)-dominant cannabis, i.e., marijuana, is highly prevalent. It is, therefore, important to investigate the relationship between CBD use and marijuana use to understand the antecedents and consequences of co-use of these two cannabis products. Methods: We conducted an online survey using structured questionnaires to determine differences in CBD users with (CBD+MJ) and without co-morbid marijuana use. Group comparisons were carried out using chi-square tests and ANOVA. Multiple correspondence analysis (MCA) with bootstrap ratio testing was performed to examine the relationship between the categorical data. Results: We received 182 survey responses from current CBD users. CBD+MJ had more types of CBD administration (F = 17.07, p < 0.001) and longer lifetime duration of CBD use (χ2 = 12.85, p < 0.05). Results from the MCA yielded two statistically significant dimensions that accounted for 77% of the total variance. Dimension 1 (representing 57% of the variance) associated CBD+MJ with indication of CBD use for medical ailments, use of CBD for more than once a day for longer than 2 years, applying CBD topically or consuming it via vaping or edibles, being female, and, having lower educational attainment. Dimension 2 (representing 20% of the variance) separated the groups primarily on smoking-related behaviors where CBD+MJ was associated with smoking CBD and nicotine. Conclusions: Identifying the factors that influence use of CBD and marijuana can inform future studies on the risks and benefits associated with each substance as well as the impacts of policies related to cannabis-based products.


Variation in care between pediatric and adult patients presenting with nephrolithiasis to tertiary care pediatric emergency departments in the United States (2009-2020).
Individuals with nephrolithiasis frequently present to the Emergency Department (ED). Safety and quality principles are often applied in pediatric EDs to children presenting with nephrolithiasis, such as limiting ionizing radiation exposure and opioid analgesics. However, it is unknown whether pediatric EDs apply these same principles to adult patients who present with nephrolithiasis. We hypothesized that adult patients would be associated with higher use of radiation-based imaging and opioid analgesics. To assess variations in diagnostic and treatment interventions and hospital utilization between pediatric and adult patients presenting to the pediatric ED with nephrolithiasis. A retrospective cohort study was conducted, examining outcomes for pediatric (<18-years-old) versus adult (≥18-years-old) patients in 42 pediatric EDs from 2009 to 2020 using the Pediatric Health Information System (PHIS) database. Patients with an ICD-9/10 principal diagnosis code of nephrolithiasis with no nephrolithiasis-related visits within the prior 6 months were included. Primary outcomes were imaging, medications, and surgical interventions. Secondary outcomes were hospital admissions, 90-day ED revisits, and 90-day readmissions. Generalized linear mixed models with random effects were used to adjust for confounding and clustering. In total, 16,117 patients with 17,837 encounters were included. Most hospitals were academic (95.2%), and a plurality were located in the South (38.1%). Most patients were <18-years-old (84.4%, median (interquartile range): 15 (12-17)-years-old), female (57.9%), and White (76.3%), and 17.1% were Hispanic/Latino. Most had no complex chronic conditions (89.2%) and no chronic disease per pediatric medical complexity algorithm (51.5%). For the primary outcome, adults, relative to pediatric patients, who presented to the pediatric ED with nephrolithiasis had higher adjusted odds of receiving computerized tomography (CT) scans (Odds Ratio [OR] 1.43 [95% Confidence Interval [CI] 1.29-1.59]) and opioid analgesics (OR 1.45 [95%CI 1.33-1.58]) (Summary Figure). Secondary outcomes showed that adults, relative to pediatric patients, had lower adjusted odds of hospital admissions, 90-day ED revisits, and 90-day readmissions. Our results suggest that certain pediatric safety and quality principles, such as limiting ionizing radiation exposure and opioid analgesic prescriptions, are not being equally applied to pediatric and adult patients who present to pediatric EDs with nephrolithiasis. The mechanism of these findings remains to be elucidated. Variations in care for individuals with nephrolithiasis reflect an opportunity for quality improvement in pediatric EDs and inform work exploring optimal care pathways for all patients presenting to the pediatric ED with nephrolithiasis.


The prospective association of objectively measured sleep and cerebral white matter microstructure in middle-aged and older persons.
Poor sleep may destabilize axonal integrity and deteriorate cerebral white matter. In middle-aged and older adults sleep problems increase alongside structural brain changes, but the temporal relation between these processes is poorly understood. We studied longitudinal associations between sleep and cerebral white matter microstructure. One thousand one persons (59.3 ± 7.9 years, 55% women) were followed across 5.8 years (3.9-10.8). Total sleep time (TST, hours), sleep efficiency (SE, percentage), sleep onset latency (SOL, minutes), and wake after sleep onset (WASO, minutes) were measured at baseline using a wrist-worn actigraph. White matter microstructure (global and tract-specific fractional anisotropy [FA] and mean diffusivity [MD]) was measured twice with diffusion tensor imaging (DTI). Poor sleep was associated with worse white matter microstructure up to 7 years later but did not predict trajectories of DTI over time. Longer TST was associated with higher global FA (β = 0.06, 95% CI: 0.01 to 0.12), but not with MD. Persons with higher SE had higher global FA (β = 0.01, 95% CI: 0.002 to 0.01) and lower MD (β = -0.01, 95% CI: -0.01 to -0.0004). Consistently, those with more WASO had lower global FA (β = -0.003, 95% CI: -0.005 to -0.001) and higher MD (β = 0.002, 95% CI: 0.0004 to 0.004). Global findings seemed to be driven by microstructural alterations in the cingulum, anterior forceps of corpus callosum, projection and association tracts. Middle-aged and older persons with more WASO, lower SE and shorter TST have worse microstructure of cerebral white matter. Microstructural alterations are most pronounced projection and association tracts, in the cingulum, and in the anterior forceps of corpus callosum.


Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients.
This study was designed to (a) estimate the contribution of tacrolimus nephrotoxicity to episodes of renal allograft dysfunction investigated by needle biopsy, (b) describe the temporal evolution of nephrotoxicity and its response to therapy, and (c) ascertain how often renal dysfunction is associated with concurrent extra-renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, and biopsy findings leading to a reduction in the dose of tacrolimus and a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies with sufficient clinical data for analysis. There were 13 males and 9 females, 17-75 yr in age. Tacrolimus was administered initially as a 0.075-0.1 mg/kg/d IV continuous infusion followed by an oral dose of 0.15 mg/kg twice daily. The onset of nephrotoxicity in this study occurred 1-156 wk post-operatively. The mean baseline creatinine was 212.2 +/- 168.0 mumol/l (range 88.4-875.2) and rose 40.6% +/- 14.2% (range 11-66) during episodes of nephrotoxicity (p < 0.001). The highest recorded plasma and whole-blood tacrolimus levels during the toxic episodes were respectively 2.7 +/- 0.8 ng/ml (range 1.1-3.5) and 31.6 +/- 10.6 ng/ml (range 14.5-50.5). The drug levels were considered to be beyond the therapeutic range in 18/22 (82%) patients. The highest tacrolimus level preceeded the rise in serum creatinine in 20 cases by an interval of 1.6 +/- 1.8 d. A mean reduction in tacrolimus dosage of 41% +/- 21% (range 11-89) led to a 86% +/- 18% (range 45-100) fall in the serum creatinine within 1-14 d (p < 0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinetic parameters in three cases. Serum potassium > 5.0 mequiv/l was recorded in 9/22 (41%) cases. Three or more elevations in blood glucose > 7.7 mmol/l (140 mg/dl) were recorded in 4/11 (36%) non-diabetic patients. Hand tremors were seen in two (9%) cases and elevated diastolic blood pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimus nephrotoxicity accounted for 17% of graft dysfunction episodes investigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduction in the drug dosage.


Sex-specific associations between peripheral oxytocin and emotion perception in schizophrenia.
We previously reported that higher levels of peripheral oxytocin are associated with lower levels of positive, general, and overall symptoms in women but not in men with schizophrenia. Here we investigate the influence of sex, sex steroid hormone fluctuations, and peripheral oxytocin levels on emotional processing in men and women with schizophrenia. Twenty-two women with schizophrenia and 31 female controls completed the Penn Emotion Acuity Test (PEAT), a facial emotion recognition and perception task, during two menstrual cycle phases: 1) early follicular (Days 2-4; low estrogen/progesterone) and 2) midluteal (Days 20-22; high estrogen/progesterone). Twenty-six males with schizophrenia and 26 male controls completed testing at comparable intervals. We obtained plasma hormone assays of estrogen, progesterone, testosterone, and oxytocin. No sex differences were noted on the PEAT. Plasma oxytocin levels did not fluctuate across phases of the menstrual cycle. However, female patients and controls more accurately identified facial emotions during the early follicular versus midluteal phase (p<0.05). Higher oxytocin levels related to perceiving faces as happier in both female patients (r=-0.46, p=0.04) and controls (r=-0.40, p=0.04) but not in men. Like healthy women, women with schizophrenia demonstrate menstrual-cycle dependent fluctuations in recognizing emotional cues. Like healthy women, female patients with higher levels of oxytocin perceived faces as happier. Future studies need to address whether this sex-specific relationship is associated with trust and other positive emotions, and whether exogenous oxytocin might enhance mood states and social interaction in female or all schizophrenia patients.


Structure of dihydromethanopterin reductase, a cubic protein cage for redox transfer.
Dihydromethanopterin reductase (Dmr) is a redox enzyme that plays a key role in generating tetrahydromethanopterin (H4MPT) for use in one-carbon metabolism by archaea and some bacteria. DmrB is a bacterial enzyme understood to reduce dihydromethanopterin (H2MPT) to H4MPT using flavins as the source of reducing equivalents, but the mechanistic details have not been elucidated previously. Here we report the crystal structure of DmrB from Burkholderia xenovorans at a resolution of 1.9 Å. Unexpectedly, the biological unit is a 24-mer composed of eight homotrimers located at the corners of a cubic cage-like structure. Within a homotrimer, each monomer-monomer interface exhibits an active site with two adjacently bound flavin mononucleotide (FMN) ligands, one deeply buried and tightly bound and one more peripheral, for a total of 48 ligands in the biological unit. Computational docking suggested that the peripheral site could bind either the observed FMN (the electron donor for the overall reaction) or the pterin, H2MPT (the electron acceptor for the overall reaction), in configurations ideal for electron transfer to and from the tightly bound FMN. On this basis, we propose that DmrB uses a ping-pong mechanism to transfer reducing equivalents from FMN to the pterin substrate. Sequence comparisons suggested that the catalytic mechanism is conserved among the bacterial homologs of DmrB and partially conserved in archaeal homologs, where an alternate electron donor is likely used. In addition to the mechanistic revelations, the structure of DmrB could help guide the development of anti-obesity drugs based on modification of the ecology of the human gut.


Amino acid sequence of a new mitochondrially synthesized proteolipid of the ATP synthase of Saccharomyces cerevisiae.
The purification and the amino acid sequence of a proteolipid translated on ribosomes in yeast mitochondria is reported. This protein, which is a subunit of the ATP synthase, was purified by extraction with chloroform/methanol (2/1) and subsequent chromatography on phosphocellulose and reverse phase h.p.l.c. A mol. wt. of 5500 was estimated by chromatography on Bio-Gel P-30 in 80% formic acid. The complete amino acid sequence of this protein was determined by automated solid phase Edman degradation of the whole protein and of fragments obtained after cleavage with cyanogen bromide. The sequence analysis indicates a length of 48 amino acid residues. The calculated mol. wt. of 5870 corresponds to the value found by gel chromatography. This polypeptide contains three basic residues and no negatively charged side chain. The three basic residues are clustered at the C terminus. The primary structure of this protein is in full agreement with the predicted amino acid sequence of the putative polypeptide encoded by the mitochondrial aap1 gene recently discovered in Saccharomyces cerevisiae. Moreover, this protein shows 50% homology with the amino acid sequence of a putative polypeptide encoded by an unidentified reading frame also discovered near the mitochondrial ATPase subunit 6 gene in Aspergillus nidulans.


Comprehensive 4D velocity mapping of the heart and great vessels by cardiovascular magnetic resonance.
Phase contrast cardiovascular magnetic resonance (CMR) is able to measure all three directional components of the velocities of blood flow relative to the three spatial dimensions and the time course of the heart cycle. In this article, methods used for the acquisition, visualization, and quantification of such datasets are reviewed and illustrated. Currently, the acquisition of 3D cine (4D) phase contrast velocity data, synchronized relative to both cardiac and respiratory movements takes about ten minutes or more, even when using parallel imaging and optimized pulse sequence design. The large resulting datasets need appropriate post processing for the visualization of multidirectional flow, for example as vector fields, pathlines or streamlines, or for retrospective volumetric quantification. Multidirectional velocity acquisitions have provided 3D visualization of large scale flow features of the healthy heart and great vessels, and have shown altered patterns of flow in abnormal chambers and vessels. Clinically relevant examples include retrograde streams in atheromatous descending aortas as potential thrombo-embolic pathways in patients with cryptogenic stroke and marked variations of flow visualized in common aortic pathologies. Compared to standard clinical tools, 4D velocity mapping offers the potential for retrospective quantification of flow and other hemodynamic parameters. Multidirectional, 3D cine velocity acquisitions are contributing to the understanding of normal and pathologically altered blood flow features. Although more rapid and user-friendly strategies for acquisition and analysis may be needed before 4D velocity acquisitions come to be adopted in routine clinical CMR, their capacity to measure multidirectional flows throughout a study volume has contributed novel insights into cardiovascular fluid dynamics in health and disease.


Design and simulated performance of a CARS spectrometer for dynamic temperature measurements using electronic heterodyning.
A new design for generating CARS signals and for the detection and processing of these signals is presented and evaluated. The design is based on electronic heterodyning of the CARS spectrum of nitrogen at two selected narrowband frequencies, ratioing the resulting signal strengths, and comparing this ratio with a theoretically derived temperature scale. A reference cell is incorporated into the design for system calibration and for accurate temperature measurements. The spectrometer is found capable of measuring temperature in the submillisecond time scale with an accuracy of 10% in the 1000-2000 K temperature range. A typical result using the Hg(x)Cd(1-x) Te photomixer for T = 1500 K,DeltaT = 50 K is a SNR of 21 dB and a data collection rate of 300 Hz.


Effects of energy restriction and fish oil supplementation on renal guanidino levels and antioxidant defences in aged lupus-prone B/W mice.
Energy restriction (ER) and dietary fish oil (FO) are known to reduce the severity of glomerulonephritis and increase the lifespan of lupus-prone (NZB x NZW) F1 (B/W) mice. In the present study, mice were fed either ad libitum or energy-restricted (a 40 % lower energy intake than the diet ad libitum), semi-purified diets containing 5 % maize oil or 5 % fish oil supplementation. To estimate the renal damage associated with oxidative stress, the total amounts of reactive oxygen species (ROS), cyclooxygenase-derived ROS and levels of guanidino compounds were measured. Additionally, we assessed the putative action of ER and FO on several key antioxidant enzymes measured in the kidney post-mitochondrial fraction. Results showed that the age-related increase in creatinine level was significantly reduced by ER and FO in old mice. In contrast, arginine and guanidino acetic acid levels showed a decrease with age but were increased by ER and FO. The GSH:GSSG ratio showed a significant decrease with age, whereas ER and FO feeding prevented the decrease. The age-related decrease in antioxidant scavenging superoxide dismutase, catalase and glutathione peroxidase activities were all reversed by ER and FO. The moderately decreased glutathione reductase and glutathione-S-transferase activities with age were significantly increased by ER and FO. Furthermore, the increased total ROS and cyclooxygenase-derived ROS levels were effectively reduced by ER and FO. In conclusion, our data strongly indicate that ER and FO maintain antioxidant status and GSH:GSSG ratio, thereby protecting against renal deterioration from oxidative insults during ageing.


Quantized Magnetic Flux in Superconductors: Experiments confirm Fritz London's early concept that superconductivity is a macroscopic quantum phenomenon.
The observation that the magnetic flux in a hollow superconducting cylinder is quantized in units of hc/2e has confirmed Fritz London's prediction that superconductivity is a macroscopic quantum phenomenon and that the superconducting state is a single- valued quantum state. It has also conclusively demonstrated that the pair interaction of the Bardeen-Cooper- Schrieffer theory of superconductivity is the important one, at least for the few superconductors studied. A superconducting ring or hollow cylinder must "decide" at the transition temperature what final quantum state it will be in when the temperature is lowered. This "thinking process" has been observed in experiments which demonstrate that the free energy of a hollow superconducting cylinder at the transition temperature is periodic in the magnetic flux. Very recently quantum-mechanical interference effects have been observed in the Josephson tunneling characteristics of multiply linked superconducting circuits. These experiments complement the other experiments on quantized flux and provide perhaps the most elegant proof of long-range order in the superconducting state.


Quantification of placental change in mouse models of preeclampsia using magnetic resonance microscopy.
Abnormal development of the placenta is postulated to be central to the aetiology of preeclampsia. This study investigates changes in placental histopathology in mouse models of preeclampsia compared to the morphology using magnetic resonance microscopy (MRM) (11.7 T) of intact ex vivo tissue followed by 3D analysis of the image data. Here, C57BL/6JArc pregnant mice were subject to either normal pregnancy (n=3), or to one of two experimental models of preeclampsia; TNF-α infusion (n=3) or reduced uterine perfusion pressure(RUPP) (n=3). Placental tissue was collected at gestational day (gd) 17, fixed in formalin and incubated with Magnavist™ contrast agent, and high resolution images (50 μm × 50 μm × 50 μm voxels) obtained by magnetic resonance imaging at 11.74 T. Visual segmentation into placental subregions and three dimensional (3D) reconstruction followed by volume analysis was performed with Amira™ 3D analysis software. The significance of differences between treatment groups in total and regional volumes was assessed. In a single placenta the volumes measure by standard histology were compared. Three placentas from each animal were imaged, segmented into anatomical regions and 3D reconstructions generated. Total placental volume, labyrinth and decidual volume were not significantly different between groups. The junctional zone volume was found to be significantly larger in the RUPP animals (18.5±1.5 mm3) compared to TNF-α infused animals (15.8±1.5) or control animals (15.0±0.7, P<0.01). However, the decidual/junctional zone volume was smaller in the TNF-a compared to control animals (P<0.05). Placental structural change in experimental models of preeclampsia is able to be visualized and quantified using MRM and 3-D analysis. These techniques could prove to be a powerful tool in examining changes in placental morphology.


3D phase diversity: a myopic deconvolution method for short-exposure images: application to retinal imaging.
3D deconvolution is an established technique in microscopy that may be useful for low-cost high-resolution imaging of the retina. We report on a myopic 3D deconvolution method developed in a Bayesian framework. This method uses a 3D imaging model, a noise model that accounts for both photon and detector noises, a regularization term that is appropriate for objects that are a mix of sharp edges and smooth areas, a positivity constraint, and a smart parameterization of the point-spread function (PSF) by the pupil phase. It estimates the object and the PSF jointly. The PSF parameterization through the pupil phase constrains the inversion by dramatically reducing the number of unknowns. The joint deconvolution is further constrained by an additional longitudinal support constraint derived from a 3D interpretation of the phase-diversity technique. This method is validated by simulated retinal images.


Studies on cellular resilience and adaptation following acute and repetitive exposure to ozone in cultured human epithelial (HeLa) cells.
Ozone is used to treat several medical conditions, while the underlying mechanisms of action are sometimes poorly understood. In the current study, we exposed cultured human epithelial (HeLa) cells acutely and repeatedly to ozone and investigated the effects thereof on cell viability. The involvement of anti-apoptotic pathways in observed adaptive responses to ozone were investigated by employing the Akt inhibitor (-)-deguelin. Cells were exposed to an ozone-saturated physiological solution using various dosing regimens, including acute exposure and various repetitive exposures. Cell viability was determined with Trypan Blue or MTT tests, or by a DNA-fragmentation (comet) assay. Acute ozone exposure compromised cell membrane integrity severely, while adaptation to reverse an initial reduction in mitochondrial activity was observed. Repetitive, short-duration exposures followed by a single long-duration exposure to ozone furnished a protective adaptation that was reversed by Akt inhibition. Extracellular and intracellular damage (and adaptation) occurs differentially. While acute ozone may decrease cell viability, multiple preexposures up-regulates cellular plasticity via induction of anti-apoptotic pathways in a treatment regimen-specific manner.


Screening tools for the identification of dementia for adults with age-related acquired hearing or vision impairment: a scoping review.
Cognitive screening tests frequently rely on items being correctly heard or seen. We aimed to identify, describe, and evaluate the adaptation, validity, and availability of cognitive screening and assessment tools for dementia which have been developed or adapted for adults with acquired hearing and/or vision impairment. Electronic databases were searched using subject terms "hearing disorders" OR "vision disorders" AND "cognitive assessment," supplemented by exploring reference lists of included papers and via consultation with health professionals to identify additional literature. 1,551 papers were identified, of which 13 met inclusion criteria. Four papers related to tests adapted for hearing impairment; 11 papers related to tests adapted for vision impairment. Frequently adapted tests were the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MOCA). Adaptations for hearing impairment involved deleting or creating written versions for hearing-dependent items. Adaptations for vision impairment involved deleting vision-dependent items or spoken/tactile versions of visual tasks. No study reported validity of the test in relation to detection of dementia in people with hearing/vision impairment. Item deletion had a negative impact on the psychometric properties of the test. While attempts have been made to adapt cognitive tests for people with acquired hearing and/or vision impairment, the primary limitation of these adaptations is that their validity in accurately detecting dementia among those with acquired hearing or vision impairment is yet to be established. It is likely that the sensitivity and specificity of the adapted versions are poorer than the original, especially if the adaptation involved item deletion. One solution would involve item substitution in an alternative sensory modality followed by re-validation of the adapted test.


Immunizations for patients with metabolic disorders.
Individuals with underlying metabolic disorders are a potential high-risk group for vaccine-preventable diseases. Newborn metabolic screening has provided a means of early identification and treatment for many of these disorders, whereas childhood immunization is one of the most effective means of decreasing the morbidity and mortality resulting from communicable diseases worldwide. There are very few contraindications to the routine administration of vaccines to the healthy, immunocompetent individual. In certain high-risk groups, such as immunocompromised patients, gravid females, and those with a history of previous anaphylactic reaction to a vaccine or its components, selective withholding of immunizations must be considered to decrease potential adverse events. A detailed analysis of the medical literature revealed few specific recommendations regarding appropriate immunization techniques for patients with metabolic disorders. In this review we detail the major metabolic disorder subtypes, elaborate on the available literature on immunizations for patients with these disorders, and provide suggested vaccine recommendations.


Medical management after coronary stent implantation: a review.
Percutaneous coronary intervention (PCI) with stents is currently the most commonly performed coronary revascularization procedure; hence, optimizing post-PCI outcomes is important for all physicians treating such patients. To review the contemporary literature on optimal medical therapy after PCI. We performed a comprehensive search of the PubMed and Cochrane Library databases for manuscripts on medical therapy after PCI, published between 2000 and February 2013. Bibliographies of the retrieved studies were searched by hand for other relevant studies. Priority was given to data from large randomized controlled trials, systematic reviews, and meta-analyses. Of the 6852 publications retrieved, 91 were included. Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor (eg, ticlopidine, clopidogrel, prasugrel, ticagrelor) reduces the risk of stent thrombosis and subsequent cardiovascular events post-PCI (number needed to treat, 33-53) and is the current standard of care. Aspirin should be continued indefinitely and low dose (75-100 mg daily) is preferred over higher doses. A P2Y12 inhibitor should be administered for 12 months after PCI, unless the patient is at high risk for bleeding; however, ongoing studies are assessing the value of shorter or longer duration of P2Y12 inhibitor administration. In patients with acute coronary syndromes, prasugrel and ticagrelor further reduce cardiovascular ischemic events compared with clopidogrel but are associated with higher bleeding risk. If possible, noncardiac surgery should be delayed until 12 months after coronary stenting. Patients receiving coronary stents who require warfarin are at high risk for bleeding if they also receive dual antiplatelet therapy. Omission of aspirin may be advantageous in such patients. Routine platelet function or genetic testing is currently not recommended to tailor antiplatelet therapy after PCI. Dual antiplatelet therapy remains the cornerstone of medical therapy after PCI. Continuous advances in pharmacotherapy can further enhance our capacity to improve outcomes in this high-risk patient group.


Evaluating and Refining the Conceptual Model Used in the Study of Health and Activity in Preschool Environments (SHAPES) Intervention.
This study investigated the utility of the Study of Health and Activity in Preschool Environments (SHAPES) conceptual model, which targeted physical activity (PA) behavior in preschool children, by examining the relationship between implementation monitoring data and child PA during the school day. We monitored implementation completeness and fidelity based on multiple elements identified in the conceptual model. Comparing high-implementing, low-implementing, and control groups revealed no association between implementation and outcomes. We performed post hoc analyses, using process data, to refine our conceptual model's depiction of an effective preschool PA-promoting environment. Results suggest that a single component of the original four-component conceptual model, providing opportunities for moderate-to-vigorous physical activity through recess for 4-year-old children in preschool settings, may be a good starting place for increasing moderate-to-vigorous physical activity. Interventions that are implemented with optimal levels of completeness and fidelity are more likely to achieve behavior change if they are based on accurate conceptual models. Examining the mechanisms through which an intervention produces its effects, as articulated in the conceptual model that guides it, is particularly important for environmentally focused interventions because they are guided by emerging frameworks. The results of this study underscore the utility of using implementation monitoring data to examine the conceptual model on which the intervention is based.


Effects of superfoods on risk factors of metabolic syndrome: a systematic review of human intervention trials.
Functional foods can be effective in the prevention of metabolic syndrome and subsequently the onset of cardiovascular diseases and type II diabetes mellitus. More recently, however, another term was introduced to describe foods with additional health benefits: "superfoods", for which, to date, no generally accepted definition exists. Nonetheless, their consumption might contribute to the prevention of metabolic syndrome, for example due to the presence of potentially bioactive compounds. This review provides an overview of controlled human intervention studies with foods described as "superfoods" and their effects on metabolic syndrome parameters. First, an Internet search was performed to identify foods described as superfoods. For these superfoods, controlled human intervention trials were identified until April 2017 investigating the effects of superfood consumption on metabolic syndrome parameters: waist circumference or BMI, blood pressure, or concentrations of HDL cholesterol, triacylglycerol or glucose. Seventeen superfoods were identified, including a total of 113 intervention trials: blueberries (8 studies), cranberries (8), goji berries (3), strawberries (7), chili peppers (3), garlic (21), ginger (10), chia seed (5), flaxseed (22), quinoa (1), cocoa (16), maca (1), spirulina (7), wheatgrass (1), acai berries (0), hemp seed (0) and bee pollen (0). Overall, only limited evidence was found for the effects of the foods described as superfoods on metabolic syndrome parameters, since results were not consistent or the number of controlled intervention trials was limited. The inconsistencies might have been related to intervention-related factors, such as duration or dose. Furthermore, conclusions may be different if other health benefits are considered.


Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia.
The aryl hydrocarbon receptor (AhR) regulates peripheral immunity; but its role in microglia-mediated neuroinflammation in the brain remains unknown. Here, we demonstrate that AhR mediates both anti-inflammatory and proinflammatory effects in lipopolysaccharide (LPS)-activated microglia. Activation of AhR by its ligands, formylindolo[3,2-b]carbazole (FICZ) or 3-methylcholanthrene (3MC), attenuated LPS-induced microglial immune responses. AhR also showed proinflammatory effects, as evidenced by the findings that genetic silence of AhR ameliorated the LPS-induced microglial immune responses and LPS-activated microglia-mediated neurotoxicity. Similarly, LPS-induced expressions of tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) were reduced in the cerebral cortex of AhR-deficient mice. Intriguingly, LPS upregulated and activated AhR in the absence of AhR ligands via the MEK1/2 signaling pathway, which effects were associated with a transient inhibition of cytochrome P450 1A1 (CYP1A1). Although AhR ligands synergistically enhance LPS-induced AhR activation, leading to suppression of LPS-induced microglial immune responses, they cannot do so on their own in microglia. Chromatin immunoprecipitation results further revealed that LPS-FICZ co-treatment, but not LPS alone, not only resulted in co-recruitment of both AhR and NFκB onto the κB site of TNFα gene promoter but also reduced LPS-induced AhR binding to the DRE site of iNOS gene promoter. Together, we provide evidence showing that microglial AhR, which can be activated by LPS, exerts bi-directional effects on the regulation of LPS-induced neuroinflammation, depending on the availability of external AhR ligands. These findings confer further insights into the potential link between environmental factors and the inflammatory brain disorders.


Tissue taurine content, activity of taurine synthesis enzymes and conjugated bile acid composition of taurine-deprived and taurine-supplemented rhesus monkey infants at 6 and 12 mo of age.
Concentrations of taurine were measured in a number of tissues from rhesus monkeys fed a taurine-free human infant formula with or without taurine supplementation for 6 mo and 12 mo. At 6 mo, tissue taurine content was significantly greater in the monkeys supplemented with taurine, but by 12 mo, there was no longer a significant difference. Activities of enzymes involved in taurine biosynthesis did not differ between the groups at any age. There was no difference in biliary bile acid class composition between the groups, but the proportion of bile acids conjugated with taurine reflected the tissue taurine content (i.e., was significantly greater in monkeys supplemented with taurine at 6 mo). This difference also disappeared by 12 mo. These results indicate that dependence on dietary sources of taurine persists for at least the first 6 mo but declines by 12 mo. Thus, dietary taurine content is reflected in the tissue taurine content and proportion of bile acids conjugated with taurine in infant rhesus monkeys at least until 6 mo of age, but the body taurine status in animals 12 mo old or older is not an indicator of previous status.


NanoSolveIT Project: Driving nanoinformatics research to develop innovative and integrated tools for in silico nanosafety assessment.
Nanotechnology has enabled the discovery of a multitude of novel materials exhibiting unique physicochemical (PChem) properties compared to their bulk analogues. These properties have led to a rapidly increasing range of commercial applications; this, however, may come at a cost, if an association to long-term health and environmental risks is discovered or even just perceived. Many nanomaterials (NMs) have not yet had their potential adverse biological effects fully assessed, due to costs and time constraints associated with the experimental assessment, frequently involving animals. Here, the available NM libraries are analyzed for their suitability for integration with novel nanoinformatics approaches and for the development of NM specific Integrated Approaches to Testing and Assessment (IATA) for human and environmental risk assessment, all within the NanoSolveIT cloud-platform. These established and well-characterized NM libraries (e.g. NanoMILE, NanoSolutions, NANoREG, NanoFASE, caLIBRAte, NanoTEST and the Nanomaterial Registry (>2000 NMs)) contain physicochemical characterization data as well as data for several relevant biological endpoints, assessed in part using harmonized Organisation for Economic Co-operation and Development (OECD) methods and test guidelines. Integration of such extensive NM information sources with the latest nanoinformatics methods will allow NanoSolveIT to model the relationships between NM structure (morphology), properties and their adverse effects and to predict the effects of other NMs for which less data is available. The project specifically addresses the needs of regulatory agencies and industry to effectively and rapidly evaluate the exposure, NM hazard and risk from nanomaterials and nano-enabled products, enabling implementation of computational 'safe-by-design' approaches to facilitate NM commercialization.


Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis.
Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.


Stable expression of two human UDP-glucuronosyltransferase cDNAs in V79 cell cultures.
Two human liver UDP-glucuronosyltransferase cDNA clones (HLUGP1 and HLUG25) were individually inserted into the eukaryotic expression vector pKCRH2. Each recombinant plasmid was cotransfected with a SFVneo vector, thereby allowing establishment of several V79 cell lines retaining the exogenous UDP-glucuronosyltransferase cDNA after selection with G418 (Geneticin). Southern blot analysis suggested that the cDNAs were integrated into the host cell genome. Northern blot and immunoblot analyses indicated that the cDNAs were correctly transcribed and translated for the production of functional enzymes. The established recombinant V79 cell lines stably expressed the UDP-glucuronosyltransferase activities towards 1-naphthol (HLUGP1) and hyodeoxycholic acid (HLUG25) at levels 10-20-fold higher than with transient expression, and in the range found in human liver. These high levels of expression of UDP-glucuronosyltransferase activity allowed the determination of apparent kinetic constants and substrate specificities of glucuronidation in the genetically engineered cell lines. HLUG25 cDNA encoded an isoform with restricted specificity towards the 6-OH group of the bile acid hyodeoxycholic acid. The other steroids, bile acids, endobiotics, and xenobiotics tested as substrates were glucuronidated in various samples of human liver microsomes, but not by this isoenzyme. This study, allowing the expression of individual UDP-glucuronosyltransferases in heterologous cells with no endogenous transferases, offered a unique solution for the characterization of UDP-glucuronosyltransferase functional heterogeneity.


Nuclear pore scaffold structure analyzed by super-resolution microscopy and particle averaging.
Much of life's essential molecular machinery consists of large protein assemblies that currently pose challenges for structure determination. A prominent example is the nuclear pore complex (NPC), for which the organization of its individual components remains unknown. By combining stochastic super-resolution microscopy, to directly resolve the ringlike structure of the NPC, with single particle averaging, to use information from thousands of pores, we determined the average positions of fluorescent molecular labels in the NPC with a precision well below 1 nanometer. Applying this approach systematically to the largest building block of the NPC, the Nup107-160 subcomplex, we assessed the structure of the NPC scaffold. Thus, light microscopy can be used to study the molecular organization of large protein complexes in situ in whole cells.


Air temperature suitability for Plasmodium falciparum malaria transmission in Africa 2000-2012: a high-resolution spatiotemporal prediction.
Temperature suitability for malaria transmission is a useful predictor variable for spatial models of malaria infection prevalence. Existing continental or global models, however, are synoptic in nature and so do not characterize inter-annual variability in seasonal patterns of temperature suitability, reducing their utility for predicting malaria risk. A malaria Temperature Suitability Index (TSI) was created by first modeling minimum and maximum air temperature with an eight-day temporal resolution from gap-filled MODerate Resolution Imaging Spectroradiometer (MODIS) daytime and night-time Land Surface Temperature (LST) datasets. An improved version of an existing biological model for malaria temperature suitability was then applied to the resulting temperature information for a 13-year data series. The mechanism underlying this biological model is simulation of emergent mosquito cohorts on a two-hour time-step and tracking of each cohort throughout its life to quantify the impact air temperature has on both mosquito survival and sporozoite development. The results of this research consist of 154 monthly raster surfaces that characterize spatiotemporal patterns in TSI across Africa from April 2000 through December 2012 at a 1 km spatial resolution. Generalized TSI patterns were as expected, with consistently high values in equatorial rain forests, seasonally variable values in tropical savannas (wet and dry) and montane areas, and low values in arid, subtropical regions. Comparisons with synoptic approaches demonstrated the additional information available within the dynamic TSI dataset that is lost in equivalent synoptic products derived from long-term monthly averages. The dynamic TSI dataset presented here provides a new product with far richer spatial and temporal information than any other presently available for Africa. As spatiotemporal malaria modeling endeavors evolve, dynamic predictor variables such as the malaria temperature suitability data developed here will be essential for the rational assessment of changing patterns of malaria risk.


Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease.
The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices. Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement. Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis. Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined. Clinicaltrials.gov NCT01466374.


Conventional and functional assessment of spatial neglect: Clinical practice suggestions.
Spatial neglect (SN) constitutes a substantial barrier to functional recovery after acquired brain injury. However, because of its multimodal nature, no single test can capture all the signs of SN. To provide a clinically feasible solution, we used conventional neuropsychological tests as well as the Catherine Bergego Scale (CBS) via the Kessler Foundation Neglect Assessment Process (KF-NAP). The goal was to add evidence that a global approach should detect better even subtle signs of SN. Fourteen individuals with lesions located in the right cerebral hemisphere participated in the study. Participants were assessed with a comprehensive battery of neuropsychological tests, comprising a set of visuospatial tests to evaluate several spatial domains. In addition, patients underwent functional assessment with the Barthel Index, the Functional Independence Measure (FIM), and the CBS via KF-NAP. The CBS via KF-NAP was associated with the visuospatial paper-based tests (p = .004) as well as the Motor FIM (p = .003), and was more sensitive than the Behavioral Inattention Test-Conventional in detecting SN (p = .014). We showed that the CBS via KF-NAP was able: (a) to detect functional impairment, especially motor, related to SN; (b) to selectively measures spatial rather than nonspatial dysfunctions; and (c) to be highly sensitive in detecting SN signs especially in those patients with mild severity, covering several aspects of SN manifestations. The patient's SN diagnosis based on the CBS via KF-NAP is clinically important and directly relevant to care planning and goal setting. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Criminogenic factors, psychotic symptoms, and incident arrests among people with serious mental illnesses under intensive outpatient treatment.
Although research robustly indicates that general or "criminogenic" factors predict various measures of recidivism, there is controversy about the extent to which these factors, versus untreated symptoms, lead to justice involvement for people with mental illnesses. Based on a sample of 183 people in intensive outpatient treatment followed for an average period of 34.5 months, the present study tested whether criminogenic factors (i.e., factor-analytically derived proxies of some of the "Central Eight"; Andrews & Bonta, 2010) and psychotic symptoms were independently associated with arrest. The study also compared the predictive utility of these domains. In the fully adjusted model, the antisocial subscale and male sex were associated with increased arrest rates, whereas psychosis and age were associated with decreased arrest rates. Criminogenic factors and psychotic symptoms had comparable predictive utility. We conclude that criminogenic factors-chiefly arrest history-and psychotic symptoms predict arrest rates. Both sets of variables appear useful for assessing risk of arrest among people with mental illnesses who are not under current correctional supervision.


Ventricular Septal Rupture - A Critical Condition as a Complication of Acute Myocardial Infarction.
Ventricular septal rupture is a potentially fatal complication of acute myocardial infarction. The key to management of this critical condition is an aggressive approach to haemodynamic stabilization and surgical closure of the rupture. Where there is a small rupture and the patient is in a haemodynamically stable condition, surgery can be delayed with the prospect of achieving better perioperative results. However, in unstable critically ill patients either immediate surgery or extracorporeal membranous oxygenation support and delayed surgery is indicated. In some patients, trans-catheter closure may be considered as an alternative to surgery.


Macrophage-mediated islet cell cytotoxicity in BB rats.
Islet cell killing mediated by natural killer cells and T-lymphocytes in diabetes-prone (DP) and diabetic BB rats has been described, but other killing mechanisms may also be involved. Histopathologic studies suggest that macrophages are the first immune cells to infiltrate islets. To determine if macrophages are the first cells mediating islet damage, macrophage-mediated cytotoxicity was evaluated in BB rats of different ages. Splenic macrophages isolated from DP rats at 33, 100, 120, and 140 days of age showed no enhanced islet killing compared with diabetes-resistant rats. Killing at diabetes onset (121 +/- 14 days) was markedly increased (43 +/- 9.3%) compared with age-matched diabetes-resistant controls (19 +/- 8.3%, P less than .001). Islet inflammation was monitored at all time points. At 120 and 140 days of age, 9 of 11 (82%) DP rats had insulitis, and cytotoxicity was increased in 6 of 11 (55%) rats, which is similar to the number of DP rats that progress to diabetes. At 100 days, 3 of 6 (50%) DP rats again showed diabetic levels of killing, even in the absence of insulitis. These data indicate that 1) islet inflammation is dissociated from clinical diabetes onset, 2) splenic macrophages may have islet-killing potential before islet inflammation, 3) macrophage-mediated islet killing is elevated in all animals immediately after diabetes onset, and 4) macrophages, in addition to natural killer cells and T-lymphocytes, are responsible for cell-mediated islet destruction and thus are candidates for the first cellular effector to result in islet killing.


Scalp melanoma is associated with high mitotic rate and is a poor prognostic factor for recurrence and outcome.
A small subset of head and neck melanoma, scalp melanoma comprises 3-5% of all cutaneous melanomas. So far, small numbers of researches on scalp melanoma have yielded controversial results. In this trial, we aimed to define the histopathological and clinical features specific to scalp melanoma and to compare them with melanomas that occurred on other sites by using a large group of patients from a single institution. The data of 93 patients with scalp melanoma and 1076 patients with melanomas on other sites were analyzed retrospectively. The median age of the patients was 53 (range 18-83) years. The scalp melanomas were found more frequently in male patients (79.6 vs. 52.0%, P=0.001) and they tended to have nodular histology (41.1 vs. 29.2%, P=0.01), with a higher mitotic rate (>3/mm) (56.9 vs. 40.9%, P=0.01). However, the scalp melanoma was not significantly associated with other histopathological parameters, for example, age, Clark invasion level, Breslow thickness, ulceration, regression, lymphovascular invasion, neurotropism, tumor-infiltrating lymphocyte, and BRAF mutation analysis. Besides, no correlation was found between scalp localization and either nodal involvement or metastasis (P>0.05). The scalp patients had poorer survivals compared with those with other sites. The median survival time and 5-year recurrence-free survival rates for scalp and other sites in patients were 15.6 months and 45.1% versus 23.5 months and 63.6%, respectively (P=0.001). Similarly, the median overall survival times and 5-year overall survival rates in scalp and other sites in patients were 25.6 months and 44.1% versus 28.7 months and 62.9%, respectively (P=0.0001). In conclusion, scalp melanoma patients correlate with a high mitotic rate and are associated with poorer survival than patients with melanomas on other sites.


Perceptions of physicians in Saudi Arabia on the use of international clinical guidelines for managing primary insomnia.
While there are no national clinical guidelines for managing primary insomnia in Saudi Arabia, there are also no published studies of physicians' perceptions of and attitudes towards using international guidelines. The objective of this study was to explore the knowledge, perceptions, and attitudes of physicians practising in Saudi Arabia about using international guidelines for managing insomnia. A qualitative study using in-depth, face-to-face, and semi-structured interviews with 15 physicians held in July 2017 at a tertiary care hospital in Jazan, the distal south-western province in Saudi Arabia. Interviews were audio-recorded, transcribed verbatim, coded using the qualitative software NVivo11 and analysed thematically. Data saturation was assumed as no new understandings of the broad thematic issues were produced by the last three interviews. Themes identified were: Knowledge, Resistance, Barriers and Facilitators. Participants acknowledged their lack of awareness of available guidelines and their lack of training and education about Cognitive Behavioural Therapy for Insomnia (CBT-I). They highlighted a lack of education for patients about insomnia and its treatment. Beliefs about dependence on hypnotics and the inappropriateness of international guidelines for Saudi Arabia inclined many to resist using them. Inability to document diagnosis and consultations due to limited time and lack of suitable electronic systems, lack of suitably trained practitioners for referral for CBT-I, and lack of accountability for practice were identified as key barriers to following international guidelines. Development of national guidelines was the most important facilitator suggested by participants. The health authorities in the government of the Kingdom of Saudi Arabia (KSA) should improve general public awareness about sleep disorders and provide focused training for specialists and technologists. Above all, KSA needs its own nationwide guidelines for treating sleep-disorders based on evidence-based clinical trials, consistent with its history, culture, socioeconomic conditions and traditions.


Influence of maternal obesity on the association between common pregnancy complications and risk of childhood obesity: an individual participant data meta-analysis.
Gestational diabetes and gestational hypertensive disorders are associated with offspring obesity, but the role of maternal adiposity in these associations remains unclear. We aimed to investigate whether these pregnancy complications affect the odds of offspring obesity independently of maternal obesity. We did an individual participant data (IPD) meta-analysis of mother-offspring pairs from prospective birth cohort studies that had IPD on mothers with singleton liveborn children born from 1989 onwards and had information available about maternal gestational diabetes, gestational hypertension or pre-eclampsia, and childhood body-mass index (BMI). We applied multilevel mixed-effects models to assess associations of gestational diabetes, gestational hypertension, and pre-eclampsia with BMI SD scores and the odds of overweight and obesity throughout childhood, adjusting for lifestyle characteristics (offspring's sex, maternal age, educational level, ethnicity, parity, and smoking during pregnancy). We then explored the extent to which any association was explained by maternal pre-pregnancy or early-pregnancy BMI. 160 757 mother-offspring pairs from 34 European or North American cohorts were analysed. Compared with uncomplicated pregnancies, gestational diabetes was associated with increased odds of overweight or obesity throughout childhood (odds ratio [OR] 1·59 [95% CI 1·36 to 1·86] for early childhood [age 2·0-4·9 years], 1·41 [1·26 to 1·57] for mid childhood [5·0-9·9 years], and 1·32 [0·97 to 1·78] for late childhood [10·0-17·9 years]); however, these associations attenuated towards the null following adjustment for maternal BMI (OR 1·35 [95% CI 1·15 to 1·58] for early childhood, 1·12 [1·00 to 1·25] for mid childhood, and 0·96 [0·71 to 1·31] for late childhood). Likewise, gestational hypertension was associated with increased odds of overweight throughout childhood (OR 1·19 [95% CI 1·01 to 1·39] for early childhood, 1·23 [1·15 to 1·32] for mid childhood, and 1·49 [1·30 to 1·70] for late childhood), but additional adjustment for maternal BMI largely explained these associations (1·01 [95% CI 0·86 to 1·19] for early childhood, 1·02 [0·95 to 1·10] for mid childhood, and 1·18 [1·03 to 1·36] for late childhood). Pre-eclampsia was associated with decreased BMI in early childhood only (difference in BMI SD score -0·05 SD score [95% CI -0·09 to -0·01]), and this association strengthened following additional adjustment for maternal BMI. Although lowering maternal risk of gestational diabetes, gestational hypertension, and pre-eclampsia is important in relation to maternal and fetal pregnancy outcomes, such interventions are unlikely to have a direct impact on childhood obesity. Preventive strategies for reducing childhood obesity should focus on maternal BMI rather than on pregnancy complications. EU's Horizon 2020 research and innovation programme (LifeCycle Project).


Aminosidine plus sodium stibogluconate for the treatment of Indian kala-azar: a randomized dose-finding clinical trial.
This randomized, open sequential design trial was set up to assess the efficacy, tolerability and toxicity of 20 d courses of combined intramuscular aminosidine and sodium stibogluconate at various dosages in patients with newly-diagnosed kala-azar in Bihar, India. Three successive studies of 96 patients each were originally planned with aminosidine administered at 12, 6 and 3 mg/kg/d, respectively. For each aminosidine dosage, patients were randomly assigned to receive sodium stibogluconate at 20, 10 or 5 mg/kg/d of antimony. Ninety-six patients were enrolled and assigned aminosidine 12 mg/kg/d as scheduled. In the subsequent study with aminosidine at 6 mg/kg/d, the trial was interrupted after 40 patients had entered owing to inadequacy of the treatment. With aminosidine 12 mg/kg/d the success rates with sodium stibogluconate at 20, 10 and 5 mg/kg/d were 88%, 71% and 72%, respectively and did not differ significantly. With aminosidine 6 mg/kg/d, 69%, 50% and 46% of patients were cured with the same sodium stibogluconate doses, respectively; again, there was no significant difference between the subgroups. The overall success rate with aminosidine at 12 mg/kg/d (76%) was significantly higher than that with 6 mg/kg/d (55%) (odds ratio = 2.69; 95% confidence interval, 1.11-6.4). Patients improved clinically and the treatments were equally well tolerated. The combination of aminosidine 12 mg/kg/d and sodium stibogluconate 20 mg/kg/d for 20 d appears to be an effective and safe replacement in Bihar for sodium stibogluconate alone for > or = 40 d.


Addressing proteolytic efficiency in enzymatic degradation therapy for celiac disease.
Celiac disease is triggered by partially digested gluten proteins. Enzyme therapies that complete protein digestion in vivo could support a gluten-free diet, but the barrier to completeness is high. Current options require enzyme amounts on the same order as the protein meal itself. In this study, we evaluated proteolytic components of the carnivorous pitcher plant (Nepenthes spp.) for use in this context. Remarkably low doses enhance gliadin solubilization rates, and degrade gliadin slurries within the pH and temporal constraints of human gastric digestion. Potencies in excess of 1200:1 (substrate-to-enzyme) are achieved. Digestion generates small peptides through nepenthesin and neprosin, the latter a novel enzyme defining a previously-unknown class of prolyl endoprotease. The digests also exhibit reduced TG2 conversion rates in the immunogenic regions of gliadin, providing a twin mechanism for evading T-cell recognition. When sensitized and dosed with enzyme-treated gliadin, NOD/DQ8 mice did not show intestinal inflammation, when compared to mice challenged with only pepsin-treated gliadin. The low enzyme load needed for effective digestion suggests that gluten detoxification can be achieved in a meal setting, using metered dosing based on meal size. We demonstrate this by showing efficient antigen processing at total substrate-to-enzyme ratios exceeding 12,000:1.


Perceptual and conceptual priming of environmental sounds.
It is still unknown whether sonic environments influence the processing of individual sounds in a similar way as discourse or sentence context influences the processing of individual words. One obstacle to answering this question has been the failure to dissociate perceptual (i.e., how similar are sonic environment and target sound?) and conceptual (i.e., how related are sonic environment and target?) priming effects. In this study, we dissociate these effects by creating prime-target pairs with a purely perceptual or both a perceptual and conceptual relationship. Perceptual prime-target pairs were derived from perceptual-conceptual pairs (i.e., meaningful environmental sounds) by shuffling the spectral composition of primes and targets so as to preserve their perceptual relationship while making them unrecognizable. Hearing both original and shuffled targets elicited a more positive N1/P2 complex in the ERP when targets were related to a preceding prime as compared with unrelated. Only related original targets reduced the N400 amplitude. Related shuffled targets tended to decrease the amplitude of a late temporo-parietal positivity. Taken together, these effects indicate that sonic environments influence first the perceptual and then the conceptual processing of individual sounds. Moreover, the influence on conceptual processing is comparable to the influence linguistic context has on the processing of individual words.


Multiplexed detection of serological cancer markers with plasmon-enhanced Raman spectro-immunoassay.
Circulating biomarkers have emerged as promising non-invasive, real-time surrogates for cancer diagnosis, prognostication and monitoring of therapeutic response. Emerging data, however, suggest that single markers are inadequate in describing complex pathologic transformations. Architecting assays capable of parallel measurements of multiple biomarkers can help achieve the desired clinical sensitivity and specificity while conserving patient specimen and reducing turn-around time. Here we describe a plasmon-enhanced Raman spectroscopic assay featuring nanostructured biomolecular probes and spectroscopic imaging for multiplexed detection of disseminated breast cancer markers cancer antigen (CA) 15-3, CA 27-29 and cancer embryonic antigen (CEA). In the developed SERS assay, both the assay chip and surface-enhanced Raman spectroscopy (SERS) tags are functionalized with monoclonal antibodies against CA15-3, CA27-29 and CEA, respectively. Sequential addition of biomarkers and functionalized SERS tags onto the functionalized assay chip enable the specific recognition of these biomarkers through the antibody-antigen interactions, leading to a sandwich spectro-immunoassay. In addition to offering extensive multiplexing capability, our method provides higher sensitivity than conventional immunoassays and demonstrates exquisite specificity owing to selective formation of conjugated complexes and fingerprint spectra of the Raman reporter. We envision that clinical translation of this assay may further enable asymptomatic surveillance of cancer survivors and speedy assessment of treatment benefit through a simple blood test.


Ultra-compact 8 × 8 strictly-non-blocking Si-wire PILOSS switch.
We report on a path-independent insertion-loss (PILOSS) 8 × 8 matrix switch based on Si-wire waveguides, which has a record-small footprint of 3.5 × 2.4 mm2. The PILOSS switch consists of 64 thermooptic Mach-Zehnder (MZ) switches and 49 low-crosstalk intersections. Each of the MZ switches and intersections employs directional couplers, which enable the composition of a low loss PILOSS switch. We demonstrate successful switching of digital-coherent 43-Gbps QPSK signal.


Using Deep Brain Stimulation to Unravel the Mysteries of Cardiorespiratory Control.
This article charts the history of deep brain stimulation (DBS) as applied to alleviate a number of neurological disorders, while in parallel mapping the electrophysiological circuits involved in generating and integrating neural signals driving the cardiorespiratory system during exercise. With the advent of improved neuroimaging techniques, neurosurgeons can place small electrodes into deep brain structures with a high degree accuracy to treat a number of neurological disorders, such as movement impairment associated with Parkinson's disease and neuropathic pain. As well as stimulating discrete nuclei and monitoring autonomic outflow, local field potentials can also assess how the neurocircuitry responds to exercise. This technique has provided an opportunity to validate in humans putative circuits previously identified in animal models. The central autonomic network consists of multiple sites from the spinal cord to the cortex involved in autonomic control. Important areas exist at multiple evolutionary levels, which include the anterior cingulate cortex (telencephalon), hypothalamus (diencephalon), periaqueductal grey (midbrain), parabrachial nucleus and nucleus of the tractus solitaries (brainstem), and the intermediolateral column of the spinal cord. These areas receive afferent input from all over the body and provide a site for integration, resulting in a coordinated efferent autonomic (sympathetic and parasympathetic) response. In particular, emerging evidence from DBS studies have identified the basal ganglia as a major sub-cortical cognitive integrator of both higher center and peripheral afferent feedback. These circuits in the basal ganglia appear to be central in coupling movement to the cardiorespiratory motor program. © 2020 American Physiological Society. Compr Physiol 10:1085-1104, 2020.


Cystic fibrosis presenting with the meconium plug syndrome.
The meconium plug syndrome (MPS) is a common cause of low intestinal obstruction in newborn infants. Usually, it is benign and not associated with other intestinal dysfunction. We describe the cases of three infants in whom there was intestinal obstruction consistent with the MPS and in which cystic fibrosis (CF) was later documented. We suggest that there is an association between the MPS and CF, and that the condition of all infants with the MPS be evaluated for the possibility of both Hirschsprung's disease and CF.


Achieving better health care outcomes for children in foster care.
This article reviews the challenges health care systems face as they attempt to improve health care outcomes for children in foster care. It discusses several of the promising health care strategies occurring outside the perimeter of child welfare and identifies some of the key impasses in working alongside efforts in child welfare reform. The authors posit that the greatest impasse in establishing a reasonable quality of health care for these children is placement instability, in which children move frequently among multiple homes and in and out of the child welfare system. The authors propose potential strategies in which efforts to improve placement stability can serve as a vehicle for multidisciplinary reform across the health care system.


Mortality and incidence of cancer among Swedish rubber workers, 1952-1981.
The mortality and incidence of cancer was studied among 8,734 workers from two Swedish rubber manufacturing companies. Mortality was investigated from 1952 to 1981 and cancer incidence from 1959 to 1980. The expected numbers of deaths were calculated from national statistics. No significant risk excesses were detected when the cohort was analyzed without consideration of employment time or latency period. However, the mortality from coronary heart disease and the incidence of lung cancer were increased when the study period was limited to greater than or equal 40 years since first employment. The standardized mortality ratio for coronary heart disease correlated positively with employment duration. The mortality from asthma, bronchitis, and emphysema was nonsignificantly increased. The incidence of bladder cancer was increased among individuals with heavy and long-term exposure in the weighing and mixing departments. Twenty-five percent of the individuals in the cohort were not Swedish citizens at the time of employment, and an analysis of the mortality and cancer incidence in this group showed a markedly increased lung cancer incidence for certain immigrant groups, probably mainly due to ethnic factors. The results indicate that ethnic factors must be considered in the analysis of occupational groups when a high proportion of the workers are immigrants.


Enhancing medication adherence in people with schizophrenia: an international programme of research.
This paper describes the development of an adherence therapy intervention in schizophrenia and synthesizes the results to date of a collaborative international programme of research. Sticking to treatment is essential to control symptoms and prevent relapse, but as with other long-term conditions, medication adherence is poor. Adherence therapy seeks to facilitate a process of shared decision making, where both parties work towards agreed goals. Central is the theory that when patients make shared choices with a professional they are more likely to stick with them because they are personally owned and meaningful. The results of adherence therapy trials that seek to test this theory are mixed. Outcomes of trials might have been be affected by the point in the patient's illness cycle when therapy was delivered and by sampling bias. Authors of trials of medication management and alliance training packages that aim to equip mental health workers with adherence therapy competencies show considerable promise in improving clinical outcomes. Helping patients manage their medication is central to the work of mental health nurses. We argue that the potential benefits to patients are such that there is sufficient evidence to recommend that all mental health nurses receive medication management training.