Management and outcome of acral soft-tissue sarcomas.
The aim of this study was to evaluate the surgical management and outcome of patients with an acral soft-tissue sarcoma of the hand or foot. We identified 63 patients with an acral soft-tissue sarcoma who presented to our tertiary referral sarcoma service between 2000 and 2016. There were 35 men and 28 women with a mean age of 49 years (sd 21). Of the 63 sarcomas, 27 were in the hands and 36 in the feet. The commonest subtypes were epithelioid sarcoma in the hand (n = 8) and synovial sarcoma in the foot (n = 11). In 41 patients (65%), the tumour measured less than 5 cm in its largest dimension (median size 3 cm (2 to 6)); 27 patients (43%) were diagnosed after inadvertent excision prior to their referral to the specialist sarcoma unit. After biopsy and staging, primary surgical intervention at the sarcoma unit was excision and limb salvage in 43 (68%), partial (digit or ray) amputation in 14 (22%), and more proximal amputation in six (10%). At final follow up, local recurrence had been treated by one partial amputation and six amputations, resulting in a partial amputation rate of 24% and a proximal amputation rate of 19%. The five-year survival rate was 82%. Patients who underwent inadvertent excision showed no statistically significant difference in survival or local recurrence, but were more likely to undergo amputation (p = 0.008). Large tumour size (> 5 cm) was associated with lower survival (p = 0.04) and a higher risk of local recurrence (p = 0.009;). Most acral soft-tissue sarcomas measure less than 5 cm at presentation, indicating that while size can be a useful prognostic factor, it should not be used as a diagnostic threshold for referral. Increased tumour size is associated with a higher rate of local recurrence and reduced survival. Sarcoma excision with limb preservation does not result in an increased risk of local recurrence. Cite this article: Bone Joint J 2018;100-B:1518-23.


PP2A phosphatases: the "on-off" regulatory switches of brassinosteroid signaling.
Inactivation of ligand-bound plasma membrane receptors is crucial for the regulation of their signaling outputs. The internalization of activated receptors and their subsequent targeting for recycling or degradation is controlled by posttranslational modifications, of which phosphorylation and dephosphorylation play an important role. Recent work suggests that a similar mechanism acts on the brassinosteroid (BR) receptor BR INSENSITIVE 1 (BRI1) in Arabidopsis thaliana to switch off BR signaling. The degradation of BRI1 requires a protein phosphatase 2A (PP2A)-mediated dephosphorylation that is specified by methylation of the phosphatase by a leucine carboxylmethyltransferase on membranes. PP2A is also reported to act positively on BR signaling by targeting the transcription factor BRASSINAZOLE-RESISTANT 1 (BZR1), a component downstream of BRI1. Thus, PP2A proteins play a dual role in the regulation of the BR pathway to switch between inhibition and activation of the BR signaling, depending on their substrate specificity and localization.


Mupirocin prophylaxis against nosocomial Staphylococcus aureus infections in nonsurgical patients: a randomized study.
Staphylococcus aureus nasal carriage is a major risk factor for nosocomial S. aureus infection. Studies show that intranasal mupirocin can prevent nosocomial surgical site infections. No data are available on the efficacy of mupirocin in nonsurgical patients. To assess the efficacy of mupirocin prophylaxis in preventing nosocomial S. aureus infections in nonsurgical patients. Randomized, double-blind, placebo-controlled trial. 3 tertiary care academic hospitals and 1 nonacademic hospital. 1602 culture-proven S. aureus carriers hospitalized in nonsurgical departments. Therapy with mupirocin 2% nasal ointment (n = 793) or placebo ointment (n = 809), twice daily for 5 days, started 1 to 3 days after admission. Nosocomial S. aureus infections according to defined criteria, in-hospital mortality, duration of hospitalization, and time to nosocomial S. aureus infection. Staphylococcus aureus isolates were genotyped to assess whether infection was caused by endogenous strains. The mupirocin and placebo groups did not statistically differ in the rates of nosocomial S. aureus infections (mupirocin, 2.6%; placebo, 2.8%; risk difference, 0.2 percentage point [95% CI, -1.5 to 1.9 percentage points]), mortality (mupirocin, 3.0%; placebo, 2.8%; risk difference, -0.2 percentage point [CI, -1.9 to 1.5 percentage points]), or duration of hospitalization (median for both, 8 days). However, time to nosocomial S. aureus infection was decreased in the mupirocin group from 12 to 25 days (P > 0.2). A total of 77% of S. aureus nosocomial infections were endogenous. A few infections in both groups may have been missed because investigators assessed a patient for infection only if microbiology culture results were positive for S. aureus. Routine culture for S. aureus nasal carriage at admission and subsequent mupirocin application does not provide effective prophylaxis against nosocomial S. aureus infections in nonsurgical patients.


Skateboards: are they really perilous? a retrospective study from a district hospital.
Skateboarding has been a popular sport among teenagers even with its attendant associated risks. The literature is packed with articles regarding the perils of skateboards. Is the skateboard as dangerous as has been portrayed? This was a retrospective study conducted over a 5 year period. All skateboard related injuries seen in the Orthopaedic unit were identified and data collated on patient demographics, mechanism & location of injury, annual incidence, type of injury, treatment needed including hospitalisation. We encountered 50 patients with skateboard related injuries. Most patients were males and under the age of 15. The annual incidence has remained low at about 10. The upper limb was predominantly involved with most injuries being fractures. Most injuries occurred during summer. The commonest treatment modality was plaster immobilisation. The distal radius was the commonest bone to be fractured. There were no head & neck injuries, open fractures or injuries requiring surgical intervention. Despite its negative image among the medical fraternity, the skateboard does not appear to be a dangerous sport with a low incidence and injuries encountered being not severe. Skateboarding should be restricted to supervised skateboard parks and skateboarders should wear protective gear. These measures would reduce the number of skateboarders injured in motor vehicle collisions, reduce the personal injuries among skateboarders, and reduce the number of pedestrians injured in collisions with skateboarders.


Bromination pattern of hydroxylated metabolites of BDE-47 affects their potency to release calcium from intracellular stores in PC12 cells.
Brominated flame retardants, including the widely used polybrominated diphenyl ethers (PBDEs), have been detected in humans, raising concern about possible neurotoxicity. Recent research demonstrated that the hydroxylated metabolite 6-OH-BDE-47 increases neurotransmitter release by releasing calcium ions (Ca2+) from intracellular stores at much lower concentrations than its environmentally relevant parent congener BDE-47. Recently, several other hydroxylated BDE-47 metabolites, besides 6-OH-BDE-47, have been detected in human serum and cord blood. To investigate the neurotoxic potential of other environmentally relevant PBDEs and their metabolites, we examined and compared the acute effects of BDE-47, BDE-49, BDE-99, BDE-100, BDE-153, and several metabolites of BDE-47-6-OH-BDE-47 (and its methoxylated analog 6-MeO-BDE-47), 6 -OH-BDE-49, 5-OH-BDE-47, 3-OH-BDE-47, and 4 -OH-BDE-49--on intracellular Ca2+ concentration ([Ca2+]i), measured using the Ca2+-responsive dye Fura-2 in neuroendocrine pheochromocytoma (PC12) cells. In contrast to the parent PBDEs and 6-MeO-BDE-47, all hydroxylated metabolites induced Ca2+ release from intracellular stores, although with different lowest observed effect concentrations (LOECs). The major intracellular Ca2+ sources were either endoplasmic reticulum (ER; 5-OH-BDE-47 and 6 -OH-BDE-49) or both ER and mitochondria (6-OH-BDE-47, 3-OH-BDE-47, and 4 -OH-BDE-49). When investigating fluctuations in [Ca2+]i, which is a more subtle end point, we observed lower LOECs for 6-OH-BDE-47 and 4 -OH-BDE-49, as well as for BDE-47. The present findings demonstrate that hydroxylated metabolites of BDE-47 cause disturbance of the [Ca2+]i. Importantly, shielding of the OH group on both sides with bromine atoms and/or the ether bond to the other phenyl ring lowers the potency of hydroxylated PBDE metabolites.


Bistable scattering in graphene-coated dielectric nanowires.
In nonlinear plasmonics, the switching threshold of optical bistability is limited by the weak nonlinear responses from the conventional Kerr dielectric media. Considering the giant nonlinear susceptibility of graphene, here we develop a nonlinear scattering model under the mean field approximation and study the bistable scattering in graphene-coated dielectric nanowires based on the semi-analytical solutions. We find that the switching intensities of bistable scattering can be smaller than 1 MW cm-2 at the working frequency. To further decrease the switching intensities, we show that the most important factor that restricts the bistable scattering is the relaxation time of graphene. Our work not only reveals some general characteristics of graphene-based bistable scattering, but also provides a guidance to further applications of optical bistability in the high speed all-optical signal processing.


Autonomic dysfunction in post-COVID patients with and witfhout neurological symptoms: a prospective multidomain observational study.
The autonomic nervous system (ANS) can be affected by COVID-19, and dysautonomia may be a possible complication in post-COVID individuals. Orthostatic hypotension (OH) and postural tachycardia syndrome (POTS) have been suggested to be common after SARS-CoV-2 infection, but other components of ANS function may be also impaired. The Composite Autonomic Symptom Scale 31 (COMPASS-31) questionnaire is a simple and validated tool to assess dysautonomic symptoms. The aim of the present study was to administer the COMPASS-31 questionnaire to a sample of post-COVID patients with and without neurological complaints. Participants were recruited among the post-COVID ambulatory services for follow-up evaluation between 4 weeks and 9 months from COVID-19 symptoms onset. Participants were asked to complete the COMPASS-31 questionnaire referring to the period after COVID-19 disease. Heart rate and blood pressure were manually taken during an active stand test for OH and POTS diagnosis. One-hundred and eighty participants were included in the analysis (70.6% females, 51 ± 13 years), and OH was found in 13.8% of the subjects. Median COMPASS-31 score was 17.6 (6.9-31.4), with the most affected domains being orthostatic intolerance, sudomotor, gastrointestinal and pupillomotor dysfunction. A higher COMPASS-31 score was found in those with neurological symptoms (p < 0.01), due to more severe orthostatic intolerance symptoms (p < 0.01), although gastrointestinal (p < 0.01), urinary (p < 0.01), and pupillomotor (p < 0.01) domains were more represented in the non-neurological symptoms group. This study confirms the importance of monitoring ANS symptoms as a possible complication of COVID-19 disease that may persist in the post-acute period.


Insulin Control of Blood Glucose and GLUT4 Expression in the Skeletal Muscle of Septic Rats.
Insulin resistance is common in septic patients. The level at which the serum glucose should be maintained using insulin infusions for optimal utilization by skeletal muscles is not yet established. The objective of the present study was to compare glucose transporter 4 (GLUT4) mRNA and GLUT4 expression and glucose utilization at the recommended glucose levels of 6-8 mmol/L (110-140 mg/dL) and 8-10 mmol/L (140-180 mg/dL) in septic rats. This was a prospective randomized study using 44 Sprague-Dawley rats (260-330 g). Rats were anaesthetized with gaseous diethyl ether. Catheters were implanted into the jugular vein and artery. Following a laparotomy, rats in the experimental group (n = 36) were rendered septic by standard caecal ligation and puncture (CLP) and intraperitoneal lipopolysaccharide (LPS) infusion (O111:[B4], 1 mg/kg). Control animals (n = 8) underwent laparotomy, but no caecal ligation or puncture and no LPS injection. Four experimental groups were studied: sham-operated control, sepsis treated with fluid maintenance only, sepsis treated with fluid and insulin infusion controlling blood glucose concentration at 6-8 mmol/L and sepsis treated with fluid and insulin infusion controlling blood glucose concentration at 8-10 mmol/L. Hyperinsulinaemic-euglycaemic clamp experiment was done before fluid maintenance and insulin treatment to calculate average glucose infusion rate. All septic rats were markedly hyperglycaemic compared with sham-operated controls two hours after operation. Glucose infusion rate during hyperinsulinaemic-euglycaemic clamp experiment was slower in septic rats, suggesting that they were insulin resistant. At the 12th and 24th hour, skeletal muscle was taken to observe pathological change and analyse the GLUT4 mRNA and GLUT4 levels. There were more inflammatory cells, less GLUT4 mRNA and GLUT4 expression in the skeletal muscles of septic rats. Insulin increased the expression of GLUT4 mRNA and GLUT4 in the skeletal muscle of septic rats. Among all septic rats, the expression of GLUT4 mRNA and GLUT4 was more in the 8-10 mmol/L group. Blood glucose concentration of 8-10 mmol/L results in more glucose utilization than 6-8 mmol/L in the skeletal muscle of septic rats during insulin therapy.


Cross-Cultural, Aboriginal Language, Discovery Education for Health Literacy and Informed Consent in a Remote Aboriginal Community in the Northern Territory, Australia.
Education for health literacy of Australian Aboriginal people living remotely is challenging as their languages and worldviews are quite different from English language and Western worldviews. Becoming health literate depends on receiving comprehensible information in a culturally acceptable manner. The study objective was to facilitate oral health literacy through community education about scabies and strongyloidiasis, including their transmission and control, preceding an ivermectin mass drug administration (MDA) for these diseases. A discovery education approach where health concepts are connected to cultural knowledge in the local language was used. Aboriginal and non-Aboriginal educators worked collaboratively to produce an in-depth flip-chart of the relevant stories in the local language and to share them with clan elders and 27% of the population. The community health education was well received. Feedback indicated that the stories were being discussed in the community and that the mode of transmission of strongyloidiasis was understood. Two-thirds of the population participated in the MDA. This study documents the principles and practice of a method of making important Western health knowledge comprehensible to Aboriginal people. This method would be applicable wherever language and culture of the people differ from language and culture of health professionals.


Neurological dysfunction expressed in the grooming behavior of developing weaver mutant mice.
The present study provides the first quantitative developmental analysis of movement in the weaver (wv/wv) mutant mouse. This autosomal recessive mutation affects both striatal and cerebellar circuitries that are related to motor performance. We report data on post-swim grooming behavior in 14 mutant and 14 control animals on alternate postnatal Days 13-20. Mutant animals showed a greater number, but shorter duration, of grooming bouts across this developmental period. The mutant animals also used external support during grooming, expressed various forms of ataxia, performed a higher proportion of smaller forelimb strokes than did the control animals, and failed to complete as many full stereotypic grooming sequences. These differences between mutant and control animals followed distinctive developmental courses. Our data demonstrate that previous anatomical and physiological characterizations of the weaver mutation have overt motor correlates.


Candidatus Methylumidiphilus Drives Peaks in Methanotrophic Relative Abundance in Stratified Lakes and Ponds Across Northern Landscapes.
Boreal lakes and ponds produce two-thirds of the total natural methane emissions above the latitude of 50° North. These lake emissions are regulated by methanotrophs which can oxidize up to 99% of the methane produced in the sediments and the water column. Despite their importance, the diversity and distribution of the methanotrophs in lakes are still poorly understood. Here, we used shotgun metagenomic data to explore the diversity and distribution of methanotrophs in 40 oxygen-stratified water bodies in boreal and subarctic areas in Europe and North America. In our data, gammaproteobacterial methanotrophs (order Methylococcales) generally dominated the methanotrophic communities throughout the water columns. A recently discovered lineage of Methylococcales, Candidatus Methylumidiphilus, was present in all the studied water bodies and dominated the methanotrophic community in lakes with a high relative abundance of methanotrophs. Alphaproteobacterial methanotrophs were the second most abundant group of methanotrophs. In the top layer of the lakes, characterized by low CH4 concentration, their abundance could surpass that of the gammaproteobacterial methanotrophs. These results support the theory that the alphaproteobacterial methanotrophs have a high affinity for CH4 and can be considered stress-tolerant strategists. In contrast, the gammaproteobacterial methanotrophs are competitive strategists. In addition, relative abundances of anaerobic methanotrophs, Candidatus Methanoperedenaceae and Candidatus Methylomirabilis, were strongly correlated, suggesting possible co-metabolism. Our data also suggest that these anaerobic methanotrophs could be active even in the oxic layers. In non-metric multidimensional scaling, alpha- and gammaproteobacterial methanotrophs formed separate clusters based on their abundances in the samples, except for the gammaproteobacterial Candidatus Methylumidiphilus, which was separated from these two clusters. This may reflect similarities in the niche and environmental requirements of the different genera within alpha- and gammaproteobacterial methanotrophs. Our study confirms the importance of O2 and CH4 in shaping the methanotrophic communities and suggests that one variable cannot explain the diversity and distribution of the methanotrophs across lakes. Instead, we suggest that the diversity and distribution of freshwater methanotrophs are regulated by lake-specific factors.


Global Longitudinal Strain Using Speckle-Tracking Echocardiography as a Mortality Predictor in Sepsis: A Systematic Review.
The data on speckle-tracking echocardiography (STE) in patients with sepsis are limited. This systematic review from 1975 to 2016 included studies in adults and children evaluating cardiovascular dysfunction in sepsis, severe sepsis, and septic shock utilizing STE for systolic global longitudinal strain (GLS). The primary outcome was short- or long-term mortality. Given the significant methodological and statistical differences between published studies, combining the data using meta-analysis methods was not appropriate. A total of 120 studies were identified, with 5 studies (561 patients) included in the final analysis. All studies were prospective observational studies using the 2001 criteria for defining sepsis. Three studies demonstrated worse systolic GLS to be associated with higher mortality, whereas 2 did not show a statistically significant association. Various cutoffs between -10% and -17% were used to define abnormal GLS across studies. This systematic review revealed that STE may predict mortality in patients with sepsis; however, the strength of evidence is low due to heterogeneity in study populations, GLS technologies, cutoffs, and timing of STE. Further dedicated studies are needed to understand the optimal application of STE in patients with sepsis.


Transgenerational glucose intolerance with Igf2/H19 epigenetic alterations in mouse islet induced by intrauterine hyperglycemia.
Gestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved and the possibilities of transgenerational transmission are still unclear. We intercrossed male and female adult control and first-generation offspring of GDM (F1-GDM) mice to obtain the second-generation (F2) offspring in four groups: C♂-C♀, C♂-GDM♀, GDM♂-C♀, and GDM♂-GDM♀. We found that birth weight significantly increased in F2 offspring through the paternal line with impaired glucose tolerance (IGT). Regardless of birth from F1-GDM with or without IGT, high risk of IGT appeared as early as 3 weeks in F2 offspring and progressed through both parental lineages, especial the paternal line. IGT in male offspring was more obvious than that in females, with parental characteristics and sex-specific transmission. In both F1 and F2 offspring of GDM, the expression of imprinted genes Igf2 and H19 was downregulated in pancreatic islets, caused by abnormal methylation status of the differentially methylated region, which may be one of the mechanisms for impaired islet ultrastructure and function. Furthermore, altered Igf2 and H19 gene expression was found in sperm of adult F1-GDM, regardless of the presence of IGT, indicating that changes of epigenetics in germ cells contributed to transgenerational transmission.


Mitochondrial DNA content in breast cancer: Impact on in vitro and in vivo phenotype and patient prognosis.
Reduced mitochondrial DNA (mtDNA) content in breast cancer cell lines has been associated with transition towards a mesenchymal phenotype, but its clinical consequences concerning breast cancer dissemination remain unidentified. Here, we aimed to clarify the link between mtDNA content and a mesenchymal phenotype and its relation to prognosis of breast cancer patients. We analyzed mtDNA content in 42 breast cancer cell lines and 207 primary breast tumor specimens using a combination of quantitative PCR and array-based copy number analysis. By associating mtDNA content with expression levels of genes involved in epithelial-to-mesenchymal transition (EMT) and with the intrinsic breast cancer subtypes, we could not identify a relation between low mtDNA content and mesenchymal properties in the breast cancer cell lines or in the primary breast tumors. In addition, we explored the relation between mtDNA content and prognosis in our cohort of primary breast tumor specimens that originated from patients with lymph node-negative disease who did not receive any (neo)adjuvant systemic therapy. When patients were divided based on the tumor quartile levels of mtDNA content, those in the lowest quarter (≤ 350 mtDNA molecules per cell) showed a poorer 10-year distant metastasis-free survival than patients with > 350 mtDNA molecules per cell (HR 0.50 [95% CI 0.29-0.87], P = 0.015). The poor prognosis was independent of established clinicopathological markers (HR 0.54 [95% CI 0.30-0.97], P = 0.038). We conclude that, despite a lack of evidence between mtDNA content and EMT, low mtDNA content might provide meaningful prognostic value for distant metastasis in breast cancer.


13C-methionine breath tests for mitochondrial liver function assessment.
13C-methionine breath test has been proposed as a non-invasive tool for the assessment of human hepatic mithocondrial function. Two methionine breath labeled with 13C in differents point of his molecular structure have been used for breath test analisys. Aim of this study was to compare two differently 13C-labeled methionines in the evaluation of mitochondrial oxidation in basal conditions and after an acute oxidative stress. 15 healthy male subjects (mean age 30.5 +/- 3.1) received [methyl-13C]-methionine dissolved in water. Breath samples were taken at baseline and and 10, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after the ingestion of the labeled substrate. Forthy-eight hours later, subjects underwent the same test 30 minutes after ethanol ingestion (0,3 g/kg of body weight). Seven-day later, subjects underwent breath test using (L-methionine-1-13COOH) as substrate, in basal condition and after ethanol ingestion. At basal condition, the cumulative percentage of 13CO2 recovered in breath during the test period (%cum-dose) was higher using L-methionine-1-13COOH than [methyl-13C]-methionine (10.25 +/- 1.0 vs 4.07 +/- 0.8; p < 0.01). After ethanol ingestion, % cum dose was significantly decreased at 60 and 120 minutes with both methionines (120 min: 10.25 +/- 1.0 vs 5.03% +/- 1.8; < 0.01 and 4.07 +/- 0.8 vs 2.16% +/- 0.9; p < 0.01, respectively). However, %cum-dose during L-methionine-1-13C-breath test was significantly lower than that observed during methyl-13C-methionine breath test (120 minutes: 5.03% +/- 1.8 vs 2.16% +/- 0.9; p < 0.01). In conclusion, breath test based on L-methionine-1-13COOH seems to show a greater reliability when compared to [methyl-13C]-methionine to assess mitochondrial function because a larger amount of labeled carbon that reaches the Krebs' cicle.


A randomized study of two different information-based interventions on the management of osteoporosis in minimal and moderate trauma fractures.
Despite the high risk for subsequent fracture following an initial osteoporotic fracture, the majority of subjects with minimal trauma fractures receive no treatment for osteoporosis. The primary aim of this investigation was to determine whether an information-based intervention could change post-fracture management of osteoporosis. A secondary aim was to define participant- and doctor-related barriers to osteoporosis management. Consecutive fracture patients (n=254) from the outpatient fracture clinic at St Vincent's Hospital, Sydney were interviewed over a 15-month period (February 2002-July 2003). Fracture risk factors, prior investigation and treatment for osteoporosis were collected at baseline. Participants were initially contacted after 3 months to ascertain follow-up management. All those not investigated or treated by their primary care physician were then randomized to either a personalized letter or the same letter plus an offer of a free bone mineral density (BMD) test. Participants were contacted after 9 months to record further investigations or treatment for osteoporosis. Less than 20% of the participants had a primary care physician follow-up 3 months after the fracture, leaving 159 who were randomized to a personalized letter (n=79) and a personalized letter plus the offer of a free BMD test (n=80). There was a significant increase in the number of people investigated for osteoporosis in the group receiving the letter plus BMD offer [38% (letter + BMD) vs. 7% (letter only); p=0.001). A high proportion of those tested had low BMD (49% osteopenia and 17% osteoporosis). However, the rates of treatment in both groups were very low (6%). Furthermore, even among the few individuals (23%) who contacted their primary care physician, only 25% were recommended treatment. The belief that the fracture was osteoporotic was an independent predictor of having a BMD test, a primary care physician follow-up and treatment. Other independent predictors were age over 50 years for a primary care physician follow-up, female sex for having a BMD test and having had a BMD test for treatment. This study demonstrates that an information-based intervention led to a modest increase in the proportion of people investigated for osteoporosis; however. there was no significant effect on treatment rates. The offer of a free BMD assessment was associated with a significantly higher rate of investigation than a personalized letter alone (odds ratio: 8.5; 95% confidence interval: 3.1-24.5), but this investigation did not affect treatment rate. The low uptake of either a BMD or a visit to a primary care physician together with low rates of treatment recommendation even among people who contacted their primary care physician reflects significant participant and doctor-related barriers to osteoporosis management.


Biomolecular environment, quantification, and intracellular interaction of multifunctional magnetic SERS nanoprobes.
Multifunctional composite nanoprobes consisting of iron oxide nanoparticles linked to silver and gold nanoparticles, Ag-Magnetite and Au-Magnetite, respectively, were introduced by endocytic uptake into cultured fibroblast cells. The cells containing the non-toxic nanoprobes were shown to be displaceable in an external magnetic field and can be manipulated in microfluidic channels. The distribution of the composite nanostructures that are contained in the endosomal system is discussed on the basis of surface-enhanced Raman scattering (SERS) mapping, quantitative laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) micromapping, and cryo soft X-ray tomography (cryo soft-XRT). Cryo soft-XRT of intact, vitrified cells reveals that the composite nanoprobes form intra-endosomal aggregates. The nanoprobes provide SERS signals from the biomolecular composition of their surface in the endosomal environment. The SERS data indicate the high stability of the nanoprobes and of their plasmonic properties in the harsh environment of endosomes and lysosomes. The spectra point at the molecular composition at the surface of the Ag-Magnetite and Au-Magnetite nanostructures that is very similar to that of other composite structures, but different from the composition of pure silver and gold SERS nanoprobes used for intracellular investigations. As shown by the LA-ICP-MS data, the uptake efficiency of the magnetite composites is approximately two to three times higher than that of the pure gold and silver nanoparticles.


Identification of proteins from human permanent erupted enamel.
Proteins from the extracellular matrix of enamel are highly specific and necessary for proper enamel formation. Most proteins are removed from the matrix by enamel proteases before complete mineralization is achieved; however, some residual protein fragments persist in the mineralized matrix of erupted enamel. So far, only amelogenin peptides obtained by traditional bottom-up proteomics have been recovered and identified in human permanent erupted enamel. In this study, we hypothesize that other enamel-specific proteins are also found in human permanent enamel, by analysing human erupted third molars. Pulverized enamel was used to extract proteins, and the protein extract was subjected directly to liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS) without a previous trypsin-digestion step. Amelogenin and non-amelogenin proteins (ameloblastin and enamelin) were succesfully identified. The sequences of the naturally occurring peptides of these proteins are reported, finding in particular that most of the peptides from the amelogenin X-isoform come from the tyrosine-rich amelogenin peptide (TRAP) and that some were identified in all specimens. In conclusion, our LC-MS/MS method without trypsin digestion increased the coverage of identification of the enamel proteome from a few amelogenin peptides to a higher number of peptides from three enamel-specific proteins.


Patient Satisfaction With, and Outcomes of, Ultrasound-Guided Regional Anesthesia at a Referral Hospital in Tanzania: A Cross-Sectional Study.
Regional anesthesia techniques are increasingly used in high-income countries (HICs) for both surgical anesthesia and postoperative analgesia. However, regional anesthesia has not been utilized to the same degree in low- to middle-income countries (LMICs) due to a lack of resources and trained personnel. This study evaluates patient satisfaction with, and outcomes of, ultrasound-guided regional anesthesia for extremity surgery at Kilimanjaro Christian Medical Center (KCMC) in the Northeastern zone of Tanzania. Study patients were ≥18 years of age; American Society of Anesthesiologists (ASA) physical status I, II, or III; and underwent extremity surgery under peripheral nerve block with ultrasound guidance at KCMC. After placement, blocks were assessed for effectiveness intraoperatively, as demonstrated by the need for supplemental analgesic or sedative medication or conversion to a general anesthetic. Postoperatively, patients were assessed for satisfaction with their nerve block and pain at 12 and 24 hours. Adverse events related to regional anesthesia were assessed immediately, 45 minutes after block placement, and at 12 and 24 hours postoperatively. The primary outcome was patient satisfaction at 12 hours. Secondary outcomes were block success rate and analgesia at 12 and 24 hours postoperatively. A convenience sample of 170 patients was included in the study, of whom 156 (95% confidence interval [CI], 87-95) were either satisfied or very satisfied with their block. Block placement was highly successful with only 8 of 170 participants (95% CI, 2.4-8.3), requiring conversion to a general anesthetic. Analgesia continued in the postoperative period, with 164 of 170 (95% CI, 93-98) patients and 145 of 170 (95% CI, 80-90) patients reporting acceptable analgesia at 12 and 24 hours, respectively. No major adverse events, such as local anesthetic toxicity, infection, bleeding, nerve injury, or pneumothorax, were observed. Our study found that ultrasound-guided regional anesthesia in a resource-constrained setting was effective for extremity surgery and resulted in high patient satisfaction. No complications occurred. The use of ultrasound-guided regional anesthesia shows promise for the safe and effective care of patients undergoing extremity surgery in LMICs.


Impact of BCG vaccination on tuberculin surveys to estimate the annual risk of tuberculosis infection in south India.
Annual risk of tuberculosis infection (ARTI) computed from prevalence of infection measures the extent of tuberculosis transmission in the community and it is used to monitor the tuberculosis control programme. This is usually derived from tuberculin surveys among children not vaccinated with BCG. This study explores whether the estimated ARTI among BCG vaccinated children is comparable to that of unvaccinated children. Three tuberculin surveys were undertaken among children aged >10 yr as part of assessing the impact of DOTS implemented in Tiruvallur district, south India. The prevalence of infection was estimated using the anti-mode method among vaccinated and unvaccinated children. The ARTI was computed separately and compared in all the three surveys. The prevalence of infection among unvaccinated and vaccinated children in the first survey were 7.8 per cent (95% CI: 7.1-8.6) and 7.9 per cent (95% CI: 7.1-8.8) respectively (ARTI was estimated to be 1.6 per cent in both groups) and the difference was not statistically significant. The corresponding figures for children test read in the second and third surveys were 6.9 per cent (95% CI: 6.2-7.6) and 6.8 per cent (6.0-7.5) and; 6.0 per cent (5.2-6.7) and 6.0 per cent (5.5-6.5) respectively. The computed ARTI was respectively 1.4 and 1.2 per cent among unvaccinated children in the second and third surveys; and 1.4 and 1.2 per cent among vaccinated children in the second and third rounds. There was no difference in the infection with Mycobacterium tuberculosis among vaccinated and unvaccinated children. BCG vaccinated children may thus be included for estimation of infection to assess the extent of transmission in the community as well as for monitoring purpose.


Catalytic intermolecular β-C-H alkenylation of α-enamino-ketones with simple alkynes.
A unique strategy to synthesize β-alkenylated α-enamino-ketones via catalytic C-H/alkyne coupling is described. The slow addition of alkyne substrates and the use of NaI as an additive play key roles in controlling the alkyne insertion. Replacement of the pyridyl group with carbamates was also developed. This method allows for rapid synthesis of highly functionalized vinyl-substituted enamino-ketones.


Patient-specific anisotropic model of human trunk based on MR data.
There are many ways to generate geometrical models for numerical simulation, and most of them start with a segmentation step to extract the boundaries of the regions of interest. This paper presents an algorithm to generate a patient-specific three-dimensional geometric model, based on a tetrahedral mesh, without an initial extraction of contours from the volumetric data. Using the information directly available in the data, such as gray levels, we built a metric to drive a mesh adaptation process. The metric is used to specify the size and orientation of the tetrahedral elements everywhere in the mesh. Our method, which produces anisotropic meshes, gives good results with synthetic and real MRI data. The resulting model quality has been evaluated qualitatively and quantitatively by comparing it with an analytical solution and with a segmentation made by an expert. Results show that our method gives, in 90% of the cases, as good or better meshes as a similar isotropic method, based on the accuracy of the volume reconstruction for a given mesh size. Moreover, a comparison of the Hausdorff distances between adapted meshes of both methods and ground-truth volumes shows that our method decreases reconstruction errors faster.


Interventions for chronic kidney disease in people with sickle cell disease.
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of any intervention in preventing or reducing kidney complications or CKD in people with SCD (including red blood cell transfusions, hydroxyurea and ACEI (either alone or in combination with each other)).


Protective effect of ginsenosides Rk3 and Rh4 on cisplatin-induced acute kidney injury in vitro and in vivo.
Nephrotoxicity is the major side effect in cisplatin chemotherapy. Previously, we reported that the ginsenosides Rk3 and Rh4 reduced cisplatin toxicity on porcine renal proximal epithelial tubular cells (LLC-PK1). Here, we aimed to evaluate the protective effect of ginsenosides Rk3 and Rh4 on kidney function and elucidate their antioxidant effect using in vitro and in vivo models of cisplatin-induced acute renal failure. An enriched mixture of ginsenosides Rk3 and Rh4 (KG-KH; 49.3% and 43.1%, respectively) was purified from sun ginseng (heat processed Panax ginseng). Cytotoxicity was induced by treatment of 20μM cisplatin to LLC-PK1 cells and rat model of acute renal failure was generated by single intraperitoneal injection of 5 mg/kg cisplatin. Protective effects were assessed by determining cell viability, reactive oxygen species generation, blood urea nitrogen, serum creatinine, antioxidant enzyme activity, and histopathological examination. The in vitro assay demonstrated that KG-KH (50 μg/mL) significantly increased cell viability (4.6-fold), superoxide dismutase activity (2.8-fold), and glutathione reductase activity (1.5-fold), but reduced reactive oxygen species generation (56%) compared to cisplatin control cells. KG-KH (6 mg/kg, per os) also significantly inhibited renal edema (87% kidney index) and dysfunction (71.4% blood urea nitrogen, 67.4% creatinine) compared to cisplatin control rats. Of note, KG-KH significantly recovered the kidney levels of catalase (1.2-fold) and superoxide dismutase (1.5-fold). Considering the oxidative injury as an early trigger of cisplatin nephrotoxicity, our findings suggest that ginsenosides Rk3 and Rh4 protect the kidney from cisplatin-induced oxidative injury and help to recover renal function by restoring intrinsic antioxidant defenses.


Interaction of ethanol and microwaves on the blood-brain barrier of rats.
The combined effects of ethanol and microwaves on the permeation of Evans blue dye through the mammalian blood-brain barrier was studied in male Wistar rats. Anesthetized rats were infused through a cannula in the left femoral vein with 0.1, 0.3, 0.5 or 0.7 grams of absolute ethanol per kilogram of body mass. A control group was given 0.7 g/kg of isotonic saline. The left hemisphere of the brain was irradiated by 3.15-GHz microwave energy at 3.0 W/cm2 rms for 15 min. The rat's rectal temperature was maintained at 37.0 degrees C. Immediately after irradiation, 2% Evans blue dye in saline (2.0 ml/kg body mass) was injected through the cannula. The results show that as the quantity of alcohol was increased, the degree of staining was decreased or eliminated. The temperature of the irradiated area of the brain increased for the first 4 to 5 minutes of irradiation and then stabilized for the remainder of the irradiation period. The steady-state temperature was highest in animals receiving saline or the smallest dose of alcohol. As the quantity of alcohol was increased, the steady-state temperature was reduced. These results indicate that ethanol inhibits microwave-induced permeation of the blood-brain barrier through reduced heating of the brain.


Risk of Persistence and Progression of Use of 5 Cannabis Products After Experimentation Among Adolescents.
While a diverse array of cannabis products that may appeal to youth is currently available, it is unknown whether the risk of persistent cannabis use and progression to higher frequency of use after experimentation differs among cannabis products. To estimate the comparative relative risk of experimental use of 5 cannabis products on use status and frequency of use among adolescents during 12 months of follow-up. In this cohort study, data were collected from 3065 adolescents at 10 high schools in southern California, with baseline data collected in spring 2016, when students were in 11th grade, and 6-month and 12-month follow-up surveys collected in fall 2016 and spring 2017, when students were in 12th grade. Analyses, conducted from April to June 2019, were restricted to 2685 participants who were light or nonusers of any cannabis product (ie, ≤2 days in the past 30 days) at baseline. Number of days of use of each cannabis product (ie, combustible, blunts, vaporized, edible, or concentrated) in the past 30 days at baseline (ie, 1-2 vs 0 days). Past 6-month use (ie, yes vs no) and number of days of use in the past 30 days at 6-month and 12-month follow-ups for each product. Of 2685 individuals in the analytic sample, 1477 (55.0%) were young women, the mean (SD) age was 17.1 (0.4) years, and a plurality (1231 [46.6%]) were Hispanic individuals. Among them, 158 (5.9%) reported combustible cannabis use on 1 to 2 days of the past 30 days at baseline, 90 (3.4%) reported blunt use, 78 (2.9%) reported edible cannabis use, 17 (0.6%) reported vaping cannabis, and 15 (0.6%) reported using cannabis concentrates. In regression models adjusting for demographic characteristics and poly-cannabis product use, statistically stronger associations of baseline use with subsequent past 6-month use at the 6-month and 12-month follow-ups were observed for combustible cannabis use (odds ratio, 6.01; 95% CI, 3.66-9.85) and cannabis concentrate use (odds ratio, 5.87; 95% CI, 1.18-23.80) compared with use of blunts (OR, 2.77; 95% CI, 1.45-5.29) or edible cannabis (OR, 3.32; 95% CI, 1.86-5.95) (P for comparison < .05); vaporized cannabis use (OR, 5.34; 95% CI, 1.51-11.20) was not significantly different from the other products. In similarly adjusted models, we found the association of cannabis use at baseline with mean days of use at the 6-month and 12-month follow-ups was significantly stronger for cannabis concentrate than for other cannabis products; participants who had used cannabis concentrate on 1 to 2 of the past 30 days at baseline (vs 0 days) used cannabis concentrate a mean of 9.42 (95% CI, 2.02-35.50) more days in the past 30 days at the 6-month and 12-month follow-ups (P for comparison < .05). Cannabis control efforts should consider targeting specific cannabis products, including combustible cannabis and cannabis concentrate, for maximum public health consequences.


An approach to the clinical assessment and management of syncope in adults.
Syncope, defined as a brief loss of consciousness due to an abrupt fall in cerebral perfusion, remains a frequent reason for medical presentation. The goals of the clinical assessment of a patient with syncope are twofold: (i) to identify the precise cause in order to implement a mechanism-specific and effective therapeutic strategy; and (ii) to quantify the risk to the patient, which depends on the underlying disease,rather than the mechanism of the syncope. Hence, a structured approach to the patient with syncope is required. History-taking remains the most important aspect of the clinical assessment. The classification of syncope is based on the underlying pathophysiological mechanism causing the event, and includes cardiac, orthostatic and reflex (neurally mediated) mechanisms. Reflex syncope can be categorised into vasovagal syncope (from emotional or orthostatic stress), situational syncope (due to specific situational stressors), carotid sinus syncope(from pressure on the carotid sinus, e.g. shaving or a tight collar), and atypical reflex syncope (episodes of syncope or reflex syncope that cannot be attributed to a specific trigger or syncope with an atypical presentation). Cardiovascular causes of syncope may be structural(mechanical) or electrical. Orthostatic hypotension is caused by an abnormal drop in systolic blood pressure upon standing, and is defined asa decrease of >20 mmHg in systolic blood pressure or a reflex tachycardia of >20 beats/minute within 3 minutes of standing. The main causes of orthostatic hypotension are autonomic nervous system failure and hypovolaemia. Patients with life-threatening causes of syncope should be managed urgently and appropriately. In patients with reflex or orthostatic syncope it is important to address any exacerbating medication and provide general measures to increase blood pressure, such as physical counter-pressure manoeuvres. Where heart disease is found to bet he cause of the syncope, a specialist opinion is warranted and where possible the problem should be corrected. It is important to remember that in any patient presenting with syncope the main objectives of management are to prolong survival, limit physical injuries and prevent recurrences. This can only be done if a patient is appropriately assessed at presentation, investigated as clinically indicated, and subsequently referred to a cardiologist for appropriate management.


Role of the 293b-sensitive, slowly activating delayed rectifier potassium current, i(Ks), in pacemaker activity of rabbit isolated sino-atrial node cells.
(i) to characterize the electrophysiological properties of the slowly activating delayed rectifier potassium current, i(Ks), defined as the 293b-sensitive current, during the action potential (AP) of rabbit sino-atrial node (SAN) pacemaker cells; (ii) to evaluate the contribution of i(Ks) to the pacemaker AP under physiological conditions and during beta-adrenergic stimulation. Rabbit SAN pacemaker cells were studied using the perforated patch clamp technique in voltage-, AP- and current-clamp modes. Voltage-clamp findings. Block of i(Ks) by 293b is dose-dependent, with an IC(50) (half block) in rabbit SAN cells of 1.35 microM and an IC(80) (sub-maximal block) of 5 microM. Sub-maximal concentrations of 293b have no significant effects on long-lasting and transient inward calcium currents, i(Ca,L) and i(Ca,T), inward hyperpolarization activated current, i(f), and transient outward current, i(to). AP-clamp experiments. The 293b-sensitive current activates near the peak of the SAN pacemaker action potential, reaches a mean maximal current density of 1.0+/-0.3 pA/pF (n=8, cell capacitances 27 to 62 pF, mean 35+/-4.0 pF) during late repolarization, and inactivates towards the end of repolarization. Additionally, in two smaller cells (cell capacitances 15 and 23 pF), no discernible 293b-sensitive current component was detected. Current-clamp data. In spontaneously beating SAN cells under control conditions, sub-maximal block of i(Ks) by 5 microM 293b has negligible effects on action potential characteristics and does not change average cycle length (n=11). In contrast, after pre-treatment with 10 nM isoprenaline to mimic beta-adrenergic stimulation, cells showed a 293b-induced depolarization of maximum diastolic potential by 2.2+/-1%, a decrease in diastolic depolarization rate by 9.9+/-4%, and a slowing of late action potential repolarization by 28.7+/-10.2%, resulting in a prolongation of spontaneous cycle length by 9.8+/-3.0% (P<0.05, n=10; for all parameters). Our findings suggest that in rabbit SAN: (i) i(Ks) is activated during the normal pacemaker AP; (ii) the contribution of i(Ks) to beating rate is small under control conditions; and (iii) i(Ks) contributes significantly to spontaneous pacemaker rate during beta-adrenergic stimulation.


Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials.
Clinical trials examining the therapeutic benefit of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on nonalcoholic fatty liver disease (NAFLD) have reported inconsistent results. We performed a meta-analysis of randomized controlled trials (RCTs) examining the effect of ω-3 PUFA supplementation on NAFLD, and provide substantial evidence on whether ω-3 PUFA supplementation has a favorable effect for treating NAFLD. We searched the PubMed, Cochrane Library, Springer Link, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Scientific and Technological Journal (VIP) databases for RCTs on oral ω-3 PUFA supplementation in patients with NAFLD. The data were pooled; meta-analyses were conducted using random-effect or fixed-effect models. Eighteen studies involving 1424 patients were included. We found a significant benefit for ω-3 PUFAs vs control for liver fat, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, triglycerides, insulin resistance, and glucose. However, there was significant interstudy heterogeneity. Subgroup and regression analyses showed no significantly clear methodologic discrepancy. Publication bias and serious adverse events were not detected. Our meta-analysis suggests that ω-3 PUFA supplementation may decrease liver fat and hepatic enzyme parameters. However, more large-scale, well-designed RCTs are needed to confirm the effect of ω-3 PUFA supplementation on these parameters.


Identification of a novel, dominant dwarfing gene (Ddw4) and its effect on morphological traits of rye.
Shortening rye stems to improve lodging resistance is among the major tasks awaiting breeders of this cereal. The most straightforward way to achieve this goal is the implementation of a dominant dwarfing gene into high yielding cultivars. The choice of dominant dwarfing genes in rye is limited to Ddw1 and Ddw3 loci, which are well characterized with respect to map position and tightly linked molecular markers on the long arms of chromosomes 5RL and 1RL, respectively. This paper reports on the identification and preliminary characterization of a novel dominant dwarfing gene, Ddw4, from line S44. This was mapped within the centromeric region of chromosome 3R. The Ddw4 gene is sensitive to exogenous gibberellin. Its introduction into the rye populational cultivar Dańkowskie Amber decreased plant height by c. 54% without any negative effects on spike length and number of kernels per spike. Further genetic studies are needed to determine the perspectives for application of the newly detected dwarfing gene into breeding programs for short-stem rye.


The potential use of lithium as a marker for the assessment of the sources of dietary salt: cooking studies and physiological experiments in men.
Lithium was investigated for its possible use as a marker for identifying the various sources of NaCl in the diet. Micromolar concentrations of lithium can be detected in various vegetables, tap water and also in urine specimens of adult volunteers. The lithium content of vegetables varied from 6.1 to 24.5 mumol of lithium/kg dry weight, with the exception of spinach and aubergines which had much higher concentrations. The excretion of the element in 24 h urine specimens ranged from 2 to 4 mumol of lithium/day. Experiments were performed to assess whether both lithium and sodium would penetrate foods at the same rate during cooking. The rates of penetration into food for both elements were proportional to their concentration in the cooking water despite a sodium/lithium ratio of 50:1. Physiological experiments were conducted to investigate the handling of small doses of lithium by the body. A dose of 250 mumol of lithium was chosen as optimal and given orally to healthy volunteers in either single or continuous aqueous doses of lithium carbonate. The recoveries of oral lithium in urine were 92 +/- 5% (SD) and 97 +/- 4 (SD) (n = 5) for single and continuous doses respectively. The daily addition of 100 mmol of oral NaCl to the diet of volunteers receiving a standard dose of lithium did not affect urinary lithium excretion rates nor the final recovery of the administered lithium. These studies suggest that lithium carbonate may be a useful marker for the uptake of NaCl into cooked food; after eating lithium-enriched food the monitoring of urinary lithium output may then be used to quantify the amount of sodium derived from the specific foods.


A population-based study of overweight and obesity in expectant parents: socio-demographic patterns and within-couple associations.
Overweight and obesity in pregnancy increase the risk of several adverse pregnancy outcomes. However, both mothers' and fathers' health play an important role for long-term health outcomes in offspring. While aspects of health and lifestyle of pregnant women have been reported, the health of expectant fathers and correlations of health variables within couples have received less attention. This study aimed to explore the prevalence and socio-demographic patterns of overweight and obesity in Swedish expectant parents, and to assess within-couple associations. This population-based, cross-sectional study investigated self-reported data from 4352 pregnant women and 3949 expectant fathers, comprising 3356 identified couples. Data were collected in antenatal care clinics between January 2008 and December 2011. Descriptive, correlation and logistic regression analyses were performed. The self-reported prevalence of overweight (BMI 25.0-29.99) and obesity (BMI ≥ 30.0) was 29% among women (pre-pregnancy) and 53% among expectant fathers. In a majority of couples (62%), at least one partner was overweight or obese. The odds of being overweight or obese increased relative to partner's overweight or obesity, and women's odds of being obese were more than six times higher if their partners were also obese in comparison with women whose partners were of normal weight (OR 6.2, CI 4.2-9.3). A socio-demographic gradient was found in both genders in relation to education, occupation and area of residence, with higher odds of being obese further down the social ladder. The cumulative influence of these factors showed a substantial increase in the odds of obesity for the least compared to the most privileged (OR 6.5, CI 3.6-11.8). The prevalence of overweight and obesity in expectant parents was high, with a clear social gradient, and a minority of couples reported both partners with a healthy weight at the onset of pregnancy. Partner influence on health and health behaviours, and the role both mothers and fathers play in health outcomes of their offspring, underpin the need for a more holistic and gender inclusive approach to the delivery of pregnancy care and postnatal and child health services, with active measures employed to involve fathers.


Ion-selective electrode studies on the effects of 5-hydroxytryptamine on the intracellular level of potassium in an insect salivary gland.
Potassium-sensitive microelectrodes were used to measure the intracellular level of potassium in Calliphora salivary glands. During stimulation with 1 X 10(-8) M 5-HT, the potassium concentration increased from a resting level of 133.2 to 139.0 mM. When the external concentration of potassium was reduced below 2mM there was a rapid loss of potassium which could be partially reversed by 5-HT. During 5-HT stimulation, the addition of ouabain had no effect on a number of parameters including the rate of fluid secretion, the ionic composition of the saliva and the intracellular level of potassium. The possibility that potassium enters the cells passively is discussed.


Repelled from the wound, or randomly dispersed? Reverse migration behaviour of neutrophils characterized by dynamic modelling.
Following neutralization of infectious threats, neutrophils must be removed from inflammatory sites for normal tissue function to be restored. Recently, a new paradigm has emerged, in which viable neutrophils migrate away from inflammatory sites by a process best described as reverse migration. It has generally been assumed that this process is the mirror image of chemotaxis, where neutrophils are drawn into the areas of infection or tissue damage by gradients of chemotactic cues. Indeed, efforts are underway to identify cues that drive neutrophils away by the reverse process, fugetaxis. By using photoconvertible pigments expressed in neutrophils in transparent zebrafish larvae, we were able to image the position of each neutrophil during inflammation resolution in vivo. These neutrophil coordinates were analysed within a dynamic modelling framework, using different forms of the drift-diffusion equation with model selection and parameter estimation based on approximate Bayesian computation. This analysis revealed the experimental data were best fitted by a model incorporating a diffusion term but no drift term-where the presence of drift would indicate fugetaxis. This result, for the first time, provides rigorous data-driven evidence that reverse migration of neutrophils in vivo is not a form of fugetaxis, but rather a stochastic redistribution.


Solution-phase-peptide synthesis via the group-assisted purification (GAP) chemistry without using chromatography and recrystallization.
The solution phase synthesis of N-protected amino acids and peptides has been achieved through the Group-Assisted Purification (GAP) chemistry by avoiding disadvantages of other methods in regard to the difficult scale-up, expenses of solid and soluble polymers, etc. The GAP synthesis can reduce the use of solvents, silica gels, energy and manpower. In addition, the GAP auxiliary can be conveniently recovered for re-use and is environmentally friendly and benign, and substantially reduces waste production in academic labs and industry.


cGAS-Mediated Innate Immunity Spreads Intercellularly through HIV-1 Env-Induced Membrane Fusion Sites.
Upon sensing cytoplasmic retroviral DNA in infected cells, cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide cGAMP, which activates STING to trigger a type I interferon (IFN) response. We find that membrane fusion-inducing contact between donor cells expressing the HIV envelope (Env) and primary macrophages endogenously expressing the HIV receptor CD4 and coreceptor enable intercellular transfer of cGAMP. This cGAMP exchange results in STING-dependent antiviral IFN responses in target macrophages and protection from HIV infection. Furthermore, under conditions allowing cell-to-cell transmission of HIV-1, infected primary T cells, but not cell-free virions, deliver cGAMP to autologous macrophages through HIV-1 Env and CD4/coreceptor-mediated membrane fusion sites and induce a STING-dependent, but cGAS-independent, IFN response in target cells. Collectively, these findings identify an infection-specific mode of horizontal transfer of cGAMP between primary immune cells that may boost antiviral responses, particularly in infected tissues in which cell-to-cell transmission of virions exceeds cell-free infection.


Mode-locked operation of Cr⁴⁺:YAG single-crystal fiber laser with external cavity.
We report what is to our knowledge the first mode-locked Cr⁴⁺:YAG single-crystal fiber laser, which generates pulses of 120-fs duration with an output power of 23 mW at a center wavelength of 1520 nm for a single pulse in a cavity-round-trip. The laser contains a single-crystal fiber multi-mode waveguide about 120 μm in diameter and 40-mm long. The fundamental transverse mode is selected with an external cavity. This design strategy turned out to be well suited for direct high-power-laser-diode pumping.


Pulmonary tuberculosis presenting with oral aphthae.
Tuberculosis is caused by the Mycobacterium tuberculosis bacterium. Tuberculosis primarily affects the lungs. Patients mainly complain of cough, sputum, night sweating, weight loss, and fever. However, there may be cases of atypical presentations. Although aphthous mouth ulcers are mostly present in the oral cavity in primary tuberculosis patients, our literature search showed only one case report of pulmonary tuberculosis with oral aphthae. Here we report a case of a patient with pulmonary tuberculosis admitted to the hospital with the complaint of oral aphthae.


Evidence of the growth plate and the growth of long bones in juvenile dinosaurs.
Histological and ultrastructural evaluation of the ends of long bones of juvenile dinosaurs from the Upper Cretaceous Two Medicine Formation of Montana revealed the preservation of growth plates. Growth plates are discs of cartilage present near the ends of growing long bones that generate bone elongation. Comparison of the fossils with modern taxa demonstrated homology of the growth plate in birds and dinosaurs. The presence of an avian-type growth plate in dinosaurs adds a shared derived anatomical character corroborating inclusion of birds within the Dinosauria. Additionally, possession of a growth plate, which in birds is capable of producing rapid determinate long bone growth, implies that an avian developmental pattern may have been present in these dinosaurs.


A Melanoma Brain Metastasis with a Donor-Patient Hybrid Genome following Bone Marrow Transplantation: First Evidence for Fusion in Human Cancer.
Tumor cell fusion with motile bone marrow-derived cells (BMDCs) has long been posited as a mechanism for cancer metastasis. While there is much support for this from cell culture and animal studies, it has yet to be confirmed in human cancer, as tumor and marrow-derived cells from the same patient cannot be easily distinguished genetically. We carried out genotyping of a metastatic melanoma to the brain that arose following allogeneic bone-marrow transplantation (BMT), using forensic short tandem repeat (STR) length-polymorphisms to distinguish donor and patient genomes. Tumor cells were isolated free of leucocytes by laser microdissection, and tumor and pre-transplant blood lymphocyte DNAs were analyzed for donor and patient alleles at 14 autosomal STR loci and the sex chromosomes. All alleles in the donor and patient pre-BMT lymphocytes were found in tumor cells. The alleles showed disproportionate relative abundances in similar patterns throughout the tumor, indicating the tumor was initiated by a clonal fusion event. Our results strongly support fusion between a BMDC and a tumor cell playing a role in the origin of this metastasis. Depending on the frequency of such events, the findings could have important implications for understanding the generation of metastases, including the origins of tumor initiating cells and the cancer epigenome.


Practical lessons for phone-based assessments of learning.
School closures affecting more than 1.5 billion children are designed to prevent the spread of current public health risks from the COVID-19 pandemic, but they simultaneously introduce new short-term and long-term health risks through lost education. Measuring these effects in real time is critical to inform effective public health responses, and remote phone-based approaches are one of the only viable options with extreme social distancing in place. However, both the health and education literature are sparse on guidance for phone-based assessments. In this article, we draw on our pilot testing of phone-based assessments in Botswana, along with the existing literature on oral testing of reading and mathematics, to propose a series of preliminary practical lessons to guide researchers and service providers as they try phone-based learning assessments. We provide preliminary evidence that phone-based assessments can accurately capture basic numeracy skills. We provide guidance to help teams (1) ensure that children are not put at risk, (2) test the reliability and validity of phone-based measures, (3) use simple instructions and practice items to ensure the assessment is focused on the target skill, not general language and test-taking skills, (4) adapt the items from oral assessments that will be most effective in phone-based assessments, (5) keep assessments brief while still gathering meaningful learning data, (6) use effective strategies to encourage respondents to pick up the phone, (7) build rapport with adult caregivers and youth respondents, (8) choose the most cost-effective medium and (9) account for potential bias in samples.


Multiplexed detection of antibodies using programmable bead arrays.
The detection of antibodies in sera has broad applications for detection and monitoring of infectious diseases, autoimmunity, and cancer. Proteomic methods of antigen detection, such as protein microarrays, are excellent clinical discovery tools, but due to both cost and specialization of manufacture, these are limited to screening small numbers of sera. Downstream assays for biomarker validation studies require rapid, reproducible, multiplexed assays for the simultaneous screening of fewer (<100) antigens with hundreds or thousands of sera. Traditional clinical ELISA assays use recombinant proteins, but these are limited by the ability to purify proteins free of cross-reacting contaminants and are limited to one antigen at a time. Here, we describe the application of coupled in vitro protein production with anti-tag capture onto bead arrays, for the rapid multiplexed detection of antibodies in sera. These assays can be readily adapted for detection of any protein-specific infectious, autoimmune, or cancer-specific antibodies.


Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed.
The current model of measles virus (MV) pathogenesis implies that apical infection of airway epithelial cells precedes systemic spread. An alternative model suggests that primarily infected lymphatic cells carry MV to the basolateral surface of epithelial cells, supporting MV shedding into the airway lumen and contagion. This model predicts that a mutant MV, unable to enter cells through the unidentified epithelial cell receptor (EpR), would remain virulent but not be shed. To test this model, we identified residues of the MV attachment protein sustaining EpR-mediated cell fusion. These nonpolar or uncharged polar residues defined an area located near the binding site of the signaling lymphocytic activation molecule (SLAM), the receptor for MV on lymphatic cells. We then generated an EpR-blind virus maintaining SLAM-dependent cell entry and inoculated rhesus monkeys intranasally. Hosts infected with the selectively EpR-blind MV developed rash and anorexia while averaging slightly lower viremia than hosts infected with wild-type MV but did not shed virus in the airways. The mechanism restricting shedding was characterized using primary well-differentiated human airway epithelial cells. Wild-type MV infected columnar epithelial cells bearing tight junctions only when applied basolaterally, while the EpR-blind virus did not infect these cells. Thus, EpR is probably a basolateral protein, and infection of the airway epithelium is not essential for systemic spread and virulence of MV.


Distribution of the ACME-arcA gene among meticillin-resistant Staphylococcus haemolyticus and identification of a novel ccr allotype in ACME-arcA-positive isolates.
The aim of this study was to investigate the prevalence and characteristics of ACME (arginine catabolic mobile element)-arcA-positive isolates among meticillin-resistant Staphylococcus haemolyticus (MRSH). ACME-arcA, native arcA and SCCmec elements were detected by PCR. Susceptibilities to 10 antimicrobial agents were compared between ACME-arcA-positive and -negative isolates by chi-square test. PFGE was used to investigate the clonal relatedness of ACME-arcA-positive isolates. The phylogenetic relationships of ACME-arcA and native arcA were analysed using the neighbour-joining methods of mega software. A total of 42 (47.7 %) of 88 isolates distributed in 13 PFGE types were positive for the ACME-arcA gene. There were no significant differences in antimicrobial susceptibility between ACME-arcA-positive and -negative isolates. A novel ccr allotype (ccrAB(SHP)) was identified in ACME-arcA-positive isolates. Among 42 ACME-arcA-positive isolates: 8 isolates harboured SCCmec V, 8 isolates harboured class C1 mec complex and ccrAB(SHP); 22 isolates harbouring class C1 mec complex and 4 isolates harbouring class C2 mec complex were negative for all known ccr allotypes. The ACME-arcA-positive isolates were first found in MRSH with high prevalence and clonal diversity, which suggests a mobility of ACME within MRSH. The results from this study revealed that MRSH is likely to be one of the potential reservoirs of ACME for Staphylococcus aureus.


Multiple stressor effects of predation by rotifers and herbicide pollution on different Chlamydomonas strains and potential impacts on population dynamics.
Environmental factors can interact with the effects of chemical pollutants on natural systems by inducing multiple stressor effects in individual organisms as well as by altering selection pressure on tolerant strains in heterogeneous populations. Predation is a stressful environmental factor relevant for many species. Therefore, the impact of predation by the rotifer Brachionus calyciflorus on tolerance of eight genetically different strains of the green alga Chlamydomonas reinhardtii to simultaneous exposure to each of the three herbicides (diuron, paraquat, and S-metolachlor) was tested. Interactions of combined stressors were analyzed based on the independent action model; additive, synergistic, and antagonistic effects of the combined exposure could be detected depending on the herbicide and strain tested. If cultures were acclimated (pre-exposed) to one stressor, tolerance to the second stressor could be increased. This indicates that physiological changes can induce cotolerance of predation-exposed algae to herbicides and of herbicide-treated algae to predation depending on the combination of stressors. The strain-specific differences in multiple stressor effects also changed the correlation of strains' tolerances to individual stressors determined during combined and single-stressor exposure. Changes in cotolerance to stressors affect selection pressure and population dynamics during long-term exposure. This shows that predation stress can have adverse effects on the toxicity of chemical pollutants to microalgae on the organism and population levels.


Attentional Weighting in the Face Processing Network: A Magnetic Response Image-guided Magnetoencephalography Study Using Multiple Cyclic Entrainments.
We recorded magnetoencephalography using a neural entrainment paradigm with compound face stimuli that allowed for entraining the processing of various parts of a face (eyes, mouth) as well as changes in facial identity. Our magnetic response image-guided magnetoencephalography analyses revealed that different subnodes of the human face processing network were entrained differentially according to their functional specialization. Whereas the occipital face area was most responsive to the rate at which face parts (e.g., the mouth) changed, and face patches in the STS were mostly entrained by rhythmic changes in the eye region, the fusiform face area was the only subregion that was strongly entrained by the rhythmic changes in facial identity. Furthermore, top-down attention to the mouth, eyes, or identity of the face selectively modulated the neural processing in the respective area (i.e., occipital face area, STS, or fusiform face area), resembling behavioral cue validity effects observed in the participants' RT and detection rate data. Our results show the attentional weighting of the visual processing of different aspects and dimensions of a single face object, at various stages of the involved visual processing hierarchy.


Activated cortical states: experiments, analyses and models.
In awake animals, the cerebral cortex displays an "activated" state, with distinct characteristics compared to other states like slow-wave sleep or anesthesia. These characteristics include a sustained depolarized membrane potential (V(m)) and irregular firing activity. In the present paper, we evaluate our understanding of cortical activated states from a computational neuroscience point of view. We start by reviewing the electrophysiological characteristics of activated cortical states based on recordings and analysis performed in awake cat association cortex. These analyses show that cortical activity is characterized by an apparent Poisson-distributed stochastic dynamics, both at the single-cell and population levels, and that single cells display a high-conductance state dominated by inhibition. We next overview computational models of the "awake" cortex, and perform the same analyses as in the experiments. Many properties identified experimentally are indeed reproduced by models, such as depolarized V(m), irregular firing with apparent Poisson statistics, and the determinant role of inhibitory fluctuations on spiking. However, other features are not well reproduced, such as firing statistics and the conductance state of the membrane, suggesting that the network state displayed by models is not entirely correct. We also show how networks can approach a correct conductance state, suggesting ways by which future models will generate activity fully consistent with experimental data.


LYMPHOCYTE COUNT AND PLATELET VOLUME PREDICTS POSTOPERATIVE COMPLICATIONS IN ESOPHAGECTOMY FOR CANCER: A COHORT STUDY.
Biomarkers from routine complete blood count are known predictive factors of long-term outcomes in cancer patients. The value of these biomarkers in the setting of trimodal therapy for esophageal cancer in predicting early postoperative outcomes is not studied. The present study evaluated the value of cellular blood components changes during neoadjuvant chemoradiotherapy followed by curative intent esophagectomy for cancer in predicting postoperative mortality and morbidity. A cohort of 149 consecutive patients that underwent chemoradiotherapy using platinum- and taxane-based regimens followed by esophagectomy was analyzed. Cellular components of blood collected before neoadjuvant therapy (period A) and before surgery (period B) were assessed for postoperative mortality and complications. Univariate and multivariate Cox regression models were applied to evaluate the independent prognostic significance of blood count variables. Postoperative morbidity was present in 46% of the patients. On multiple regression analysis platelet volume (B) (OR: 1.53; 95% CI: 1.2-2.33) was an independent predictor of general complications. Severe postoperative surgical complications were present in 17% of the patients. On multiple regression analysis, lymphocyte decrease between B-A periods (OR: 0.992; 95% CI: 0.990-0.997) was related to higher risk for severe complications. Cervical anastomotic leakage was present in 25.6% of the patients. On univariate analysis eosinophil count in A and B periods was related to cervical anastomotic leakage. For this outcome, multivariate joint model could not identify independent risk variables of cellular components of blood. The 30-day mortality rate was 7.4%. On univariate analysis, platelet count in period B was associated to higher risk for mortality. The multivariate joint model could not accurately predict mortality due to the few number of patients in the mortality group. This is the first study to assess the relationship between peripheral blood count variables changes during neoadjuvant chemoradiotherapy using a platinum- and taxane-based regimen followed by curative intent esophagectomy for cancer in predicting postoperative complications. The platelet volume prior to surgery is related to postoperative complications and the lymphocyte count change prior to surgery predicts severe postoperative complications in the setting of trimodal therapy for esophageal cancer.


A novel function of adipocytes in lipid antigen presentation to iNKT cells.
Systemic low-grade chronic inflammation has been intensively investigated in obese subjects. Recently, various immune cell types, such as macrophages, granulocytes, helper T cells, cytotoxic T cells, and B cells, have been implicated in the pathogenesis of adipose tissue inflammation. However, the roles of invariant natural killer T cells (iNKT cells) and the regulation of iNKT cell activity in adipose tissue are not thoroughly understood. Here, we demonstrated that iNKT cells were decreased in number in the adipose tissue of obese subjects. Interestingly, CD1d, a molecule involved in lipid antigen presentation to iNKT cells, was highly expressed in adipocytes, and CD1d-expressing adipocytes stimulated iNKT cell activity through physical interaction. iNKT cell population and CD1d expression were reduced in the adipose tissue of obese mice and humans compared to those of lean subjects. Moreover, iNKT cell-deficient Jα18 knockout mice became more obese and exhibited increased adipose tissue inflammation at the early stage of obesity. These data suggest that adipocytes regulate iNKT cell activity via CD1d and that the interaction between adipocytes and iNKT cells may modulate adipose tissue inflammation in obesity.


Expression of secreted Wnt pathway components reveals unexpected complexity of the planarian amputation response.
Regeneration is widespread throughout the animal kingdom, but our molecular understanding of this process in adult animals remains poorly understood. Wnt/β-catenin signaling plays crucial roles throughout animal life from early development to adulthood. In intact and regenerating planarians, the regulation of Wnt/β-catenin signaling functions to maintain and specify anterior/posterior (A/P) identity. Here, we explore the expression kinetics and RNAi phenotypes for secreted members of the Wnt signaling pathway in the planarian Schmidtea mediterranea. Smed-wnt and sFRP expression during regeneration is surprisingly dynamic and reveals fundamental aspects of planarian biology that have been previously unappreciated. We show that after amputation, a wounding response precedes rapid re-organization of the A/P axis. Furthermore, cells throughout the body plan can mount this response and reassess their new A/P location in the complete absence of stem cells. While initial stages of the amputation response are stem cell independent, tissue remodeling and the integration of a new A/P address with anatomy are stem cell dependent. We also show that WNT5 functions in a reciprocal manner with SLIT to pattern the planarian mediolateral axis, while WNT11-2 patterns the posterior midline. Moreover, we perform an extensive phylogenetic analysis on the Smed-wnt genes using a method that combines and integrates both sequence and structural alignments, enabling us to place all nine genes into Wnt subfamilies for the first time.


Sub-Tenon's injection for local anesthesia in posterior segment surgery.
To determine whether the sub-Tenon's parabulbar approach for local anesthesia is a safe and effective choice for posterior segment surgery. Prospective, noncomparative case series. Two hundred seventy-six consecutive patients underwent posterior segment surgery at the University of Texas Medical Branch. Two hundred patients received sub-Tenon's parabulbar anesthesia containing an 11 -ml mixture of 5-ml 2% lidocaine (Xylocaine), 5-ml 0.5% bupivacaine (Marcaine), and 1 ml of 150 hyaluronidase (Wydase) units as primary anesthesia. The method did not involve a separate transcutaneous lid nerve or subconjunctival injection. The proportion of cases receiving supplementation (significant intravenous anesthesia, intraoperative local anesthesia, or both) was estimated. Its relationship to duration of surgery and surgical procedures deemed painful was assessed. Surgery lasting 3 hours or more was considered a long duration. Both scleral buckle and cryotherapy were considered painful procedures. The proportion of cases receiving additional local anesthesia preoperatively was also evaluated. Complications associated with sub-Tenon's parabulbar injection were monitored. There were 101 instances of patients receiving additional anesthesia. Nineteen received additional preoperative sub-Tenon's anesthesia, 12 received intraoperative local anesthesia supplementation, and 70 received intravenous medication. Of these 70, 19 required what the authors defined as a significant amount of intravenous medication, three of whom also received intraoperative local anesthesia supplementation. Consequently, 28 of 200 patients (14%; 95% confidence interval: 9.5, 19.6) received supplementation (significant intravenous anesthesia, intraoperative local anesthesia, or both). The proportion of cases receiving supplementation was directly related to duration of surgery. Patients involved in longer cases (51.7% vs. 7.6%; P < 0.001) and those involved in more painful procedures (48.2% vs. 8.7%; P < 0.001) were more likely to receive supplementation. Adjusting for surgery duration, a greater proportion of patients undergoing painful procedures required supplementation (31.3% vs. 0.5% for surgery < 3 hours, P = 0.003; 72.7% vs. 38.9% for surgery > or = 3 hours, P = 0.13). No associated ocular or systemic complications were observed. The results of this large study demonstrate that a single injection of sub-Tenon's anesthesia is relatively safe and effective for achieving local anesthesia during vitrectomies, with or without other intraocular procedures, lasting less than 3 hours. Other types of posterior segment surgery may require supplementation if they are more painful procedures, such as scleral buckle or cryotherapy, or last longer than 3 hours.


Detection and analysis of depolarization artifacts in rotating-compensator polarimeters.
Absolute constraints, namely, the Schwarz inequality and a complementary expression derived by us, are used to obtain corresponding absolute constraints on the Fourier coefficients of the intensity transmitted through rotating-compensator polarimeters and ellipsometers. These expressions allow the investigation of artifacts that result in mixed or apparently mixed polarization states over the cross section of the beam, the averaging time of the detector, or the frequency passband of the dispersing element. Examples include multiple internal reflections or inhomogeneous strain within an element, scattered light, and other types of system and component defects that cannot be accessed by means of polarization-state data alone. We apply these results to our polarizer-sample-compensator-analyzer (PSCA) ellipsometer to illustrate capabilities. A simple analytic model is shown to give a quantitative description of depolarization in systems for which the resolution is finite and the retardation varies with wavelength.


Modelling the effects of meteorological parameters on water temperature using artificial neural networks.
Water temperature affects all biological and chemical processes in water; therefore, it is an extremely important water quality parameter. Meteorological factors are among the most important factors that affect water temperatures. The aim of this study is to develop an artificial neural network (ANN) model to investigate the effects of meteorological parameters on water temperatures at Kızılırmak River in Turkey. Water temperature data were collected from gauging stations on Kızılırmak River, and meteorological data were acquired from the nearest meteorological stations. Air temperature, wind speed, relative humidity, and previous water temperatures were formed the input parameters. The model output included water temperatures. All data were available for the 1995-2007 period, with occasional missing records. The activation functions of the ANN model and the number of neurons in the hidden layer were selected by trial-and-error method to find the best results. The root mean square error and the correlation coefficient between observed and simulated water temperatures were used to assess the model success. The best results were obtained by using sigmoid activation function and scaled conjugate gradient algorithm. This study showed that meteorological data can be used to simulate water temperature with ANN model for Kızılırmak River.


The p150 Isoform of ADAR1 Blocks Sustained RLR signaling and Apoptosis during Influenza Virus Infection.
Signaling through retinoic acid inducible gene I (RIG-I) like receptors (RLRs) is tightly regulated, with activation occurring upon sensing of viral nucleic acids, and suppression mediated by negative regulators. Under homeostatic conditions aberrant activation of melanoma differentiation-associated protein-5 (MDA5) is prevented through editing of endogenous dsRNA by RNA editing enzyme Adenosine Deaminase Acting on RNA (ADAR1). In addition, ADAR1 is postulated to play pro-viral and antiviral roles during viral infections that are dependent or independent of RNA editing activity. Here, we investigated the importance of ADAR1 isoforms in modulating influenza A virus (IAV) replication and revealed the opposing roles for ADAR1 isoforms, with the nuclear p110 isoform restricting versus the cytoplasmic p150 isoform promoting IAV replication. Importantly, we demonstrate that p150 is critical for preventing sustained RIG-I signaling, as p150 deficient cells showed increased IFN-β expression and apoptosis during IAV infection, independent of RNA editing activity. Taken together, the p150 isoform of ADAR1 is important for preventing sustained RIG-I induced IFN-β expression and apoptosis during viral infection.


Idiopathic intracranial hypertension; research progress and emerging themes.
Idiopathic intracranial hypertension (IIH) is a condition characterised by increased intracranial pressure of unknown cause predominantly seen in obese women of childbearing age and associated with a history of recent weight gain. The aetiology is poorly understood and there are no evidence-based guidelines on the management of the disease. We aim to provide a review of the recent literature outlining the latest advances in this field over the past few years. Areas of emerging interest related to the pathophysiology of IIH will be discussed, such as the role of obesity, adipose tissue and 11β-hydroxysteroid dehydrogenase type 1. We consider the latest research on the role of venous sinus stenosis in IIH and ex vivo advances into cerebrospinal fluid drainage via the arachnoid granulation tissue. The latest techniques for optic nerve head evaluation and the role of optical coherence tomography will be summarised. Finally, we will discuss recent advances in the management of IIH, including weight loss, and medical and surgical treatment strategies.


Final transitions to place of death: patients and families wishes.
This four-country study (Belgium, the Netherlands, Italy and Spain) examines prevalence and types of final transitions between care settings of cancer patients and the extent to which patient/family wishes are cited as a reason for the transition. Data were collected from the EUROSENTI-MELC study over a 2-year period. General practitioners within existing Sentinel Networks registered weekly all deaths of patients within practices using a standardized questionnaire. This registration included place of care in the final 3 months and wishes for the final transition to place of death. All non-sudden deaths due to cancer (+18 years) were included in the analyses. We included 2048 non-sudden cancer deaths; 63% of patients had at least one transition between care settings in the final 3 months of life. 'Hospital death from home' (25-55%) and 'home death from hospital' (16-30%) were the most frequent types of final transitions in all countries. Patients' or families' wishes were mentioned as a reason for a final transition in 5-27% (P < 0.001) and 10-22% (P = 0.002) across countries. 'Hospital deaths from home' is the most prevalent final transition in three of four countries studied, in a significant minority of cases because of patient/family wishes.


Breast-conserving therapy for ductal carcinoma in situ.
This retrospective analysis evaluates the treatment results and prognostic factors of 114 patients with ductal carcinoma in situ (DCIS) undergoing breast conserving therapy (BCT) at Keio University Hospital Department of Radiology, between 1988 and 1997. A total of 132 patients with DCIS of the breast came to our hospital between 1988 and 1997, and 114 cases were suitable candidates for BCT. All of the patients were female and ranged in age from 26 to 81 years (median 46). Ninety-one patients were premenopausal, and 23 were postmenopausal. Median clinical tumor size was 2.0 cm (0-8.0 cm). Postoperatively 48 cases received 50 Gy/25 fractions of external irradiation to the whole breast via tangential ports. The follow-up period after treatment ranged from 11 to 162 months (median 46.7). The local relapse-free rate and overall survival rate of the 114 patients were 89.5% and 100%, respectively. Local failure and regional nodal failure occurred in 12 and 1 patient, respectively. Radiotherapy was a significant risk factor for local failure (p=0.05). No postmenopausal patients developed local failure, but the difference did not reach statistical significance (p=0.103). The 12 recurrent cases underwent additional surgery and all remain alive without recurrence, to date, i.e., at least 16 months. Breast-conserving surgery plus irradiation is appropriate treatment for DCIS patients.


Effects of physical characteristics of carbon black on metabolic regulation in mice.
Potential adverse effects of human exposure to carbon black (CB) have been reported, but limited knowledge regarding CB-regulated metabolism is currently available. To evaluate how physical parameters of CB influence metabolism, we investigated CB and diesel exhaust particles (DEPs) and attempted to relate various physical parameters, including the hydrodynamic diameter, zeta potential, and particle number concentrations, to lung energy metabolism in female BALB/c mice. A body weight increase was arrested by 3 months of exposure to CB of smaller-size fractions, which was negatively correlated with pyruvate in plasma. There were no significant differences in cytotoxic lactate dehydrogenase (LDH) or total protein in bronchoalveolar lavage fluid (BALF) after 3 months of CB exposure. However, we observed alterations in acetyl CoA and the NADP/NADPH ratio in lung tissues with CB exposure. Additionally, the NADP/NADPH ratio was associated with the zeta potential of CB. Mild peribronchiovascular and interstitial inflammation and multinucleated giant cells (macrophages) with a transparent and rhomboid appearance and containing foreign bodies were observed in lung sections. We suggest that physical characteristics of CB, such as the zeta potential, may disrupt metabolism after pulmonary exposure. These results, therefore, provide the first evidence of a link between pulmonary exposure to CB and metabolism.


Religious coping strategies in patients diagnosed with breast cancer in the UK.
The use of religious/spiritual coping strategies may be particularly prevalent when dealing with the stress of a cancer diagnosis. There has, however, been very little research conducted on this topic outside the USA. Existing measures of coping largely ignore the complexity of religious/spiritual coping and its potential to be adaptive as well as maladaptive. The aim of this study was to examine the prevalence of various religious coping strategies in a UK cancer sample. A longitudinal design assessed religious coping strategies in patients newly diagnosed with breast cancer at the time of surgery and at 3 and 12 months post surgery. We recruited 202 patients of which, at 12 months, 160 remained. A non-religious coping measure was included for comparison. The use of religious coping strategies was overall common; up to 73% of patients used positive religious coping to some degree at surgery and up to 53% experienced various religious/spiritual struggles. The use of some religious coping strategies showed differing patterns of change across time while others remained stable. Using religious/spiritual resources in the coping process during the early stages of breast cancer appears common in the UK. Patients may benefit from having their spiritual needs addressed as experiencing some form of religious/spiritual struggle may serve as a barrier to illness adjustment. Health-care professionals should also be aware that some religious coping strategies may be more prevalent at different times during the first year of illness.


Higher-order Kerr effect and harmonic cascading in gases.
The higher-order Kerr effect (HOKE) has recently been advocated to explain measurements of the saturation of the nonlinear refractive index in gases. Here we show that cascaded third-harmonic generation results in an effective fifth-order nonlinearity that is negative and significant. Higher-order harmonic cascading will also occur from the HOKE, and the cascading contributions may significantly modify the observed nonlinear index change. At lower wavelengths, cascading increases the HOKE saturation intensity, while for longer wavelengths cascading will decrease the HOKE saturation intensity.


Contribution of university departments of rural health to rural health research: An analysis of outputs.
To assess the research contribution of eleven University Departments of Rural Health (UDRH) which were established as a rural health workforce program in the late 1990s through analysis of peer-reviewed journal output. Descriptive study based on validated publications from publication output reported in annual key performance indicator (KPI) reports to the Commonwealth Department of Health, Australia. In addition to counts and the type of publications, articles were examined to assess fields of research, evidence of research collaboration, and potential for influencing policy. Funding acknowledgement was examined to provide insight into funding sources and research consultancies. Of the 182 peer-reviewed articles, UDRH staff members were the first and corresponding author for 45% (n = 82); most (69%, n = 126) were original research. Most publications examined included Australian data only (80%, n = 101). Over half (56%; n = 102) of the articles addressed rural health issues; Aboriginal health was the main subject in 14% (n = 26). Thirty-three articles (18%) discussed the policy implications of the research and only half (51%, n = 93) of the articles listed sources of funding. Number of authors per article ranged from 1-19, with a mean of 5 (SD = 3.2) authors per article, two-thirds of articles included authors from 2-5 universities/organisations but only 5% of articles included an author from more than one UDRH. Staff from UDRHs are regularly publishing peer-reviewed articles, and research productivity demonstrated cooperation with external partners. Better collaboration between UDRH staff and others may help increase the quality and value of Australian rural health research.


High-grade squamous intraepithelial lesion arising adjacent to vulvar lymphangioma circumscriptum: a tertiary institutional experience.
Lymphangioma circumscriptum of the vulva occurs in patients who have undergone radical hysterectomy, lymph node dissection, or radiation therapy for management of advanced uterine cancer. Since vulvar lymphangioma circumscriptum typically presents as multiple, grossly verrucous vesicles of various sizes, it may be impossible to clinically distinguish vulvar lymphangioma circumscriptum from other vulvoperineal cutaneous diseases. In the present study, 16 (1.6%) out of the 1,024 vulvar biopsy or excision specimens were diagnosed as lymphangioma circumscriptum. In two (12.5%) out of the 16 cases, unusual histopathological findings were observed. Both patients had previously undergone radical hysterectomy with lymph node dissection and postoperative radiation therapy or concurrent chemoradiation therapy for advanced cervical cancer. Microscopic examination revealed high-grade squamous intraepithelial lesions, which were located immediately adjacent to the normal squamous epithelium covering the dilated subepithelial lymphatic vessels. Further, human papillomavirus genotyping confirmed that both patients were infected with high-risk human papillomavirus. High-grade squamous intraepithelial lesion cannot be grossly distinguished from vulvar lymphangioma circumscriptum because the multiple, verrucous vesicles that constitute the characteristic gross appearance of vulvar lymphangioma circumscriptum hinder its distinction. In this regard, our cases of high-grade squamous intraepithelial lesion, located adjacent to vulvar lymphangioma circumscriptum, support the notion that active surgical excision is necessary for the treatment of vulvar lymphangioma circumscriptum.