Comparative Evaluation of Water Sorption of Heat-Polymerized Polymethyl Methacrylate Denture Base Resin Reinforced with Different Concentrations of Silanized Titanium Dioxide Nanoparticles: An In vitro Study.
Polymethyl methacrylate (PMMA) is the most regularly used material in denture fabrication. Water sorption of denture base PMMA denture base resin has negative effects on physical properties, may lead to harmful tissue reactions in patients, and also has detrimental effects on color stability of the denture base. The purpose of this study was to evaluate the effect on water sorption of heat-cured PMMA denture base material after incorporation of 1%, 3%, and 5% by weight of silanized titanium dioxide (TiO2) nanoparticles. For preparation of test samples, TiO2 nanoparticles (PCode: 700339, Sigma-Aldrich, USA) were coated with a layer of trimethoxysilylpropylmethacrylate (PCode: 440159, Sigma-Aldrich, USA) before sonicated in monomer (MMA) (DPI Heat Cure) with the percentages 1%, 3%, and 5% by weight; after sonication, it was mixed with PMMA powder using conventional denture fabrication procedure. Then, we prepared total 40 samples for study; 10 samples for each four groups, i.e. that is one control group and three experimental groups. The first group was prepared from PMMA without addition of TiO2 nanoparticles (control group), the second group with the addition of 1 wt% TiO2 nanoparticles, the third group with 3 wt% TiO2 nanoparticles, and the fourth one with 5 wt% TiO2 nanoparticles (experimental groups). Water sorption test was then conducted on each sample. Each group was evaluated for water sorption test, and it was found that increasing the wt% of nanoparticles, there was a significant decrease in water sorption of denture base resin from 1.74 to 1.46 mean wt%. P value suggested that the difference of mean percent increase across all groups was statistically significant with P = 0.034. The maximum decrease in water sorption was observed in denture base resin incorporated with 5 wt% TiO2 nanoparticles.


Hippocampal and cognitive aging across the lifespan: a bioenergetic shift precedes and increased cholesterol trafficking parallels memory impairment.
Multiple hippocampal processes and cognitive functions change with aging or Alzheimer's disease, but the potential triggers of these aging cascades are not well understood. Here, we quantified hippocampal expression profiles and behavior across the adult lifespan to identify early aging changes and changes that coincide with subsequent onset of cognitive impairment. Well powered microarray analyses (N = 49 arrays), immunohistochemistry, and Morris spatial maze learning were used to study male F344 rats at five age points. Genes that changed with aging (by ANOVA) were assigned to one of four onset age ranges based on template pattern matching; functional pathways represented by these genes were identified statistically (Gene Ontology). In the earliest onset age range (3-6 months old), upregulation began for genes in lipid/protein catabolic and lysosomal pathways, indicating a shift in metabolic substrates, whereas downregulation began for lipid synthesis, GTP/ATP-dependent signaling, and neural development genes. By 6-9 months of age, upregulation of immune/inflammatory cytokines was pronounced. Cognitive impairment first appeared in the midlife range (9-12 months) and coincided and correlated primarily with midlife upregulation of genes associated with cholesterol trafficking (apolipoprotein E), myelinogenic, and proteolytic/major histocompatibility complex antigen-presenting pathways. Immunolabeling revealed that cholesterol trafficking proteins were substantially increased in astrocytes and that myelination increased with aging. Together, our data suggest a novel sequential model in which an early-adult metabolic shift, favoring lipid/ketone body oxidation, triggers inflammatory degradation of myelin and resultant excess cholesterol that, by midlife, activates cholesterol transport from astrocytes to remyelinating oligodendrocytes. These processes may damage structure and compete with neuronal pathways for bioenergetic resources, thereby impairing cognitive function.


Schisanhenol Attenuates OxLDL-Induced Endothelial Dysfunction via an AMPK-Dependent Mechanism.
Atherosclerotic cardiovascular diseases, commonly known as the formation of fibrofatty lesions in the artery wall, are the leading causes of death globally. Oxidized low-density lipoprotein (oxLDL) is one of the major components of atherosclerotic plaques. It is evident that dietary supplementation containing sources of antioxidants can prevent atherogenic diseases. Schisanhenol (SAL), a dibenzocyclooctene lignin, has been shown to attenuate oxLDL-induced apoptosis and the generation of reactive oxygen species (ROS) in endothelial cells. However, the underlying molecular mechanisms are still largely unknown. In this study, human umbilical vein endothelial cells (HUVECs) were pre-treated with SAL and oxLDL. Our results showed that adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was enhanced in cells pre-treated with SAL in time-dependent and dose-dependent manners. Subsequently, oxLDL-induced AMPK dephosphorylation and protein kinase C (PKC) phosphorylation were significantly reversed in the presence of SAL. In addition, SAL treatment led to an inhibiting effect on the oxLDL-induced membrane assembly of NADPH oxidase subunits, and a similar effect was observed in ROS generation. This effect was further confirmed using knockdown AMPK with small interfering RNA (siRNA) and pharmaceutical reagents, such as the AMPK activator (AICAR), PKC inhibitor (Gö 6983), and ROS inhibitor (DPI). Furthermore, the oxLDL-induced intracellular calcium rise and the potential collapse of the mitochondrial membrane reduced the Bcl-2/Bax ratio, and released cytochrome c from the mitochondria, leading to the subsequent activation of caspase-3 in HUVECs, which were also markedly suppressed by SAL pretreatment. The results mentioned above may provide additional insights into the possible molecular mechanisms underlying the cardiovascular protective effects of SAL.


Atheroembolism presenting as selective muscle embolisation.
Two cases of occult aneurysmal disease presenting with select muscle embolisation are described. Both cases were characterised by symptomatology suggestive of occlusive disease but in the presence of normal pulses. It is concluded that the clinical features allow early diagnosis of this uncommon presentation of aneurysmal disease.


Quadruplex-forming sequences occupy discrete regions inside plant LTR retrotransposons.
Retrotransposons with long terminal repeats (LTR) form a significant proportion of eukaryotic genomes, especially in plants. They have gag and pol genes and several regulatory regions necessary for transcription and reverse transcription. We searched for potential quadruplex-forming sequences (PQSs) and potential triplex-forming sequences (PTSs) in 18 377 full-length LTR retrotransposons collected from 21 plant species. We found that PQSs were often located in LTRs, both upstream and downstream of promoters from which the whole retrotransposon is transcribed. Upstream-located guanine PQSs were dominant in the minus DNA strand, whereas downstream-located guanine PQSs prevailed in the plus strand, indicating their role both at transcriptional and post-transcriptional levels. Our circular dichroism spectroscopy measurements confirmed that these PQSs readily adopted guanine quadruplex structures-some of them were paralell-stranded, while others were anti-parallel-stranded. The PQS often formed doublets at a mutual distance of up to 400 bp. PTSs were most abundant in 3'UTR (but were also present in 5'UTR). We discuss the potential role of quadruplexes and triplexes as the regulators of various processes participating in LTR retrotransposon life cycle and as potential recombination sites during post-insertional retrotransposon-based genome rearrangements.


mGlu5 receptor antagonist blocks bromocriptine-induced conditioned place preference in bilateral mesolimbic-lesioned rat.
Dopamine dysregulation syndrome (DDS) has been attributed to both dopamine replacement therapies (DRT) and the mesencephalic dopaminergic lesion. The DRT reinforcement effect is due to its action on the reward system, particularly on the nucleus accumbens (NAc). This nucleus receives two major projections, a glutamatergic from the prefrontal cortex and a dopaminergic from the posterior ventral tegmental area (pVTA). The latter modulate the former within the NAc. pVTA has been demonstrated to be implicated in the motivational effect of bromocriptine (dopamine 2 receptor (D2R) agonist) in bilateral pVTA-lesioned animals. Therefore the potential implication of the metabotropic glutamate receptor 5 (mGluR5) antagonist (MTEP: 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine) on bromocriptine-induced conditioned place preference (CPP) was explored. Results showed that the administration of the MTEP blocked completely the bromocriptine-induced CPP in bilateral pVTA-lesioned rats. Both the CPP acquisition and expression were abolished. These effects are due, at least to an increase of the glutamate concentration and that of mGlu5 receptor expression in the NAc shell of the pVTA-lesioned animals. Altogether these data demonstrated the importance of the mGlu5 receptor in the bromocriptine induced-reinforcement and that DDS is probably due to DRT effect on this glutamate receptor.


Rational elicitation of cold-sensitive phenotypes.
Cold-sensitive phenotypes have helped us understand macromolecular assembly and biological phenomena, yet few attempts have been made to understand the basis of cold sensitivity or to elicit it by design. We report a method for rational design of cold-sensitive phenotypes. The method involves generation of partial loss-of-function mutants, at either buried or functional sites, coupled with selective overexpression strategies. The only essential input is amino acid sequence, although available structural information can be used as well. The method has been used to elicit cold-sensitive mutants of a variety of proteins, both monomeric and dimeric, and in multiple organisms, namely Escherichia coli, Saccharomyces cerevisiae, and Drosophila melanogaster This simple, yet effective technique of inducing cold sensitivity eliminates the need for complex mutations and provides a plausible molecular mechanism for eliciting cold-sensitive phenotypes.


Influence of voriconazole and fluconazole on reconstituted multilayered oesophageal epithelium infected by Candida albicans.
Reconstituted multilayered oesophageal epithelium appears to be a good basis to test the efficacy of voriconazole (VOR) and fluconazole (FLU) in the tissue. The resulting model of a Candida oesophagitis was approaching the in vivo situation. We infected the tissue with 2 x 10(6) cfu of the Candida albicans strain SC5314. In the trials with FLU we also used clinical strains. Four hours after infection a good growth of C. albicans appeared mainly with hyphae on the surface of the tissue and a tendency to invasion. The destruction of the tissue began after 36 h. VOR (2 and 16 microg ml-1, respectively) prevented the penetration of hyphae into the tissue, when it was given 4-8 h after infection. It was less effective in reduction of Candida growth on the tissue surface. When VOR was given 16-24 h postinfection, the Candida infiltration stopped more slowly. Thirty-six hours after infection VOR application could not stop the destruction of the tissue despite reducing the fungi. The results with FLU (32 microg ml-1) were in principle the same, but not so distinct. FLU seems to be more effective against clinical strains of C. albicans than against the type strain.


Does Clinical Governance influence the quality of medical records?
Clinical Governance (CG) is a validated framework for continuous quality improvement in health care settings. Quality medical records may reflect the quality of care delivered and are a viable tool to implement CG skills. Aim of this study is to investigate the correlation between the level of implementation of CG dimensions and the quality of medical records. A cross-sectional study was carried out in an Italian Teaching Hospital. CG implementation levels were quantified through a systematic methodology (OPTIGOV©). The overall quality of medical records was measured through a revised version of a National-validated scale. A multiple linear regression model was used to test the likely influence of all the variables constituting the OPTIGOV evaluation on the quality of medical records. 47 hospital wards and 1458 medical records were assessed. A significant and positive association between the quality of medical records and the accountability score (β = 0.15; p < 0.01) and the clinical audit score (b = 0.11; p = 0.02), was found. Conversely, the risk management score shown a negative and significant correlation (b = -0.17; p < 0.01). This study confirms that CG plays a central role in driving quality improvement and advocates a systematic implementation of such an approach within healthcare organizations.


Bilaterality of ulnar neuropathy at the elbow.
The electrodiagnostic records of 49 patients with ulnar neuropathy at the elbow (UNE) on at least one side were reviewed. Of these, 18 (36.7%) had contralateral and 1 (2.0%) had probable contralateral involvement, for a total of 19 patients (38.8%) with bilateral UNE. The upper extremity presenting symptoms were unilateral in 13 (68.4%) of the patients with bilateral UNE. Differences in associated clinical history data and concurrent electrodiagnostic findings were not clinically or statistically significant between the unilateral and bilateral UNE groups. This pilot study suggests the incidence of UNE bilaterality may be high in some populations and that, when UNE is encountered electrodiagnostically, the contralateral extremity should also be tested. Further studies to determine what factors are related to the bilaterality of UNE appear indicated.


The Brazilian version of the High-Activity Arthroplasty Score: cross-cultural adaptation.
The High Activity Arthroplasty Score (HAAS) is a self-administered questionnaire, developed in British English, that reliably and validly measures the levels of sports activities in patients following hip and knee arthroplasty surgery. To cross-culturally adapt the HAAS to Brazilian Portuguese language. A cross-sectional study was conducted at a public university hospital in Brazil. The Brazilian version of the HAAS was created through a six-step process: translation, synthesis, committee review, pretesting, back-translation, and submission to developers. The translation step was conducted by two independent bilingual translators, both native speakers of Brazilian Portuguese. The back-translation was performed by an independent translator, a native speaker of British English. To ensure the questionnaire's comprehensibility, 46 volunteers (51% men; average age 34-63) participated in the pre-testing step. The cross-cultural adaptation process necessitated modifications to certain terms and expressions to achieve cultural equivalence with the original HAAS. The HAAS has been translated from English into Brazilian Portuguese and culturally adapted for Brazil. The validation process for HAAS-Brazil is currently underway.


Efficacy and Safety of Danirixin (GSK1325756) Co-administered With Standard-of-Care Antiviral (Oseltamivir): A Phase 2b, Global, Randomized Study of Adults Hospitalized With Influenza.
Excessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases neutrophil activation and transmigration to areas of inflammation. This study evaluated the efficacy and safety of intravenous (IV) danirixin co-administered with oseltamivir for the treatment of adults hospitalized with influenza. In this phase 2b, double-blind, 3-arm study (NCT02927431), influenza-positive participants were randomized 2:2:1 to receive danirixin 15mg intravenously (IV) twice daily (bid) + oral oseltamivir 75mg bid (OSV), danirixin 50mg IV bid + OSV, or placebo IV bid + OSV, for up to 5 days. The primary endpoint was time to clinical response (TTCR). In total, 10 participants received study treatment (danirixin 15mg + OSV, n = 4; danirixin 50mg + OSV, n = 4; placebo + OSV, n = 2) before the study was terminated early due to low enrollment. All participants achieved a clinical response. Median (95% confidence interval) TTCR was 4.53 days (2.95, 5.71) for danirixin 15mg + OSV, 4.76 days (2.71, 5.25) for danirixin 50mg + OSV, and 1.33 days (0.71, 1.95) for placebo + OSV. Adverse events (AEs) were generally of mild or moderate intensity; no serious AEs were considered treatment-related. Interleukin-8 levels increased in nasal samples (using synthetic absorptive matrix strips) and decreased serum neutrophil-elastase-mediated degradation of elastin decreased in danirixin-treated participants, suggesting effective target engagement. Interpretation of efficacy results is restricted by the low participant numbers. The safety and tolerability profile of danirixin was consistent with previous studies. The registration data for the trial are in the ClinicalTrials.gov database, number NCT02927431, and in the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) as GSK study 201023, EudraCT 2016-002512-40. Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.


Calculation of cellular oxygen concentration for photodynamic therapy in vitro.
In vitro photodynamic therapy experiments are usually performed by irradiating cells in confluent or nearly confluent monolayer cultures. Oxygen is consumed in the monolayer by photodynamic reactions and cellular respiration and is supplied by diffusion from the overlying medium. Calculations of oxygen concentration by numerical solution of the time-dependent diffusion equation show that hypoxia can be induced in the monolayer under typical PDT conditions and that this will limit the total treatment effect. There is an optimum fluence rate at which the greatest singlet oxygen dose can be delivered before hypoxia becomes limiting. It is recommended that researchers use these calculations to avoid hypoxia or confirm that fortuitous oxygen transport by other mechanisms (e.g., convection) is adequate to prevent it.


Violence Towards Family Caregivers by Their Relative with Schizophrenia in Japan.
There have been several violence-related deaths in Japan due to family violence by persons with severe mental illness against their caregivers. However, it is not often acknowledged that these violent acts are mainly directed at family members. This study aimed to clarify what acts of violence family caregivers experienced from their relative with schizophrenia, and how frequently these violent incidents occurred in their lifetime. We also examined caregivers' thoughts of death about themselves and their relatives, as well as their consultation efforts and escape from the violence perpetrated by their relative. Of the 277 caregivers, 87.7% had experienced psychological violence and 75.8% had experienced physical violence perpetrated by their relative. Of 210 caregivers who had experienced physical violence, 26.7% had thought of murder-suicide and 31.0% had wished for their relative's death. Family violence by persons with schizophrenia is not rare but a common occurrence in Japan and may have fatal consequences.


Highly CO2 Selective Microporous Metal-Imidazolate Framework-Based Mixed Matrix Membranes.
Microporous metal-imidazolate framework (MMIF), a highly CO2 selective MOF, was incoporated into a polymeric membrane for separation of CO2 from CH4 and N2 for the first time. MMIF nanoparticles of 50-200 nm were synthesized using the sonication method and dispersed into Matrimid, a commercial polyimide, with MOF loading of 10% and 20% by weight to fabricate mixed matrix membranes (MMMs). Morphology, thermal behavior, and glass transition temperature of the membranes were characterized, and single and mixed gas permeation measurements at 35 °C and 4 bar feed pressure were carried out to reveal their separation performance. Both 10% and 20% MMIF containing Matrimid membranes exhibited enhanced gas permeabilities for all three gases. Contrary to expectations, ideal selectivity of membranes was not improved possibly due to the flexible framework of MMIF. On the other hand, mixed gas permeability measurements showed significant improvement in CO2/CH4 separation factor by 130% and CO2/N2 separation factor by 79% due to competitive adsorption favoring CO2.


Polymers for mucoadhesive drug delivery system: a current status.
To overcome the relatively short gastrointestinal (GI) time and improve localization for oral controlled or sustained release drug delivery systems, bioadhesive polymers that adhere to the mucin/epithelial surface are effective and lead to significant improvement in oral drug delivery. Improvements are also expected for other mucus-covered sites of drug administration. Bioadhesive polymers find application in the eye, nose, and vaginal cavity as well as in the GI tract, including the buccal cavity and rectum. This article lays emphasis mainly on mucoadhesive polymers, their properties, and their applications in buccal, ocular, nasal, and vaginal drug delivery systems with its evaluation methods.


Surface modification of poly(methyl methacrylate) microfluidic devices for high-resolution separations of single-stranded DNA.
While polymer-based microfluidic devices offer some unique opportunities in developing low-cost systems for a variety of application areas, the ability to sort electrophoretically with high efficiency a number of different targets has remained somewhat elusive with an example consisting of achieving single base resolution as required for DNA sequencing. While the reasons for this are many-fold, it is clear that some type of coating is required on the polymer substrate to suppress the EOF and/or minimize potential solute/wall interactions. To this end, we report on a simple grafting procedure to allow the formation of polymer coats, which in this example used linear polyarcylamides (LPAs), onto a poly(methyl methacrylate) (PMMA) microfluidic device. The procedure involved creating an amine-terminated PMMA surface by appropriately functionalizing the PMMA through either a chemical or photochemical process. The aminated surface could then be used to covalently anchor methacrylic acid, which was used as a scaffold to produce LPAs on the surface through radical polymerization of acrylamide. The resulting surfaces demonstrated EOFs that were nearly an order of magnitude smaller than native PMMA. In addition, these LPA-coated devices could produce highly reproducible migration times of over approximately 20 runs with plate numbers exceeding 10(5) m(-1). Using gel electrophoretic analysis of a single base track generated from an M13mp18 template using Sanger cycle sequencing and dye-primer chemistry, the resolution value obtained for bases 199 and 200 was 0.18 while for bases 208 and 209 it was 0.21. For the native PMMA, these bands were found to comigrate.


Encoding strategy training and self-reported everyday prospective memory in people with Parkinson disease: a randomized-controlled trial.
Objective To compare the effects of laboratory-based training in implementation intentions (II; experimental strategy) and verbal rehearsal (VR; control strategy) on self-reported everyday prospective memory among people with Parkinson disease (PD) and to investigate potential correlates of change in self-reported everyday prospective memory in response to this training. Method This was a randomized-controlled trial. Participants with mild to moderate PD without dementia underwent one session of training in either II (n = 25) or VR (n = 27). Then they were instructed to use their strategy as much as possible in their everyday lives to help them remember to do things. The Prospective and Retrospective Memory Questionnaire Prospective Scale (PRMQ-Pro) administered at baseline and one month after training assessed training-related change in self-reported everyday prospective memory. Baseline depressive symptoms, perceptions of the strategy (credibility, expectancy), prospective memory-related awareness, global cognition, and disease severity were correlated to PRMQ-Pro Change scores (post minus pre) to determine their association with response to training. Results The VR group's PRMQ-Pro scores declined from pre to post training, while the II group's remained stable (p = .03). This effect was driven by change in self-cued everyday prospective memory tasks. Higher baseline depressive symptoms, treatment expectancy, and global cognition related to better response to training in the II group (rs ≤ -.40, ps ≤ .05). Conclusions II training may prevent everyday prospective memory decline among people with PD. In addition, people with higher depression, stronger expectations of improvement from strategy training, or better global cognition may benefit the most from II training.


Genomically Hardwired Regulation of Gene Activity Orchestrates Cellular Iron Homeostasis in Arabidopsis.
Iron (Fe) is an essential micronutrient which plays pivotal roles as electron donor and catalyst across organisms. In plants, variable, often insufficient Fe supply necessitates mechanisms that constantly attune Fe uptake rates and recalibrate cellular Fe homoeostasis. Here, we show that short-term (0.5, 6, and 12 h) exposure of Arabidopsis thaliana plants to Fe deficiency triggered massive changes in gene activity governed by transcription and alternative splicing (AS), regulatory layers that were to a large extent mutually exclusive. Such preclusion was not observed for genes that are directly involved in the acquisition of Fe, which appears to be concordantly regulated by both expression and AS. Generally, genes with lower splice site strengths and higher intron numbers were more likely to be regulated by AS, no dependence on gene architecture was observed for transcriptionally controlled genes. Conspicuously, specific processes were associated with particular genomic features and biased towards either regulatory mode, suggesting that genomic hardwiring is functionally biased. Early changes in splicing patterns were, in many cases, congruent with later changes in transcript or protein abundance, thus contributing to the pronounced transcriptome-proteome discordance observed in plants.


Does posterior cortical atrophy on MRI discriminate between Alzheimer's disease, dementia with Lewy bodies, and normal aging?
Previous studies suggest that posterior cortical atrophy may be a useful marker for early onset Alzheimer's disease (AD). Dementia with Lewy bodies (DLB) is associated with less temporal lobe atrophy than AD, though posterior cortical atrophy may be greater. Therefore, we assessed whether visual rating scales for assessing posterior atrophy (PA), medial temporal lobe atrophy (MTA), and ventricular enlargement (VEn) aid in the discrimination between AD, DLB, and normal aging. T1-weighted MRI scans acquired at 3 Tesla were visually rated for PA (range 0-3), MTA (range 0-4), and VEn (range 0-3) in older subjects with AD (n = 36), DLB (n = 35), and healthy controls (n = 35). The diagnostic utility of MTA, PA, and VEn visual ratings in distinguishing AD and DLB from controls as well as AD from DLB was investigated. Significantly higher MTA ratings were associated with AD and DLB compared to controls (p < 0.001). MTA ratings were greater in AD relative to DLB (U = 384.5, p = 0.004). For PA ratings, scores did not differ between groups (p = 0.20). VEn ratings were significantly higher in AD and DLB compared to controls (p = 0.003), but similar between AD and DLB (U = 384.5, p = 0.4). Unlike findings reported in younger subjects, visual ratings for PA are not a reliable marker at older ages for distinguishing AD from controls, or for distinguishing DLB from AD. However, visual ratings of MTA and VEn may be useful markers in distinguishing both AD and DLB from older subjects without dementia.


Shoot production per responsive leaf explant increases exponentially with explant organogenic potential in Nicotiana species.
As part of the effort to develop optimal plant varieties for the production and molecular farming of plant-made pharmaceuticals, this study evaluated shoot organogenic potential of a total of 115 Nicotiana accessions, representing 53 species. To induce shoots, leaves from seedling grown in vitro were cut into pieces, cultured on shoot-induction medium under low light for 3 weeks, and then subcultured onto the same medium for another 4 weeks under normal light. Statistical analysis detected significant differences among the 115 accessions for the percentage of leaf explants producing shoots and the number of shoots produced per responsive leaf explant. Importantly, regression analysis also found an exponential relationship between the number of shoots produced per responsive leaf explant and the percentage of leaf explants producing shoots. The number of shoots produced per responsive leaf explant increased rather slowly, ranging from zero to around five, as the percentage of leaf explants producing shoots increased from 0 to 80%, but the increase became dramatic as the percentage increased from 80% to 100%, reaching as high as 35 shoots per responsive leaf explant. This exponential relationship is the first of its kind to be established in plant regeneration studies using either organogenesis or somatic embryogenesis systems. A possible mechanism that governs the establishment of the exponential relationship is discussed.


Temporal association between food distribution and human caregiver presence and the development of affinity to humans in lambs.
The presence of the caregiver around feeding favors the development of a human-animal relationship. To understand the underlying mechanism, we tested various temporal associations between food distribution and human presence: from an early age, a person was repeatedly present for 2 min just before milk distribution ("Forward"), during milk distribution ("Simultaneous"), and 20 min afterwards ("Delayed"). The "Control" group received no human contacts. During the treatments, "Forward" and "Delayed" lambs had more physical contacts with the person than "Simultaneous" lambs. When tested in unfamiliar environments, they stood longer near the person than did "Control" or "Simultaneous" lambs, which did not differ. Only "Forward" and "Delayed" lambs bleated when separated from the person. Fasting before testing had no effect. "Forward" and "Delayed" seemed to produce the same human-animal relationship, showing that this did not rely only on a conditioning process associating the caregiver with food. The caregiver may acquire properties for social support through other mechanisms (attachment and/or postingestive effects).


Serum Hepcidin and Soluble Transferrin Receptor in the Assessment of Iron Metabolism in Children on a Vegetarian Diet.
The aim of this study was to assess the effect of vegetarian diet on iron metabolism parameters paying special attention to serum hepcidin and soluble transferrin receptor (sTfR) concentrations in 43 prepubertal children (age range 4.5-9.0 years) on vegetarian and in 46 children on omnivorous diets. There were no significant differences according to age, weight, height, and body mass index (BMI) between vegetarian and omnivorous children. Vegetarians had similar intake of iron and vitamin B12 and a significantly higher intake of vitamin C (p < 0.05) compared with non-vegetarians. Hematologic parameters and serum iron concentrations were within the reference range in both groups of children. Serum transferrin levels were similar in all subjects; however, ferritin concentrations were significantly (p < 0.01) lower in vegetarians than in omnivores. In children on a vegetarian diet, median hepcidin levels were lower (p < 0.05) but sTfR concentrations significantly higher (p < 0.001) compared with omnivorous children. In the multivariate regression model, we observed associations between hepcidin level and ferritin concentration (β = 0.241, p = 0.05) in the whole group of children as well as between hepcidin concentration and CRP level (β = 0.419, p = 0.047) in vegetarians. We did not find significant associations with concentration of sTfR and selected biochemical, anthropometric, and dietary parameters in any of the studied groups of children. As hematologic parameters and iron concentrations in vegetarians and omnivores were comparable and ferritin level was lower in vegetarians, we suggest that inclusion of novel markers, in particular sTfR (not cofounded by inflammation) and hepcidin, can better detect subclinical iron deficiency in children following vegetarian diets.


Regionally specific levels and patterns of keratin 8 expression in the mouse embryo visceral endoderm emerge upon anterior-posterior axis determination.
The mechanical properties of the different germ layers of the early mammalian embryo are likely to be critical for morphogenesis. Cytoskeleton components (actin and myosin, microtubules, intermediate filaments) are major determinants of epithelial plasticity and resilience to stress. Here, we take advantage of a mouse reporter for Keratin 8 to record the pattern of the keratin intermediate filaments network in the first epithelia of the developing mouse embryo. At the blastocyst stage, Keratin 8 is strongly expressed in the trophectoderm, and undetectable in the inner cell mass and its derivatives, the epiblast and primitive endoderm. Visceral endoderm cells that differentiate from the primitive endoderm at the egg cylinder stage display apical Keratin 8 filaments. Upon migration of the Anterior Visceral Endoderm and determination of the anterior-posterior axis, Keratin 8 becomes regionally distributed, with a stronger expression in embryonic, compared to extra-embryonic, visceral endoderm. This pattern emerges concomitantly to a modification of the distribution of Filamentous (F)-actin, from a cortical ring to a dense apical shroud, in extra-embryonic visceral endoderm only. Those regional characteristics are maintained across gastrulation. Interestingly, for each stage and region of the embryo, adjacent germ layers display contrasted levels of keratin filaments, which may play a role in their adaptation to growth and morphological changes.


Extended Follow-up of Treated and Untreated Retinopathy in Incontinentia Pigmenti: Analysis of Peripheral Vascular Changes and Incidence of Retinal Detachment.
Extended follow-up of treated and untreated retinopathy in incontinentia pigmenti (IP) has not previously been documented, to our knowledge. To determine which eyes with IP are at risk for retinal detachment. Observational cohort study of patients with IP who were retrospectively identified at a tertiary care academic center between 1976 and 2013. Fifty eyes of 25 female participants meeting clinical criteria for IP were followed up for at least 6 months. The last year of follow-up was between 1987 and 2014. Progression of retinopathy or the development of retinal detachment was assessed with fluorescein angiography, clinical examination, or both. The median duration of follow-up was 9.3 years (range, 0.5-22.8 years). Over this period, 11 eyes (22%; 95% CI, 11%-33%) developed retinal detachment. The odds of retinal detachment were increased if there was retinal neovascularization (odds ratio, 11.61; 95% CI, 1.34-100.56; P = .03) or ischemic optic neuropathy (odds ratio, 5.27; 95% CI, 1.61-17.23; P = .006) on initial examination. A bimodal distribution of retinal detachments was observed, with most tractional detachments (7 eyes) occurring by age 2.5 years (median, 1.5 years; range, 14 days-7.0 years) and most rhegmatogenous detachments (4 eyes) occurring in adults (median age, 31.5 years; range, 14.0-47.0 years). Three eyes of young patients (≤2.5 years) developed tractional detachment, despite prophylactic ablation in 4 eyes; only one eye of older patients (≥14.0 years) developed retinal detachment following prophylactic ablation in 6 eyes. Persistent fetal vasculature appears to occur more commonly in IP (14%; 95% CI, 4%-25%) than in the general population. All eyes with retinopathy due to IP should be monitored throughout adulthood for the development of retinal complications. During infancy and early childhood, ophthalmoscopic examination should be performed frequently so that prompt treatment can be initiated if there is progressive disease. Because of the nonrandomized nature of this study, the indications for prophylactic ablation and its success rate remain uncertain. Patients with less than 6 months of follow-up were excluded from the analysis, which could have biased this study cohort toward patients with more severe or less severe disease.


Local and distant response to intratumoral immunotherapy assessed by immunoPET in mice.
Despite the promising efficacy of immune checkpoint blockers (ICB), tumor resistance and immune-related adverse events hinder their success in cancer treatment. To address these challenges, intratumoral delivery of immunotherapies has emerged as a potential solution, aiming to mitigate side effects through reduced systemic exposure while increasing effectiveness by enhancing local bioavailability. However, a comprehensive understanding of the local and systemic distribution of ICBs following intratumoral administration, as well as their impact on distant tumors, remains crucial for optimizing their therapeutic potential.To comprehensively investigate the distribution patterns following the intratumoral and intravenous administration of radiolabeled anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and to assess its corresponding efficacy in both injected and non-injected tumors, we conducted an immunoPET imaging study. CT26 and MC38 syngeneic colorectal tumor cells were implanted subcutaneously on both flanks of Balb/c and C57Bl/6 mice, respectively. Hamster anti-mouse CTLA-4 antibody (9H10) labeled with zirconium-89 ([89Zr]9H10) was intratumorally or intravenously administered. Whole-body distribution of the antibody was monitored by immunoPET imaging (n=12 CT26 Balb/c mice, n=10 MC38 C57Bl/6 mice). Tumorous responses to injected doses (1-10 mg/kg) were correlated with specific uptake of [89Zr]9H10 (n=24). Impacts on the tumor microenvironment were assessed by immunofluorescence and flow cytometry. Half of the dose was cleared into the blood 1 hour after intratumoral administration. Despite this, 7 days post-injection, 6-8% of the dose remained in the intratumoral-injected tumors. CT26 tumors with prolonged ICB exposure demonstrated complete responses. Seven days post-injection, the contralateral non-injected tumor uptake of the ICB was comparable to the one achieved through intravenous administration (7.5±1.7% ID.cm-3 and 7.6±2.1% ID.cm-3, respectively) at the same dose in the CT26 model. This observation was confirmed in the MC38 model. Consistent intratumoral pharmacodynamic effects were observed in both intratumoral and intravenous treatment groups, as evidenced by a notable increase in CD8+T cells within the CT26 tumors following treatment. ImmunoPET-derived pharmacokinetics supports intratumoral injection of ICBs to decrease systemic exposure while maintaining efficacy compared with intravenous. Intratumoral-ICBs lead to high local drug exposure while maintaining significant therapeutic exposure in non-injected tumors. This immunoPET approach is applicable for clinical practice to support evidence-based drug development.


Angioedema after long-term enalapril use.
A case of life-threatening angioedema occurring after 13 months of enalapril therapy is reported. Clinicians should be aware that such severe reactions can occur, even after long-term therapy. Patients who take angiotensin-converting enzyme inhibitors should be carefully questioned during each follow-up examination concerning angioedema symptoms.


American pediatric society's 2017 John Howland award acceptance lecture: a tale of two toxicants: childhood exposure to lead and tobacco.
This article summarizes the presentation of the 2017 Howland Award to Michael Weitzman, MD, at the Annual Pediatric Academic Society Meetings. It summarizes the remarkable advances in understanding the effects and pathways of exposure of the two most common and pernicious of our nation's child environmental exposures, namely lead and tobacco. It also summarizes the profound effect of the translation of these findings into prudent and effective clinical and public health policies such that exposure to both has dramatically decreased over the past 40 years due to the tenacious activities of pediatricians, other child-related professionals, government agencies at all levels, and the American Academy of Pediatrics. Research and clinical activities, although essential, were not sufficient to produce these successes, but required extensive mentoring to produce a generation of academic pediatricians capable of conducting the requisite research, and extensive advocacy by pediatricians and others to overcome the formidable inertia and outright opposition to efforts to protect our children from these exposures. Moreover, the article highlights that both of these environmental exposures have roots in social and environmental injustice and neither is solved, and that there is no safe level of exposure to either of these toxicants.


Effects of functional training on sprinting, jumping, and functional movement in athletes: A systematic review.
This systematic review aims to illuminate the effects of functional training on sprinting, jumping, and functional movements in athletes. A systematic search of electronic databases-that include PubMed, EBSCOhost (Sport Discus), SCOPUS, ProQuest, Google Scholar, and additional references-was carried out using keywords associated with functional training, jumping, sprinting, functional movement skills, and athletes, in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement criteria. The Physiotherapy Evidence Database (PEDro) scale was used to measure the methodological quality of the studies included in the systematic review. Results: From a total of 220 studies, 15 included ones met all eligibility criteria and were scored between 4-5 points-considered as" moderate quality"-by the PEDro scale. Most studies recorded positive effects of functional training on athletes' sprinting, jumping, and functional movement. In contrast, a small number of studies did not find any positive effects of functional training on sprinting, squat jump, vertical jump, and countermovement jump due to the short duration and frequency of the training, as well as the lack of additional exercises that come with the interventions. Furthermore, the reviewed studies reveal that there is limited research within the literature on 5, 15, 25, and 50 m sprinting, squat jump, quadrant jump, and functional movement in athletes. Conclusion: Although the length of training interventions varied across studies in this systematic review, functional training interventions were found to help improve athletes' performance. The review reveals that training duration, intensity, and frequency are some critical variables that need to be taken into account when developing a successful functional training intervention for athletes. More studies are required to evaluate the influence of different accessible functional training durations on athletes' sprinting, jumping performance, and functional movement. Finally, further research needs to be done to investigate the impacts of functional training on performance and movement skills of male and female athletes at all levels in other sports. Systematic Review Registration: https://inplasy.com/inplasy-2022-5-0130/, identifier INPLASY202250130.


Avascular necrosis rate in early reduction after failed Pavlik harness treatment of developmental dysplasia of the hip.
Our hypothesis is that hips with developmental dysplasia (DDH), which fail Pavlik harness treatment and are reduced within 3 months of age, have a low rate of avascular necrosis (AVN). Inclusion criteria are as follows: diagnosis of DDH within 2 months of birth, failure of reduction or stabilization by Pavlik harness treatment, surgical reduction of the hip advised to be performed within 3 months of age, and follow-up for Salter criteria of AVN. Twenty-one consecutive cases (35 hips) met the inclusion criteria. Nineteen cases (31 hips) were initially reduced within 3 months of age, and none of these cases developed AVN. After Pavlik harness failure, initial closed reduction was achieved in 33 (94%) of 35 hips, and open reduction required in 2 (6%) of 35 hips. At latest follow-up, one (3%) of 35 hips had AVN. At the time of reporting, 1 (3%) of the 35 hips has required an additional procedure (Pemberton osteotomy) for residual dysplasia. There were 2 outlier cases (4 hips) in which the parents delayed the reduction and 1 case developed unilateral AVN, which was reduced after the proximal femoral ossification center developed at 7 months of age. The data presented in the current study support our hypothesis.


[Phylogenesis, etiology and pathogenesis of insulin resistance. Differences from type II diabetes mellitus].
We believe that etiological factor of insulin resistance is phylogenetically late formation of insulin and its specific functionality, i.e., providing energy substrates for the biological function of locomotion. According to biological subordination, insulin cannot change regulation formed at the early stages of phylogenesis in all cells, including those that become insulin-dependent at the late stages of phylogenesis. This involves a) beta-oxidation of fatty acids in the mitochondria, b) synthesis of C 16:0 palmitic saturated fatty acid, c) glucose metabolism in pro- and eukaryotes, d) regulation of biochemical reactions in insulin-independent cells, e) humoral effects of mediators at the level of paracrine cell communities which are structural and functional units of all internal organs, and f) hormonal regulation at the entire organism level. Pathogenetic factors of insulin resistance are biochemical and functional disorders occurring in vivo upon activation of biological functions and reactions that formed phylogenetically earlier than insulin. During phylogenesis the insulin system has intrinsically built up over the regulatory mechanisms of mitochondria, early unicellular organisms and paracrine cell communities. Insulin functionally interacts with them all, but it cannot abolish the effects of any phylogenetically earlier humoral mediator. Insulin resistance is a pathophysiological disparity between humoral regulation of metabolism at the level of phylogenetically earlier paracrine cell communities and at the level of phylogenetically late total organism, on the one hand, and successive phylogenetic formation of passive cellular uptake of fatty acids as unesterified fatty acids and later triglycerides, on the other. If insulin resistance results from changes in the primary structure of transport proteins, in glucose storage and cellular insulin reception, it can be referred to as type II diabetes mellitus.


Clostridium difficile infection in solid organ transplant recipients.
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, and the threat associated with CDI continues to grow in all patient populations. There is increasing evidence that CDI has a substantial impact on the morbidity and mortality in solid organ transplant (SOT) recipients. Furthermore, new diagnostic and treatment options and strategies for CDI have emerged over the last decade. The purpose of this review is to provide a general understanding of CDI and its evidence-based diagnosis and management strategies, with a focus on SOT recipients. The incidence and severity of CDI have significantly increased since the year 2000. Studies have identified novel risk factors for CDI, and a new epidemic strain, the NAP1/BI/027, has emerged. Despite the development of newer testing methods and approaches, including nucleic acid amplification tests and testing algorithms, the optimal method for diagnosing CDI is an area of controversy. New agents for treating CDI are being developed, and the use of fecal microbiota transplantation to treat recurrent CDI in SOT recipients is also evolving. CDI is a significant problem for SOT recipients. Further studies on diagnostic and therapeutic strategies with a focus on SOT recipients are needed to further improve patient outcomes.


Cardiac arrest in an American Cocker Spaniel during a deep ear flush procedure.
CASE DESCRIPTION A 14-year-old spayed female American Cocker Spaniel with bilateral otitis media and no evidence of cardiovascular instability was anesthetized to allow performance of a deep ear flush. CLINICAL FINDINGS Otoscopic examination of the left ear revealed evidence of chronic inflammation; the ear was flushed with sterile saline (0.9% NaCl) solution. Examination of the right ear revealed more severe chronic inflammation than in the left ear, including a ruptured tympanum (timing of rupture unknown). The right ear was flushed with sterile saline solution, and several drops of otic medication were instilled. During infusion of saline solution, the ECG revealed a rapid decrease in heart rate until no more electrical activity was noted. Pulse also ceased to be detectable via pulse oximetry and femoral artery palpation. TREATMENT AND OUTCOME Isoflurane was discontinued immediately after recognition of cardiac arrest. Shortly after, atropine (0.04 mg/kg [0.02 mg/lb]) and epinephrine (0.3 mg/kg [0.14 mg/lb]) were administered IV, chest compressions and ventilation were performed for 2 to 3 minutes, and 3 boluses (each 5 mL/kg) of lactated Ringer solution were administered IV. The dog was extubated 8 minutes after anesthesia was discontinued, and its recovery was monitored for the next 5 hours. No further incidents of cardiac arrest occurred after recovery from anesthesia. CLINICAL RELEVANCE This case represented a rarely documented potential complication associated with otic manipulation in a dog: cardiac arrest secondary to stimulation of the auricular branch of the vagus nerve. Veterinarians should be prepared for and warn clients of this possibility prior to otic flushing.


The homeostasis but not the differentiation of T cells is regulated by p27(Kip1).
The cyclin-dependent kinase inhibitor p27(Kip1) is a critical regulator of T cell proliferation. To further examine the relationship of T cell proliferation and differentiation, we examined the ability of T cells deficient in p27(Kip1) to differentiate into Th subsets. We observed increased Th2 differentiation in p27(Kip1)-deficient cultures. In addition to increases in CD4(+) and CD8(+) T cells, there is a similar increase in gamma delta T cells in p27(Kip1)-deficient mice compared with wild-type mice. The increase in Th2 differentiation is correlated to an increase of IL-4 secretion by CD4(+)DX5(+)TCR alpha beta(+)CD62L(low) T cells but not to increased expansion of differentiating Th2 cells. While STAT4- and STAT6-deficient T cells have diminished proliferative responses to IL-12 and IL-4, respectively, proliferative responses are increased in T cells doubly deficient in p27(Kip1) and STAT4 or STAT6. In contrast, the increased proliferation and differentiative capacity of p27(Kip1)-deficient T cells has no effect on the ability of STAT4/p27(Kip1)- or STAT6/p27(Kip1)-deficient CD4(+) cells to differentiate into Th1 or Th2 cells, respectively. Thus, while p27(Kip1) regulates the expansion and homeostasis of several T cell subsets, it does not affect the differentiation of Th subsets.


Cerebellar mutism syndrome: cause and rehabilitation.
Mutism of cerebellar origin may occur in the context of various causes but is most frequent in children after resection of a large midline cerebellar tumour. In this review, the endeavour to reach a consensus on name and definition of postoperative mutism of cerebellar origin and associated symptoms is highlighted. In addition, progress in understanding of cause and risk factors for the syndrome is discussed as well as the rehabilitation issues. Consensus on the term cerebellar mutism syndrome (CMS) has been reached. The exact pathogenesis of CMS remains unclear. Recently, attention was drawn to the hypothesis that thermal injury might be an important mechanism in the pathogenesis of CMS. Diffusion tensor imaging tractography was found to visualize the damage to relevant pathways that are associated with persistent impairments after recovery of CMS. There is still no established treatment for CMS to date. By reaching a consensus on terminology and description of CMS, a firm basis has been created for future research. The pathogenesis of CMS seems multifactorial and important risk factors have been found. However, CMS cannot be effectively prevented yet and no established or specific treatment is available, apart from very general rehabilitation and cognitive interventions.


[Whipple's disease. Involvement of the small intestine with submucosal presentation].
An unusual case of Whipple's disease is described; the involvement was restricted to the sub-mucosa of the large and small intestine, but the mucosa was spared. The involvement was characterized by the presence of large eosinophilic PAS positive histiocytic cells in the sub-mucosa. A Ziehl-Neelsen stain allowed to rule out an atypical mycobacterial infection. In the axillary lymph node removed previously, a retrospective survey demonstrated the presence of large histiocytic cells containing granular PAS positive material. The diagnosis of Whipple's disease of the large and small intestine with lymph node involvement was confirmed by the response to therapy followed by a new biopsy control. It appears from our observation that in Whipple's disease, an attentive examination of the sub-mucosal tissue may allow to discover more cases of this condition, even when the mucosa appears normal.


RNA editing catalytic complexes edit multiple mRNA sites non-processively in Trypanosoma brucei.
RNA editing generates mature mitochondrial mRNAs in T. brucei by extensive uridine insertion and deletion at numerous editing sites (ESs) as specified by guide RNAs (gRNAs). The editing is performed by three RNA Editing Catalytic Complexes (RECCs) which each have a different endonuclease in addition to 12 proteins in common resulting in RECC1 that is specific for deletion ESs and RECC2 and RECC3 that are specific for insertion ESs. Thus, different RECCs are required for editing of mRNA sequence regions where single gRNAs specify a combination of insertion and deletion ESs. We investigated how the three different RECCs might edit combinations of insertion and deletion ESs that are specified by single gRNAs by testing whether their endonuclease compositions are stable or dynamic during editing. We analyzed in vivo BirA* proximity labeling and found that the endonucleases remain associated with their set of common RECC proteins during editing when expressed at normal physiological levels. We also found that overexpression of endonuclease components resulted in minor effects on RECCs but did not affect growth. Thus, the protein stoichiometries that exist within each RECC can be altered by perturbations of RECC expression levels. These results indicate that editing of consecutive insertion and deletion ESs occurs by successive engagement and disengagement of RECCs, i.e., is non-processive, which is likely the case for consecutive pairs of insertion or deletion ESs. This clarifies the nature of the complex patterns of partially edited mRNAs that occur in vivo.


A mathematical model of the rat proximal tubule.
The equations of mass conservation and electroneutrality are used to extend a nonequilibrium thermodynamic model of the rat proximal tubule epithelium to a representation of a 0.5-cm segment of tubule. The output of the tubule model includes the luminal profiles and absolute proximal reabsorption of Na, K, Cl, HCO3, HPO4, H2PO4, glucose, and urea, generated by the epithelial model. Transport rates and permeabilities, chosen in agreement with those of the rat, result in luminal glucose and bicarbonate depletion and a transition from an electronegative to positive lumen. Despite the development of significant transepithelial osmotic driving forces (a transepithelial glucose gradient and Cl-HCO3 asymmetry), intraepithelial solute-solvent coupling remains an important force for water reabsorption along the proximal tubule length. In particular, this means that when osmotic gradients that appear under free-flow conditions are used in the calculation of the epithelial water permeability, a substantial overestimate of this permeability will be obtained. A single first-order differential equation has been derived in conjunction with an approximate nonelectrolyte model of the proximal tubule that represents both coupled and gradient-driven water reabsorption. In the present work, this equation is shown to yield an accurate description of water transport by the comprehensive tubule model.


Optical radiation safety of medical light sources.
The phototoxicity of medical ultraviolet (UV) sources used in dermatology has long been recognized. Less obvious are potential hazards to the eye and skin from many other optical sources-both to the patient and to the health-care worker. To assess potential hazards, one must consider not only the optical and radiometric parameters of the optical source in question but also the geometrical exposure factors. This knowledge is required to accurately determine the irradiances (dose rates) to exposed tissues. Both photochemically and thermally induced damage are possible from intense light sources used in medicine and surgery; however, thermal injury is rare unless the light source is pulsed or nearly in contact with tissue. Generally, photochemical interaction mechanisms are most pronounced at short wavelengths (UV) where photon energies are greatest, and also will be most readily observed for lengthy exposure durations.


Totally tubular: ASO-mediated knock-down of G2019S -Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages.
Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). LRRK2 levels have become an appealing target for potential PD-therapeutics with LRRK2 antisense oligonucleotides (ASOs) now in clinical trials. However, LRRK2 has been suggested to play a fundamental role in peripheral immunity, and it is currently unknown if targeting increased LRRK2 levels in peripheral immune cells will be beneficial or deleterious. Furthermore, the precise role of LRRK2 in immune cells is currently unknown, although it has been suggested that LRRK2-mediated lysosomal function may be crucial to immune responses. Here, it was observed that G2019S macrophages exhibited increased stimulation-dependent lysosomal tubule formation (LTF) and MHC-II trafficking from the perinuclear lysosome to the plasma membrane in an mTOR dependent manner with concomitant increases in pro-inflammatory cytokine release. Both ASO-mediated knock down of mutant Lrrk 2 and LRRK2 kinase inhibition ameliorated this phenotype and decreased these immune responses in control cells. Given the critical role of antigen presentation, lysosomal function, and cytokine release in macrophages, it is likely LRRK2-targetting therapies may have therapeutic value with regards to mutant LRRK2 but deleterious effects on the peripheral immune system, such as altered pathogen control and infection resolution.


Glycosylation differences between a cystic fibrosis and rescued airway cell line are not CFTR dependent.
Altered glycosylation of mucus and membrane glycoconjugates could explain reported differences in binding of bacterial pathogens to cystic fibrosis (CF) versus normal tissue. However, because bacteria can alter cell surface glycoconjugates, it is not possible to assess the role of cystic fibrosis transmembrane conductance regulators (CFTR) in glycosylation in these studies. To address this issue, we have developed quantitative lectin binding assays to compare cell surface glycosylation in well-matched immortalized CF cells and rescued cell lines. The CF airway bronchial epithelial cell line IB3-1 consistently bound more peanut agglutinin (PNA) than its clonal derivative S9, which stably expresses functional wild-type CFTR. Pretreatment with neuraminidase increased PNA binding and abolished the difference between the two cell lines. However, infection of the IB3-1 cells with a replication-deficient recombinant adenovirus encoding CFTR restored CFTR function but did not alter PNA binding to cells. In contrast, treatment with the weak base ammonium chloride increased PNA binding to both cell lines as expected. Our data show that even clonally related CF and rescued cells can exhibit significant differences in carbohydrate processing. Although the differences that we found are consistent with the proposed role for CFTR in modulating intraorganellar pH, our data strongly suggest that they are CFTR independent. These studies add a cautionary note to the interpretation of differences in glycosylation between CF and normal primary tissues and immortalized cells.


Immune reconstitution inflammatory syndrome in HIV-infected patients with and without prior tuberculosis.
We conducted a nested case-control study in a cohort of patients initiating antiretroviral therapy (ART) to identify risk factors and common manifestations of immune reconstitution inflammatory syndrome (IRIS) and to validate the Robertson criteria for IRIS prediction. HIV-infected patients at the Tuberculosis Research Centre clinics, Chennai and Madurai, India, initiating ART between July 2004 and June 2005 were prospectively studied. Of 97 patients (62% men, median age 32 years, median CD4 count 63 cells/μL) included, 34 developed IRIS. IRIS was more common in patients with a prior history of tuberculosis (74% versus 52%, P = 0.04), median time to development was 46 days and the sensitivity and specificity of the Robertson criteria to predict IRIS were 91% and 22%, respectively. In this population, IRIS was a common event, more so among patients with prior tuberculosis, and neither the rate of CD4 increase nor the Robertson criteria were useful in predicting its development.


Development and Validation of the Chinese Version Non-Nutritive Sweetener Food Frequency Questionnaire with Urinary Biomarker in Children and Adolescents.
The purpose of this study was to develop a validated food frequency questionnaire (FFQ) to evaluate the intake of non-nutritive sweeteners (NNSs) in child and adolescent Asian populations. Intensive and overall market research was performed to create the applicable NNS-FFQ with 13 food categories and 305 items. Six intense sweeteners, including acesulfame potassium, aspartame, sucralose, glycyrrhizin, steviol glycosides and sorbitol, were investigated. The validity and reproducibility of the NNS-FFQ were evaluated. The validity was further assessed by examining the consistency of reported NNS intake compared with urinary biomarkers using Cohen's κ analysis. This work was considered to be relevant in Asian societies. One hundred and two children and adolescents recruited from several clinics were invited to participate in this study. High content validity indices and high content validity ratio levels were revealed for each sweetener and food category. Reproducibility among subjects was satisfactory. Significant moderate correlations between estimated steviol glycoside/sucralose consumption and sensitive urinary biomarker levels were demonstrated (κ values were 0.59 and 0.45 for steviol glycosides and sucralose, respectively), indicating that the NNS-FFQ can be used to assess an individual's NNS intake. The dietary intense sweetener consumption pattern evaluated in this measurement was similar to those observed in other Asian countries but differed from those observed in Western populations with respect to types and amounts of NNSs. This validated NNS-FFQ can be an applicable and useful tool to evaluate NNS intake in future epidemiological and clinical studies.


Monoclonal Antibodies Bind A SNP-Sensitive Epitope that is Present Uniquely in Mycobacterium avium Subspecies Paratuberculosis.
Due to a close genetic relatedness, there is no known antibody that detects Mycobacterium avium subspecies paratuberculosis (MAP), which causes Johne's disease in cattle and sheep, and does not cross-react with other M. avium subspecies. In the present study, a monoclonal antibody (MAb; 17A12) was identified from mice immunized with a cell membrane fraction of MAP strain K-10. This antibody is 100% specific as it detected a 25-kDa protein in all 29 MAP whole cell lysates, but did not bind to any of the 29 non-paratuberculosis strains tested in immunoblot assays. However, the antibody revealed variable reactivity levels in MAP strains as it detected higher levels in bovine isolates but comparably lower levels in ovine isolates of MAP. In order to identify the target binding protein for 17A12, a lambda phage expression library of MAP genomic fragments was screened with the MAb. Four reactive clones were identified, sequenced and all shown to be overlapping. Further analysis revealed all four clones expressed an unknown protein encoded by a sequence that is not annotated in the K-10 genome and overlapped with MAP3422c on the opposing DNA strand. The epitope of 17A12 was precisely defined to seven amino acids and was used to query the K-10 genome. Similarity searches revealed another protein, encoded by MAP1025, possessed a similar epitope (one-amino acid mismatch) that also reacted strongly to the antibody. A single nucleotide polymorphism (SNP) in MAP1025 was then identified by comparative sequence analysis, which results in a Pro28His change at residue 28, the first amino acid within the 17A12 epitope. This SNP is present in all MAP strains but absent in all non-MAP strains and accounts for the specificity of the 17A12 antibody. This new antibody is the first ever isolated that binds only to the paratuberculosis subspecies of M. avium and opens new possibilities for the specific detection of this significant ruminant pathogen.


Drinking water source and reproductive outcomes in Sprague-Dawley rats.
As part of our work on the influence of water source on reproductive outcome, Sprague-Dawley rats were randomized to tap water, bottled water, or deionized water treatment groups, utilizing 160 animals per treatment; animals received the water prior to and during pregnancy. Rats were shipped in four batches (A-D). Batch effects were seen for several reproductive parameters. Because the tap water supply was interrupted by an earthquake resulting in an unbalanced design, primary analyses utilized only batches C and D, which included most of the tap water-treated rats. A treatment effect with respect to resorption frequency was seen that was marginally significant using a fixed-effects analysis of variance (P = 0.053), but not when batch was entered as a random effect (P = 0.36). The data were modeled by logistic regression, controlling for batch, litter size, and batch-treatment interaction. The odds ratio comparing tap to bottled water was 1.8 (95% CI 1.0 to 3.3, P = 0.05), which was similar to the epidemiologic result that prompted this study. The magnitude of this association varied by batch, and the difference in resorption frequency was within the range of variation seen for control animals. Although these findings do not justify public health action at this time, further investigation is warranted.


Hydration of hydrogels regulates vascularization in vivo.
The key barrier to the clinical application of tissue engineering scaffolds is the limitation of rapid and sufficient vascularization. Adipose-derived stem cells (ASCs), especially multicellular aggregates, exhibited a promising angiogenic activity. Herein, we designed a series of poly(l-glutamic acid) (PLGA)-based hydrogels with tunable hydration to control the in situ formation of multicellular spheroids. Oligo(ethylene glycol)s (OEGs) were employed to regulate the hydration of hydrogels. The hydrogel cross-linked with ethylene glycol (OEG1) supported the most excellent adhesion and proliferation of human ASCs in vitro. However, as the hydration of hydrogels strengthened, the adherent ASCs were gradually replaced with multicellular spheroids. Moreover, the in situ formation of spheroids was more effective in upregulating hypoxia-adaptive signals (e.g., hypoxia-inducible factor-1α, HIF-1α) and enhancing the secretion of angiogenic factors (e.g., vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2)) compared to adherent cells in OEG1 hydrogels. The hydrogel cross-linked with oligo(ethylene glycol)400 (OEG9) carrying spheroids induced a high angiogenic response of host tissue in vivo, resulting in an improved system vascularization, compared to adherent cells in the OEG1 hydrogel. These features indicated that the PLGA-based hydrogels were expected to be applied toward bone and fat tissue regeneration.


[Conservative methods of treating breast cancer metastases to the lungs].
An analysis is presented of different routine methods of treatment (radiotherapy, mono- and polychemotherapy; chemo-radiation treatment) used in 77 patients with breast cancer metastases in the lung. According to the data obtained positive results were gained in 53% of cases, a considerable effect being noted in 46% of patients.


Stress and crystallization of plasma enhanced chemical vapour deposition nanocrystalline silicon films.
Nanocrystalline Si films were prepared with a RF-PECVD system using different SiH4/H2 ratios, plasma powers, substrate temperatures and annealing conditions. The film's intrinsic stress was characterized in relation to the crystallization fraction. Results show that an increasing H2 gas ratio, plasma power or substrate temperature can shift the growth mechanism across a transition point, past which nanocrystalline Si is dominant in the film structure. The film's intrinsic stress normally peaks during this transition region. Different mechanisms of stress formation and relaxation during film growth were discussed, including ion bombardment effects, hydrogen induced bond-reconstruction and nanocomposite effects (nanocrystals embedded in an amorphous Si matrix). A three-parameter schematic plot has been proposed which is based on the results obtained. The film structure and stress are presented in relation to SiH4 gas ratio, plasma power and temperature.


Cigarette availability and price in low and high socioeconomic areas.
To determine whether tobacco retailer density and cigarette prices differ between low and high socioeconomic status suburbs in South-East Queensland. A survey of retail outlets selling cigarettes was conducted in selected suburbs over a two-day period. The suburbs were identified by geographical cluster sampling based on their Index of Relative Socio-economic Advantage and Disadvantage score and size of retail complex within the suburb. All retail outlets within the suburb were visited and the retail prices for the highest ranking Australian brands were recorded at each outlet. A significant relationship was found between Index of Relative Socioeconomic Advantage and Disadvantage score (in deciles) and the number of tobacco retail outlets (r=0.93, p=0.003), with the most disadvantaged suburbs having a greater number of tobacco retailers. Results also demonstrate that cigarettes were sold in a broader range of outlets in suburbs of low SES. The average price of the packs studied was significantly lower in the most disadvantaged suburbs compared to the most advantaged. While cigarettes were still generally cheaper in the most disadvantaged suburbs, the difference was no longer statistically significant when the average price of cigarette packs was compared according to outlet type (supermarket, newsagent, etc). In South-East Queensland, cigarettes are more widely available in the most disadvantaged suburbs and at lower prices than in the most advantaged suburbs.


Hybrid pn-junction solar cells based on layers of inorganic nanocrystals and organic semiconductors: optimization of layer thickness by considering the width of the depletion region.
We report the formation and characterization of hybrid pn-junction solar cells based on a layer of copper diffused silver indium disulfide (AgInS2@Cu) nanoparticles and another layer of copper phthalocyanine (CuPc) molecules. With copper diffusion in the nanocrystals, their optical absorption and hence the activity of the hybrid pn-junction solar cells was extended towards the near-IR region. To decrease the particle-to-particle separation for improved carrier transport through the inorganic layer, we replaced the long-chain ligands of copper-diffused nanocrystals in each monolayer with short-ones. Under illumination, the hybrid pn-junctions yielded a higher short-circuit current as compared to the combined contribution of the Schottky junctions based on the components. A wider depletion region at the interface between the two active layers in the pn-junction device as compared to that of the Schottky junctions has been considered to analyze the results. Capacitance-voltage characteristics under a dark condition supported such a hypothesis. We also determined the width of the depletion region in the two layers separately so that a pn-junction could be formed with a tailored thickness of the two materials. Such a "fully-depleted" device resulted in an improved photovoltaic performance, primarily due to lessening of the internal resistance of the hybrid pn-junction solar cells.


VAMP-7 mediates vesicular transport from endosomes to lysosomes.
A more complete picture of the molecules that are critical for the organization of membrane compartments is beginning to emerge through the characterization of proteins in the vesicle-associated membrane protein (also called synaptobrevin) family of membrane trafficking proteins. To better understand the mechanisms of membrane trafficking within the endocytic pathway, we generated a series of monoclonal and polyclonal antibodies against the cytoplasmic domain of vesicle-associated membrane protein 7 (VAMP-7). The antibodies recognize a 25-kD membrane-associated protein in multiple tissues and cell lines. Immunohistochemical analysis reveals colocalization with a marker of late endosomes and lysosomes, lysosome-associated membrane protein 1 (LAMP-1), but not with other membrane markers, including p115 and transferrin receptor. Treatment with nocodozole or brefeldin A does not disrupt the colocalization of VAMP-7 and LAMP-1. Immunoelectron microscopy analysis shows that VAMP-7 is most concentrated in the trans-Golgi network region of the cell as well as late endosomes and transport vesicles that do not contain the mannose-6 phosphate receptor. In streptolysin- O-permeabilized cells, antibodies against VAMP-7 inhibit the breakdown of epidermal growth factor but not the recycling of transferrin. These data are consistent with a role for VAMP-7 in the vesicular transport of proteins from the early endosome to the lysosome.


Effective elimination of contaminants after oral care in elderly institutionalized individuals.
After mechanical cleaning in oral care, eliminating residual oral contaminants has an important role in preventing their aspiration, especially in individuals with weak airway protection. We examined the effectiveness of wiping the oral cavity after oral care on eliminating contaminants in 31 patients who were hospitalized in our neurology inpatient unit. The amount of bacteria on the tongue, palate, and buccal vestibule was counted before and just after oral care, after eliminating contaminants either by rinsing with water and suction or by wiping with mouth wipes, and 1 h after oral care. Oral bacteria amounts were decreased significantly by both elimination procedures after oral care. These findings suggest that wiping with mouth wipes is as effective as mouth rinsing to decrease bacteria following oral care. With a lower risk of contaminant aspiration, wiping may be a suitable alternative to rinsing, especially in dysphagic individuals.


Visualization of structural changes accompanying activation of N-methyl-D-aspartate (NMDA) receptors using fast-scan atomic force microscopy imaging.
NMDA receptors are widely expressed in the central nervous system and play a major role in excitatory synaptic transmission and plasticity. Here, we used atomic force microscopy (AFM) imaging to visualize activation-induced structural changes in the GluN1/GluN2A NMDA receptor reconstituted into a lipid bilayer. In the absence of agonist, AFM imaging revealed two populations of particles with heights above the bilayer surface of 8.6 and 3.4 nm. The taller, but not the shorter, particles could be specifically decorated by an anti-GluN1 antibody, which recognizes the S2 segment of the agonist-binding domain, indicating that the two populations represent the extracellular and intracellular regions of the receptor, respectively. In the presence of glycine and glutamate, there was a reduction in the height of the extracellular region to 7.3 nm. In contrast, the height of the intracellular domain was unaffected. Fast-scan AFM imaging combined with UV photolysis of caged glutamate permitted the detection of a rapid reduction in the height of individual NMDA receptors. The reduction in height did not occur in the absence of the co-agonist glycine or in the presence of the selective NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid, indicating that the observed structural change was caused by receptor activation. These results represent the first demonstration of an activation-induced effect on the structure of the NMDA receptor at the single-molecule level. A change in receptor size following activation could have important functional implications, in particular by affecting interactions between the NMDA receptor and its extracellular synaptic partners.


Ultra-broadband water window supercontinuum generation with high efficiency in a three-color laser field.
We propose an efficient method to generate an ultra-broadband supercontinuum by using a three-color field synthesized by a 1600 nm driving pulse and two weak (3200 nm and 400 nm) control pulses. The results show that the acceleration and ionization steps in the HHG process are simultaneously controlled in our scheme, which can not only broaden the bandwidth but also enhance the harmonic yields of the generated spectrum. Thus a high-efficiency supercontinuum with the photon energies ranging from 205 eV to 480 eV is observed. Based on our 3D propagation simulations, we show that the short quantum path of the supercontinuum is well phase-matched and can be selected under suitable propagation conditions. Thereby, the modulation due to quantum path interference is largely reduced and intense isolated sub-100 as pulses with tunable central wavelengths are directly obtained within water window spectral region.


Cytodiagnosis of cutaneous metastasis from renal cell carcinoma: A case report with review of literature.
Cytodiagnosis of cutaneous metastasis of renal cell carcinoma (RCC) in the absence of history of primary tumor is difficult as it can be confused with other clear cell tumors. We report here a case of cytodiagnosis of cutaneous metastasis of RCC in a patient who had nephrectomy done 9 years back at some other centre, but did not have any records with him. Clinicians should be aware of the possibility of primary internal organ malignancy in patients presenting with cutaneous lesions and therefore conduct a careful examination and get necessary investigations. Prompt diagnosis and treatment will have its bearing on the eventual outcome.


Central vein catheterization. Failure and complication rates by three percutaneous approaches.
We prospectively studied the results of 714 attempts at central venous catheterization during an eight-month period in our intensive care department. We compared the rates of failure of catheterization and early complications among three percutaneous approaches: subclavian, anterior jugular, and posterior jugular veins. The procedures were performed by experienced staff or resident physicians and inexperienced interns and residents under teaching supervision. Overall rates of failure and complication were similar for each percutaneous approach within each group of physicians. Overall failure rate was 10.1% for the experienced group and 19.4% for the inexperienced. The complication was 5.4% for experienced and 11% for inexperienced. Among inexperienced physicians, the success rate was 86.7% and the complication rate 7.6% in unconscious patients, whereas in conscious patients these rates were 70.5% and 13.8%, respectively. The inexperienced physicians caused fewer complications in mechanically ventilated than in spontaneously breathing patients. We suggest that inexperienced physicians should first attempt central vein catheterizations in unconscious and mechanically ventilated patients.


Type D personality predicts poor medication adherence in myocardial infarction patients.
Type D personality, the combination of negative affectivity (NA) and social inhibition (SI), is an emerging risk factor in cardiovascular disease. This study aimed to examine one possible behavioural mechanism to explain the link between Type D and ill-health. It was hypothesised that Type D personality would predict medication adherence in myocardial infarction (MI) patients. In a prospective study, 192 MI patients (54 females and 138 males) completed measures of Type D personality and provided demographic and medical information 1 week post-MI, and then 131 patients went on to complete a self-report measure of medication adherence 3 months post-MI. It was found that Type D personality predicts adherence to medication, after controlling for demographic and clinical risk factors. Critically, the constituent components of Type D, NA and SI, interact to predict medication adherence, after controlling for the effects of each component separately. Poor adherence to medication may represent one mechanism to explain why Type D cardiac patients experience poor clinical outcome, in comparison to non-Type D patients. Interventions, which target the self-management of medication, may be useful in these high-risk patients.


Fundus findings in chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease that has been reported to present with various chorioretinal findings, predominantly in men. We report a case of a 17-year-old girl with a known diagnosis of CGD referred to the ophthalmology clinic for evaluation of an inflamed pingueculum. Upon clinical examination and ophthalmic imaging, high-quality montage fundus photographs demonstrated a wide array of bilaterally asymmetric chorioretinal findings known to be characteristic of the ophthalmic manifestations of CGD, including chorioretinitis and focal subretinal granuloma. This report also adds to the body of evidence that the chorioretinal findings associated with this disease have the potential to worsen over time.


Bend loss in all-solid bandgap fibres.
Experimental measurements of all-solid photonic bandgap fibres with an array of high-index rods in a low-index background revealed an unexpected variation of bend loss across different bandgaps. This behaviour was confirmed by calculations of photonic band structure, and explained with reference to the differing field distributions of the modes of the cladding rods. Our understanding was confirmed by further experiments, leading to proposals for the improvement of these fibres.


How to run an effective and efficient dermatooncology unit: a Dutch approach.
The worldwide incidence of skin cancer (especially non-melanoma skin cancer) has risen dramatically over the last decades. Skin cancer, including pre-malignant lesions, is becoming a chronic disease. Adjustments in skin cancer health care need to be made. A disease management system for skin cancer is mandatory in order to avoid waiting lists and insure adequate treatment quality with ever growing numbers of patients requiring treatment. At the Catharina Hospital Eindhoven adjustments are being made on several levels of the dermato-oncology unit in collaboration with Eindhoven University of Technology. The model combines technological improvements, training health care workers, training of general practitioners and prevention of skin cancer. We discuss our ideas and clinical experiences with managing a dermatooncology unit.


Analysis of information needs of users of the Stanford Health Information Network for Education.
To examine the information needs of users of the Stanford Health Information Network for Education (SHINE), an integrated information retrieval (IR) system. A subset of queries from the SHINE log were categorized into one or more of 33 categories. Drugs and infectious disease accounted for 25% of categorizations, and otherwise the distribution of categorizations was quite broad. Attention should be paid to the selection of drug information resources in medical knowledge information retrieval systems. The distribution of query categorizations also suggests that IR systems include a wide range of knowledge resources.


G9a inhibition by CM-272: Developing a novel anti-tumoral strategy for castration-resistant prostate cancer using 2D and 3D in vitro models.
Castration-resistant prostate cancer (CRPC) is an incurable form of prostate cancer (PCa), with DNMT1 and G9a being reported as overexpressed, rendering them highly attractive targets for precision medicine. CM-272 is a dual inhibitor of both methyltransferases' activity. Herein, we assessed the response of different PCa cell lines to CM-272, in both 2D and 3D models, and explored the molecular mechanisms underlying CM-272 inhibitory effects. CRPC tissues displayed significantly higher DNMT1, G9a and H3K9me2 expression than localized PCa. In vitro, CM-272 caused a significant decrease in PCa cell viability and proliferation alongside with increased apoptotic levels. We disclose that, under the evaluated dose, CM-272 led to G9a activity inhibition, while not significantly affecting DNMT1 activity. Upon G9a knockdown, DU145 and PC3 showed decreased cell viability. Remarkably, DU145 cells treated with CM-272 or with G9a knockdown displayed no differences in viability, suggesting a SET-dependent mechanism. Contrarily, PC3 cell viability impact was higher in G9a knockdown, compared with CM-272 treatment, suggesting an additional G9a function. Moreover, DU145 cells overexpressing catalytically functional G9a disclosed higher resistance to CM-272 treatment, reinforcing that the drug mechanism of action is dependent on G9a catalytic function. Importantly, we successfully assembled spheroids from several prostate cell lines. Our results showed that CM-272 retained its anti-tumoral effects in 3D PCa models, leading to a clear reduction in cancer cell survival. We concluded that inhibition of G9a methyltransferase activity by CM-272 has anti-tumor effect in PCa cells, holding therapeutic potential against CRPC.


Racial and Socioeconomic Disparities in Utilization of Telehealth in Patients with Liver Disease During COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic resulted in a rapid expansion of telehealth services in hepatology. However, known racial and socioeconomic disparities in internet access potentially translate into barriers for the use of telehealth, particularly video technology. The specific aim of this study was to determine if disparities in race or socioeconomic status exist among patients utilizing telehealth visits during COVID-19. We performed a retrospective cohort study of all adult patients evaluated in hepatology clinics at Duke University Health System. Visit attempts from a pre-COVID baseline period (January 1, 2020 through February 29, 2020; n = 3328) were compared to COVID period (April 1, 2020 through May 30, 2020; n = 3771). On multinomial regression modeling, increasing age was associated with higher odds of a phone or incomplete visit (canceled, no-show, or rescheduled after May 30,2020), and non-Hispanic Black race was associated with nearly twice the odds of completing a phone visit instead of video visit, compared to non-Hispanic White patients. Compared to private insurance, Medicaid and Medicare were associated with increased odds of completing a telephone visit, and Medicaid was associated with increased odds of incomplete visits. Being single or previously married (separated, divorced, widowed) was associated with increased odds of completing a phone compared to video visit compared to being married. Though liver telehealth has expanded during the COVID-19 pandemic, disparities in overall use and suboptimal use (phone versus video) remain for vulnerable populations including those that are older, non-Hispanic Black, or have Medicare/Medicaid health insurance.


Effects of follicle-stimulating hormone on fat metabolism and cognitive impairment in women during menopause.
Lipid metabolism disorder is a common pathological manifestation of menopausal women, and is also an important risk factor for many diseases at this stage of life. Epidemiological studies have shown that high levels of follicle-stimulating hormone (FSH) in menopausal women are closely associated with changes in body composition, central obesity, and cognitive decline. Exogenous FSH causes growth and proliferation of adipose, whereas blockage of the FSH signaling pathway leads to decline in adipose. Mechanistically, FSH, FSH receptor (FSHR), G protein coupling, gene mutation and other pathways are involved in adipogenesis and cognitive impairment. Here, we review the critical role and potential interactions of FSH in adipogenesis and cognitive impairment in menopausal women. Further understanding of the exact mechanisms of FSH aggravating obesity and cognitive impairment may provide a new perspective for promoting healthy aging in menopausal women.


Training prosocial behaviors to young children: an analysis of reciprocity with untrained peers.
We examined the effects of a social skills training package on the play behaviors of three young girls. Two children were taught to invite their peers to play and to use social amenities during their conversations with other children. A combined reversal and multiple baseline across responses design demonstrated that both children directed more social behaviors to their classroom peers after training and that these two children's play invitations were maintained in the later absence of experimental contingencies. In addition, both target children received a greater number of play invitations from their peers during the free play periods. In contrast, a third child's play invitations were not reciprocated by peers; her invitations subsequently decreased in rate after training was discontinued. An interdependent group contingency produced a reciprocal exchange of invitations between this child and her classroom peers. A reversal design demonstrated partial maintenance of subject-peer exchanges after the group intervention was discontinued. The results obtained with the three target children suggest that peer reciprocity may facilitate the maintenance of children's play invitations over time.


Predictors of human PBDE body burdens for a UK cohort.
Human exposure to polybrominated diphenyl ethers (PBDEs) was investigated in a cohort of 20 UK adults along with their anthropometric covariates and relevant properties such as room surveys, lifestyle, diet and activity details. Selected PBDE congeners were measured in matched samples of indoor dust (n = 41), vehicles (n = 8), duplicate diet (n = 24), serum (n = 24) and breast milk (n = 6). Combined exposure estimates via dust and diet revealed total PBDE intakes of 104 to 1,440 pg kg-1 bw d-1 for ΣBDEs3-7 and 1,170 to 17,000 pg kg-1 bw d-1 for BDE-209. These adult intakes are well within health reference doses suggested by the European Food Safety Authority (EFSA) and the US EPA. Diet was the primary source of intake of BDE3-7 congeners for the majority of the cohort, with dust the primary source of BDE-209. Primary sources of PBDE exposure vary between countries and regions with differing fire prevention regulations. Estimated infant exposures (ages 1.5-4.5 years) showed that BDE-99 intake for one of the households did not meet EFSA's recommended margin of exposure, a further two households had borderline PBDE exposures for high level dust and diet intake. Males and those having a lower body fat mass had higher serum BDE-153. Higher meat consumption was significantly correlated with higher BDEs3-7 in serum. A reduction in dietary BDEs3-7 would therefore result in the greatest reduction in BDE-99 exposure. Rooms containing PUF sofas or armchairs over 20 years old had more BDEs3-7 in their dust, and rooms with carpets or rugs of that age had higher dust BDE-209. Dusting rooms more frequently resulted in significantly lower concentrations of all major congeners in their dust. Correlation between BDE-209 body burden and dust or diet exposure was limited by its low bioaccessibility. Although vehicle dust contained the highest concentrations of BDEs3-7 and BDE-209, serum BDEs3-7 correlated most strongly with bedroom dust.


Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome.
The polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder of obscure pathogenesis associated with osteosclerotic myeloma. Circulating levels of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) interleukin-1 beta [IL-1 beta], IL-2, IL-6, and interferon-gamma [IFN-gamma]), anti-inflammatory cytokines (transforming growth factor beta 1 [TGF beta 1], IL-4, IL-10, and IL-13), the cytokine carrier protein alpha 2 macroglobulin, IL-1 receptor antagonist (IL-1ra), soluble TNF receptors (sTNFr) p55 and p75, and soluble IL-6 receptor (sIL-6r) were determined in 15 patients with POEMS syndrome and 15 with multiple myeloma. Patients with POEMS syndrome had higher serum levels of IL-1 beta, TNF-alpha, and IL-6 and lower serum levels of TGF beta 1 than did patients with multiple myeloma. Serum levels of IL-2, IL-4, IL-10, IL-13, IFN-gamma, alpha 2 macroglobulin, and sIL-6r were similar in both groups. IL-1ra and sTNFrs were increased in POEMS syndrome, but out of proportion to the increase of IL-1 beta and TNF-alpha. Serial evaluations in 1 patient showed that proinflammatory cytokine serum levels paralleled disease activity assessed by platelet count and neurologic involvement. Our results suggest that the manifestations of POEMS syndrome might be regarded as the result of a marked activation of the proinflammatory cytokine network (IL-1 beta, IL-6, and TNF-alpha) associated with a weak or even decreased (TGF beta 1) antagonistic reaction insufficient to counteract the noxious effects of cytokines.


Measuring neighborhood deprivation for childhood health and development - scale implications in rural and urban context.
Neighborhood deprivation plays an important role in childhood health and development, but defining the appropriate neighborhood definition presents theoretical as well as practical challenges. Few studies have compared neighborhood definitions outside of highly urbanized settings. The purpose of the current study was to evaluate how various administrative and ego-centric neighborhood definitions may impact measured exposure to deprivation across the urban-rural continuum. We do so using the Family Life Project, a prospective longitudinal population-based sample of families living in North Carolina and Pennsylvania (USA), which also sets the stage for future investigations of neighborhood impacts on childhood health and development. To measure neighborhood deprivation, a standardized index of socioeconomic deprivation was calculated using data from the 2007-2011 American Community Survey. Families' residential addresses when children were 2 months of age (n=1036) were geocoded and overlaid onto a deprivation index layer created at the census block group level to construct multiple administrative and ego-centric neighborhood definitions. Friedman tests were used to compare distributions of neighborhood deprivation across these neighborhood definitions within urbanized areas, urban clusters, and rural areas. Results indicated differences in urbanized areas (Chisquare= 897.75, P<0.001) and urban clusters (Chi-square=687.83, P<0.001), but not in rural areas (Chi-square=13.52, P=0.332). Findings imply that in urban areas, choice of neighborhood definition impacts measured exposure to neighborhood deprivation. Although exposure to neighborhood deprivation appears to be less sensitive to neighborhood definition in rural areas, researchers should apply theoretical reasoning to choose appropriate definitions of children's neighborhood.