Partnering to develop a continuing professional development program in a low-resource setting: Cambodia.
To design and implement a continuing professional development (CPD) program for Cambodian ophthalmologists. Partnering (twinning) between the Royal Australian and New Zealand College of Ophthalmologists (RANZCO) and the Cambodian Ophthalmological Society (COS). Practicing ophthalmologists in Cambodia. A conjoint committee comprising 4 ophthalmologists from RANZCO and 3 ophthalmologists from COS was established, supported by a RANZCO administrative team experienced in CPD administration. CPD requirements and recording were adapted from the RANZCO CPD framework. Cambodian ophthalmologists were surveyed during program implementation and after handover to COS. At the end of the 3-year program at handover to COS, a CPD program and online recording system was established. All 47 (100%) practicing ophthalmologists in Cambodia were registered for CPD, and 21/47 (45%) were actively participating in the COS CPD program online recording. Surveys of attitudes toward CPD demonstrated no significant change. Partnering was moderately effective in establishing a CPD program for Cambodian ophthalmologists. Uptake of CPD may have been limited by lack of a requirement for CPD for continuing medical licensure in Cambodia. Follow-up will be necessary to demonstrate CPD program longevity.


Parachute mitral valve incidentally diagnosed in an adult patient with hypertension.
We describe a 52-year-old woman incidentally diagnosed as having parachute mitral valve (PMV). Echocardiography displayed a parachute-like deformity of the mitral valve characterized by a unifocal attachment of mitral valve chordae. PMV is a congenital cardiac malformation that causes stenosis of the mitral valve and is often found in combination with left-heart obstruction in the pediatric population. The incidence of PMV in adults is extremely low. This patient had no related cardiac complications, which accounts for the long asymptomatic period. Thus, rare forms of congenital heart disease in late adulthood need attention in echocardiographic study.


Constructing an Adaptive Heterojunction as a Highly Active Catalyst for the Oxygen Evolution Reaction.
Electrochemical water splitting is of prime importance to green energy technology. Particularly, the reaction at the anode side, namely the oxygen evolution reaction (OER), requires a high overpotential associated with OO bond formation, which dominates the energy-efficiency of the whole process. Activating the anionic redox chemistry of oxygen in metal oxides, which involves the formation of superoxo/peroxo-like (O2 )n - , commonly occurs in most highly active catalysts during the OER process. In this study, a highly active catalyst is designed: electrochemically delithiated LiNiO2 , which facilitates the formation of superoxo/peroxo-like (O2 )n - species, i.e., NiOO*, for enhancing OER activity. The OER-induced surface reconstruction builds an adaptive heterojunction, where NiOOH grows on delithiated LiNiO2 (delithiated-LiNiO2 /NiOOH). At this junction, the lithium vacancies within the delithiated LiNiO2 optimize the electronic structure of the surface NiOOH to form stable NiOO* species, which enables better OER activity. This finding provides new insight for designing highly active catalysts with stable superoxo-like/peroxo-like (O2 )n - for water oxidation.


In-Person Versus Telehealth Setting for the Delivery of Substance Use Disorder Treatment: Ecologically Valid Comparison Study.
The COVID-19 pandemic has profoundly transformed substance use disorder (SUD) treatment in the United States, with many web-based treatment services being used for this purpose. However, little is known about the long-term treatment effectiveness of SUD interventions delivered through digital technologies compared with in-person treatment, and even less is known about how patients, clinicians, and clinical characteristics may predict treatment outcomes. This study aims to analyze baseline differences in patient demographics and clinical characteristics across traditional and telehealth settings in a sample of participants (N=3642) who received intensive outpatient program (IOP) substance use treatment from January 2020 to March 2021. The virtual IOP (VIOP) study is a prospective longitudinal cohort design that follows adult (aged ≥18 years) patients who were discharged from IOP care for alcohol and substance use-related treatment at a large national SUD treatment provider between January 2020 and March 2021. Data were collected at baseline and up to 1 year after discharge from both in-person and VIOP services through phone- and web-based surveys to assess recent substance use and general functioning across several domains. Initial baseline descriptive data were collected on patient demographics and clinical inventories. No differences in IOP setting were detected by race (χ22=0.1; P=.96), ethnicity (χ22=0.8; P=.66), employment status (χ22=2.5; P=.29), education level (χ24=7.9; P=.10), or whether participants presented with multiple SUDs (χ28=11.4; P=.18). Significant differences emerged for biological sex (χ22=8.5; P=.05), age (χ26=26.8; P<.001), marital status (χ24=20.5; P<.001), length of stay (F2,3639=148.67; P<.001), and discharge against staff advice (χ22=10.6; P<.01). More differences emerged by developmental stage, with emerging adults more likely to be women (χ23=40.5; P<.001), non-White (χ23=15.8; P<.001), have multiple SUDs (χ23=453.6; P<.001), have longer lengths of stay (F3,3638=13.51; P<.001), and more likely to be discharged against staff advice (χ23=13.3; P<.01). The findings aim to deepen our understanding of SUD treatment efficacy across traditional and telehealth settings and its associated correlates and predictors of patient-centered outcomes. The results of this study will inform the effective development of data-driven benchmarks and protocols for routine outcome data practices in treatment settings.


Evaluation of the first phase of sulfur dioxide and nitrogen oxides provisions of the 1990 Clean Air Act: a plant-based approach.
Electric power generating plants that use coal were among the key targets of Title IV of the 1990 Clean Air Act. Under the first phase of the act, 110 coal-fired electric power plants were required to reduce their sulfur dioxide emissions by 1995 and nitrogen oxide emissions by 1996. Phase 2 of the act requires even greater reduction of sulfur dioxide emissions by 2000 and nitrogen oxide emissions by 2008. This study examines whether the 107 targeted plants (three plants went off-line) have achieved the desired sulfur dioxide and nitrogen oxide emission levels. The analysis of sulfur dioxide is based on data from 1990, 1995, and 1999. The findings show that although sulfur oxide increased by 3% from 1995 to 1999, it decreased by 45% over the 1990-1999 period at the firm level for the targeted firms. The findings also indicate that the overall reduction in sulfur dioxide was achieved by utilizing low sulfur coal and by purchasing emission allowances. So far as nitrogen oxides are concerned, there has been a reduction of 14% over the 1990-1999 period, of which 7% was achieved during the 1995-1999 period. An evaluation of emissions at the plant level indicates that several plants do not meet the emissions level for sulfur dioxide or nitrogen oxides. These results provide a mixed scorecard for reduction in emissions both for sulfur dioxide and nitrogen oxides. Even though there is reduction in the emissions on an overall basis at the firm level, several plants that have not been able to reduce emissions deserve special attention to meet the goals of the act in reducing emissions.


Protofibrils of amyloid beta-protein inhibit specific K+ currents in neocortical cultures.
Protofibrils (PFs) are recently described intermediate assemblies formed during the fibrillogenesis of amyloidogenic proteins and may play an important pathogenic role in Parkinson's and Alzheimer's disease (AD). Here we show for the first time that amyloid beta-protein (Abeta) attenuation of specific K(+) currents is dependent on the aggregation state; PFs inhibit K(+) currents, whereas low-molecular-weight assemblies have no effect. Using patch clamp analysis in whole cell current-clamp mode, we showed that at low nanomolar concentrations Abeta(1-42) PFs induce reversible, Ca(2+)-dependent increases in spontaneous action potentials and membrane depolarizations. The low nanomolar PF concentrations used, the instantaneous responses observed, and the reversibility of the effect all suggest that PFs may bind to specific channels or membrane proteins. Switching to voltage-clamp mode, we found that PFs at 1-2 microM can inhibit specifically the 4AP-sensitive K(+) currents, A-type and D-type, but not other outward or inward rectifying K(+) channels. Finally, we show that a consequence of PF-induced membrane activity is an increase in intracellular Ca(2+) spikes that are dependent on synaptic connections in the neural network formed in culture. Our data strongly support the concept that PFs can induce subtle synaptic alterations that may underlie early symptoms of AD.


[UV-A exposure of the human epidermis enhances the binding of antibodies to SSA/Ro in vitro].
Normal and psoriatic skin specimens (n = 15) were processed to give 4-micron-thick frozen sections and exposed to a single UV irradiation in vitro. We used monochromatic UV-B (313 nm) and UV-A (365 nm). The doses were as follows: 10(3)/10(4) J/m2 (UV-B) or 4.10(3)/8.10(4) J/m2 (UV-A). We investigated the effect on epidermal binding of antibodies to SSA/Ro using the indirect immunofluorescence technique. Untreated and UV-B-treated human skin failed to bind anti-SSA/Ro. UV-A exposure disclosed reticular or granular staining of epidermal nuclei and a perinuclear halo. The effect was nearly the same throughout the dosage range. The combination of UV-A and methoxsalen increased the intensity of staining. Normal and psoriatic skin behaved in the same way.


Relationship between obstructive sleep apnea syndrome and functional capacity in patients with diabetes mellitus type 2: an observational transversal study.
The aim of this study was to verify the association among obstructive sleep apnea, functional capacity, and metabolic control. This was a cross-sectional study involving individuals of both sexes with clinical diagnosis of diabetes mellitus type 2 who were above 18 years of age. The assessment consisted of a volunteer identification form, a 2-minute step test, and the Stop-Bang questionnaire. In order to assess metabolic control, HbA1c and fasting glucose data were collected from medical records. A total of 100 individuals with diabetes mellitus type 2, of whom 61% were women, were included in this study. According to the Stop-Bang instrument, 26, 57, and 17% of patients had low, intermediate, and high risk of developing OSA, respectively. There was no association between the 2-minute step test and metabolic variables and diabetes mellitus type 2 chronicity with Stop-Bang. We concluded that there is no association among obstructive sleep apnea measured by means of Stop-Bang instrument, functional capacity measured by means of 2-minute step test, and metabolic variables in individuals with diabetes mellitus type 2.


Intracellular localization of acetylcholinesterase in nerve terminals and capillaries of the rat superior cervical ganglion.
The ultrastructural localization of acetylcholinesterase (AChE) has been studied in the superior cervical ganglion of the rat. Previous descriptions of the general pattern of localization were confirmed, but in addition, AChE reaction product was found within vesicles in preganglionic nerve terminals, and in pinocytotic vesicles and along the basement lamina of capillaries. There was indication of a continuity between AChE reaction product in the cisternae of the rough endoplasmic reticulum of the principal ganglion cells and extracellular reaction product. These observations are discussed with particular reference to AChE as a secretory protein.


Endometrial polyp is associated with a higher prevalence of chronic endometritis in infertile women.
To assess the prevalence of chronic endometritis (CE) among infertile women with endometrial polyps (EP). From June 2017 to October 2021, 583 patients in the polyp group (group A-group A1: single-polyp group, 322 patients; group A2: multiple-polyp group, 261 patients) and 4534 patients in the non-polyp group (group B) were included in this retrospective study. Hysteroscopic polypectomy was performed in group A. Endometrial biopsy and CD138 immunohistochemistry staining for specimens was carried out in all groups. Prevalence of CE was significantly higher in group A than in group B (45.28% vs. 27.94%, P < 0.001). A significantly higher prevalence of CE was found in group A1 and group A2 compared with group B (42.24% vs. 27.94%, P < 0.001; 49.04% vs. 27.94%, P < 0.001; respectively). No significant difference in the comparison of CE prevalence was found between group A1 and group A2. Similar results were achieved in the subgroup analysis among patients aged 40 years or older and patients younger than 40 years. EP, either single EP or multiple EP, positively correlates with CE. The prevalence of CE was similar between the single-polyp group and the multiple-polyp group.


Factors determining the structure and diversity of parasitoid complexes in tephritid fruit flies.
The relative importance of phylogenetic affinity of hosts versus their ecological characteristics in determining the composition of their parasitoid complexes was examined using the parasitoid complexes of six species of frugivorous fruit flies from Central Europe. The hosts were four Rhagoletis and two other trypetine species, ranging in their relatedness from host races to members of different genera. They also differed in ecological characteristics, utilizing host plants of three different families, and developing either as pulp- or seedfeeders inside the host fruit. These features made it feasible to test the following pair of hypotheses. The ecological hypothesis predicts that ecological traits such as host-plant and fruit fly phenologies and host-fruit texture should be more important for the composition of parasitoid complexes than the taxonomic relatedness of the fly species. Assuming that ecological relationships do not parallel phylogenetic ones, the alternative phylogenetic hypothesis predicts the opposite. In fruit and soil samples, taken between 1983 and 1989, three guilds of parasitoids comprising 20 species were found: guild 1 - koinobiotic larval parasitoids (e.g. Opius spp., which attack the host larvae but develop inside the host puparia); guild 2 - idiobiotic larval parasitoids (e.g. Pteromalus spp., which consume the host larvae at once); and guild 3 - idiobiotic puparium parasitoids (e.g. Phygadeuon spp.). Although some results support the phylogenetic hypothesis, the majority of results support the ecological hypothesis.


Extending the limits of Bacillus for novel biotechnological applications.
Bacillus, generally regarded as safe, has emerged as a robust organism that can withstand adverse environmental conditions and grows easily to very high densities. Bacillus has been recognized for its biotechnological applications on an industrial scale. Recent efforts have shown the potential of Bacillus to generate biofuels (hydrogen), biopolymers (polyhydroxyalkanoates), and bioactive molecules (acyl-homoserine lactonases). Bacillus can be considered the dark horse in the race to generate sustainable energy, ecofriendly non-fossil fuel-based polymers, and bioactive molecules for use as therapeutics.


Self-Powered Tactile Sensor with Learning and Memory.
Fabrication of human-like intelligent tactile sensors is an intriguing challenge for developing human-machine interfaces. As inspired by somatosensory signal generation and neuroplasticity-based signal processing, intelligent neuromorphic tactile sensors with learning and memory based on the principle of a triboelectric nanogenerator are demonstrated. The tactile sensors can actively produce signals with various amplitudes on the basis of the history of pressure stimulations because of their capacity to mimic neuromorphic functions of synaptic potentiation and memory. The time over which these tactile sensors can retain the memorized information is alterable, enabling cascaded devices to have a multilevel forgetting process and to memorize a rich amount of information. Furthermore, smart fingers by using the tactile sensors are constructed to record a rich amount of information related to the fingers' current actions and previous actions. This intelligent active tactile sensor can be used as a functional element for artificial intelligence.


Phase I and pharmacologic study of weekly amrubicin in patients with refractory or relapsed lung cancer: Central Japan Lung Study Group (CJLSG) 0601 trial.
To evaluate the safety and tolerability of amrubicin (AMR), determine its maximum tolerated dose (MTD), its dose-limiting toxicities (DLTs), and its recommended dose (RD), and to conduct a pharmacokinetic study of weekly AMR administrations in patients with chemotherapy-refractory or recurrent small cell or non-small cell lung cancer. Patients with refractory or relapsed non-small cell and small cell lung cancer after 1 or 2 regimens of chemotherapy were eligible. AMR was initiated at 45 mg/m(2) weekly (repetition of dose on 1st and 8th day with a rest on day 15). The dose level was increased by 5 mg/m(2) by modified Fibonacci dose escalation scheme. Seven patients had small cell lung cancer and 9 had non-small cell lung cancer. Fifty-four courses (median: 3, range: 1-6) were administered at 5 dose levels. At 65 mg/m(2), 3 patients had DLTs as follows: 1 was grade 3 (CTCAE v3.0) in AST/ALT, 1 was grade 3 febrile neutropenia, and 1 was grade 4 neutropenia. Leukocytopenia and neutropenia were correlated with amrubicinol (AMR-OH) C (max) (P = 0.042, P = 0.047, respectively). The AUC (area under the curve of plasma concentration versus time extrapolated to concentration zero) of AMR and AMR-OH did not depend on the dose levels. In the present phase I study of AMR administered weekly to previously treated lung cancer patients, the maximum tolerated dose and RD were 65 and 60 mg/m(2), respectively. The best response rate was 15.4%, and adverse events with this schedule were tolerable.


Molecular phylogeny of metazoan intermediate filament proteins.
We have cloned cytoplasmic intermediate filament (IF) proteins from a large number of invertebrate phyla using cDNA probes, the monoclonal antibody IFA, peptide sequence information, and various RT-PCR procedures. Novel IF protein sequences reported here include the urochordata and nine protostomic phyla, i.e., Annelida, Brachiopoda, Chaetognatha, Echiura, Nematomorpha, Nemertea, Platyhelminthes, Phoronida, and Sipuncula. Taken together with the wealth of data on IF proteins of vertebrates and the results on IF proteins of Cephalochordata, Mollusca, Annelida, and Nematoda, two IF prototypes emerge. The L-type, which includes 35 sequences from 11 protostomic phyla, shares with the nuclear lamins the long version of the coil 1b subdomain and, in most cases, a homology segment of some 120 residues in the carboxyterminal tail domain. The S-type, which includes all four subfamilies (types I to IV) of vertebrate IF proteins, lacks 42 residues in the coil 1b subdomain and the carboxyterminal lamin homology segment. Since IF proteins from all three phyla of the chordates have the 42-residue deletion, this deletion arose in a progenitor prior to the divergence of the chordates into the urochordate, cephalochordate, and vertebrate lineages, possibly already at the origin of the deuterostomic branch. Four phyla recently placed into the protostomia on grounds of their 18S rDNA sequences (Brachiopoda, Nemertea, Phoronida, and Platyhelminthes) show IF proteins of the L-type and fit by sequence identity criteria into the lophotrochozoic branch of the protostomia.


Modeling and interpretation of single-cell proteogenomic data.
Biological functions stem from coordinated interactions among proteins, nucleic acids and small molecules. Mass spectrometry technologies for reliable, high throughput single-cell proteomics will add a new modality to genomics and enable data-driven modeling of the molecular mechanisms coordinating proteins and nucleic acids at single-cell resolution. This promising potential requires estimating the reliability of measurements and computational analysis so that models can distinguish biological regulation from technical artifacts. We highlight different measurement modes that can support single-cell proteogenomic analysis and how to estimate their reliability. We then discuss approaches for developing both abstract and mechanistic models that aim to biologically interpret the measured differences across modalities, including specific applications to directed stem cell differentiation and to inferring protein interactions in cancer cells from the buffing of DNA copy-number variations. Single-cell proteogenomic data will support mechanistic models of direct molecular interactions that will provide generalizable and predictive representations of biological systems.


Use of differential DNA-repair host mediated assays to investigate the biotransformation of xenobiotics in Drosophila melanogaster. I. Genotoxic effects of nitrosamines.
A rapid differential DNA-repair assay procedure was developed to investigate the biotransformation of xenobiotics in Drosophila melanogaster in vivo. Indicator of genotoxic activity was a pair of streptomycin-dependent Escherichia coli strains differing vastly in DNA repair capacity (uvr+/rec+ vs. uvrB/recA). Prior to the experiments with test compounds, mixtures of the two strains were injected into the abdomina of untreated animal hosts (male Berlin-K flies) and the time-dependent recovery kinetics determined. Subsequently, different aliphatic and aromatic nitrosamines were tested. Solutions of the compounds were injected simultaneously with the indicator cells. Three hours later, the flies were killed, homogenized and the induction of (repairable) DNA damage determined by comparison of the survival rates of the two strains in single animals. Eight carcinogenic compounds (nitrosodiethylamine, NDEA; nitrosodimethylamine, NDMA; nitrosodi-npropylamine, NDPA; nitrosodiethanolamine, NDELA; nitrosomethylaniline, NMA; 4-methyl-nitrosopiperidine, MNPIP; nitrosopyrrolidine, NPYR; nitrosomorpholine, NMOR) and one whose tumorigenic activities are still controversially discussed (nitrosodiphenylamine, NDPhA) induced dose-dependent differential killing effects in the present system. One agent which has not been found carcinogenic in rodents (2.6-dimethyl-nitrosopiperidiine. NDMPIP) gave negative results. The ranking order of genotoxic activities of the nitrosamines found in Drosophila in vivo is in good agreement with those of carcinogenic potencies established on the basis of experiments with rats. The most pronounced exceptions are the rather weak response towards NMA and the stronger DNA damaging activity of NMPIP compared to NDMA. Phenobarbital (5-ethyl-5-phenyl-2,4,6-trioxohepatahydropyramidine) (PB) feeding of the flies resulted in an increase of the DNA damaging potencies of all nitrosamines tested. Substantial enhancement of the induction of DNA damage was however, restricted to NDEA, NPYR and NMOR, whereas with nitrosodiphenylamine (NDPhA), NDELA and NDMA only a moderate (less than 25%) increase of differential killing effects was found. In the case of the two latter compounds, these results might be due to the fact that enzymes other than the MFO are involved in their activation. Attempts to localize the formation and/or distribution of metabolites in the bodies of fruitflies by separation of the tagmata of chemically treated animals and determination of genotoxic effects in the different segments indicate that the most pronounced effects occur in the abdomina whereas in heads and thoraxes comparatively lower activities are detectable.


Kids speak: effective communication with the school-aged/adolescent patient.
Caring for school-aged and adolescent children presents unique challenges to the acute healthcare provider. In today's healthcare industry, children should be informed and should participate in the medical decision-making process. Thus, the art of successful school-aged and adolescent communication is vital in today's economically driven market. Practitioners evaluating pediatric patients must immediately establish a rapport and trust--not only with the parents, but also with the child--through effective communication techniques. Effective communication skills and challenges are discussed, along with current research trends to improve patient-provider relations.


LRRK2 and parkin immunoreactivity in multiple system atrophy inclusions.
Certain genetic defects in LRRK2 and parkin are pathogenic for Parkinson's disease (PD) and both proteins deposit in the characteristic Lewy bodies. LRRK2 is thought to be involved in the early initiation of Lewy bodies. The involvement of LRRK2 and parkin in the similar cellular deposition of fibrillar alpha-synuclein in glial cytoplasmic inclusions (GCI) in multiple system atrophy (MSA) has not yet been assessed. To determine whether LRRK2 and parkin may be similarly associated with the abnormal deposition of alpha-synuclein in MSA GCI, paraffin-embedded sections from the basal ganglia of 12 patients with MSA, 4 with PD and 4 controls were immunostained for LRRK2, parkin, alpha-synuclein and oligodendroglial proteins using triple labelling procedures. The severity of neuronal loss was graded and the proportion of abnormally enlarged oligodendroglia containing different combinations of proteins assessed in 80-100 cells per case. Parkin immunoreactivity was observed in only a small proportion of GCI. In contrast, LRRK2 was found in most of the enlarged oligodendroglia in MSA and colocalised with the majority of alpha-synuclein-immunopositive GCI. Degrading myelin sheaths containing LRRK2-immunoreactivity were also observed, showing an association with one of the earliest oligodendroglial abnormalities observed in MSA. The proportion of LRRK2-immunopositive GCI was negatively associated with an increase in neuronal loss and alpha-synuclein-immunopositive dystrophic axons. Our results indicate that an increase in LRRK2 expression occurs early in association with myelin degradation and GCI formation, and that a reduction in LRRK2 expression in oligodendroglia is associated with increased neuronal loss in MSA.


Cryptic clues as to how water-soluble protein toxins form pores in membranes.
Pore-forming protein toxins possess the remarkable property that they can exist either in a stable water-soluble state or as an integral membrane pore. In order to convert from the water-soluble to the membrane state, the toxin must undergo large conformational changes. Recent work on a class of pore-forming toxins that are rich in beta-sheet content suggests a common mechanism of membrane insertion may exist despite these toxins possessing very different primary, tertiary and quaternary structures.


Expression of the protein chaperone, clusterin, in spinal cord cells constitutively and following cellular stress, and upregulation by treatment with Hsp90 inhibitor.
Clusterin, a protein chaperone found at high levels in physiological fluids, is expressed in nervous tissue and upregulated in several neurological diseases. To assess relevance to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders, clusterin expression was evaluated using long-term dissociated cultures of murine spinal cord and SOD1(G93A) transgenic mice, a model of familial ALS. Motor neurons and astrocytes constitutively expressed nuclear and cytoplasmic forms of clusterin, and secreted clusterin accumulated in culture media. Although clusterin can be stress inducible, heat shock failed to increase levels in these neural cell compartments despite robust upregulation of stress-inducible Hsp70 (HspA1) in non-neuronal cells. In common with HSPs, clusterin was upregulated by treatment with the Hsp90 inhibitor, geldanamycin, and thus could contribute to the neuroprotection previously identified for such compounds in disease models. Clusterin expression was not altered in cultured motor neurons expressing SOD1(G93A) by gene transfer or in presymptomatic SOD1(G93A) transgenic mice; however, clusterin immunolabeling was weakly increased in lumbar spinal cord of overtly symptomatic mice. More striking, mutant SOD1 inclusions, a pathological hallmark, were strongly labeled by anti-clusterin. Since secreted, as well as intracellular, mutant SOD1 contributes to toxicity, the extracellular chaperoning property of clusterin could be important for folding and clearance of SOD1 and other misfolded proteins in the extracellular space. Evaluation of chaperone-based therapies should include evaluation of clusterin as well as HSPs, using experimental models that replicate the control mechanisms operant in the cells and tissue of interest.


Isolation of succinate dehydrogenase from Desulfobulbus elongatus, a propionate oxidizing, sulfate reducing bacterium.
Succinate dehydrogenase was purified from the particulate fraction of Desulfobulbus. The enzyme catalyzed both fumarate reduction and succinate oxidation but the rate of fumarate reduction was 8-times less than that of succinate oxidation. Quantitative analysis showed the presence of 1 mol of covalently bound flavin and 1 mol of cytochrome b per mol of succinate dehydrogenase. The enzyme contained three subunits with molecular mass 68.5, 27.5 and 22 kDa. EPR spectroscopy indicated the presence of at least two iron sulfur clusters. 2-Heptyl-4-hydroxy-quinoline-N-oxide inhibited the electron-transfer between succinate dehydrogenase and a high redox potential cytochrome c3 from Desulfobulbus elongatus.


The nucleolus: an emerging target for cancer therapy.
For over 100 years, pathologists have utilised an increase in size and number of nucleoli, the subnuclear site of ribosome synthesis, as a marker of aggressive tumours. Despite this, the contribution of the nucleolus and ribosomal RNA synthesis to cancer has been largely overlooked. This concept has recently changed with the demonstration that the nucleolus indirectly controls numerous other cellular functions, in particular, the cellular activity of the critical tumour suppressor protein, p53. Moreover, selective inhibition of ribosomal gene transcription in the nucleolus has been shown to be an effective therapeutic strategy to promote cancer-specific activation of p53. This article reviews the largely untapped potential of the nucleolus and ribosomal gene transcription as exciting new targets for cancer therapy.


[The thyroid gland in old age : Physiology and pathology].
In healthy older people the metabolism of thyroid hormones is physiologically altered and can possibly even actively contribute to longevity. This should also be taken into consideration in the treatment of diseases of the thyroid and principally also for younger patients. For example, with progressing age comorbidities become more prevalent and especially in cardiovascular diseases, hyperthyroidism is less well tolerated, and should be treated more aggressively. Benign multinodular goiter also becomes more prevalent in old age and should be surgically treated when causing mechanical symptoms. The treatment concept for malignant diseases should be adapted to the holistic situation of the patient but principally in the same manner as in younger patients. Old and very old patients also benefit from adequate, risk-adapted treatment of thyroid gland diseases so that appropriate diagnostics and clarification are meaningful, regardless of age.


Bacteria in the CF Lung: Isolation Drives Diversity.
In-host pathogen evolution influences disease progression and chronicity, but forces that shape this remain poorly understood. In this issue of Cell Host & Microbe, Jorth et al. (2015) describe regional subpopulations of Pseudomonas aeruginosa in lungs from cyctic fibrosis patients and provide support for compartmentalization-driven evolution of this bacterium.


Hippocampal volume and memory in narcoleptics with cataplexy.
The objective of this study was to investigate the differences in hippocampal volume (HV) between narcoleptics and normal controls and determine if HV is associated with memory function in narcoleptics. Left and right HV and intracranial volumes (ICV) were manually measured and compared between two groups. The study consisted of 36 drug-naïve narcoleptics with cataplexy and 36 age- and sex-matched controls (mean age 29.0 years). All subjects underwent 1.6-mm-thick spoiled gradient recalled magnetic resonance imaging and took the Korean California Verbal Learning Test and the Rey Complex Figure Test to assess verbal and visual memory. The mean ICV was not different between groups (1599.2 cm(3) in narcoleptics vs. 1623.5 cm(3) in controls, p = .450). Bilateral mean HVs were significantly smaller in narcoleptics (left, 2907.2mm(3) in narcoleptics vs. 3092.3mm(3) in controls, p = 0.005; right, 2990.8mm(3) in narcoleptics vs. 3184.3mm(3) in controls, p = 0.004). Significance of HV differences between groups remained after corrections were made for gender, age, and ICV. In narcoleptics, bilateral HV was positively correlated with mean sleep and REM sleep latencies in Multiple Sleep Latency Tests. Absolute memory scores were not different between groups and were not correlated with HV in narcoleptics. Narcoleptics had smaller bilateral HVs compared to controls. HV had a significant relationship with sleep and REM sleep latencies. This study provides supportive evidence of the functional and anatomical deficits in medial temporal areas that are related to the severity of narcolepsy.


Differences in engineers' brain activity when CAD modelling from isometric and orthographic projections.
A way of presenting information in visual representations of technical systems influences the progress and the outcome of the engineering design process. Consequently, improving the means by and through which information is utilised during the process is one suggested approach to advancing engineering design. Engineers' interaction with visual representations of technical systems is mainly visual and virtual. Although such interactions are cognitively complex, little is known about cognition (mental information processing) underlying the utilisation of design information during engineering design. To narrow the research gap, this study explores how visual representations of technical systems affect engineers' brain activity while generating computer-aided design (CAD) models based on them. More precisely, the brain activity of 20 engineers is captured and analysed using electroencephalography (EEG) during the visuospatially-intensive design tasks of CAD modelling in two conditions; when technical systems are presented with orthographic and isometric projections in technical drawings. The results imply the sensitivity of engineers' brain activity in CAD modelling to the visual representation from which a technical system is interpreted. In particular, significant differences are found in theta, alpha, and beta task-related power (TRP) over the cortex when interpreting the technical drawings and CAD modelling from them. Furthermore, the results reveal significant differences in theta and alpha TRP when considering the individual electrodes, the cortical hemispheres, and the cortical areas. In particular, theta TRP over the right hemisphere and the frontal area seems essential in distinguishing neurocognitive responses to the orthographic and isometric projections. As such, the conducted exploratory study sets the foundations for exploring engineers' brain activity while performing visuospatially-intensive design tasks, whose segments are relatable to the aspects of visuospatial thinking. Future work will explore brain activity in other design activities that are highly visuospatial, with a larger sample size and an EEG device of a higher spatial resolution.


Short-term depression of gap junctional coupling in reticular thalamic neurons of absence epileptic rats.
Gap junctional electrical coupling between neurons of the reticular thalamic nucleus (RTN) is critical for hypersynchrony in the thalamo-cortical network. This study investigates the role of electrical coupling in pathological rhythmogenesis in RTN neurons in a rat model of absence epilepsy. Rhythmic activation resulted in a Ca(2+) -dependent short-term depression (STD) of electrical coupling between pairs of RTN neurons in epileptic rats, but not in RTN of a non-epileptic control strain. Pharmacological blockade of gap junctions in RTN in vivo induced a depression of seizure activity. The STD of electrical coupling represents a mechanism of Ca(2+) homeostasis in RTN aimed to counteract excessive synchronization. Neurons in the reticular thalamic nucleus (RTN) are coupled by electrical synapses, which play a major role in regulating synchronous activity. This study investigates electrical coupling in RTN neurons from a rat model of childhood absence epilepsy, genetic absence epilepsy rats from Strasbourg (GAERS), compared with a non-epileptic control (NEC) strain, to assess the impact on pathophysiological rhythmogenesis. Whole-cell recordings were obtained from pairs of RTN neurons of GAERS and NEC in vitro. Coupling was determined by injection of hyperpolarizing current steps in one cell and monitoring evoked voltage responses in both activated and coupled cell. The coupling coefficient (cc) was compared under resting condition, during pharmacological interventions and repeated activation using a series of current injections. The effect of gap junctional coupling on seizure expression was investigated by application of gap junctional blockers into RTN of GAERS in vivo. At resting conditions, cc did not differ between GAERS and NEC. During repeated activation, cc declined in GAERS but not in NEC. This depression in cc was restored within 25 s and was prevented by intracellular presence of BAPTA in the activated but not in the coupled cell. Local application of gap junctional blockers into RTN of GAERS in vivo resulted in a decrease of spike wave discharge (SWD) activity. Repeated activation results in a short-term depression (STD) of gap junctional coupling in RTN neurons of GAERS, depending on intracellular Ca(2+) mechanisms in the activated cell. As blockage of gap junctions in vivo results in a decrease of SWD activity, the STD observed in GAERS is considered a compensatory mechanism, aimed to dampen SWD activity.


Holobionts, Multispecies Ecologies, and the Biopolitics of Care: Emerging Landscapes of Praxis in a Medical Anthropology of the Anthropocene.
Medical anthropology, given its diversity of practical and historical entanglements with (and outside of) numerous threads of anthropology, is a key site for productive theoretical and methodological confluences in the Anthropocene. Multispecies approaches, ethnographically, theoretically and methodologically, are developing as central locations for the hybridization and mingling of diverse and innovative research questions, particularly those engaging the processes, patterns, and constructs of health.


Mice can count and optimize count-based decisions.
Previous studies showed that rats and pigeons can count their responses, and the resultant count-based judgments exhibit the scalar property (also known as Weber's Law), a psychophysical property that also characterizes interval-timing behavior. Animals were found to take a nearly normative account of these well-established endogenous uncertainty characteristics in their time-based decision-making. On the other hand, no study has yet tested the implications of scalar property of numerosity representations for reward-rate maximization in count-based decision-making. The current study tested mice on a task that required them to press one lever for a minimum number of times before pressing the second lever to collect the armed reward (fixed consecutive number schedule, FCN). Fewer than necessary number of responses reset the response count without reinforcement, whereas emitting responses at least for the minimum number of times reset the response counter with reinforcement. Each mouse was tested with three different FCN schedules (FCN10, FCN20, FCN40). The number of responses emitted on the first lever before pressing the second lever constituted the main unit of analysis. Our findings for the first time showed that mice count their responses with scalar property. We then defined the reward-rate maximizing numerical decision strategies in this task based on the subject-based estimates of the endogenous counting uncertainty. Our results showed that mice learn to maximize the reward-rate by incorporating the uncertainty in their numerosity judgments into their count-based decisions. Our findings extend the scope of optimal temporal risk-assessment to the domain of count-based decision-making.


Anti-TMV effects of seco-pregnane C21 steroidal glycosides isolated from the roots of Cynanchum paniculatum.
Tobacco mosaic virus (TMV) is known to infect a wide range of plants, resulting in reduced yield and productivity. Novel, effective, and plant-based pesticides are required to protect plants against TMV infection. To identify novel anti-TMV agents from natural sources, we systematically studied the roots of Cynanchum paniculatum and isolated six new seco-pregnane C21 steroidal glycosides, along with 14 known compounds. Their structures were elucidated by comprehensive spectroscopic data analysis. The anti-TMV activity of compounds were screened using the half-leaf method. Biological tests revealed that compounds 1, 2, 5, 9, 10, 15, and 16 displayed significant anti-TMV activities compared with the positive control ningnanmycin. In addition, reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis confirmed the antiviral activity of these compounds, as evident from reduced TMV coat protein (TMV-CP) gene replication and TMV-CP protein expression. These compounds downregulated the expression of NtHsp70-1 and NtHsp70-261, indicating that these steroidal glycosides possibly inhibit the TMV infection by suppressing the expression of NtHsp70-1 and NtHsp70-061 expression.


The transposed word effect is consistent with serial word recognition and varies with reading speed.
The scientific study of reading has long been animated by questions of parallel vs. serial processing. Do readers recognize words serially, adding each one sequentially to a representation of the sentence structure? One fascinating phenomenon to emerge from this research is the transposed word effect: when asked to judge whether sentences are grammatical, readers often fail to notice grammatical errors caused by transposing two words. This effect could be evidence that readers recognize multiple words in parallel. Here we provide converging evidence that the transposed word effect is also consistent with serial processing because it occurs robustly when the words in each sentence are presented serially. We further investigated how the effect relates to individual differences in reading speed, to gaze fixation patterns, and to differences in difficulty across sentences. In a pretest, we first measured the natural English reading rate of 37 participants, which varied widely. In a subsequent grammatical decision task, we presented grammatical and ungrammatical sentences in two modes: one with all words presented simultaneously, and the other with single words presented sequentially at each participant's natural rate. Unlike prior studies that used a fixed sequential presentation rate, we found that the magnitude of the transposed word effect was at least as strong in the sequential presentation mode as in the simultaneous mode, for both error rates and response times. Moreover, faster readers were more likely to miss transpositions of words presented sequentially. We argue that these data favor a "noisy channel" model of comprehension in which skilled readers rely on prior knowledge to rapidly infer the meaning of sentences, allowing for apparent errors in spatial or temporal order, even when the individual words are recognized one at a time.


Nucleosome transactions on the Hypocrea jecorina (Trichoderma reesei) cellulase promoter cbh2 associated with cellulase induction.
The 5' regulatory region of the cbh2 gene of Hypocrea jecorina contains the cbh2 activating element (CAE) which is essential for induction of cbh2 gene expression by sophorose and cellulose. The CAE consists of two motifs, a CCAAT box on the template strand and a GTAATA box on the coding strand, which cooperate during induction. Northern analyses of cbh2 gene expression has revealed an absolute dependence on induction, but no direct effect of Cre1-mediated carbon catabolite repression. Investigation of the chromatin structure in the wild-type strain showed that, under repressing conditions, there is a nucleosome free region (nfr) around the CAE, which is flanked by strictly positioned nucleosomes. Induction results in a loss of positioning of nucleosomes -1 and -2 downstream of the CAE, thus making the TATA box accessible. Simultaneous mutation of both motifs of the CAE, or of the CCAAT-box alone, also leads to shifting of nucleosome -1, which normally covers the TATA-box under repressing conditions, whereas mutation of the GTAATA element results in a narrowing of the nfr, indicating that the proteins that bind to both motifs in the CAE interact with chromatin, although in different ways. A cellulase-negative mutant strain, which has previously been shown to be altered in protein binding to the CAE, still displayed the induction-specific changes in nucleosome structure, indicating that none of the proteins that directly interact with CAE are affected, and that nucleosome rearrangement and induction of cbh2 expression are uncoupled. Interestingly, the carbon catabolite repressor Cre1 is essential for strict nucleosome positioning in the 5' regulatory sequences of cbh2 under all of the conditions tested, and induction can occur in a promoter that lacks positioned nucleosomes. These data suggest that Cre1, the Hap2/3/5 complex and the GTAATA-binding protein are all involved in nucleosome assembly on the cbh2 promoter, and that the latter two respond to inducing conditions by repositioning nucleosome -1.


Biological phosphorus removal inhibition by roxarsone in batch culture systems.
Roxarsone has been extensively used in the feed of animals, which is usually excreted unchanged in the manure and eventually enter into animal wastewater, challenging the biological phosphorus removal processes. Knowledge of its inhibition effect is key for guiding treatment of roxarsone-contaminated wastewater, and is unfortunately keeping unclear. We study the inhibition of roxarsone on biological phosphorus removal processes for roxarsone-contaminated wastewater treatment, in terms of the removal and rates of chemical oxygen demand (COD), phosphate. Results showed that presence of roxarsone considerably limited the COD removals, especially at roxarsone concentration exceeding 40 mg L(-1). Additionally, roxarsone inhibited both phosphorus release and uptake processes, consistent with the phosphate profiles during the biological phosphorus removal processes; whereas, roxarsone is more toxic to phosphorus uptake process, than release function. The results indicated that it is roxarsone itself, rather than the inorganic arsenics, inhibit biological phosphorus removal processes within both aerobic and anaerobic roxarsone-contaminated wastewater treatment.


Hepatitis E virus: host tropism and zoonotic infection.
Hepatitis E virus (HEV), the causative agent of hepatitis E, is an understudied but important pathogen. HEV typically causes self-limiting acute viral hepatitis, however chronic infection with neurological and other extrahepatic manifestations has increasingly become a significant clinical problem. The discovery of swine HEV from pigs and demonstration of its zoonotic potential led to the genetic identification of very diverse HEV strains from more than a dozen other animal species. HEV strains from pig, rabbit, deer, camel, and rat have been shown to cross species barriers and infect humans. Zoonotic HEV infections through consumption of raw or undercooked animal meat or direct contact with infected animals have been reported. The discovery of a large number of animal HEV variants does provide an opportunity to develop useful animal models for HEV. In this mini-review, we discuss recent advances in HEV host range, and cross-species and zoonotic transmission.


In situ synthesis of Ag/Ag2O-cellulose/chitosan nanocomposites via adjusting KOH concentration for improved photocatalytic and antibacterial applications.
This work proposed a facile way to construct cellulose/chitosan-loaded Ag/Ag2O nanocomposite films (ACC) from alkali/urea solution by increasing the content of alkali KOH in the solvent. The saturated alkali and hydroxyl groups of the cellulose and chitosan chains were accelerated to convert AgNO3 to Ag0. Ag2O served as nuclei to lower the energy barrier. The formation of Ag/Ag2O nanoparticles (NPs) endowed the cellulose bio-reduced Ag composites with multifunction and stronger photocatalytic activity. Ag/Ag2O NPs with the diameter of 139-360 nm were uniformly dispersed in the composite films, resulting in superior mechanical properties (64.6 MPa) and thermal stability. Almost 92 % of methyl orange was degraded under UV-irradiation within 40 min by ACC. After 3 runs of degradation, the photocatalytic abilities of ACC remained. Moreover, the films exhibited good antibacterial activities. The width of inhibition zones around ACC reached 9.2-12 mm and 8.6-10.4 mm for S. aureus and E. coli. The strategy provided a new avenue to construct multifunctional cellulose/chitosan materials for various applications, such as wastewater treatment, and electrocatalysis.


Interactions between the rod and the cone pathways in the cat retina.
The receptive field centers of 21 on-center X retinal ganglion cells in cat were tested with stimuli designed to detect nonlinear interactions between the rod and the cone systems. One red and one green stimulus light were always present, at a level such that modulation of the red light essentially affected only cones, and that of the green light only rods. The two lights could be superimposed spatially (overlapped configuration) or fall on separate subareas of the receptive field center (nonoverlapped configuration). In most cases, there was less complete summation of the responses to modulation of the lights in the overlapped than in the nonoverlapped configuration, with a corresponding difference in the summation of sensitivities. In 1/6 of the experiments, there was more complete summation of the responses to the lights in the overlapped configuration, with a corresponding difference in the summation of sensitivities. The mean magnitude of the interaction for all experiments was equivalent to an antagonistic interaction between the rod and cone pathways such that the signal in each was diminished by a quantity slightly greater than 30% of the signal in the other.


Comparison of steroidogenic gene expression in mummichog (Fundulus heteroclitus) testis tissue following exposure to aromatizable or non-aromatizable androgens.
Androgens are a recognized class of endocrine disrupting compounds with the ability to impact reproductive status in aquatic organisms. The current study utilized in vitro exposure of mummichog (Fundulus heteroclitus) testis tissue to either the aromatizable androgen 17α-methyltestosterone (MT) or the non-aromatizable androgen 5α-dihydrotestosterone (DHT) over the course of 24 h to determine if there were differential effects on steroidogenic gene expression. Testis tissue was exposed to androgen concentrations of 10-12 M, 10-9 M and 10-6 M for 6, 12, 18 or 24 h, after which a suite of steroidogenic genes, including steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase (3βhsd) and cytochrome P450 17A1 (cyp17a1), were quantified using real-time polymerase chain reaction. Both androgens affected steroidogenic gene expression, with most alterations occurring at the 24-hour time point. The gene with the highest fold-change, and shortest interval to expression alteration, was 3βhsd for both androgens. Potential differences between the two model androgens were observed in increased expression of cyp17a1 and 11β-hydroxysteroid dehydrogenase (11βhsd), which were only altered after exposure to DHT and in expression levels of cytochrome P450 11A1 (cyp11a1), which was upregulated by MT but not altered by DHT. Results from this study show both androgens interact at the gonadal level of the hypothalamus-pituitary-gonadal axis and may possess some distinct gene expression impacts. These data strengthen the current research initiatives of establishing in vitro test systems that allow toxic potential of untested chemicals to be predicted from molecular perturbations.


A gene-targeted mouse model for familial hypobetalipoproteinemia. Low levels of apolipoprotein B mRNA in association with a nonsense mutation in exon 26 of the apolipoprotein B gene.
Familial hypobetalipoproteinemia, a syndrome characterized by abnormally low plasma levels of low density lipoprotein cholesterol, is caused by mutations in the apolipoprotein (apo) B gene that interfere with the synthesis of a full-length apoB100. In many cases of familial hypobetalipoproteinemia, nonsense or frameshift mutations result in the synthesis of a truncated apoB protein. To understand why these mutations result in low plasma cholesterol levels, we used gene targeting in mouse embryonic stem cells to introduce a nonsense mutation (N1785Stop) into exon 26 of the mouse Apob gene. The sole product of this mutant Apob allele was a truncated apoB, apoB39. Mice homozygous for this "apoB39-only" (Apob39) allele had low plasma levels of apoB39 and markedly reduced plasma levels of very low density lipoprotein and low density lipoprotein cholesterol when fed a high fat diet. Analysis of liver and intestinal RNA from heterozygous apoB39-only mice revealed that the Apob39 mRNA levels were 60-70% lower than those from the wild-type allele. Interestingly, apoB39 was not cleared as rapidly from the plasma as apoB48. The apoB39-only mice provide new insights into the mechanisms of familial hypobetalipoproteinemia and the structural features of apoB that are important for lipoprotein metabolism.


Effect of spinal cord stimulation in patients with refractory angina: evidence from observational studies.
To review the evidence in observational studies of the effect of spinal cord stimulation (SCS) in patients with refractory angina pectoris (RAP) due to obstructive coronary artery disease. The effect of SCS in patients with refractory microvascular angina (MVA) also was assessed. We reviewed the observational studies, published from 1987 to 2010, which investigated the effects of SCS on RAP. The number of angina attacks and that of taken nitrate tablets, as well as the class of angina, were considered as main outcome variables. The occurrence of adverse events related to the treatment also was assessed. The results showed a consistent reduction of the number of angina attacks (by 45-84%) and of consumption of short-acting nitrate tablets (by -75% to -94%), whereas the New York Heart Association and Canadian Cardiovascular Society class of angina were significantly improved in some studies. No case fatalities related to the therapy were reported. Significant clinical benefits were observed in some studies in patients with refractory MVA. Device-related infections and catheter dislodgment were the most significant and frequent side-effects, respectively. In observational studies, SCS showed to be an effective form of treatment for RAP, including refractory MVA. The treatment appears to be safe both at short- and long-term follow-up.


Concomitant nitrates enhance clopidogrel response during dual anti-platelet therapy.
Despite advances in modern anti-platelet strategies, clopidogrel still remains the cornerstone of dual anti-platelet therapy (DAPT) in patients undergoing percutaneous coronary interventions (PCI). There is some inconclusive evidence that response after clopidogrel may be impacted by concomitant medications, potentially affecting clinical outcomes. Sustained released nitrates (SRN) are commonly used together with clopidogrel in post-PCI setting for mild vasodilatation and nitric oxide-induced platelet inhibition. We prospectively enrolled 458 patients (64.5 ± 9.6 years old, and 73.4% males) following PCI undergoing DAPT with clopidogrel and aspirin. Platelet reactivity was assessed by the VerifyNow™ P2Y12 assay at the maintenance outpatient setting. Concomitant SRN (n=266) significantly (p=0.008) enhanced platelet inhibition after DAPT (251.6 ± 80.9PRU) when compared (232.1 ± 73.5PRU) to the SRN-free (n=192) patients. Multivariate logistic regression analysis with the cut-off value of 253 PRU for defining heightened platelet reactivity confirmed independent correlation of more potent platelet inhibition during DAPT and use of SRN (Relative risk=1.675; Odds ratio [1.059-2.648]; p=0.027). In contrast, statins, calcium-channel blockers, beta blockers, angiotensin receptor blockers, ACE-inhibitors, diuretics, and anti-diabetic agents did not significantly impact platelet inhibition following DAPT. The synergic ability of SRN to enhance response during DAPT may have important clinical implications with regard to better cardiovascular protection, but extra bleeding risks, requiring further confirmation in a large randomized study.


Recent advances in hydrogels as strategy for drug delivery intended to vaginal infections.
Vaginal infections represent a clear women health problem due to the several issues as high recurrence rate, drug resistence and emergence of persistent strains. However, achieving improvements in therapeutic efficacy by using conventional formulations intended to vaginal drug delivery remains as a challenge due to anatomy and physiology of the vagina, since the secretion and renewal of vaginal fluids contribute to the removal of the dosage form. Hydrogels have been widely exploited aiming to achieve drug delivery directly into vaginal mucosa for local therapy due to their attractive features as increased residence time of the drug at the action site and control of drug release rates. Some polymers can aggregate specific properties to hydrogels as mucoadhesive, stimuli-responsive and antimicrobial, improving their interaction with the biological interface and therapeutic response. In this review, we highlight the advances, advantages and challenges of the hydrogels as drug and/or nanocarrier vehicles intended to the treatment of vaginal infections, emphasizing also the polymers and their properties more explored on the design these systems to improve the therapeutic effect on the vaginal tissue. In addition, this review can contribute for better exploitation these systems in search of new local treatments for bacterial vaginosis, candidiasis and trichomoniasis.


The necessity of a loading dose when prescribing intravenous colistin in critically ill patients with CRGNB-associated pneumonia: a multi-center observational study.
The importance or necessity of a loading dose when prescribing intravenous colistin has not been well established in clinical practice, and approximate one-third to half of patients with carbapenem-resistant gram-negative bacteria (CRGNB) infection did not receive the administration of a loading dose. The aim of this study is to investigate the efficacy and risk of acute kidney injury when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB. This was a multicenter, retrospective study that recruited ICU-admitted patients who had CRGNB-associated nosocomial pneumonia and were treated with intravenous colistin. Then, we classified the patients into colistin loading dose (N = 85) and nonloading dose groups (N = 127). After propensity-score matching for important covariates, we compared the mortality rate, clinical outcome and microbiological eradication rates between the groups (N = 67). The loading group had higher percentages of patients with favorable clinical outcomes (55.2% and 35.8%, p = 0.037) and microbiological eradication rates (50% and 27.3%, p = 0.042) at day 14 than the nonloading group. The mortality rates at days 7, 14 and 28 and overall in-hospital mortality were not different between the two groups, but the Kaplan-Meier analysis showed that the loading group had a longer survival time than the nonloading group. Furthermore, the loading group had a shorter length of hospital stay than the nonloading group (52 and 60, p = 0.037). Regarding nephrotoxicity, there was no significant difference in the risk of developing acute kidney injury between the groups. The administration of a loading dose is recommended when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.


Convergent and parallel evolution: a model illustrating selection, phylogeny and phenetic similarity.
A model is proposed which considers the structural relationships of body characteristics and their role in a concept wherein the phylogenetic relationship of the organisms under study is interpreted as constituting degrees of convergent or parallel evolution. The model also accounts for the relationships between selection pressures, phylogeny, and phenetic expression. The phenomena of convergent and parallel evolution are based upon the observations of similar characteristics, the geometric concept, magnitude and similarity of selection pressures, and the phylogenetic relationship of the groups in question.


Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection.
Congenital cytomegalovirus (CMV) infection is the most common infectious cause of sensorineural hearing loss in children. Here, we established an experimental model of hearing loss after systemic infection with murine CMV (MCMV) in newborn mice. Although almost no viral infection was observed in the inner ears and brains by intraperitoneal (i.p.) infection with MCMV in newborn mice, infection in these regions was induced in combination with intracerebral (i.c.) injection of bacterial lipopolysaccharide (LPS). The susceptibility of the inner ears was higher than that of the brains in terms of viral titer per unit weight. In the labyrinths, the viral infection was associated with the mesenchymal vessels and accompanied by inflammatory cells induced by LPS, causing hematogenous targets of infection in the labyrinths. Viral infection also spread in the perilymph regions such as the scala tympani and scala vestibuli, probably from infected brains via meningogenic and cochlear nerve routes. Viral infection was not observed in the scala media in the endolymph, including the Corti organ. However, viral infection was observed in the spiral limbus, including the stria vascularis. These results suggest that hearing loss caused by labyrinthitis after congenital CMV infection may be enhanced by inflammation caused by systemic bacterial infection in the neonatal period.


BRG1 expression is increased in human glioma and controls glioma cell proliferation, migration and invasion in vitro.
The purposes of our study were to elucidate the role of BRG1 in the development of human glioma and to determine the effect of BRG1 on glioma cell growth, migration and invasion. Using tissue microarray and immunohistochemistry, we evaluated BRG1 staining in 190 glioma tissues, 8 normal brain tissues and 8 tumor adjacent normal brain tissues. We studied glioma cell proliferative ability with reduced BRG1 expression by siRNA using CCK-8 cell proliferation assay and cell cycle analysis. We studied the role of BRG1 in glioma cell migration and invasion by cell migration assay and matrigel invasion assay. We performed western blot to detect cyclin D1, cyclin B1 and MMP-2 protein expression. We also detected MMP-2 enzyme activity by gelatin zymography. Our results showed that BRG1 expression was increased in benign tumor and malignant tumor compared with tumor adjacent normal brain tissue (P < 0.01 for both). We did not find any correlation between BRG1 expression and clinicopathological parameters. In addition, we found that knockdown of BRG1 in glioma cell lines inhibits cell growth due to the G1 phase arrest by downregulating cyclin D1. We further demonstrated that silencing of BRG1 in glioma cells inhibited the cell migration and invasion abilities, and downregulation of MMP-2 expression greatly contributed to the reduced cell invasion and migration abilities. Our data indicated that BRG1 expression is significantly increased in human glioma and it may be involved in the process of glioma cell proliferation, migration and invasion.


The reversibility of catheter-associated polypoid cystitis.
Cystoscopic and histologic evidence of polypoid cystitis was recorded in 20 hospitalized patients with indwelling urethral catheters followed by cystoscopy, biopsies and repeated urine samples before and after catheter removal. The majority of the lesions were located in the posterior wall or dome. The lesions disappeared after removal of the catheter in 13 of the 15 patients followed for up to 28 weeks despite persistent bacteriuria. Polypoid cystitis still remained 28 weeks after catheter removal in 1 patient. The lesion is important as a differential diagnosis to bladder tumor. The importance of adequate biopsies is emphasized.


Long-term follow-up after intracoronary streptokinase therapy for acute myocardial infarction.
This article describes the effects on patients treated with intracoronary streptokinase during acute myocardial infarction and long-term follow-up. The mortality and the incidence of cardiac events were assessed during a follow-up period of 35 +/- 5 months. Coronary artery bypass grafting was undertaken in 37% of the patients. Hospital mortality was 11%, (n = 8); none of these deaths was due to myocardial rupture. The postdischarge mortality was 10%; three of these patients experienced sudden death. Serial assessment of left ventricular function in 35 patients showed an increase of angiographic ejection fraction prior to intervention from 50 +/- 4% to 58 +/- 12% (p = 0.005) 36 +/- 53 days later. Gated-blood pool imaging after 16 +/- 7 months (n = 35) and 32 +/- 9 months (n = 31) revealed no change in ejection fraction. Angina pectoris recurred in four of the 35 patients. We studied a historical comparison group, that consisted of 66 patients, who were treated at the same institution prior to the advent of intracoronary intervention techniques; this group was followed for 48 +/- 9 months. Baseline clinical and angiographic parameters were comparable in the two groups. Coronary artery bypass grafting was performed in only 18 of these patients. Mortality during hospitalization and postdischarge was not significantly different in the two groups. Ejection fraction decreased significantly in the comparison group from the first to the second evaluation and remained unchanged during the follow-up period. We conclude that no major adverse effects were associated with intracoronary streptokinase infusion over a long follow-up period. This may be related to the high frequency of coronary artery bypass surgery following reperfusion.


Direct observation and dynamics of spontaneous skyrmion-like magnetic domains in a ferromagnet.
The structure and dynamics of submicrometre magnetic domains are the main factors determining the physical properties of magnetic materials. Here, we report the first observation of skyrmion-like magnetic nanodomains in a ferromagnetic manganite, La0.5Ba0.5MnO3, using Lorentz transmission electron microscopy (LTEM). The skyrmion-like magnetic domains appear as clusters above the Curie temperature. We found that the repeated reversal of magnetic chirality is caused by thermal fluctuation. The closely spaced clusters exhibit dynamic coupling, and the repeated magnetization reversal becomes fully synchronized with the same chirality. Quantitative analysis of such dynamics was performed by LTEM to directly determine the barrier energy for the magnetization reversal of skyrmion-like nanometre domains. This study is expected to pave the way for further investigation of the unresolved nature and dynamics of magnetic vortex-like nanodomains.


Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells.
T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.


Rectopexy.
Many surgical procedures have been described for the management of full-thickness rectal prolapse. Currently, the three procedures most frequently used are anterior resection with or without suture rectopexy, transabdominal mesh fixation without resection, and perineal proctosigmoidectomy. Only the latter procedure avoids a laparotomy, and the mesh fixation technique has a high incidence of severe constipation postoperatively. Recently, there have been two reports of laparoscopic mesh fixation for rectal prolapse which were successful. However, the long-term concerns are probably very similar. Therefore, the purpose of this paper is to report a series of 6 laparoscopic-assisted anterior resections performed for rectal prolapse at Ferguson-Blodgett Hospital from January 1, 1992 through October 30, 1992. There were no perioperative mortalities and the only complication was a port site bleed which required re-exploration. The mean time for resumption of oral intake was 2.75 +/- 1.5 days and the length of hospital stay was 4.0 +/- 0.8 days. No early recurrences (< 1 yr) have been noted in this series. The authors feel that laparoscopic-assisted anterior resection is a safe and effective method of treating full-thickness rectal prolapse, thereby avoiding a laparotomy and reducing hospital stay.


Fostering trust and understanding in social and healthcare services with migrant-origin parents: qualitative focus-group interviews of foreign-born mothers living in Finland.
Migrant-origin families may have a pronounced need for psychosocial support and healthcare services, but they face barriers in using services. To ensure the timely use of services, it is important that families understand how service systems work and trust care providers. Thirty-two migrant-origin mothers living in Finland participated in five focus-group interviews and shared their wishes for social and healthcare professionals on how trust and understanding can be increased. The data were analyzed with Qualitative Content Analysis. We identified six main themes related to the use of services and professionals' behavior. These were the need for professionals to justify and explain questions, to meet each family as individuals, the importance of non-verbal communication, the need to talk about racism and discrimination, the importance of cultural sensitivity in services, and a discussion of positive aspects of life after migration and children`s strengths. To foster trust and mutual understanding in social and healthcare services, professionals should be aware of potential cultural differences in family life, while avoiding pre-conceived ideas. Misunderstandings can rise from language barriers and unclear or intimidating questions. It is important that professionals explain what they do and justify why they might inquire about a family's personal matters. Working with interpreters is necessary when professionals and parents do not share a common fluent language. Professionals should also pay attention to their non-verbal communication and to being friendly. Finally, it is important to show interest in families' experienced hardships such as racism as well as their strengths.


Characterization of a commercial cellulase for hydrolysis of agroindustrial substrates.
This work is focused on the characterization of a commercial cellulase in terms of optimum pH and temperature, stability to pH and temperature and affinity of this enzyme to several substrates, determining the Michaelis-Menten parameters. Maximum activity of cellulase was obtained for the temperature range from 40 to 50 °C and pH from 5.2 to 5.5. Enzyme activity decreased only 15% after 150 h of reaction at temperatures between 30 and 50 °C. No loss of activity was observed at pH 5.0 and 5.5. The cellulase showed satisfactory results in the hydrolysis of agroindustrial substrates, since similar activity was verified on filter paper and other agroindustrial substrates.


Direct Visualization of Atomic Structure in Multivariate Metal-Organic Frameworks (MOFs) for Guiding Electrocatalysts Design.
The direct utilization of metal-organic frameworks (MOFs) for electrocatalytic oxygen evolution reaction (OER) has attracted increasing interests. Herein, we employ the low-dose integrated differential phase contrast-scanning transmission electron microscopy (iDPC-STEM) technique to visualize the atomic structure of multivariate MOFs (MTV-MOFs) for guiding the structural design of bulk MOFs for efficient OER. The iDPC-STEM images revealed that incorporating Fe3+ or 2-aminoterephthalate (ATA) into Ni-BDC (BDC: benzenedicarboxylate) can introduce inhomogeneous lattice strain that weaken the coordination bonds, which can be selectively cleaved via a mild heat treatment to simultaneously generate coordinatively unsaturated metal sites, conductive Ni@C and hierarchical porous structure. Thus, excellent OER activity with current densities of 10 and 100 mA cm-2 are achieved over the defective MOFs at small overpotentials of 286 mV and 365 mV, respectively, which is superior to the commercial RuO2 catalyst and most of the bulk MOFs.


Characterization of tumor microenvironment infiltration and therapeutic responses of cell cycle-related genes' signature in breast cancer.
It is unknown how the cell cycle plays a role in breast cancer (BC). This study aimed to establish a clinically applicable predictive model to predict the therapeutic responses and overall survival in BC patients. Cell cycle-related genes (CCGs) were identified within the Cancer Genome Atlas cohort (n is equal to 1001) and the Gene Expression Omnibus cohort (n is equal to 3265). An analysis of univariate and multivariate Cox was then conducted to develop a nomogram based on CCGs. After validating the nomogram, risk cohort stratification was established and the predictive value was examined. Finally, immune cell infiltration and therapeutic responses were analysed. Based on 15 CCGs, 4 prognostic predictors were identified and entered into the nomogram. According to the curves of calibration, the estimated and observed value of the nomogram is in optimal agreement. Subsequently, stratification into two risk cohorts showed that the predictive value, immune cell infiltration and overall survival were better among patients with low risk. Immune checkpoint expression in patients with BC at higher risk was downregulated. Furthermore, the results of the study revealed that doxorubicin, paclitaxel, docetaxel, cisplatin and vinorelbine all had higher IC50 values in patients with high-risk BC. The nomogram based on CCG could assess tumour immune micro-environment regulation and therapeutic responses of immunotherapy in BC. Moreover, it may provide novel information on the control of immune micro-environment infiltration in BC and aid in the development of targeted immunotherapy.


Home-Based Indoor Physical Activity Programs for Community-Dwelling Older Adults: A Systematic Review.
Home-based exercise programs are a good strategy to promote benefits to health for people who cannot visit gyms, clinics, or have limited time for physical activity outside. To synthesize the effect of home-based indoor physical activity on psychosocial outcomes and mobility in community-dwelling older adults. A comprehensive search was conducted in the MEDLINE, PubMed, Embase, SPORTDiscus, Cochrane Library, Scopus, and Google Scholar databases. A total of 11 studies (13 publications) were included involving a total of 1004 older adults. A systematic review of randomized controlled trials was conducted using the aforementioned 7 databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Level 2. Two authors independently selected studies, extracted data, and determined the risk of bias and evidence level using the Grading quality of evidence and strength of recommendations (GRADE) guidelines. We conducted a synthesis without meta-analysis (SWiM) to assess the outcome. There is moderately certain evidence that home-based exercise programs reduced the fear of falling. Psychosocial (mental health and quality of life) and mobility outcomes may improve after participating in the intervention inside the home. The review found very low to certain evidence that home-based exercises programs improved psychosocial outcomes (mental health and quality of life) and walking speed (mobility). Moderately certain evidence suggests that home-based exercises improved fear of falling. CRD42020182008.


Factors associated with the use of outpatient services among the elderly in Indonesia.
Elderly people tend to have greater healthcare utilization because of their health status. However, with the 4th largest population in the world, little is known concerning the use of services among the Indonesian elderly. Hence, this study aimed to identify factors related to the use of outpatient services among the Indonesian elderly. This is cross sectional study using data from the Indonesian Family Life Survey 5 (IFLS 5), conducted in 2014 and 2015. Only those who were 60 years or older were included in the analyses. We used a logistic regression analysis to determine factors associated with use of outpatient services. Among 2912 participants, only 22.7% of respondents had visited health workers or doctors within the previous 4 weeks before the survey. After controlling for other variables, factors associated with the use of outpatient services were socioeconomic status, insurance status, regions of residence, self-rated health, and the number of chronic conditions. Inequality in outpatient services was observed among the elderly in Indonesia. More effort is need to expand insurance coverage for the elderly, particularly for those in the lower economic status, and to improve access to outpatient services in rural regions by allocating the needed resources.


Alteration in cerebrospinal fluid (CSF) markers associated with α-synucleinopathies.
Rapid eye movement sleep behavior disorder (RBD) is linked to other α-synucleinopathies such as Parkinson's disease and Lewy body dementia. It is essential to consider and exclude RBD while studying CSF markers in the latter two to avoid confounding bias and improve test results' specificity.


Spontaneous coronary artery dissection.
Spontaneous coronary artery dissection (SCAD) is an infrequent condition that is underdiagnosed. There is a predilection for young women without traditional cardiovascular risk factors, and it is increasingly diagnosed in women who are not peripartum. We discovered an association between SCAD and fibromuscular dysplasia (FMD), in which most women with nonatherosclerotic SCAD were found to have FMD in another vascular territory. We suspect that these seemingly healthy patients have underlying coronary FMD that predisposed them to coronary dissection. Medical treatment of SCAD includes antiplatelet therapy and β-blockade. Revascularization of SCAD patients might be challenging, and the recommendation for stenting or surgery depends on their clinical status and the dissected coronary anatomy. The long-term outcome of patients who survived their SCAD event is generally good, however, they are at risk for recurrent dissection and major cardiovascular events, and thus should be closely monitored by cardiovascular specialists. This review summarizes the epidemiology, associated etiology, diagnosis, management, and outcome of patients with SCAD.


Left ventricular morphology and systolic function in sleep-disordered breathing: the Sleep Heart Health Study.
Whether sleep-disordered breathing (SDB) is a risk factor for left ventricular (LV) hypertrophy and dysfunction is controversial. We assessed the relation of SDB to LV morphology and systolic function in a community-based sample of middle-aged and older adults. The present study was a cross-sectional observational study of 2058 Sleep Heart Health Study participants (mean age 65+/-12 years; 58% women; 44% ethnic minorities) who had technically adequate echocardiograms. A polysomnographically derived apnea-hypopnea index (AHI) and hypoxemia index (percent of sleep time with oxyhemoglobin saturation < 90%) were used to quantify SDB severity. LV mass index was significantly associated with both AHI and hypoxemia index after adjustment for age, sex, ethnicity, study site, body mass index, current and prior smoking, alcohol consumption, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and prevalent myocardial infarction. Adjusted LV mass index was 41.3 (SD 9.90) g/m(2.7) in participants with AHI < 5 (n=957) and 44.1 (SD 9.90) g/m(2.7) in participants with AHI > or = 30 (n=84) events per hour. Compared with participants with AHI < 5, those with AHI > or = 30 had an adjusted odds ratio of 1.78 (95% confidence interval 1.14 to 2.79) for LV hypertrophy. A higher AHI and higher hypoxemia index were also associated with larger LV diastolic dimension and lower LV ejection fraction, with a trend toward lower LV fractional shortening. LV wall thickness was significantly associated with the hypoxemia index but not with AHI. Left atrial diameter was not associated with either SDB measure. In a community-based cohort, SDB is associated with echocardiographic evidence of increased LV mass and reduced LV systolic function.


Influence of Guided Waves in Tibia on Non-linear Scattering of Contrast Agents.
The aim of this study was to elucidate the linear and non-linear responses of ultrasound contrast agent (UCA) to frequency-dispersive guided waves from the tibia cortex, particularly two individual modes, S0 (1.23 MHz) and A1 (2.06 MHz). The UCA responses to guided waves were illustrated through the Marmottant model derived from measured guided waves, and then verified by continuous infusion experiments in a vessel-tibia flow phantom. These UCA responses were further evaluated by the enhanced ratio of peak values and the resolutions of UCA backscattered echoes. Because of the individual modes S0 and A1 in the tibia, the peak values of the UCA backscattered echoes were enhanced by 83.57 ± 7.35% (p < 0.05) and 80.77 ± 6.60% (p < 0.01) in the UCA subharmonic frequency and subharmonic imaging, respectively. However, corresponding resolutions were 0.78 ± 0.07 (p < 0.05) and 0.72 ± 0.12 (p < 0.01) times those without guided wave disturbances, respectively. Even though the resolution was partly degenerated, the subharmonic detection sensitivity of UCA was improved by the guided waves. Thus, UCA responses to the double-frequency guided waves should be further explored to benefit the detection of capillary perfusion in tissue layers near the bone cortex, particularly for perfusion imaging in the free flaps and skeletal muscles.


Yeast communities associated with Drosophila species and related flies in an eastern oak-pine forest: a comparison with western communities.
Intestinal yeast mycobiota were studied in 14 species of Drosophila and in the drosophilid species Chymomyza amoena, captured at Pinery Provincial Park, Ontario. Over 56 yeast species, some undescribed, were isolated. These yeast communities were compared with those from two similar surveys conducted in western portions of North America. The community structures were influenced significantly by the habitat rather than phylogeny of the flies. Geographic separation was a factor affecting yeast taxa frequencies in the fly species, but it was largely overshadowed by ecological factors when the communities were described physiologically. The notion that habitats are filled by yeasts which add up to a suitable physiological potential, more or less independently of their taxonomic affinities, was thus confirmed.


The NOGO receptor NgR2, a novel αVβ3 integrin effector, induces neuroendocrine differentiation in prostate cancer.
Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype.


Paraprofessional role in a mental health continuing care program.
The authors report on a unique program in which paraprofessionals provide continuing care services to patients in a large public psychiatric hospital, both before and after discharge. Data from one hundred patients indicate that paraprofessional caseworkers effectively managed 85 percent of the patients' post-discharge problems without needing to directly involve their professional teammates.


Temporal distribution of Fukushima-derived 137Cs in coniferous forest soil evaluated based on compartment-exponential model.
Based on the compartment and exponential models, the distribution of Fukushima-derived 137Cs was evaluated at four sampling dates in undisturbed coniferous forest soil. The compartment model was employed to evaluate the dynamic of 137Cs in the three sub-sections of the forest floor (FF), namely undergrowth (UG), litter layer (OL), and fragmented litter layer (OF), while the exponential model was administrated to describe its distribution below the FF. According to the compartment model, the derived ecological half-life of 137Cs in the UG, OL, and OF layers was 0.97, 1.1, and 4.9 years, respectively, indicating 137Cs resides much longer in the OF layer. Hence, this soil section remains a potential source of radiation dose mainly due to its high 137Cs content associated with low attenuation effect. Below the OF layer, the 137Cs distribution was well described by exponential model and its derived relaxation lengths were in the range of 0.8-1.4 cm, implying the migration of 137Cs in mineral soil is very slow and almost intact during the observation time. Collectively, our results highlighted that the compartment model for the FF and the exponential model for the soil below the FF are adequate enough to generate essential information. Thus, the potential decontamination measures should have to be chosen on their effect on the FF's 137Cs. Graphical abstract.


Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-kappaB signaling.
The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylaminofluorene (2-AAF) efficiently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NF-kappaB binding site located -167 to -158 of the rat mdr1b promoter. 2-AAF activates IkappaB kinase (IKK), resulting in degradation of IkappaBbeta and activation of NF-kappaB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic fibroblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at -6092 which contains a NF-kappaB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream effectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream effector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple effectors of the PI3K signaling pathway.


TSH-receptor antibodies, HLA B8 and thyroid autoantibodies in patients with Graves' disease in therapeutically induced euthyroidism.
The prevalence of TSH-receptor antibodies and of thyroid autoantibodies was studied in 48 HLA-typed patients with Graves' disease, who were in an euthyroid state after antithyroid therapy with methimazole. TSH-receptor antibodies, which were found in 35% of the patients, did not correlate with the positivity of HLA B8. By contrast the persistence of thyroid microsomal antibodies was significantly associated with HLA B8.


[Robot-assisted pancreatic resection].
Although robot-assisted pancreatic surgery has been considered critically in the past, it is nowadays an established standard technique in some centers, for distal pancreatectomy and pancreatic head resection. Compared with the laparoscopic approach, the use of robot-assisted surgery seems to be advantageous for acquiring the skills for pancreatic, bile duct and vascular anastomoses during pancreatic head resection and total pancreatectomy. On the other hand, the use of the robot is associated with increased costs and only highly effective and professional robotic programs in centers for pancreatic surgery will achieve top surgical and oncological quality, acceptable operation times and a reduction in duration of hospital stay. Moreover, new technologies, such as intraoperative fluorescence guidance and augmented reality will define additional indications for robot-assisted pancreatic surgery.


Mass produced village health workers and the promise of primary health care.
The most evident aspect of primary health care (PHC) development in many countries is the mass recruitment and training of village health workers (VHWs). These VHW schemes are often merely an extension of the organized government health services. This paper takes the view that over emphasis of VHWs is a fatal limitation and narrowing of the original idea of PHC. In the spirit of PHC, communities should be allowed to go through the process of identifying their problems, sorting out their priorities, means of solving identified problems through the material and human resources they have at their disposal. Before communities have been allowed to go through such a process, the selection of VHWs is at best, an imposition from above. PHC is thus robbed of its most fundamental components, of community participation, self-determination and self-reliance.


Pupil diameter as a biomarker of effort in goal-directed gait.
Subjects' eye movement behavior related to cognitive effort during gait was measured as subjects walked to perform low and high cognitive load tasks. We found that all pupil diameter measures, fixation durations, and the proportion of blink duration changed significantly during gait as a function of task load. In contrast, the number of fixations, saccade durations and travel time did not change significantly as a function of task load. Findings showed that pupil diameter was the best predictor of task load during one's gait preceding the performance of the task. While other studies have demonstrated the importance of eye fixation characteristics during gait, our findings showed that eye measures related to pupil diameter were better at detecting cognitive load while walking to perform a task compared to eye fixation data. We also found that cognitive effort was not limited to just the performance of the task, but that it was also exerted during one's gait preceding the performance of the task. Therefore, the additional attention demand caused by an increase in task complexity may result in less attentional resources being available to adequately handle distractions (such as obstacle avoidance) while walking to perform the task. Consequently, this may increase the likelihood of falls in those individuals with lower attentional capacity.


The impact of follicular (FL) and other indolent non-Hodgkin's lymphomas (NHL) on work productivity-a preliminary analysis.
Although much is known about the efficacy, toxicity, and direct costs of treatment for follicular lymphoma (FL), there is no data assessing the impact of this diagnosis on the work productivity of affected individuals. We conducted a cross-sectional survey study of consecutive patients attending a malignant haematology clinic at a large multi-disciplinary cancer centre. Patients with a diagnosis of FL or other indolent non-Hodgkin's lymphoma completed questionnaires assessing health status, work productivity, and activity impairment. Eighty-four patients completed the survey study (95% response). Patients who continued to work reported a minimal impact on their work productivity (10%+/-standard deviation SD 20; 0%=no effect and 100%=complete impairment of activity) and on their daily activities (13%+/-SD 25) attributable to their cancer. Prior to lymphoma diagnosis, over 71% of patients were working while 14% were retired. At the time of survey administration, only 41% of patients were still able to work with a significant proportion of patients having transitioned to retirement (36%), sick leave (10%), or unemployment (4%). On multivariate analysis, significant activity impairment (daily activity impairment>50%) was predicted by poor self-rated health status (OR 32.1; 95% CI: 5.9-174.2; p<0.0001) and active chemotherapy treatment (OR 14.5; 95% CI: 0.91-230.9; p=0.059). Although few patients with indolent lymphoma identified significant impairment in productivity, many were unable to continue employment following diagnosis, needed to miss days from work, or imposed a significant burden on caregivers. The greatest impact on activity is apparent in patients who rate their health status as poor and in those who are currently receiving systemic therapy.


Presentation in patients with angiographically documented coronary artery disease and type II diabetes mellitus (from the BARI 2D Clinical Trial).
Clinically stable patients with type 2 diabetes mellitus and coronary artery disease are not often thought to present with the symptom of typical angina. The aims of this study were to enumerate the proportion of patients presenting with typical angina or other cardiac symptoms and to elucidate what important clinical variables are associated with the presence of typical angina in patients with type 2 diabetes mellitus and angiographically documented coronary artery disease. Symptoms of angina, anginal equivalents, or an absence of symptoms were obtained using baseline data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial (n = 2,319). A bivariate analysis stratified by the presence or absence of previous revascularization and logistic regression modeling with a stepwise covariate selection was used. Eighty-two percent of patients had symptoms, while 18% presented asymptomatically. This was further divided approximately into typical angina (1/5), anginal equivalents (1/5), combination (2/5), and asymptomatic (1/5). A history of previous revascularization was a determinant of the type of symptom presentation with regard to the variables gender, age, current insulin use, myocardial jeopardy index score, and use of β blockers. In the multivariate logistic regression analysis, of the available candidate variables, only a history of β-blocker use (odds ratio 1.53, 95% confidence interval 1.24 to 1.94, p <0.0001) and previous percutaneous coronary intervention (odds ratio 1.55, 95% confidence interval 1.24 to 1.94, p <0.0001) had higher odds of an association with typical angina. In conclusion, a large proportion of patients with type 2 diabetes mellitus and coronary artery disease indeed have symptoms. Future studies of long-term outcomes associated with these symptoms are needed.