[The use of coca leaves in traditional communities: perspectives in health, society, and culture].
The article focuses on the sociocultural issues associated with the use of coca leaves in the Andes and Amazon regions. Approaching from a theoretical perspective, it explores scientific articles and magazine and newspaper interviews of distinguished professionals. The study's findings suggest that the tendency to indiscriminately link coca to cocaine, and consequently to drug-trafficking, stems from a historically constructed bias that eclipses the historical and cultural roots of the age-old use of this plant. It is up to psychology as a science to break the silence surrounding indigenous issues and come to understand the dynamics of these peoples' sociocultural processes so that it can figure in spaces where differentiated treatment is required.


Balance confidence and falls in nondemented essential tremor patients: the role of cognition.
To examine (1) the effect of cognitive ability on balance confidence and falls, (2) the relationship of balance confidence and falls with quantitative measures of gait, and (3) measures that predict falls, in people with essential tremor (ET). Cross-sectional study. General community. People with ET (n=132) and control subjects (n=48). People with ET were divided into 2 groups based on the median score on the Modified Mini-Mental State Examination: those with lower cognitive test scores (ET-LCS) and those with higher cognitive test scores (ET-HCS). Not applicable. Six-item Activities of Balance Confidence (ABC-6) Scale and falls in the previous year. Participants with ET-LCS had lower ABC-6 scores and a greater number of falls than those with ET-HCS (P<.05 for all measures) or control subjects (P<.01 for all measures). Quantitative gait measures were significantly correlated with ABC-6 score and falls. Gait speed (P<.007) and ABC-6 score (P<.02) were significant predictors of falls. Receiver operating characteristic curve analysis revealed that gait speed <0.9m/s and ABC-6 score <51% were associated with moderate sensitivity and specificity in identifying fallers. People with ET-LCS have impaired gait and report lower balance confidence and a higher number of falls than their counterparts (ET-HCS) and than control subjects. We have identified assessments that are easily administered (gait speed, ABC-6 Scale) and are associated with falls in ET.


Hsp60 in Skeletal Muscle Fiber Biogenesis and Homeostasis: From Physical Exercise to Skeletal Muscle Pathology.
Hsp60 is a molecular chaperone classically described as a mitochondrial protein with multiple roles in health and disease, participating to the maintenance of protein homeostasis. It is well known that skeletal muscle is a complex tissue, rich in proteins, that is, subjected to continuous rearrangements, and this homeostasis is affected by many different types of stimuli and stresses. The regular exercise induces specific histological and biochemical adaptations in skeletal muscle fibers, such as hypertrophy and an increase of mitochondria activity and oxidative capacity. The current literature is lacking in information regarding Hsp60 involvement in skeletal muscle fiber biogenesis and regeneration during exercise, and in disease conditions. Here, we briefly discuss the functions of Hsp60 in skeletal muscle fibers during exercise, inflammation, and ageing. Moreover, the potential usage of Hsp60 as a marker for disease and the evaluation of novel treatment options is also discussed. However, some questions remain open, and further studies are needed to better understand Hsp60 involvement in skeletal muscle homeostasis during exercise and in pathological condition.


Leprosy research and elimination.
The contribution of leprosy research to the progress being made toward elimination of leprosy has been critical. A major development in the promotion of leprosy research during the last 25 years has been the initiative taken by the WHO Special Programme for Research and Training in Tropical Diseases (TDR) through two of its scientific working groups, one on the immunology of leprosy (IMMLEP) and the other on the chemotherapy of leprosy (THELEP), which were set up in 1974 and 1976, respectively. IMMLEP and THELEP have greatly facilitated inputs from scientists not usually active in leprosy research. The coordinated efforts of IMMLEP and THELEP also facilitated goal-oriented research toward high-priority target areas such as an anti-leprosy vaccine and newer and better drug-combinations for the treatment of leprosy. Whereas the prospects for a leprosy vaccine appeared very promising in the early years, the first vaccine produced did not meet expectations for several reasons. Moreover, the possibility of using a vaccine in leprosy is not bright, because of both the technical problems as well as the reduced relevance of a vaccine at a time when leprosy is becoming less and less common. On the other hand, the modest expectations for newer and better drug combinations led to multi-drug therapy (MDT) for the control of leprosy. It is the introduction of MDT that is credited with the current global reduction of leprosy and the progress thus far made toward eliminating the disease as a public health problem. Nevertheless, many areas in leprosy, such as nerve damage, remain that require major research inputs in the future.


Age determination and validation studies of marine fishes: do deep-dwellers live longer?
Age determination and validation studies on deep-water marine fishes indicate they are difficult to age and often long-lived. Techniques for the determination of age in individual fish includes growth-zone analysis of vertebral centra, fin rays and spines, other skeletal structures, and otoliths (there are three sets of otoliths in most bony fish semicircular canals, each of which is made of calcium carbonate). Most have regular increments deposited as the fish (and its semicircular canals) grows. The most commonly used otolith for age determination is the largest one called the sagitta. Age validation techniques include: (1) tag-recapture, often combined with oxytetracycline injection and analysis in growth-zones of bone upon recapture; (2) analysis of growth-zones over time; and (3) radiometric approaches utilizing a known radioactive decay series as an independent chronometer in otoliths from bony fishes. We briefly summarize previous studies using these three validation approaches and present results from several of our radiometric studies on deep-water, bony fishes recently subjected to expanding fisheries. Radiometric age validation results are presented for four species of scorpaenid fishes (the bank, Sebastes rufus, and bocaccio, S. paucispinis, rockfishes, and two thornyhead species, Sebastolobus altivelis and S. alascanus). In addition, our analysis of scorpaenids indicates that longevity increases exponentially with maximum depth of occurrence. The reason that the deep-water forms of scorpaenid fishes are long-lived is uncertain. Their longevity, however, may be related to altered physiological processes relative to environmental parameters like low temperature, high pressures, low light levels, low oxygen, and poor food resources.


Microduplications of 10q24 Detected in Two Chinese Patients with Split-hand/foot Malformation Type 3.
Split hand/foot malformation (SHFM) is a congenital heterogeneous disorder with prominent limb deficiency. Seven loci have been identified to associate with SHFM, including SHFM1 to SHFM6 and SHFM/SHFLD. SHFM3 is an autosomal dominant disease, of which the pathogenesis is closely related to the genomic rearrangements at 10q24.We described two Chinese patients with the SHFM3 phenotype by high-resolution SNP array technology. We detected a 534kb microduplication at 10q24 encompassing TLX1, LBX1, BTRC and POLL, and a 600kb duplication with TLX1, LBX1, BTRC, POLL, and FBXW4 located. Sequencing analysis did not find any pathogenic mutations in genes within the region detected by SNP Array Analysis. Our findings may offer more evidence for the further mechanism research of limb-specific congenital disease and will give more precise diagnosis to SHFM3 patients.


The role of transcription factors in the guidance of granulopoiesis.
In recent years, the prospective isolation of hematopoietic stem and progenitor cells has identified the hierarchical structure of hematopoietic development and lineage-commitment. Moreover, these isolated cell populations allowed the elucitation of the molecular mechansims associated with lineage choice and revealed the indispensable functions of transcription factors as lineage determinants. This review summarizes current concepts regarding adult murine granulopoiesis and illustrates the importance of the transcription factors C/EBPα, PU.1 and GATA-2 for the development of neutrophil, eosinophil and basophil granulocytes.


Identification of the bicarbonate secretory cell of the turtle bladder.
The turtle bladder consists primarily of two mucosal cell types, mitochondrial rich (MR) and granular (G) cells. The MR cells secrete H+. In addition, the bladder secretes HCO3-, an energy-requiring Cl(-)-dependent transport system. These studies were designed to identify the cell type responsible for HCO3- secretion. Specific HCO3- and H+ secretory inhibitors were added to alter O2 consumption of MR and G cells. Cells were separated by Ficoll density centrifugation. Ouabain (10(-4) M) was used in all studies to eliminate O2 consumption associated with Na+ transport. O2 consumption of cells treated with 10(-4) M 4-acetamido-4'-isothiocyanostilbene-2,2'-sulfonic acid (SITS), which indirectly inhibits H+ secretion, was compared with cells additionally treated with 5 X 10(-4) M acetazolamide, an inhibitor of both H+ and HCO3- secretion. O2 consumption of MR cells treated with SITS alone was significantly greater than that of MR cells additionally treated with acetazolamide (delta = 0.56 +/- 0.10 microliter O2 X h-1 X mg protein-1, n = 6, P less than 0.003). There was no significant difference in G cells similarly treated. Another means of selectively altering H+ and HCO3- transports and their associated metabolic rates is to manipulate the Cl- concentration of the incubation medium. In a Cl(-)-rich medium, HCO3- and H+ transports are maximized. In low Cl(-)-SO2-4 medium, HCO3- secretion is selectively reduced.(ABSTRACT TRUNCATED AT 250 WORDS)


Tanshinone IIA attenuates renal damage in STZ-induced diabetic rats via inhibiting oxidative stress and inflammation.
Oxidative stress and inflammation have been demonstrated to be involved in the onset and promotion of diabetic nephropathy (DN).Tanshinone IIA (Tan) possesses both antioxidant and anti-inflammatory properties. Here, the aim of the present study was to explore whether Tan could attenuate renal damage in the rats with streptozotocin (STZ)-induced diabetes and its potential mechanisms. Tan was gavaged to STZ-induced diabetic rats at the dose of 10mg/kg once a day for 12 weeks. Tan treatment significantly attenuated albuminuria and renal histopathology in diabetic rats. Besides, Tan treatment also effectively inhibited oxidative stress and inflammatory reaction in the kidneys of diabetic rats. Our study provided evidence that the protective effect of Tan on diabetes-induced renal injury is associated with inhibition of oxidative stress and inflammation. Tan may be a potential candidate for the treatment of DN.


Addressing Chemotherapy-Induced Peripheral Neuropathy Using Multi-Frequency Vibrometry and Patient-Reported Outcomes.
(1) The study evaluated correlations between multi-frequency vibrometry (MF-V) and the measure of chemotherapy-induced peripheral neuropathy developed by the European Organization for the Research and Treatment of Cancer (CIPN18). (2) Patients with cancer scheduled to undergo treatment with capecitabine and oxaliplatin (CAPOX) or carboplatin and paclitaxel (Carbo-Tax) were recruited in a prospective, observational study with MF-V and the CIPN18 from baseline to one year after end of treatment. (3) The study recruited 31 evaluable patients. All MF-V measurements correlated significantly with the CIPN18 scores (r = 0.25−0.48, p > 0.003), with a low frequency (32 Hz) from metatarsals showing the best correlation coefficients (0.059 Z-score per CIPN18 point change, r = 0.48, CI-95 = [0.32; 0.60], p > 0.0001). The largest change in MF-V scores from baseline was seen in low-frequency VPTs taken from metatarsals at 8 Hz three months after end of treatment (from −0.26, CI-95 [−0.85, 0.38] to 1.15, CI-95 [0.53, 1.84]) for patients treated with oxaliplatin and at 32 Hz one year after end of treatment (from 0.09, CI-95 [−0.56, 0.77] to 0.88, CI-95 [0.34, 1.47]) for patients treated with paclitaxel. (4) Low-frequency vibration perception thresholds (8 and 32 Hz) correlated better with CIPN18 scores than high-frequency ones (128 and 250 Hz). If validated, this finding will advance CIPN pathophysiological understanding and inform the development of assessment methods.


[Opportunities of electrogastroenterography in pediatric gastroenterological practice].
The aim of the investigation is to identify opportunities electrogastroenterography (EGEG) in the survey and individualization treatment of children with inflammatory diseases of the gastrointestinal tract. We examined five children 10-15 years apparatus Gastroskan-HEV standard overlay electrodes. All children were treated with chronic gastritis in hospital. This diagnosis was confirmed by fibrogastrocopy. The study was conducted in the morning after fasting for 10-12 hours hunger for 40 minutes, and starting in 5-6 minutes after application of the electrodes. Investigated the maximal fluctuations in the range 3.5-4.2 and minimal changes. All children identified acceleration motor-evacuation function of the gastrointestinal tract on the background of hypersecretory reaction. EGEG method is noninvasive, has no contraindications and is well tolerated, allowing multiple examine patients regardless of their age and the severity of the condition and correct the assigned therapy.


A cyclic nucleotide-independent protein kinase in Leishmania donovani.
Leishmania donovani promastigotes labelled for 2 h with 32Pi incorporated radioactivity into at least 21 different proteins, as determined by SDS/polyacrylamide-gel electrophoresis. Pulse-chase studies with 32Pi demonstrated that the labelled proteins were in a dynamic state: some radiolabelled proteins rapidly disappeared and others appeared after the chase. The possibility of an ectokinase on the parasite was examined; incubation of intact parasites for 10 min at 25 degrees C in an osmotically buffered medium containing [gamma-32P]ATP, but not [alpha-32P]ATP, resulted in the labelling of 10 different protozoal proteins, presumably localized to the surface of the organism's plasma membrane. Intact promastigotes also catalysed the transfer of 32P from [gamma-32P]ATP to histones. The histone-dependent kinase was solubilized by repeated freezing and thawing, and sonication, and purified 118-fold by chromatographing the high-speed (200,000 g, 1 h) supernatant fraction on QAE-Sephadex, Sephadex G-150 and hydroxyapatite columns. The kinase eluted as a single activity peak from all three columns. The partially purified histone-dependent kinase had the following properties: pH optimum, 7.0; optimum temperature, 37 degrees C; Km for mixed calf thymus histone, 0.15 mM; Km for ATP, 0.8 mM; preferred fractionated histone acceptors, H2b greater than H4 greater than H2a greater than H3 (H1 does not serve as an acceptor); optimum activity required 10-20 mM-Mg2+; inhibited 50-80% by 0.01 mM- and 1 mM-Ca2+; activity was not stimulated by calmodulin, cyclic AMP (1 mM) or cyclic GMP (1 mM) nor inhibited by a cyclic AMP-dependent protein kinase inhibitor (50 micrograms/assay); apparent Mr 75,000, as determined by Sephadex G-150 gel filtration chromatography; phosphorylated exclusively serine residues. Protein kinase activity was low in the early exponential phase of the growth curve and increased 6-fold upon entry into the stationary phase.


[Analysis of artefacts by virtual endoscopy visualization of spiral CT data].
Analysis of patterns and causes of artifacts found in endographic visualization of spiral CT data. A straight perspex tube with a diameter of 20 mm was scanned in three different positions with ten scan protocols of varying table feed, increment, kernel, and signal to noise ratio (Tomoscan AVE, Philips). The resulting 30 CT datasets were visualized as a virtual endoscopy (VE) with ten different visualization protocols (Easy Vision 4.2, Philips) of varying threshold, resolution, and perspective angle. 300 VE datasets were analyzed by two radiologists and compared with the visualization of a software-generated tube in order to differentiate scanning and software artifacts. Five different classes of artifacts have been identified. Two of them result from the scanning process and two from the specific visualization method. Spiral patterns and the unevenness of the tube wall vary with the scanning parameter. Moiré-like patterns are caused by the VE software and depend on the visualization matrix. A high perspective angle distorts the size and form of the tube and makes it difficult for the observer to locate his position within the tube. The appearance of pseudoforamina depends on both the scanning and the visualization parameters. The knowledge of the patterns and potential causes of artifacts in endographic visualization of spiral CT scans are the basis for interpretation and optimization of this visualization method.


Specificity of cholesterol and analogs to modulate BK channels points to direct sterol-channel protein interactions.
The activity (Po) of large-conductance voltage/Ca(2+)-gated K(+) (BK) channels is blunted by cholesterol levels within the range found in natural membranes. We probed BK channel-forming α (cbv1) subunits in phospholipid bilayers with cholesterol and related monohydroxysterols and performed computational dynamics to pinpoint the structural requirements for monohydroxysterols to reduce BK Po and obtain insights into cholesterol's mechanism of action. Cholesterol, cholestanol, and coprostanol reduced Po by shortening mean open and lengthening mean closed times, whereas epicholesterol, epicholestanol, epicoprostanol, and cholesterol trisnorcholenic acid were ineffective. Thus, channel inhibition by monohydroxysterols requires the β configuration of the C3 hydroxyl and is favored by the hydrophobic nature of the side chain, while having lax requirements on the sterol A/B ring fusion. Destabilization of BK channel open state(s) has been previously interpreted as reflecting increased bilayer lateral stress by cholesterol. Lateral stress is controlled by the sterol molecular area and lipid monolayer lateral tension, the latter being related to the sterol ability to adopt a planar conformation in lipid media. However, we found that the differential efficacies of monohydroxysterols to reduce Po (cholesterol≥coprostanol≥cholestanol>>>epicholesterol) did not follow molecular area rank (coprostanol>>epicholesterol>cholesterol>cholestanol). In addition, computationally predicted energies for cholesterol (effective BK inhibitor) and epicholesterol (ineffective) to adopt a planar conformation were similar. Finally, cholesterol and coprostanol reduced Po, yet these sterols have opposite effects on tight lipid packing and, likely, on lateral stress. Collectively, these findings suggest that an increase in bilayer lateral stress is unlikely to underlie the differential ability of cholesterol and related steroids to inhibit BK channels. Remarkably, ent-cholesterol (cholesterol mirror image) failed to reduce Po, indicating that cholesterol efficacy requires sterol stereospecific recognition by a protein surface. The BK channel phenotype resembled that of α homotetramers. Thus, we hypothesize that a cholesterol-recognizing protein surface resides at the BK α subunit itself.


Phylogenetic analysis of transformable strains of thermophilic Bacillus species.
Few strains of thermophilic Bacillus spp are readily transformable with plasmid DNA. Given the considerable phylogenetic and phenotypic diversity amongst thermophilic bacilli, we have examined whether transformability is a trait associated with a particular phylogenetic group, by sequencing the 16S ribosomal RNA genes from transformable strains NUB3621, K1041, and NRRL1174. Although all of these strains were described in the literature as B. stearothermophilus, only NRRL1174 is closely related to the type strain of this species. Based on its 16S rDNA sequence and physiological data K1041 appeared to belong to the species B. thermodenitrificans, while NUB3621 showed a slightly closer relationship to B. thermoglucosidasius than to B. stearothermophilus. Therefore we conclude that the trait of transformability, though possibly strain-specific, is not limited to a single species of thermophilic Bacillus.


Ipilimumab targeting CD28-CTLA-4 axis: new hope in the treatment of melanoma.
Ipilimumab, a fully human monoclonal antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), is the new hope in the treatment of patients with advanced melanoma. Anti-CTLA-4 antibodies enhance T cell responses in vitro and in vivo and activate proliferation of tumour-specific T cells. The blockade of CTLA-4 by ipilimumab leads to immune-mediated tumor regression. Ipilimumab has been studied in metastatic melanoma in a number of clinical trials. Recently, a phase III, multi-center, randomized, double-blind trial showed a significant improvement in overall survival in patients with advanced melanomas treated with ipilimumab. Thus, ipilimumab was the first drug to demonstrate effect on overall survival in patients with metastatic melanoma. However, patients treated with ipilimumab develop various immune-related adverse events (irAEs), which are associated with objective and durable clinical responses. Use of new immune-related response criteria is recommended in patients on ipilimumab therapy to avoid premature treatment discontinuation. Further research is necessary to elucidate role of ipilimumab in adjuvant setting as well as in synergy with other novel modalities for the treatment of metastatic melanoma.


Release and skin distribution of silicone-related compound(s) from a silicone gel sheet in vitro.
The efficacy of topical silicone gel sheeting in prevention and/or reduction of keloids and hypertrophic scars is well recognized. In the present study, we reexamined the possible release of silicone-related compound(s) from a commercially available silicone gel sheet (Cica-Care, Smith and Nephew, Hull, England) in aqueous media in vitro. The silicone gel sheet was also applied on the excised skin surface to examine the possible distribution of silicone-related compounds into the skin in vitro. Silicone-related compounds were measured as silicon by an inductively coupled plasma-atomic emission spectrophotometer. When a piece of silicone gel sheet was placed in phosphate buffer solution (pH 3-9) at 37 degrees C for 7 days, the concentration of silicon in the medium increased with time, depending on the pH of the medium. This indicates that the released silicone-related compounds are water-soluble. When Cica-Care was applied on the surface of excised rat skin, human axilla skin and hypertrophic scars under hydrated conditions in vitro, silicon was detected in all skin samples. Greater distribution was observed in rat skin than in human axilla skin and hypertrophic scars. The release of silicone-related compounds from a silicone gel sheet (Cica-Care) and their distribution into the skin were demonstrated in vitro. Silicone-related compounds distributed into the skin may have pharmacological effects on the skin. Further investigation will be necessary to investigate in detail the action of silicone-related compounds on the proliferation of fibroblasts and excessive production of collagen.


Synthesis of 1-Boc-3-fluoroazetidine-3-carboxylic acid.
Synthetic strategies toward 3-fluoroazetidine-3-carboxylic acid, a new cyclic fluorinated beta-amino acid with high potential as building block in medicinal chemistry, were evaluated. The successful pathway includes the bromofluorination of N-(diphenylmethylidene)-2-(4-methoxyphenoxymethyl)-2-propenylamine, yielding 1-diphenylmethyl-3-hydroxymethyl-3-fluoroazetidine after reduction of the imino bond, ring closure, and removal of the 4-methoxybenzyl group. Changing the N-protecting group to a Boc-group allows further oxidation to 1-Boc-3-fluoroazetidine-3-carboxylic acid, a new fluorinated heterocyclic amino acid.


A population-based observational study on the factors associated with the completion of palliative chemotherapy among patients with oesophagogastric cancer.
Palliative chemotherapy is routinely given to patients diagnosed with locally advanced or metastatic oesophagogastric (O-G) cancer. We examine which patients with O-G cancer in England receive palliative chemotherapy, and identify factors associated with treatment completion. A prospective population-based observational study. All English National Health Service (NHS) trusts diagnosing patients with O-G cancer. Data were prospectively collected on patients diagnosed with invasive epithelial cancer of the oesophagus or stomach between 1 October 2007 and 30 June 2009 in English NHS hospitals, and those who had palliative treatment intent. We calculated the proportion of patients with different characteristics (eg, age, sex, stage at diagnosis, performance status) starting palliative chemotherapy. Multiple logistic regression was used to identify characteristics associated with non-completion of chemotherapy. There were 9768 patients in the study whose treatment intent was palliative. Among these, 2313 (24%) received palliative chemotherapy. It was received by 51% of patients aged under 55 years but only 9% of patients aged 75 years or over. Overall, 917 patients (53%) completed their treatment among the 1741 patients for whom information on treatment completion was recorded. Treatment completion ranged from 50-60% for patients with good performance status but was under 35% for patients aged 55 years or older with poor performance status. Treatment completion was not associated with site of cancer, pretreatment stage, sex, comorbidities or histology. Completion rates of palliative chemotherapy in patients with O-G cancer are low and elderly patients with poor performance status are very unlikely to complete a palliative chemotherapy treatment. Clinicians and patients should consider this information when balancing potential (survival) benefits, toxicity of treatment and its effect on quality of life.


[Vaccinations and malaria prophylaxis for international travelers].
The prevention of infectious diseases by vaccination and by counselling about malaria prophylaxis is a central aspect of travel medicine. Besides mandatory vaccinations required for entry to certain countries various vaccinations may be indicated depending on destination and type of travel as well as on individual risks of the traveler. In addition, pre-travel counselling should always include a check-up of standard vaccinations. Protection against mosquito bites is the basis of malaria prophylaxis. The addition of chemoprophylaxis is warranted in high risk areas. When regular chemoprophylaxis is not applied it is recommended to carry an appropriate antimalarial drug which can be used for emergency stand-by treatment in case of unexplained fever and when medical attention is not available within 24 hours. Travelers should realize that self-treatment is a first-aid measure and that they should still seek medical advice as soon as possible.


Global Variation in Opioid Use in Prostate Cancer Trials.
Regional variation in opioid use may be attenuated when pharmaceutical-sponsored trials include care that is often standardized by protocols. Understanding such variation is important for global trials that sometimes include time to opioid use as an end point. To identify whether regional and country-level variation in opioid use exists among prostate cancer clinical trials across the world. International phase 3 randomized clinical trials with patients with metastatic prostate cancer and initiation from January 1, 2008, or later were identified through internal databases of the US Food and Drug Administration. Data of patients in the intention-to-treat population from each trial were pooled. Descriptive and regression analyses of the collected data were conducted from September 2018 to February 2019. Cancer therapy. Opioid use data were from concomitant medications reported in the database for each trial. Logistic regression models, descriptive statistics, and χ2 tests were used to compare opioid use across world regions while adjusting for patient age, presence of visceral disease, bony disease, and baseline Eastern Cooperative Oncology Group Performance Status score and pain score. In total, 9670 patients (mean [SD] age of 69.2 [8.3] years) from 8 prostate cancer clinical trials in 46 countries were included. Patients in Eastern Europe (adjusted odds ratio [AOR], 0.19; 95% CI, 0.16-0.22) and Asia (AOR, 0.31; 95% CI, 0.25-0.38) were less likely to use opioids compared with patients in North America. These findings held even when the analysis was restricted to patients who reported moderate to high pain levels at baseline (Eastern Europe: AOR, 0.16 [95% CI, 0.12-0.22]; Asia: AOR, 0.47 [95% CI, 0.29-0.79]). Within North America, rates of opioid use were similar between the United States and Canada (AOR, 1.13; 95% CI, 0.93-1.37). This study found that, despite the clinical trial setting, opioid use appeared to vary by world regions, suggesting that this variability should be considered in international clinical trials.


Intestinal dysbiosis in spondyloarthritis - chicken or egg?
The well-established link between intestinal inflammation and spondyloarthritis (SpA) remains largely unexplained. Recent sequencing technologies have given access to a thorough characterization of the gut microbiota in healthy and disease conditions. This showed that inflammatory bowel disease (IBD) is associated with dysbiosis - i.e., disturbed gut microbiota composition - which may contribute to disease pathogenesis. Whether gut dysbiosis exists in SpA and could contribute to disease development or be a bystander consequence of chronic inflammation is a question of major interest. Several metagenomic studies have been performed in SpA. Most of them concerned faecal samples and showed dysbiosis consisting in a reduction of microbial biodiversity in a way similar to what has been described in IBD. They also highlighted changes in microbial taxa composition that could contribute to the inflammatory process. Likewise, healthy carriers of human leukocyte antigen (HLA)-B27 exhibited gut dysbiosis, indicating that this predisposing allele could exert its pathogenic effect by influencing microbiota composition, and possibly by driving antigen-specific cross-reactive immune response. On the other hand, SpA treatments were associated with a reduction of dysbiosis, showing that it is at least in part a consequence of inflammation. Recent insights from metagenomic studies warrant further investigations to identify the mechanisms by which microbial dysbiosis could contribute to SpA development. This would bring novel therapeutic opportunities aiming at correcting detrimental changes.


Sequential preoperative fluorodeoxyglucose-positron emission tomography assessment of response to preoperative chemoradiation: a means for determining longterm outcomes of rectal cancer.
We have previously demonstrated that fluorodeoxyglucose-positron emission tomography (FDG-PET) can assess extent of pathologic response of primary rectal cancer to preoperative chemoradiation. Our goal was to determine the prognostic significance of FDG-PET assessment of rectal cancer response to preoperative chemoradiation. Fifteen patients with locally advanced primary rectal cancer (clinically bulky or tethered, or ultrasound evidence of T3-4 disease, N1 disease, or both) deemed eligible for preoperative radiation and 5-FU-based chemotherapy (5,040 cGy to the pelvis and 2 cycles of bolus 5-FU/leucovorin) were prospectively enrolled from May 1997 to September 1998. FDG-PET was performed before and 4 to 5 weeks after completion of preoperative chemoradiation. FDG-PET parameters included maximum standard uptake value (SUV(max)), total lesion glycolysis (TLG), and visual response score. Patients were prospectively followed after operation, and disease status was determined. All patients demonstrated some degree of response to preoperative therapy based on pathologic examination. At a median followup of 42 months (range 23 to 54 months), 11 patients had no evidence of disease and 4 had died of disease. The mean percentage decrease in SUV(max) (DeltaSUV(max)) was 69% for patients free from recurrence and 37% for patients with recurrence (p = 0.004). DeltaSUV(max) >or= 62.5 and deltaTLG >or= 69.5 were the best predictors of no-evidence-of-disease status and freedom from recurrence. Patients with DeltaSUV(max) >or= 62.5 and deltaTLG >or= 69.5 had significantly improved disease-specific and recurrence-free survival (p = 0.08, 0.02 and p = 0.03, 0.01, respectively). Our results indicate that FDG-PET assessment of locally-advanced rectal cancer response to preoperative chemoradiation may predict longterm outcomes.


Comparison of contrast-enhanced harmonic ultrasonography and power Doppler ultrasonography for depicting vascularity of hepatocellular carcinoma identified by angiography-assisted CT.
The sensitivity of contrast-enhanced harmonic gray scale imaging was compared with that of power Doppler sonography in depicting tumor vascularity and contrast enhancement of hepatocellular carcinoma (HCC) identified by angiography-assisted computed tomography (CT). One hundred thirty-nine classic HCC nodules (108 patients), each appearing as a high-attenuation mass on early-phase CT during hepatic arteriography and as a perfusion defect on CT during arterial portography, were evaluated. Vascular findings and contrast enhancement patterns were evaluated by contrast-enhanced harmonic gray scale imaging. Arterial pulsatile flow into each nodule was checked by power Doppler sonography. Sensitivity of each modality for depicting tumor vascularity was examined by angiography-assisted CT findings as the gold standard. The sensitivity of contrast-enhanced harmonic gray scale imaging (134/139, 96.4%) was significantly greater than that of power Doppler sonography (96/139, 69.1%) (P<0.05). Twenty-six of twenty-seven nodules (96.3%) in the lateral segment, in which motion artifact is likely, were enhanced by contrast-enhanced harmonic gray scale imaging. Contrast-enhanced harmonic gray scale imaging is more sensitive than power Doppler sonography and is a noninvasive method that can be used as effectively as angiography-assisted CT to evaluate tumor vessels and contrast enhancement of HCC.


Nitrogen eutrophication particularly promotes turf algae in coral reefs of the central Red Sea.
While various sources increasingly release nutrients to the Red Sea, knowledge about their effects on benthic coral reef communities is scarce. Here, we provide the first comparative assessment of the response of all major benthic groups (hard and soft corals, turf algae and reef sands-together accounting for 80% of the benthic reef community) to in-situ eutrophication in a central Red Sea coral reef. For 8 weeks, dissolved inorganic nitrogen (DIN) concentrations were experimentally increased 3-fold above environmental background concentrations around natural benthic reef communities using a slow release fertilizer with 15% total nitrogen (N) content. We investigated which major functional groups took up the available N, and how this changed organic carbon (Corg) and N contents using elemental and stable isotope measurements. Findings revealed that hard corals (in their tissue), soft corals and turf algae incorporated fertilizer N as indicated by significant increases in δ15N by 8%, 27% and 28%, respectively. Among the investigated groups, Corg content significantly increased in sediments (+24%) and in turf algae (+33%). Altogether, this suggests that among the benthic organisms only turf algae were limited by N availability and thus benefited most from N addition. Thereby, based on higher Corg content, turf algae potentially gained competitive advantage over, for example, hard corals. Local management should, thus, particularly address DIN eutrophication by coastal development and consider the role of turf algae as potential bioindicator for eutrophication.


Protein Disulfide Isomerases Regulate IgE-Mediated Mast Cell Responses and Their Inhibition Confers Protective Effects During Food Allergy.
The thiol isomerase, protein disulfide isomerase (PDI), plays important intracellular roles during protein folding, maintaining cellular function and viability. Recent studies suggest novel roles for extracellular cell surface PDI in enhancing cellular activation and promoting their function. Moreover, a number of food-derived substances have been shown to regulate cellular PDI activity and alter disease progression. We hypothesized that PDI may have similar roles during mast cell-mediated allergic responses and examined its effects on IgE-induced mast cell activity during cell culture and food allergy. Mast cells were activated via IgE and antigen and the effects of PDI inhibition on mast cell activation were assessed. The effects of PDI blockade in vivo were examined by treating mice with the irreversible PDI inhibitor, PACMA-31, in an ovalbumin-induced model of food allergy. The role of dietary PDI modulators was investigated using various dietary compounds including curcumin and quercetin-3-rutinoside (rutin). PDI expression was observed on resting mast cell surfaces, intracellularly, and in the intestines of allergic mice. Furthermore, enhanced secretion of extracellular PDI was observed on mast cell membranes during IgE and antigen activation. Insulin turbidimetric assays demonstrated that curcumin is a potent PDI inhibitor and pre-treatment of mast cells with curcumin or established PDI inhibitors such as bacitracin, rutin or PACMA-31, resulted in the suppression of IgE-mediated activation and the secretion of various cytokines. This was accompanied by decreased mast cell proliferation, FcεRI expression, and mast cell degranulation. Similarly, treatment of allergic BALB/c mice with PACMA-31 attenuated the development of food allergy resulting in decreased allergic diarrhea, mast cell activation, and fewer intestinal mast cells. The production of TH2-specific cytokines was also suppressed. Our observations suggest that PDI catalytic activity is essential in the regulation of mast cell activation, and that its blockade may benefit patients with allergic inflammation.


Aging and reflective processes of working memory: binding and test load deficits.
It was hypothesized that age-related deficits in episodic memory for feature combinations (e.g., B. L. Chalfonte & M. K. Johnson, 1996) signal, in part, decrements in the efficacy of reflective component processes (e.g., M. K. Johnson, 1992) that support the short-term maintenance and manipulation of information during encoding (e.g., F. 1. M. Craik. R. G. Morris. & M. L. Gick, 1990; T. A. Salthouse, 1990). Consistent with this, age-related binding deficits in a working memory task were found in 2 experiments. Evidence for an age-related test load deficit was also found: Older adults had greater difficulty than young adults when tested on 2 features rather than 1, even when binding was not required. Thus, disruption of source memory in older adults may involve deficits in both encoding processes (binding deficits) and monitoring processes (difficulty accessing multiple features, evaluating them, or both).


Variation in styles of rifting in the Gulf of California.
Constraints on the structure of rifted continental margins and the magmatism resulting from such rifting can help refine our understanding of the strength of the lithosphere, the state of the underlying mantle and the transition from rifting to seafloor spreading. An important structural classification of rifts is by width, with narrow rifts thought to form as necking instabilities (where extension rates outpace thermal diffusion) and wide rifts thought to require a mechanism to inhibit localization, such as lower-crustal flow in high heat-flow settings. Observations of the magmatism that results from rifting range from volcanic margins with two to three times the magmatism predicted from melting models to non-volcanic margins with almost no rift or post-rift magmatism. Such variations in magmatic activity are commonly attributed to variations in mantle temperature. Here we describe results from the PESCADOR seismic experiment in the southern Gulf of California and present crustal-scale images across three rift segments. Over short lateral distances, we observe large differences in rifting style and magmatism--from wide rifting with minor synchronous magmatism to narrow rifting in magmatically robust segments. But many of the factors believed to control structural evolution and magmatism during rifting (extension rate, mantle potential temperature and heat flow) tend to vary over larger length scales. We conclude instead that mantle depletion, rather than low mantle temperature, accounts for the observed wide, magma-poor margins, and that mantle fertility and possibly sedimentary insulation, rather than high mantle temperature, account for the observed robust rift and post-rift magmatism.


A new mucosal propeller flap (deep lingual artery axial propeller): the renaissance of lingual flaps.
Lingual flaps provide ideal mucosal coverage for intraoral defects but traditionally require two surgical stages. The authors present an axial mucosal propeller flap for single-stage intraoral reconstruction. The flap includes the mucosa of the lateral side of the tongue, islanded on the deep lingual vessels. Between 2011 and 2013, 23 patients underwent intraoral mucosal reconstruction with a deep lingual artery axial propeller flap after cancer resection in the cheek (n = 16), floor of the mouth (n = 2), retromolar trigone (n = 2), hard palate (n = 2), and soft palate (n = 1). Mean defect size was 19.5 cm. Preoperative and postoperative intraoral function was evaluated with the Functional Intraoral Glasgow Scale. The authors always achieved one-stage reconstruction with primary donor-site closure. The only complications were an infection treated conservatively and a late oronasal fistula caused by radiotherapy. All patients resumed an oral diet after 1 week and none required surgical revision. Mean 12-month postoperative Functional Intraoral Glasgow Scale score was better than the preoperative score (13.5 versus 12.8). The deep lingual artery axial propeller flap combines the advantages of the traditional lingual flap (i.e., reliable axial vascularization and like-with-like reconstruction) with those of a propeller flap (i.e., one-stage transfer of like tissue and extreme mobility) and has wider indications than a conventional lingual flap. The technique is fast and has low morbidity and good functional results, and the authors recommend it as a first-choice technique to reconstruct moderate to large intraoral defects. Therapeutic, IV.


The Effect of Anti-Amoebic Agents and Ce6-PDT on Acanthamoeba castellanii Trophozoites and Cysts, In Vitro.
The purpose of this study was to analyze the concentration-dependent effects of biguanides (polyhexamethylene biguanide [PHMB], chlorhexidine [CH]); diamidines (hexamidine-diisethionate [HD], propamidine-isethionate [PD], dibromopropamidine-diisethionate [DD]); natamycin (NM); miltefosine (MF); povidone iodine (PVPI), and chlorin e6 PDT on Acanthamoeba trophozoites and cysts, in vitro. Strain 1BU was cultured in peptone-yeast extract-glucose medium. Trophozoites or cysts were cultured in PYG medium containing each agent at 100%, 50%, and 25% of maximum concentration for 2 hours. The percentage of dead trophozoites was determined using a non-radioactive cytotoxicity assay and trypan blue staining. Treated cysts were also maintained on non-nutrient agar Escherichia coli (E.coli) plates and observed for 3 weeks. All tested drugs displayed significant cytotoxic effects on 1BU cells based on the biochemical and staining-based viability assays tested. On non-nutrient agar E. coli plates, neither trophozoites nor freshly formed cysts were observed after PHMB, PD, NM, and PVPI treatment, respectively, within 3 weeks. However, CH-, HD-, DD-, and MF-treated cysts could excyst, multiply, and encyst again. The off-label drugs PHMB, PD, NM, and PVPI are under in vitro conditions more effective against strain 1BU than CH, HD, DD, and MF. Our findings also suggest that the non-nutrient agar E.coli plate assay should be considered as method of choice for the in vitro analysis of the treatment efficacy of anti-amoebic agents. Ophthalmologists may optimize the treatment regime against Acanthamoeba keratitis by pre-testing the in vitro susceptibilities of the Acanthamoeba strain against drugs of interest with the non-nutrient E.coli agar plate assay.


Not just a pathogen: The importance of recognizing genetic variability to mitigate a wildlife pandemic.
Emerging infectious diseases (EIDs) are increasingly recognized as a threat to both biodiversity and human health (Scheele et al., 2019; Wells et al., 2020). But pathogens cannot been seen as unique entities; their intraspecific genetic variability represented in variants, strains, antigenic types or genetic lineages may cause different impacts at the population level (Nelson and Holmes, 2007; Greenspan et al., 2018). The global spread of pathogens has been largely facilitated by globalization of transport, which particularly intensified during the last century (O'Hanlon et al., 2018). As seen with SARS-CoV-2, air travel can rapidly spread a pathogen globally (Wells et al., 2020). Furthermore, after initial introduction subsequent translocations of a pathogen may cause the contact of different variants facilitating the rise of novel genotypes that may have higher pathogenicity or transmissibility (Nelson and Holmes, 2007; Greenspan et al., 2018). Chytridiomycosis is an EID caused by the fungus Batrachochytrium dendrobatidis (Bd), that infects amphibian skin causing population declines to extinction in susceptible species. Now a wildlife pandemic, Bd has been recognized as the single pathogen causing the greatest loss of biodiversity on Earth (Scheele et al., 2019). Recent advances in genetics have made novel tools for pathogen detection and characterization more accessible and reliable (Boyle et al., 2004; Byrne et al., 2019). In this issue of Molecular Ecology Resources, Ghosh et al. (2021) report the development of a new genotyping qPCR assay targeting mitochondrial DNA (mtDNA) of Bd, and based on noninvasive swab samples (Figure 1), discriminate between the two most globally widespread and pathogenic genetic lineages of Bd. Having a better understanding of how the genetic diversity of a pathogen is distributed is crucial to understand their spread patterns and develop timely mitigation strategies.


Veterinary epidemiology--a key to sustainable pig production in Switzerland.
Sustainable animal production requires a healthy production system including healthy animals producing wholesome products. Epidemiology as a discipline is concerned with the occurrence of disease or disease indicators in populations as well as with factors influencing disease occurrence. By providing this information, epidemiology contributes significantly to the development and maintenance of healthy livestock. This is illustrated with the example of the enzootic pneumonia (EP) eradication programme of Switzerland. A series of observational studies were conducted in order to obtain the necessary knowledge to implement an area-wide EP eradication programme. The issues of economical eradication strategies at the herd level and the risk of re-infections were addressed. Simulation modelling and economical analysis were also applied. These research projects led to the successful start of a national eradication programme. The example of the EP eradication programme illustrates that applied epidemiological research provides critical information for the planning, implementation and evaluation of disease control programmes and is thus a key tool in developing sustainable animal production.


The spatial dimension in population fluctuations
Theoretical research into the dynamics of coupled populations has suggested a rich ensemble of spatial structures that are created and maintained either by external disturbances or self-reinforcing interactions among the populations. Long-term data of the Canadian lynx from eight Canadian provinces display large-scale spatial synchrony in population fluctuations. The synchronous dynamics are not time-invariant, however, as pairs of populations that are initially in step may drift out of phase and back into phase. These observations are in agreement with predictions of a spatially-linked population model and support contemporary population ecology theory.


The rescue of dentin matrix protein 1 (DMP1)-deficient tooth defects by the transgenic expression of dentin sialophosphoprotein (DSPP) indicates that DSPP is a downstream effector molecule of DMP1 in dentinogenesis.
Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) are essential for the formation of dentin. Previous in vitro studies have indicated that DMP1 might regulate the expression of DSPP during dentinogenesis. To examine whether DMP1 controls dentinogenesis through the regulation of DSPP in vivo, we cross-bred transgenic mice expressing normal DSPP driven by a 3.6-kb rat Col1a1 promoter with Dmp1 KO mice to generate mice expressing the DSPP transgene in the Dmp1 KO genetic background (referred to as "Dmp1 KO/DSPP Tg mice"). We used morphological, histological, and biochemical techniques to characterize the dentin and alveolar bone of Dmp1 KO/DSPP Tg mice compared with Dmp1 KO and wild-type mice. Our analyses showed that the expression of endogenous DSPP was remarkably reduced in the Dmp1 KO mice. Furthermore, the transgenic expression of DSPP rescued the tooth and alveolar bone defects of the Dmp1 KO mice. In addition, our in vitro analyses showed that DMP1 and its 57-kDa C-terminal fragment significantly up-regulated the Dspp promoter activities in a mesenchymal cell line. In contrast, the expression of DMP1 was not altered in the Dspp KO mice. These results provide strong evidence that DSPP is a downstream effector molecule that mediates the roles of DMP1 in dentinogenesis.


The quantitative surface analysis of an antioxidant additive in a lubricant oil matrix by desorption electrospray ionization mass spectrometry.
Chemical additives are incorporated into commercial lubricant oils to modify the physical and chemical properties of the lubricant. The quantitative analysis of additives in oil-based lubricants deposited on a surface without extraction of the sample from the surface presents a challenge. The potential of desorption electrospray ionization mass spectrometry (DESI-MS) for the quantitative surface analysis of an oil additive in a complex oil lubricant matrix without sample extraction has been evaluated. The quantitative surface analysis of the antioxidant additive octyl (4-hydroxy-3,5-di-tert-butylphenyl)propionate in an oil lubricant matrix was carried out by DESI-MS in the presence of 2-(pentyloxy)ethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate as an internal standard. A quadrupole/time-of-flight mass spectrometer fitted with an in-house modified ion source enabling non-proximal DESI-MS was used for the analyses. An eight-point calibration curve ranging from 1 to 80 µg/spot of octyl (4-hydroxy-3,5-di-tert-butylphenyl)propionate in an oil lubricant matrix and in the presence of the internal standard was used to determine the quantitative response of the DESI-MS method. The sensitivity and repeatability of the technique were assessed by conducting replicate analyses at each concentration. The limit of detection was determined to be 11 ng/mm(2) additive on spot with relative standard deviations in the range 3-14%. The application of DESI-MS to the direct, quantitative surface analysis of a commercial lubricant additive in a native oil lubricant matrix is demonstrated.


New insights into the distributions of nitrogen fixation and diazotrophs revealed by high-resolution sensing and sampling methods.
Nitrogen availability limits marine productivity across large ocean regions. Diazotrophs can supply new nitrogen to the marine environment via nitrogen (N2) fixation, relieving nitrogen limitation. The distributions of diazotrophs and N2 fixation have been hypothesized to be generally controlled by temperature, phosphorus, and iron availability in the global ocean. However, even in the North Atlantic where most research on diazotrophs and N2 fixation has taken place, environmental controls remain contentious. Here we measure diazotroph composition, abundance, and activity at high resolution using newly developed underway sampling and sensing techniques. We capture a diazotrophic community shift from Trichodesmium to UCYN-A between the oligotrophic, warm (25-29 °C) Sargasso Sea and relatively nutrient-enriched, cold (13-24 °C) subpolar and eastern American coastal waters. Meanwhile, N2 fixation rates measured in this study are among the highest ever recorded globally and show significant increase with phosphorus availability across the transition from the Gulf Stream into subpolar and coastal waters despite colder temperatures and higher nitrate concentrations. Transcriptional patterns in both Trichodesmium and UCYN-A indicate phosphorus stress in the subtropical gyre. Over this iron-replete transect spanning the western North Atlantic, our results suggest that temperature is the major factor controlling the diazotrophic community structure while phosphorous drives N2 fixation rates. Overall, the occurrence of record-high UCYN-A abundance and peak N2 fixation rates in the cold coastal region where nitrate concentrations are highest (~200 nM) challenges current paradigms on what drives the distribution of diazotrophs and N2 fixation.


The guidance of axons from transplanted neurons through aneural Drosophila wings.
The sensory neurons of the wing of Drosophila arise during the first 24 hr of metamorphosis, and their axons converge to form a stereotyped set of nerves projecting proximally from the peripherally located cell bodies through the wing and towards the CNS. To better characterize the cues guiding this stereotyped axon outgrowth, we have performed a series of transplantation studies in which neurons from a variety of sources (wing, eye, antenna, and leg disks) were placed into mutant, aneural wings. Axons growing from such implants in effect assay the host wing for the presence and location of guidance cues. Our results show, first, that such axons prefer to grow in the normal, proximal direction and, second, that they prefer to grow along the approximate site of one of the normal nerves, that of the third longitudinal vein. It therefore appears that the aneural wing epithelium contains cues capable of directing both the polarity and the location of axonal outgrowth. These cues are relatively non-specific, in that a variety of neuronal types are capable of responding to them.


Functional tissue engineering parameters toward designing repair and replacement strategies.
Abnormal joint kinematics and loads induced after soft tissue injuries are assumed to contribute to long-term degenerative joint disease and osteoarthritis. Controlling abnormal kinematics after repair and reconstruction of these injured structures would seem to be important for limiting wear of the articular cartilage surfaces. In this paper, we propose to expand the paradigm of functional tissue engineering to more fully characterize normal joint function and to establish design parameters for soft tissue repair and reconstruction to ultimately protect joint surfaces after surgery. Structure-function relationships are examined for tissues of increasing complexity, from tendons to menisci. Emphasis is placed on understanding normal in vivo function of tissues by conducting biomechanical experiments in vitro that better mimic in vivo conditions. This process yields nine classes of functional tissue engineering parameters: differential fiber length, in vivo force and displacement, variations in relative attachment site locations, loading from adjacent structures, fiber interactions, types of insertion, regional variations in material properties, nonparallel fiber orientations, and complex loading within the structure. These functional tissue engineering parameters are useful not only for understanding the function of normal tissues but for more effectively designing their repair and replacement. This paper concludes with a discussion of research directions that investigators might take to establish tissue-specific functional tissue engineering parameters for improving joint function and reducing articular surface degradation and osteoarthritis.


Transition to work: Perspectives from the autism spectrum.
To improve employment outcomes for adults with autism spectrum disorder, it is necessary to identify factors associated with successful transition to work from the perspectives of the individual and from those who work with or support them. This study involved focus groups with adults with autism spectrum disorder ( n = 9) participating in a 3-year employment and training programme, as well as focus groups with family members ( n = 6), support staff ( n = 7) and co-workers ( n = 6). The aim was to gain better understanding of the experience of transition to work, barriers and also the factors that promote workplace success. Main themes included factors that facilitated success at work ( Enablers), barriers to success ( Challenges) and programme outcomes ( Outcomes). Organisation support, advice from co-workers, supportive leadership, allowance of environmental modifications and presence of a consultant were identified as enablers that most facilitated success at work. Challenges included task-related difficulties, individual factors, social difficulties and distractibility, not managing work-related stress, and being perceived to be too frank. Outcomes were rated as positive and encompassed work-related outcomes, as well as outcomes related to sense of purpose, achieving personal independence and improvements in social relationships, both with work colleagues and within families.


A Comparison Study of Marginal and Internal Fit Assessment Methods for Fixed Dental Prostheses.
Numerous studies have previously evaluated the marginal and internal fit of fixed prostheses; however, few reports have performed an objective comparison of the various methods used for their assessment. The purpose of this study was to compare five marginal and internal fit assessment methods for fixed prostheses. A specially designed sample was used to measure the marginal and internal fit of the prosthesis according to the cross-sectional method (CSM), silicone replica technique (SRT), triple scan method (TSM), micro-computed tomography (MCT), and optical coherence tomography (OCT). The five methods showed significant differences in the four regions that were assessed (p < 0.001). The marginal, axial, angle, and occlusal regions showed low mean values: CSM (23.2 µm), TSM (56.3 µm), MCT (84.3 µm), and MCT (102.6 µm), respectively. The marginal fit for each method was in the range of 23.2-83.4 µm and internal fit (axial, angle, and occlusal) ranged from 44.8-95.9 µm, 84.3-128.6 µm, and 102.6-140.5 µm, respectively. The marginal and internal fit showed significant differences depending on the method. Even if the assessment values of the marginal and internal fit are found to be in the allowable clinical range, the differences in the values according to the method should be considered.


SARS-CoV-2: Review of Conditions Associated With Severe Disease and Mortality.
The 2019 Coronavirus Virus Disease (COVID-19) represents a global public health challenge in the twenty-first century. As of June 2020, the virus had spread across 216 countries across the globe. This paper aims to analyze and identify those existing comorbidities among COVID-19 patients that represent potential risk factors for COVID-19 complications, severe illness, and death. Multiple database resources were searched. The resources include the University of Saskatchewan library USearch, Google Scholar, PubMed, Medline, and the Google search engine. Thirty-seven articles, which included 15 different types of chronic diseases, were selected. Among the reviewed diseases and conditions, cancer, diabetes, lymphopenia, hypertension, kidney disease, smoking, chronic obstructive pulmonary disease (COPD), and organ transplant were found to represent potential risk factors for COVID-19 complications, severe illness, and death. Other conditions that require further research as to whether they predispose subjects to severe illness and death include coronary artery disease, cerebrovascular disease, valvular heart disease, gastrointestinal diseases, HIV/AIDS, asthma, and liver disease. In conclusion, this article explains the association between diseases mentioned above and the severity of COVID-19 and clearly shows the population at risk. This paper will help government bodies and decision-makers prioritize resources for these populations to reduce mortality rates and overall quality of life.


Interference Effect of Prior Explicit Information on Motor Sequence Learning in Relapsing-Remitting Multiple Sclerosis Patients.
Multiple sclerosis (MS) is the most widespread disabling neurological condition in young adults around the world. The purpose of this study was to investigate the impact of explicit information (EI) on motor-sequence learning in MS patients. Thirty patients with relapsing-remitting MS (RRMS), age: 29.5 (SD = 5.6) years and 30 healthy gender-, age-, and education-matched control group participants, age: 28.8 (SD = 6.0) years, were recruited for this study. The participants in the healthy group were then randomly assigned into an EI (n = 15) group and a no-EI (n = 15) group. Similarly, the participants in the control group were then randomly assigned into EI (n = 15) and no-EI (n = 15) groups. The participants performed a serial reaction time (SRT) task and reaction times. A retention test was performed after 48 hours. All participants reduced their reaction times across acquisition (MS group: 46.4 (SD = 3.3) minutes, P < 0.001, and healthy group: 39.4 (SD = 3.3) minutes, P < 0.001). The findings for the within-participants effect of repeated measures of time were significant (F(5.06, 283.7) = 71.33. P < 0.001). These results indicate that the interaction between group and time was significant (F(5.06, 283.7) = 6.44. P < 0.001), which indicated that the reaction time in both groups was significantly changed between the MS and healthy groups across times (B1 to B10). The main effect of the group (MS and healthy) (F(1, 56) = 22.78. P < 0.001) and also the main effect of no-EI vs EI (F(1, 56) = 4.71. P < 0.001) were significant. This study demonstrated that that RRMS patients are capable of learning new skills, but the provision of EI prior to physical practice is deleterious to implicit learning. It is sufficient to educate MS patients on the aim and general content of the training and only to provide feedback at the end of the rehabilitative session.


Gastric emptying of glucose in the dog.
The 30-minute gastric emptying of test meals consisting of 2.5%, 4%, 7%, 15%, or 25% glucose was evaluated in healthy, nonoperated dogs, using an orogastric intubation technique. An inversely proportional exponential relationship was found between test meal glucose concentration and amount of test meal emptied from the stomach in 30 minutes. For the 7%, 15%, and 25% glucose test meals, a mean (+/- SEM) of 1.11 +/- 0.03 kcal/min emptied into the duodenum, which represented 0.054 +/- 0.004 kcal/min/kg of body weight. Test meals of 2.5% and 4% glucose supplied significantly fewer kcal per minute to the duodenum than did the other 3 meals, indicating that control of gastric emptying of hypotonic glucose meals may be different than that of isotonic or hypertonic test meals in the dog.


Quality improvement in pediatric emergency medicine.
Pediatric patients, who accounted for 17.4% of US emergency department (ED) visits in 2010, present unique challenges that can impede an ED's ability to provide optimal care. To meet the growing demand for comprehensive, high-quality care, health care systems are incorporating quality improvement (QI) methods to reduce costs and variations in care and to improve access, safety, and ultimately the outcomes of medical care. This overview of QI initiatives within the field of pediatric emergency medicine explores how proven QI strategies are being integrated into efforts that target the care of children within the broader emergency care community. These initiatives are categorized within the domains of education, infrastructures supporting QI efforts, research, and community/government collaborations. Professional societies supporting education, such as the American Academy of Pediatrics, have made several strides to cultivate new health leaders that will use QI methodology to improve outcomes in pediatric emergency care. In addition to educational pursuits, professional societies and QI organizations (eg, Children's Hospital Association) offer stable infrastructures from which QI initiatives, either disease specific or broadly targeted, can be implemented as large-scale QI initiatives (eg, quality collaboratives). This overview also provides examples of how QI methodology has been integrated into research strategies and describes how the pediatric emergency medicine community can spread innovation and best practices into the larger emergency care community.


Protect your heart: a culture-specific multimedia cardiovascular health education program.
South Asians, the second fastest growing racial/ethnic minority in the United States, have high rates of coronary heart disease. Few coronary heart disease prevention efforts target this population. The authors developed and tested a culture-specific, multimedia coronary heart disease prevention education program in English and Hindi for South Asians. Participants were recruited from community organizations in Chicago, Illinois, between June and October of 2011. Bilingual interviewers used questionnaires to assess participants' knowledge and perceptions before and after the patient education program. The change from pretest score to posttest score was calculated using a paired t test. Linear regression was used to determine the association between posttest scores and education and language. Participants' (N = 112) average age was 41 years, 67% had more than a high school education, and 50% spoke Hindi. Participants' mean pretest score was 15 (SD = 4). After the patient education program, posttest scores increased significantly among all participants (posttest score = 24, SD = 4), including those with limited English proficiency. Lower education was associated with a lower posttest score (β = -2.2, 95% CI [-0.68, -3.83]) in adjusted regression. A culture-specific, multimedia patient education program significantly improved knowledge and perceptions about coronary heart disease prevention among South Asian immigrants. Culturally salient multimedia education may be an effective and engaging way to deliver health information to diverse patient populations.


Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression.
An endocrine disrupting chemical (EDC) is a global health concern. In this study, we examined the effects of genistein (GEN) on bisphenol A (BPA) or 17β-estradiol (E2)-induced cell growth and gene alterations of BG-1 ovarian cancer cells expressing estrogen receptors (ERs). In an in vitro cell viability assay, E2 or BPA significantly increased the growth of BG-1 cells. This increased proliferative activity was reversed by treatment with ICI 182,780, a well-known ER antagonist, while cell proliferation was further promoted in the presence of propyl pyrazole triol (PPT), an ERα agonist. These results imply that cell proliferation increased by E2 or BPA was mediated by ERs, particularly ERα. BPA clearly acted as a xenoestrogen in BG-1 ovarian cancer cells by mimicking E2 action. In contrast, GEN effectively suppressed BG-1 cell proliferation promoted by E2 or BPA by inhibiting cell cycle progression. E2 and BPA increased the expression of cyclin D1, a factor responsible for the G1/S cell cycle transition. They also decreased the expression of p21, a potent cyclin-dependent kinase (CDK) inhibitor that arrests the cell cycle in G1 phase, and promoted the proliferation of BG-1 cells. As shown by its repressive effect on cell growth, GEN decreased the expression of cyclin D1 augmented by E2 or BPA. On the other hand, GEN increased the p21 expression downregulated by E2 or BPA. Collectively, our findings suggest that GEN, a dietary phytoestrogen, has an inhibitory effect on the growth of estrogen-dependent cancers promoted by E2 or BPA.


Water content and proton magnetic resonance relaxation times of the brain in newborn rabbits.
The present study, using proton nuclear magnetic resonance relaxation (H1 NMR) measurements, was undertaken to quantitate water fractions with different mobility in the brain tissue obtained form New Zealand White rabbit pups. Serial studies were carried out at the postnatal age of 0-1, 24, 48, 72, and 96 h in pups nursed with their mothers and suckling ad libitum (group I) and in those pups separated from their mothers and completely withheld from suckling (group II). Tissue water content (desiccation method) and T1 and T2 relaxation times (H1 NMR method) were measured. Free, loosely bound, and tightly bound water fractions were calculated by applying multicomponent fits of the T2 relaxation curves. It was demonstrated that brain water content and T1 and T2 relaxation times did not change with age in the suckling pups. In pups withheld from suckling brain water decreased from 89.4 +/- 0.5% at birth to 87.7 +/- 0.1% at the age of 96 h (p < 0.05), T1 remained unchanged, and there was a significant fall in T2 by the age of 72 h (188 +/- 12 versus 178 +/- 4 ms, p < 0.05) and 96 h (171 +/- 6 ms, p < 0.01). Partition of brain water into bound and free fractions as derived from biexponential fits of T2 decay curve showed that the percent contribution of bound water fraction in pups of group I fell progressively from 61% at birth to 3% at the age of 72-96 h (p < 0.05). This fall was accelerated by the complete deprival of fluid intake, and the level of about 4% could be attained as early as the age of 24 h. Triexponential analysis of T2 relaxation curves revealed that the loosely bound fraction (middle component) predominated over the free (slow component) and the tightly bound (fast component) water fractions. In response to withholding fluid intake, the free water fraction increased 4-fold at the expense of tightly bound brain water. It is concluded that the majority of neonatal brain water is motion-constrained. The free, the loosely bound, and the tightly bound water fractions appear to be interrelated; from the brain water store water can be released to supply free water for volume regulation.


Integration preferences of wildtype AAV-2 for consensus rep-binding sites at numerous loci in the human genome.
Adeno-associated virus type 2 (AAV) is known to establish latency by preferential integration in human chromosome 19q13.42. The AAV non-structural protein Rep appears to target a site called AAVS1 by simultaneously binding to Rep-binding sites (RBS) present on the AAV genome and within AAVS1. In the absence of Rep, as is the case with AAV vectors, chromosomal integration is rare and random. For a genome-wide survey of wildtype AAV integration a linker-selection-mediated (LSM)-PCR strategy was designed to retrieve AAV-chromosomal junctions. DNA sequence determination revealed wildtype AAV integration sites scattered over the entire human genome. The bioinformatic analysis of these integration sites compared to those of rep-deficient AAV vectors revealed a highly significant overrepresentation of integration events near to consensus RBS. Integration hotspots included AAVS1 with 10% of total events. Novel hotspots near consensus RBS were identified on chromosome 5p13.3 denoted AAVS2 and on chromsome 3p24.3 denoted AAVS3. AAVS2 displayed seven independent junctions clustered within only 14 bp of a consensus RBS which proved to bind Rep in vitro similar to the RBS in AAVS3. Expression of Rep in the presence of rep-deficient AAV vectors shifted targeting preferences from random integration back to the neighbourhood of consensus RBS at hotspots and numerous additional sites in the human genome. In summary, targeted AAV integration is not as specific for AAVS1 as previously assumed. Rather, Rep targets AAV to integrate into open chromatin regions in the reach of various, consensus RBS homologues in the human genome.


The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors.
The Forkhead box O (FOXO) protein family is an evolutionarily conserved subclass of transcription factors recently identified as bona fide tumor suppressors. Preventing the accumulation of cellular damage due to oxidative stress is thought to underlie its tumor-suppressive role. Oxidative stress, in turn, also feedback controls FOXO4 function. Regulation of this process, however, is poorly understood but may be relevant to the ability of FOXO to control tumor suppression. Here, we characterize novel FOXO4 phosphorylation sites after increased cellular oxidative stress and identify the isomerase Pin1, a protein frequently found to be overexpressed in cancer, as a critical regulator of p27(kip1) through FOXO4 inhibition. We show that Pin1 requires these phosphorylation events to act negatively on FOXO4 transcriptional activity. Consistent with this, oxidative stress induces binding of Pin1 to FOXO, thereby attenuating its monoubiquitination, a yet uncharacterized mode of substrate modulation by Pin1. We have previously shown that monoubiquitination is involved in controlling nuclear translocation in response to cellular stress, and indeed, Pin1 prevents nuclear FOXO4 accumulation. Interestingly, Pin1 acts on FOXO through stimulation of the activity of the deubiquitinating enzyme HAUSP/USP7. Ultimately, this results in decreased transcriptional activity towards target genes, including the cell cycle arrest gene p27(kip1). Notably, in a primary human breast cancer panel, low p27(kip1) levels inversely correlated with Pin1 expression. Thus, Pin1 is identified as a novel negative FOXO regulator, interconnecting FOXO phosphorylation and monoubiquitination in response to cellular stress to regulate p27(kip1).


Programmable large area digital microfluidic array with integrated droplet sensing for bioassays.
We describe a new device concept for digital microfluidics, based on an active matrix electrowetting on dielectric (AM-EWOD) device. A conventional EWOD device is limited by the number of electrical connections that can be made practically, which restricts the number and type of droplet operations. In an AM-EWOD, the patterned electrodes of a conventional EWOD device are replaced by a thin film transistor (TFT) array, as found in a liquid crystal display (LCD), facilitating independent control of each electrode. The arrays can have many thousand individually addressable electrodes, are fully reconfigurable and can be programmed to support multiple simultaneous operations. Each element is 210 μm × 210 μm in size and contains a circuit that measures the electrical impedance of the liquid above it. This is used to determine the presence and size of a droplet, a method that can improve assay reliability and accuracy. This sensor provides feedback, error detection and closed loop control of an assay sequence. We describe the design, fabrication and testing of a 64 × 64 format AM-EWOD device with impedance sensor functionality. A colorimetric assay is implemented on the device and used to measure glucose in human blood serum. Results are compared with the same assay performed on a microtitre plate.


Inhibition of DNA methylation by S-adenosylethionine with the production of methyl-deficient DNA in regenerating rat liver.
Ethionine, a liver carcinogen, was administered p.o. (300 mg/kg) to rats 17 hr after partial hepatectomy. At 6 hr after administration of the ethionine, hepatic S-adenosylethionine levels were 30- to 40-fold greater than the hepatic level of S-adenosylmethionine. A 10-fold ratio of S-adenosylethionine to S-adenosylmethionine still persited at 24 hr after ethionine administration. When given at 17 hr after partial hepatectomy, ethionine produced a 30% inhibition of DNA synthesis, measured by the incorporation of [methyl-3H]thymidine at 23 to 24 hr after partial hepatectomy (6 to 7 hr after ethionine administration). DNA synthesized during this interval was methyl deficient as judged by the reduced incorporation of radioactivity from L-[methyl-3H]methionine into 5-methylcytosine residues of DNA. In an assay for DNA methylation in vitro using whole nuclei, the methyl-deficient DNA was methylated by S-adenosylmethionine 8 times more than was control DNA; the DNA methylation was competitively inhibited by S-adenosylethionine. These data suggest that S-adenosylethionine, formed in vivo from ethionine, competitively inhibits the methylation of DNA in vivo by S-adenosylmethionine, resulting in the production of methyl-deficient DNA.


Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome.
Oxidative stress (OS) and inflammation are often present in polycystic ovary syndrome (PCOS). We examined the effects of salsalate treatment on nutrient-induced OS and inflammation, ovarian androgen secretion, ovulation, and insulin sensitivity in PCOS. Eight lean insulin-sensitive women with PCOS and eight age- and body composition-matched ovulatory controls for baseline comparison participated in the study. The women with PCOS underwent a 12-wk treatment of salsalate, a nonsteroidal anti-inflammatory drug, at a dose of 3 g daily. Markers of OS and inflammation were quantified in mononuclear cells (MNC) and plasma from blood drawn fasting and 2 h after saturated fat ingestion before and after treatment. Ovarian androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration before and after treatment. Ovulation was documented based on biphasic basal body temperatures and luteal range progesterone elevations. A two-step pancreatic clamp was performed pre- and posttreatment to measure basal endogenous glucose production (EGP) and the steady-state glucose disposal rate (GDR) during the euglycemic phase and markers of OS and inflammation in MNC and plasma during the hyperglycemic phase. Salsalate administration suppressed lipid- and glucose-stimulated reactive oxygen species generation, activated nuclear factor-κB and circulating tumor necrosis factor-α, normalized basal androgen levels, and lowered HCG-stimulated androgen secretion without altering EGP or GDR. Four salsalate-treated subjects responded with two consecutive ovulations. We conclude that in PCOS, salsalate-induced suppression of OS and inflammation ameliorates ovarian androgen hypersecretion and may induce ovulation while maintaining insulin action.


Development of a Novel Nanoarchitecture of the Robust Photosystem I from a Volcanic Microalga Cyanidioschyzon merolae on Single Layer Graphene for Improved Photocurrent Generation.
Here, we report the development of a novel photoactive biomolecular nanoarchitecture based on the genetically engineered extremophilic photosystem I (PSI) biophotocatalyst interfaced with a single layer graphene via pyrene-nitrilotriacetic acid self-assembled monolayer (SAM). For the oriented and stable immobilization of the PSI biophotocatalyst, an His6-tag was genetically engineered at the N-terminus of the stromal PsaD subunit of PSI, allowing for the preferential binding of this photoactive complex with its reducing side towards the graphene monolayer. This approach yielded a novel robust and ordered nanoarchitecture designed to generate an efficient direct electron transfer pathway between graphene, the metal redox center in the organic SAM and the photo-oxidized PSI biocatalyst. The nanosystem yielded an overall current output of 16.5 µA·cm-2 for the nickel- and 17.3 µA·cm-2 for the cobalt-based nanoassemblies, and was stable for at least 1 h of continuous standard illumination. The novel green nanosystem described in this work carries the high potential for future applications due to its robustness, highly ordered and simple architecture characterized by the high biophotocatalyst loading as well as simplicity of manufacturing.


Lipid-Based Nutrient Supplements Plus Malaria and Diarrhea Treatment Increase Infant Development Scores in a Cluster-Randomized Trial in Burkina Faso.
Adequate nutrition is necessary for the rapid brain development that occurs during infancy. We tested the hypothesis that the provision of small-quantity, lipid-based nutrient supplements (SQ-LNSs) plus malaria and diarrhea treatment positively affects infant development. We also tested the effect of various doses of zinc provided in SQ-LNSs or in a tablet. In a partially masked, cluster-randomized controlled trial, communities in rural Burkina Faso were stratified by selected characteristics and then randomly assigned within strata to the intervention (IC; 25 communities, 2435 children) or the nonintervention (NIC; 9 communities, 785 children) cohorts. IC children were randomly assigned to 4 groups. As secondary outcomes, a subsample of 3 of these 4 groups (n = 747) and of the NIC (n = 376) were assessed for motor, language, and personal-social development at age 18 mo by using the Developmental Milestones Checklist II. The 3 IC groups received 20 g SQ-LNSs/d containing 0 or 10 mg added zinc with a placebo tablet or 20 g SQ-LNSs/d containing 0 mg added zinc with a tablet containing 5 mg Zn. All IC groups received treatment of malaria and diarrhea from age 9 to 18 mo. Data collectors and participants were aware of allocation to the IC or NIC but did not know the particular IC subgroup. Children in the IC scored 0.34 (95% CI: 0.21, 0.46), 0.30 (95% CI: 0.15, 0.44), and 0.32 (95% CI: 0.16, 0.48) SDs higher in motor, language, and personal-social development, respectively, than did children in the NIC (All P < 0.001). Children who received different amounts of zinc did not differ significantly in any of the scores. No effect on caregiver-child interaction was found. In rural Burkina Faso, the provision of SQ-LNSs to infants from age 9 to 18 mo, regardless of added zinc content, plus malaria and diarrhea treatment positively affected motor, language, and personal-social development at age 18 mo. This trial was registered at clinicaltrials.gov as NCT00944281.


Synthesis of sulfinamides via photocatalytic alkylation or arylation of sulfinylamine.
Sulfinamides are a versatile class of compounds that find applications in both organic synthesis and pharmaceuticals. Here we developed an efficient photocatalytic approach for the convenient preparation of sulfinamides. Commercially available potassium trifluoro(organo)borates and readily available sulfinyl amines are rationally used and converted to a series of alkyl or aryl sulfinamides in moderate to high yields. The reaction allows for the gram-scale preparation of sulfinamides. Moreover, sulfonimidamides, sulfonimidate esters and sulfonyl amides could be obtained in one pot.


Robotic positioning of standard electrophysiology catheters: a novel approach to catheter robotics.
Robotic systems have been developed to manipulate and position electrophysiology (EP) catheters remotely. One limitation of existing systems is their requirement for specialized catheters or sheaths. We evaluated a system (Catheter Robotics Remote Catheter Manipulation System [RCMS], Catheter Robotics, Inc., Budd Lake, New Jersey) that manipulates conventional EP catheters placed through standard introducer sheaths. The remote controller functions much like the EP catheter handle, and the system permits repeated catheter disengagement for manual manipulation without requiring removal of the catheter from the body. This study tested the hypothesis that the RCMS would be able to safely and effectively position catheters at various intracardiac sites and obtain thresholds and electrograms similar to those obtained with manual catheter manipulation. Two identical 7 Fr catheters (Blazer II; Boston Scientific Corp., Natick, Massachusetts) were inserted into the right femoral veins of 6 mongrel dogs through separate, standard 7 Fr sheaths. The first catheter was manually placed at a right ventricular endocardial site. The second catheter handle was placed in the mating holder of the RCMS and moved to approximately the same site as the first catheter using the Catheter Robotics RCMS. The pacing threshold was determined for each catheter. This sequence was performed at 2 right atrial and 2 right ventricular sites. The distance between the manually and robotically placed catheters tips was measured, and pacing thresholds and His-bundle recordings were compared. The heart was inspected at necropsy for signs of cardiac perforation or injury. Compared to manual positioning, remote catheter placement produced the same pacing threshold at 7/24 sites, a lower threshold at 11/24 sites, and a higher threshold at only 6/24 sites (p > 0.05). The average distance between catheter tips was 0.46 +/- 0.32 cm (median 0.32, range 0.13-1.16 cm). There was no difference between right atrial and right ventricular sites (p > 0.05). His-bundle electrograms were equal in amplitude and timing. Further, the remote navigation catheter was able to be disengaged, manually manipulated, then reengaged in the robot without issue. There was no evidence of perforation. The Catheter Robotics remote catheter manipulation system, which uses conventional EP catheters and introducer sheaths, appears to be safe and effective at directing EP catheters to intracardiac sites and achieving pacing thresholds and electrograms equivalent to manually placed catheters. Further clinical studies are needed to confirm these observations.


Curved π-conjugated corannulene dimer diradicaloids.
So far, most reported open-shell singlet diradicaloids are based on planar π-conjugated molecules. Herein, we report the bridged corannulene dimer diradicaloids, Cor-D1 and Cor-D2, both showing a three-dimensional curved π-conjugated structure. Cor-D1 has a small diradical character (y0 = 5.4%) and behaves more like a closed-shell quinoidal compound at room temperature, while Cor-D2 is a typical open-shell diradicaloid with a larger diradical character (y0 = 16.9%). Both compounds exhibited paramagnetic activity at elevated temperatures, with a singlet-triplet energy gap (ΔES-T) of -8.4 and -3.0 kcal mol-1, respectively. X-ray crystallographic analysis revealed that both molecules have a dumbbell-shaped geometry, with the two terminal corannulene bowls bent to opposite directions. The spin is largely delocalized onto the two bowls in Cor-D2 and there are multiple [CH···π] interactions between the neighboring bowls. Chemical oxidation/reduction to their respective dications/dianions results in global aromaticity with [4n + 2] π-electrons delocalized through the periphery of the whole framework.


Nitrogen aspects of hydrological processes: a case study in Likeng landfill, Guangzhou, China.
The nitrogen aspects of hydrological processes must be determined to identify nitrogen sources and relevant mechanisms. Landfills are the dominant disposal approach to deal with solid waste in urban areas in China. Landfills require adequate land and pose a potential threat to aquifer contamination, particularly in the humid zone, such as Guangzhou. The unlined Likeng landfill in Guangzhou was investigated in three campaigns during the period 2001-2007: water was sampled and analyzed for major ions, heavy metals, and stable isotopes of (18)O and (2)H in water, and (18)O and (15)N in nitrate. Contamination sources, water components, and groundwater flow were examined, revealing a mixture of various sources from landfill effluent, septic tank leakage, fertilizer, and manure following complex processes of recharge, mixing, and denitrification. The effluent from the landfill was rich in Na(+), Ca(2+), K(+), HCO3(-), and Cl(-) ions. A similar process of high NH4(+) in effluent resulting in episodic increases in NO3(-) because of NH4(+) oxidation was found in Likeng landfill when compared with landfills in Denmark and the USA. Twenty-five percent of the precipitation was lost to evaporation before recharging the aquifer, indicating a possible maximum recharge rate of 75% and the potential for a large amount of water penetration to the landfill if not well constructed. Apparent groundwater flow velocity of 3.7 × 10(-7) m s(-1) (11.67 m/a) was found for the front of the effluent under the landfill by considering the vertical and horizontal flow. These findings provide background to delineate the plume from Likeng landfill and to conceptualize the natural attenuation processes of other toxic compounds, which are imperative for any remediation strategy.


The psychological maltreatment of children--technical report.
Psychological maltreatment is a common consequence of physical and sexual abuse but also may occur as a distinct entity. Until recently, there has been controversy regarding the definition and consequences of psychological maltreatment. Sufficient research and consensus now exist about the incidence, definition, risk factors, and consequences of psychological maltreatment to bring this form of child maltreatment to the attention of pediatricians. This technical report provides practicing pediatricians with definitions and risk factors for psychological maltreatment and details how pediatricians can prevent, recognize, and report psychological maltreatment. Contemporary references and resources are provided for pediatricians and parents


Changes of voltage-gated sodium channels in sensory nerve regeneration and neuropathic pain models.
The present study was conducted to determine changes in the expression of voltage-gated sodium channels (VGSCs) α-subunits after nerve injury and their relation with development of neuropathic pain. We used the crush injury model of regeneration of the sciatic nerve (Crush) and the spared nerve injury (SNI) model of neuropathic pain in the rat. Measurements of thermal and mechanical pain thresholds were performed until 3 months after injury. Real-time PCR and immunohistochemistry of VGSC α-subunits were used to evaluate the mRNA and protein expression in the DRG. Both nerve injuries induced similar alterations in the VGSCs expression at 7 dpi, with upregulation of Nav1.3, and downregulation of Nav1.7, Nav1.8 and Nav1.9. These changes persisted until 28 days, when hyperalgesia was still present in SNI but not in Crush rats. At 90 days, mRNA expression of all analyzed α-subunits returned to basal levels in the Crush group. However, SNI rats still showed altered expression of VGSCs, and neuropathic pain responses. Immunohistochemical staining revealed that Nav1.8 and Nav1.9 were widely expressed in IB4-positive neurons of the DRG, relevant in pain processing. The population of neurons coexpressing each α-subunit and IB4 was also affected by the injury, more markedly after the Crush. Shifts in VGSCs expression occur in parallel to neuropathic pain behavior in rats early after injury, while at later times they appear to be more related to sensory nerve degeneration and regeneration processes.


Prolonged coma and loss of brainstem reflexes following amitriptyline overdose.
Severe tricyclic antidepressant (TCA) overdose is generally manifested by cardiovascular and/or central nervous system toxicity. Although the majority of patients who are comatose following these overdoses regain consciousness within 24 h, this case had 5-days of coma with associated loss of brainstem reflexes. Severe central nervous system depression can occur as a sole manifestation of TCA overdose without concomitant cardiovascular toxicity.


The role of Aspartyl aminopeptidase (Ape4) in Cryptococcus neoformans virulence and authophagy.
In order to survive and cause disease, microbial pathogens must be able to proliferate at the temperature of their infected host. We identified novel microbial features associated with thermotolerance in the opportunistic fungal pathogen Cryptococcus neoformans using a random insertional mutagenesis strategy, screening for mutants with defective growth at 37°C. Among several thermosensitive mutants, we identified one bearing a disruption in a gene predicted to encode the Ape4 aspartyl aminopeptidase protein. Ape4 metalloproteases in other fungi, including Saccharomyces cerevisiae, are activated by nitrogen starvation, and they are required for autophagy and the cytoplasm-to-vacuole targeting (Cvt) pathway. However, none have been previously associated with altered growth at elevated temperatures. We demonstrated that the C. neoformans ape4 mutant does not grow at 37°C, and it also has defects in the expression of important virulence factors such as phospholipase production and capsule formation. C. neoformans Ape4 activity was required for this facultative intracellular pathogen to survive within macrophages, as well as for virulence in an animal model of cryptococcal infection. Similar to S. cerevisiae Ape4, the C. neoformans GFP-Ape4 fusion protein co-localized with intracytoplasmic vesicles during nitrogen depletion. APE4 expression was also induced by the combination of nutrient and thermal stress. Together these results suggest that autophagy is an important cellular process for this microbial pathogen to survive within the environment of the infected host.


High-precision measurement of mercury isotope ratios in sediments using cold-vapor generation multi-collector inductively coupled plasma mass spectrometry.
An on-line Hg reduction technique using stannous chloride as the reductant was applied for accurate and precise mercury isotope ratio determinations by multi-collector (MC)-ICP/MS. Special attention has been paid to ensure optimal conditions (such as acquisition time and mercury concentration) allowing precision measurements good enough to be able to significantly detect the anticipated small differences in Hg isotope ratios in nature. Typically, internal precision was better than 0.002% (1 RSE) on all Hg ratios investigated as long as approximately 20 ng of Hg was measured with a 10-min acquisition time. Introducing higher amounts of mercury (50 ng Hg) improved the internal precision to <0.001%. Instrumental mass bias was corrected using (205)Tl/(203)Tl correction coupled to a standard-sample bracketing approach. The large number of data acquired allowed us to validate the consistency of our measurements over a one-year period. On average, the short-term uncertainty determined by repeated runs of NIST SRM 1641d Hg standard during a single day was <0.006% (1 RSD) for all isotope pairs investigated ((202)Hg/(198)Hg, (202)Hg/(199)Hg, (202)Hg/(200)Hg, and (202)Hg/(201)Hg). The precision fell to <0.01% if the long-term reproducibility, taken over 11 months (over 100 measurements), was considered. The extent of fractionation has been investigated in a series of sediments subject to various Hg sources from different locations worldwide. The ratio (202)Hg/(198)Hg expressed as delta values (per mil deviations relative to NIST SRM 1641d Hg standard solution) displayed differences from +0.74 to -4.00 per thousand. The magnitude of the Hg fractionation per amu was constant within one type of sample and did not exceed 1.00 per thousand. Considering all results (the reproducibility of Hg standard solutions, reference sediment samples, and the examination of natural samples), the analytical error of our delta values for the overall method was within +/-0.28 per thousand (1 SD), which was an order of magnitude lower than the extent of fractionation (4.74 per thousand) observed in sediments. This study confirmed that analytical techniques have reached a level of long-term precision and accuracy that is sufficiently sensitive to detect even small differences in Hg isotope ratios that occur within one type of samples (e.g., between different sediments) and so far have unequivocally shown that Hg isotope ratios in sediments vary within approximately 5 per thousand.


Draft genome and description of Chryseobacterium manosquense strain Marseille-Q2069T sp. nov., a new bacterium isolated from human healthy skin.
In 2019, by culturing a skin swab from the hand of a 35-year-old healthy woman using culturomics methods, we isolated the new bacterial strain Marseille-Q2069T =CSUR-Q2069. Matrix-assisted desorption/ionization time-of-flight mass spectrometry failed to identify this isolate. Analysis of the 16S rRNA gene and Genome-to-Genome comparison suggested that this taxon belongs to a novel bacterial species within the family Flavobacteriaceae in the phylum Bacteroidetes. We described here the main phenotypic characteristics, genome sequence and annotation of Chryseobacterium manosquense strain Marseille-Q2069T, a new member of the Chryseobacterium genus, that we propose as type strain.