GSK-3β phosphorylation of DHX33 leads to its ubiquitination mediated protein degradation.
DHX33 is a member of DEAD/H box protein family, and is involved in both RNA and DNA metabolism. It plays diverse roles in multiple cellular activities. DHX33 overexpression has been found to promote the development of many human cancers. However, the underlying mechanism to explain its high expression in cancer cells remains incompletely resolved. In this study, with both human cancer cell lines and normal fibroblasts, we found glycogen synthase kinase 3β (GSK-3β) regulates DHX33 protein stability. This is through its direct phosphorylation of DHX33 on T482, which triggers ubiquitination mediate protein degradation. We further identified one of the major ubiquitination sites of DHX33 to be on its N-terminal K94, a critical residue previously found to be important and highly conserved for ATP binding and helicase activity. Our study for the first time reveals an important upstream regulator, GSK-3β, as a critical kinase to phosphorylate DHX33 at the post-translational level leading to its degradation. Moreover, cancer cells have frequent GSK3β deactivation to disrupt this signaling cascade. Therefore, DHX33 is stabilized in many cancer cells as compared to normal cells. Our study unveils an important post-translational regulation of DHX33 in cells and further unveils a novel mechanism for DHX33 overexpression in cancer cells.


Magnesium metabolism in health and disease.
Magnesium is an important element for health and disease. Magnesium, the second most abundant intracellular cation, has been identified as a cofactor in over 300 enzymatic reactions involving energy metabolism and protein and nucleic acid synthesis. Approximately half of the total magnesium in the body is present in soft tissue, and the other half in bone. Less than 1% of the total body magnesium is present in blood. Nonetheless, the majority of our experimental information comes from determination of magnesium in serum and red blood cells. At present, we have little information about equilibrium among and state of magnesium within body pools. Magnesium is absorbed uniformly from the small intestine and the serum concentration controlled by excretion from the kidney. The clinical laboratory evaluation of magnesium status is primarily limited to the serum magnesium concentration, 24-hour urinary excretion, and percent retention following parenteral magnesium. However, results for these tests do not necessarily correlate with intracellular magnesium. Thus, there is no readily available test to determine intracellular/total body magnesium status. Magnesium deficiency may cause weakness, tremors, seizures, cardiac arrhythmias, hypokalemia, and hypocalcemia. The causes of hypomagnesemia are reduced intake (poor nutrition or IV fluids without magnesium), reduced absorption (chronic diarrhea, malabsorption, or bypass/resection of bowel), redistribution (exchange transfusion or acute pancreatitis), and increased excretion (medication, alcoholism, diabetes mellitus, renal tubular disorders, hypercalcemia, hyperthyroidism, aldosteronism, stress, or excessive lactation). A large segment of the U.S. population may have an inadequate intake of magnesium and may have a chronic latent magnesium deficiency that has been linked to atherosclerosis, myocardial infarction, hypertension, cancer, kidney stones, premenstrual syndrome, and psychiatric disorders. Hypermagnesemia is primarily seen in acute and chronic renal failure, and is treated effectively by dialysis.


Fibromuscular dysplasia of the superficial femoral artery: an unusual localization.
The authors describe an uncommon localization of fibromuscular dysplasia in the superficial femoral artery. The treatment consisted in surgical resection of the lesion. The follow-up showed extension of the disease. Review of the literature.


Comparing the xylose reductase/xylitol dehydrogenase and xylose isomerase pathways in arabinose and xylose fermenting Saccharomyces cerevisiae strains.
Ethanolic fermentation of lignocellulosic biomass is a sustainable option for the production of bioethanol. This process would greatly benefit from recombinant Saccharomyces cerevisiae strains also able to ferment, besides the hexose sugar fraction, the pentose sugars, arabinose and xylose. Different pathways can be introduced in S. cerevisiae to provide arabinose and xylose utilisation. In this study, the bacterial arabinose isomerase pathway was combined with two different xylose utilisation pathways: the xylose reductase/xylitol dehydrogenase and xylose isomerase pathways, respectively, in genetically identical strains. The strains were compared with respect to aerobic growth in arabinose and xylose batch culture and in anaerobic batch fermentation of a mixture of glucose, arabinose and xylose. The specific aerobic arabinose growth rate was identical, 0.03 h-1, for the xylose reductase/xylitol dehydrogenase and xylose isomerase strain. The xylose reductase/xylitol dehydrogenase strain displayed higher aerobic growth rate on xylose, 0.14 h-1, and higher specific xylose consumption rate in anaerobic batch fermentation, 0.09 g (g cells)-1 h-1 than the xylose isomerase strain, which only reached 0.03 h-1 and 0.02 g (g cells)-1h-1, respectively. Whereas the xylose reductase/xylitol dehydrogenase strain produced higher ethanol yield on total sugars, 0.23 g g-1 compared with 0.18 g g-1 for the xylose isomerase strain, the xylose isomerase strain achieved higher ethanol yield on consumed sugars, 0.41 g g-1 compared with 0.32 g g-1 for the xylose reductase/xylitol dehydrogenase strain. Anaerobic fermentation of a mixture of glucose, arabinose and xylose resulted in higher final ethanol concentration, 14.7 g l-1 for the xylose reductase/xylitol dehydrogenase strain compared with 11.8 g l-1 for the xylose isomerase strain, and in higher specific ethanol productivity, 0.024 g (g cells)-1 h-1 compared with 0.01 g (g cells)-1 h-1 for the xylose reductase/xylitol dehydrogenase strain and the xylose isomerase strain, respectively. The combination of the xylose reductase/xylitol dehydrogenase pathway and the bacterial arabinose isomerase pathway resulted in both higher pentose sugar uptake and higher overall ethanol production than the combination of the xylose isomerase pathway and the bacterial arabinose isomerase pathway. Moreover, the flux through the bacterial arabinose pathway did not increase when combined with the xylose isomerase pathway. This suggests that the low activity of the bacterial arabinose pathway cannot be ascribed to arabitol formation via the xylose reductase enzyme.


Analysis of Selection of Recipient Vein, Number of Outflows, Style and Technique in Head and Neck Venous Anastomosis and a Proposed Algorithm.
Surgeons have preferential ways of performing venous anastomosis in head and neck microsurgery. However, controversies exist regarding the superiority of each method. This study aims to determine the effects of these variables on the rates of thrombosis and flap failure, and propose an algorithm to be used as a facilitator in the decision-making process. A total of 208 microsurgical reconstructions on 199 patients from a single surgeon's data were evaluated. Selection of recipient vein (superficial vs. deep), style of anastomosis (end-to-end vs. end-to-side), number of outflows (one vs. two) and technique of anastomosis (hand-sewn vs. coupler) were compared. Selection was done according to the pre- and intraoperative plan, as well as, surgeon's clinical judgement. Outcomes were determined as rates of venous thrombosis and flap failure. Five patients (2.4%) had venous problems, leading to two partial and three total flap failures. Selection of the recipient vein, style and number of outflows did not affect the outcomes, whereas coupler use decreased the rates of venous thrombosis and flap failure (p=0.008). Although it is difficult to set dogmatic criteria to achieve consistent outcomes, coupler use in this study prevented flap failure. An algorithmic approach was proposed with the results of the data and literature to increase the success in microsurgical anastomosis. Surgeons should use algorithms and sound judgement with adherence to microsurgical principles to obtain the best results for each patient.


Functional neuroimaging studies in functional dyspepsia patients: a systematic review.
There is increasing evidence in support of the presence of abnormal central changes (compared to healthy controls) in functional dyspepsia (FD) in addition to the peripheral changes in gastrointestinal tract. This systematic review aims to provide an integrative understanding of the abnormal functional brain activity, visceral sensation, dyspeptic symptoms, and psychological changes of FD. Electronic and hand searches were conducted to identify functional neuroimaging studies involving FD patients. Sixteen studies were selected and divided into three categories: 10 resting state studies, three visceral distention studies, and three acupuncture studies. Changes were reported in several brain areas in FD patients including the frontal cortex, somatosensory cortex, insula, anterior cingulate cortex, thalamus, hippocampus, and amygdala. These brain activity changes were associated with visceral hypersensitivity, dyspeptic symptoms, poorer quality of life, anxiety, and depression. The results show that FD is associated with functional abnormalities in sensory and pain modulation, emotion, saliency, and homeostatic processing regions. The diversity of conditions, heterogeneous results, poorly standardized diagnoses of FD, and various comorbidities may be responsible for the variability in the results.


Exploring the role of mitochondrial proteins as molecular target in Alzheimer's disease.
Brain is a fully differentiated organ and is sensitive towards oxidative damage of various compounds including lipids, proteins, and DNA that occurs during process of normal aging and is mainly due to its high energy metabolism and reduced activity of anti-oxidative defense mechanism. Mitochondria are dynamic ATP-generating organelles which constitutes cellular functions such as regulation of intracellular calcium, bio-energetic processes, and reduction-oxidation of cells. Such functioning is negatively affected due to the presence of amyloid β peptide (Aβ) which is involved in pathogenesis of Alzheimer disease (AD). Aβ interacts with mitochondria and leads to mitochondrial dysfunction. Mitochondrial dysfunction, abnormal interactions, oxidative stress, and mis-folding of synaptic proteins inside nervous system are explored and regarded as primary or initial features in insurgence of pathology (AD and other neurological disease). The major histopathological hallmarks of AD are characterized by presence of these hallmarks intracellularly, its further progression and exacerbation which leads to excessive accumulation of oligomeric as well as fibrillar-β-amyloid peptides (present extracellularly) and accumulation of neurofibrillary tangles intracellularly. The current review will focus on alterations and variation in mitochondria/mitochondrial DNA (mtDNA) and the rationale for involvement of related abnormalities in pathogenesis of AD.


Physiochemical responses of earthworms (Eisenia fetida) under exposure to lanthanum and cerium alone or in combination in artificial and contaminated soils.
Rare earth elements inevitably release into the soil due to their widespread application. However, it is unclear how they affect the soil animals. The study surveyed the growth and physiological responses of earthworm (Eisenia fetida) exposed into artificial soils spiked with La, Ce, and their mixture, and actual mine soil collected from an abandoned La-Ce mining area (Mianning, Sichuan). The results showed that the 1000-1200 mg/kg combined exposure in two soils induced significant histopathological and phenotypic changes of earthworms. Concentration significantly affected the superoxide dismutase (SOD), peroxidase (POD), malondialdehyde (MDA), and protein of E. fetida and the effects differentiated with the prolonging duration. These indicators were negatively affected under the La stress ≥800 mg/kg (SOD, POD, and protein), the 1200 mg/kg (SOD), Ce stress ≥1000 mg/kg (protein), and the combination ≥800 mg/kg (SOD, POD) and ≥1000 mg/kg (protein). Artificial combination had -15.04% (SOD), 8.87% (POD), 5.64% (MDA), and -8.34% (protein) difference compared with the contamination soil, respectively. Overall, E. fetida respond sensitively under the La and Ce stress, the antioxidant defense system and the lipid peroxidation were stimulated, and the artificial soil might overestimate eco-toxicological effect.


Erosion of the scapula by a benign lipoma: computed tomography diagnosis.
A lipoma eroding the scapula is diagnosed by computed tomography.


Diagnostic yields in patients with suspected prostate cancer undergoing MRI as the first-line investigation in routine practice.
To document cancer yields of magnetic resonance imaging (MRI)-directed biopsies in men with suspected prostate cancer referred to secondary care. Men with suspected cancer undergoing multiparametric prostate MRI as the first-line investigation were included in the present study. Systematic transrectal prostate biopsies with/without cognitive targeted biopsies were performed. Diagnostic yields of International Society of Urological Pathology (ISUP) ≥2 cancers by the Prostate Imaging Reporting and Data System (PI-RADS) category were recorded. Impacts of prostate-specific antigen (PSA) density on biopsy results and yields of non-targeted biopsies in MRI non-suspicious prostate sextants assessed. Of 262 men (90.5% biopsy naive), 86 (33%) MRI examinations were negative (PI-RADS 1-2) and 176 (67%) positive (PI-RADS 3: 8%; PI-RADS 4: 21%; PI-RADS 5: 38%). Two hundred and thirteen of 262 patients underwent a biopsy. ISUP ≥2 cancer detection rates were 8% (5/61) for PI-RADS 1-2, 18% (3/17) for PI-RADS 3, 49% (22/45) for PI-RADS 4, and 80% (72/90) for PI-RADS 5. Proportions of ISUP ≥2 increased with higher PSA densities in positive patients (%ISUP ≥2 for PSA density groups <0.12, 0.12 to <0.15 and ≥ 0.15 was 0%, 0%, 25% for PI-RADS 3, 21%, 33%, 68% for PI-RADS 4 and 40%, 83%, 89% for PI-RADS 5 respectively). ISUP ≥2 cancers were twice as likely in tumour adjacent sextants (52% versus 24%), without upgrading of gland level histology from insignificant to clinically significant prostate cancer by the sampling of normal-appearing tumour non-adjacent sextants. One third of men can avoid biopsy after negative MRI. Cancer detection rates increase with PSA density values within positive MRI suspicion categories. Sampling normal-appearing tumour non-adjacent sextants may be unnecessary for whole-gland therapy.


Characterization of Vibrio anguillarum strains isolated from diseased fish in Finland.
Characterization of V. anguillarum strains (n = 109) isolated from diseased salmonids was performed. Eight O serovars were found among the strains. Serovar O1 was predominant (90%), while serovars O2, O3, O5, O8, O9, and a new serovar Va NT2, were represented by 1 or 2 strains. Two strains remained non-typeable. One of these was cross-reactive with several antisera, but had a LPS profile identical to that of serovar O8. All serovars showed specific LPS profiles. All but 1 of the O1 strains had a plasmid comparable in size to the pJM1 virulence plasmid, while plasmids of different sizes were found in O2, Va NT2 and the non-typeable strains. Apart from a single strain resistant to tetracycline, all the strains were sensitive to oxolinic acid, tetracycline, and trimethoprim-sulfonamides. By their biochemical and antigenic properties strains causing vibriosis among salmonids in Finland closely resemble Scandinavian strains. Predominance of the serovars O1 and O2 suggests that commercial vaccines containing these serovars should afford sufficient protection against vibriosis in Finland.


Spinal cord clinical trials and the role for bioengineering.
There is considerable need for bringing effective therapies for spinal cord injury (SCI) to the clinic. Excellent medical and surgical management has mitigated poor prognoses after SCI; however, few advances have been made to return lost function. Bioengineering approaches have shown great promise in preclinical rodent models, yet there remains a large translational gap to carry these forward in human trials. Herein, we provide a framework of human clinical trials, an overview of past trials for SCI, as well as bioengineered approaches that include: directly applied pharmacologics, cellular transplantation, biomaterials and functional neurorehabilitation. Success of novel therapies will require the correct application of comprehensive preclinical studies with well-designed and expertly conducted human clinical trials. While biologics and bioengineered strategies are widely considered to represent the high potential benefits for those who have sustained a spinal injury, few such therapies have been thoroughly tested with appreciable efficacy for use in human SCI. With these considerations, we propose that bioengineered strategies are poised to enter clinical trials.


Analysis of the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas.
The purpose of this retrospective study was to investigate the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas (ASDH). A total of 256 patients who underwent decompressive craniectomy for isolated traumatic ASDH between April 2013 and December 2020 were included. We evaluated the risk factors for intraoperative acute diffuse brain swelling using a multivariate logistic regression analysis. The incidence of intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH was 21.88% (56/256). Dilated pupils (OR = 24.78), subarachnoid haemorrhage (OR = 2.41), and the time from injury to surgery (OR = 0.32) were independent risk factors for intraoperative acute diffuse brain swelling, while no independent associations were observed between these risk factors and sex, age, the mechanism of injury, the Glasgow Coma Scale score, site of haematoma, thickness of haematoma, midline shift and the status of the basal cistern, although the mechanism of injury, the Glasgow Coma Scale score and the status of the basal cistern were correlated with the incidence of intraoperative acute diffuse brain swelling in the univariate analyses. This study identified the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH. An increased risk of intraoperative acute diffuse brain swelling occurs in patients with bilaterally dilated pupils, subarachnoid haemorrhage and a shorter time from injury to surgery. These findings should help neurosurgeons obtain information before surgery about intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH.


Protective effect of a multiantigenic DNA vaccine against Toxoplasma gondii with co-delivery of IL-12 in mice.
In this study, we constructed a multiantigenic DNA vaccine, pSAG1-ROP2-SAG2 and examined its effect with co-delivery of a plasmid encoding IL-12 (pIL-12) as an adjuvant in BALB/c mice against Toxoplasma gondii. After a lethal challenge of T. gondii RH strain, survival of the mice immunized with this pSAG1-ROP2-SAG2 vaccine was significantly prolonged in comparison to the control groups. Furthermore, the protection was significantly augmented by pIL-12 co-delivery. As demonstrated by lymphocyte proliferation assay, cytokine and antibody level determinations, the humoral and Th1-type cellular responses elicited by this multiantigenic DNA vaccine were significantly stronger than those elicited by double-antigenic, or single-antigenic DNA vaccines. Our data suggest that multiantigenic DNA vaccine with pIL-12 co-delivery is a very effective approach in the protection against T. gondii.


Eye movements simultaneously recorded by electrooculographic and photoelectric methods.
Three types of eye movements, saccadic, reading, and pursuit, were recorded from 6 college subjects, two in each by the electrooculographic and photoelectric methods simultaneously. A deviation index (DI), which is the standard deviation divided by the mean, was devised to compare the precision of recording amplitude deflection, and a proportion index (PI), which is ml divided by M2, was devised to compare the mean amplitude indirectly between these two methods. Results showed that the proportion indexes of three types of eye movements were comparable, and the mean index of 0.54 indicated that the amplification in the electrooculographic method was about half as much as that in the photoelectric. The mean deviation index of 0.132 vs 0.135 was, again, comparable, meaning that these two methods of recording amplitude deflections are of about the same degree of magnitude and precision. Certain qualitative differences regarding the amplitude and velocity peak deflection between these two methods were also noted.


Functional Integration and Individuality in Prokaryotic Collective Organisations.
Both physiological and evolutionary criteria of biological individuality are underpinned by the idea that an individual is a functionally integrated whole. However, a precise account of functional integration has not been provided so far, and current notions are not developed in the details, especially in the case of composite systems. To address this issue, this paper focuses on the organisational dimension of two representative associations of prokaryotes: biofilms and the endosymbiosis between prokaryotes. Some critical voices have been raised against the thesis that biofilms are biological individuals. Nevertheless, it has not been investigated which structural and functional obstacles may prevent them from being fully integrated physiological or evolutionary units. By contrast, the endosymbiotic association of different species of prokaryotes has the potential for achieving a different type of physiological integration based on a common boundary and interlocked functions. This type of association had made it possible, under specific conditions, to evolve endosymbionts into fully integrated organelles. This paper therefore has three aims: first, to analyse the organisational conditions and the physiological mechanisms that enable integration in prokaryotic associations; second, to discuss the organisational differences between biofilms and prokaryotic endosymbiosis and the types of integration they achieve; finally, to provide a more precise account of functional integration based on these case studies.


Effect of purified phospholipases on glucose transport, insulin binding, and insulin action in isolated rat adipocytes.
The influence of alterations in phospholipid structure by phospholipase treatment on insulin action and glucose transport in rat adipocytes was studied. It appeared that phospholipase A2 from bee venom caused a breakdown of approximately 50% of phosphotidylcholine without lysis of the cells. Because of this treatment, insulin binding was increased, resulting in an increased sensitivity of glucose transport towards lower insulin concentrations. Moreover, an increased affinity of the transport system for 2-deoxyglucose was observed. Phospholipase C from Clostridium welchii caused complete lysis of adipocytes. Phospholipase A2 from Crotalus adamenteus was without effect.


Thiourea leaching gold and silver from the printed circuit boards of waste mobile phones.
The present communication deals with the leaching of gold and silver from the printed circuit boards (PCBs) of waste mobile phones using an effective and less hazardous system, i.e., a thiourea leaching process as an alternative to the conventional and toxic cyanide leaching of gold. The influence of particle size, thiourea and Fe(3+) concentrations and temperature on the leaching of gold and silver from waste mobile phones was investigated. Gold extraction was found to be enhanced in a PCBs particle size of 100 mesh with the solutions containing 24 g/L thiourea and Fe(3+) concentration of 0.6% under the room temperature. In this case, about 90% of gold and 50% of silver were leached by the reaction of 2h. The obtained data will be useful for the development of processes for the recycling of gold and silver from the PCBs of waste mobile phones.


Studies in epidemiology of maedi/visna in sheep.
Lambs born to ewes from flocks with a high incidence of maedi/visna were separated from their dams at birth (group 1), or after 10 h (group 2), six weeks (group 3) or one year (group 4) and were observed for periods of up to eight years. Group 1 lambs remained free of infection while 28 per cent, 76 per cent and 81 per cent respectively of lambs in the other groups developed clinical, serological or histopathological evidence of infection during the observation period. It is therefore concluded that vertical transmission, if it occurs at all, is of little significance in the epidemiology of the disease. The number of serologically, virologically and histopathologically maedi/visna positive sheep, the time of onset of disease and the severity of lesions were related to the duration of exposure to the parent flock. In a separate trial no evidence was obtained for the transmission of maedi/visna by Muellerius capillaris larvae.


A study on the effect of natural products against the transmission of B.1.1.529 Omicron.
The recent outbreak of the Coronavirus pandemic resulted in a successful vaccination program launched by the World Health Organization. However, a large population is still unvaccinated, leading to the emergence of mutated strains like alpha, beta, delta, and B.1.1.529 (Omicron). Recent reports from the World Health Organization raised concerns about the Omicron variant, which emerged in South Africa during a surge in COVID-19 cases in November 2021. Vaccines are not proven completely effective or safe against Omicron, leading to clinical trials for combating infection by the mutated virus. The absence of suitable pharmaceuticals has led scientists and clinicians to search for alternative and supplementary therapies, including dietary patterns, to reduce the effect of mutated strains. This review analyzed Coronavirus aetiology, epidemiology, and natural products for combating Omicron. Although the literature search did not include keywords related to in silico or computational research, in silico investigations were emphasized in this study. Molecular docking was implemented to compare the interaction between natural products and Chloroquine with the ACE2 receptor protein amino acid residues of Omicron. The global Omicron infection proceeding SARS-CoV-2 vaccination was also elucidated. The docking results suggest that DGCG may bind to the ACE2 receptor three times more effectively than standard chloroquine. The emergence of the Omicron variant has highlighted the need for alternative therapies to reduce the impact of mutated strains. The current review suggests that natural products such as DGCG may be effective in binding to the ACE2 receptor and combating the Omicron variant, however, further research is required to validate the results of this study and explore the potential of natural products to mitigate COVID-19.


Mating systems of two Bombacaceous trees of a neotropical moist forest.
A multilocus mixed mating model was used to analyze the mating systems of two tropical canopy trees in the Bombacaceae that differ in successional status and overall abundance. One population of each species was studied on Barro Colorado Island, Republic of Panama. Population outcrossing estimates of 0.57 and 0.35 from two years indicate a mixed-mating system with intermediate outcrossing levels for the gap-specialist Cavanillesia platanifolia, a relatively rare component of the island flora. Population and individual outcrossing estimates were associated with flowering tree density or degree of spatial isolation. Trees within clusters of flowering individuals have a higher degree of outcrossing than isolated trees. Annual estimates of individual tree outcrossing rates varied greatly as a function of flowering in its nearest neighbors. In contrast to C. platanifolia, Quararibea asterolepis was completely outcrossed and may be self incompatible. Maternal trees of both species had significantly heterogeneous pollen pools indicating non-random outcrossing. Apomixis by sporophytic agamospermy was rejected in C. platanifolia as contributing to the apparent selfing rate.


Identification of a novel HLA-DRB1 allele, DRB1*116502, by sequence-based typing in an African-American individual.
The novel allele HLA-DRB1*116502 differs from HLA-DRB1*110201 by nucleotide substitutions at codon 59 (GAG-->GAC) and 93 (CGG-->AGG).


Postural instability years after stroke.
Following a stroke, balance disturbances often persist despite full recovery of the paretic side. The aims were to determine how long postural instability could be detected after stroke and the differences in post-stroke patients under and above 65 years of age. Static and dynamic posturography (passing weights from hand to hand around the body) measurements were performed on 29 patients with stroke after 3 ± 2.4 years (≤65 years) and 4.7 ± 3.3 years. (> 65 years) compared with 38 controls. Only the pathway and the velocity assessed by dynamic posturography were significantly higher (p < 0.05) in the younger group of patients compared with the controls. The older group of patients had significantly elevated parameters measured by both static (p < 0.01) and dynamic posturography (p < 0.05). we conclude, using a sensitive and reproducible method to assess both static and dynamic adjustments to maintain balance, that postural instability is significantly greater in post-stroke patients than control subjects. This difference is demonstrable up to 4 years after stroke, despite full recovery of the affected side.


Left upper quadrant approach in gynecologic laparoscopic surgery using reusable instruments.
To determine the usefulness of the left upper quadrant approach in gynecologic laparoscopic surgery. Retrospective study (Canadian Task Force classification II-2). University referral center. Twenty-four women with longitudinal scars from previous laparotomy through or close to the umbilicus. Left upper quadrant was chosen as the site of primary entry of the reusable Veress needle (ninth or tenth left intercostal space) and reusable primary cannula (left upper quadrant just below the left subcostal margin). Intraabdominal adhesions between old longitudinal scars and underlying bowel or omentum were present in 14 patients. Adhesions involving omentum only were present in 10 patients, bowel only in 2, and both omentum and bowel in 2. The only intraoperative complication was emphysema in one woman. All operative procedures were completed laparoscopically. The left upper quadrant approach is a safe entry point for reusable instruments at laparoscopic surgery in patients with midline incisions close to the umbilicus.


Panax notoginseng-microbiota interactions: From plant cultivation to medicinal application.
Microbiomes and their host plants are closely linked with each other; for example, the microbiome affects plant growth, fitness, nutrient uptake, stress tolerance and pathogen resistance, whereas the host plant supports the photosynthetically carbon-rich nutrition of the microbiome. The importance of the microbiome in plant‒soil ecosystems is unquestioned and has expanded to influence the medicinal application of some herbal plants via the gut microbiota. Herbal plant-microbiome interactions may provide novel knowledge to enhance the robustness of herbal plant crop performance and medicinal applications, which requires a systematic review and preceding discussion. The interactions between Panax notoginseng and microorganisms (from soil to host) were reviewed from the literature. The terms "Panax notoginseng" and "microbiota" were used in combination with the keywords "microbiota/microbes", "bacteria/bacterium" or "fungi/fungus" or "endophyte", as well as our targeted bioactive phytochemicals, including saponins and ginsenosides. Our study focuses on the famous medicinal herb Panax notoginseng F. H. Chen and proposes that the microbiota is a crucial participant not only in the cultivation of this herbal plant but also in its medicinal application. We also summarize and discuss how these plant‒microbe co-associations shape the assembly of plant-related microbiomes and produce bioactive phytochemicals, as well as influence beneficial herbal traits, such as herbal plant health and pharmacology. In addition, we also highlight future directions. The rhizosphere and endophytic microbiome of Panax notoginseng are indirectly or directly involved in plant health, biomass production, and the synthesis/biotransformation of plant secondary metabolites. Harnessing the microbiome to improve the quality of traditional Chinese medicine and improve the value of medicinal plants for human health is highly promising.


Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.
Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.


Challenges in assessing hospital-level stroke mortality as a quality measure: comparison of ischemic, intracerebral hemorrhage, and total stroke mortality rates.
Public reporting efforts currently profile hospitals based on overall stroke mortality rates, yet the "mix" of hemorrhagic and ischemic stroke cases may impact this rate. Using the 2005 to 2006 New York state data, we examined the degree to which hospital stroke mortality rankings varied regarding ischemic versus hemorrhagic versus total stroke. Observed/expected ratio was calculated using the Agency for Healthcare Research and Quality Inpatient Quality Indicator software. The observed/expected ratio and outlier status based on stroke types across hospitals were examined using Pearson correlation coefficients (r) and weighted κ. Overall 30-day stroke mortality rates were 15.2% and varied from 11.3% for ischemic stroke and 37.3% for intracerebral hemorrhage. Hospital risk-adjusted ischemic stroke observed/expected ratio was weakly correlated with its own intracerebral hemorrhage observed/expected ratio (r=0.38). When examining hospital performance group (mortality better, worse, or no different than average), disagreement was observed in 35 of 81 hospitals (κ=0.23). Total stroke mortality observed/expected ratio and rankings were correlated with intracerebral hemorrhage (r=0.61 and κ=0.36) and ischemic stroke (r=0.94 and κ=0.71), but many hospitals still switched classification depending on mortality metrics. However, hospitals treating a higher percent of hemorrhagic stroke did not have a statistically significant higher total stroke mortality rate relative to those treating fewer hemorrhagic strokes. Hospital stroke mortality ratings varied considerably depending on whether ischemic, hemorrhagic, or total stroke mortality rates were used. Public reporting of stroke mortality measures should consider providing risk-adjusted outcome on separate stroke types.


Homozygosity for the C-->T polymorphism at nucleotide 46 in the 5' untranslated region of the factor XII gene protects from development of acute coronary syndrome.
Recently, a C-->T polymorphism at nucleotide 46 in the 5'-untranslated region of the factor XII (FXII) gene was shown to be associated with lower levels of FXII. To study the impact of this polymorphism on the development of an acute coronary syndrome (ACS), we compared 303 patients with ACS and 227 patients with stable coronary artery disease (CAD). In the latter group, 54.2% of individuals carried wild-type FXII:46C, 37.9% were heterozygous FXII:C46T and 7.9% were homozygous for FXII:46T. In contrast, in the ACS group (n = 303), 54.1% were wild-type FXII:46C, 42.6% were heterozygous FXII:C46T and only 3.3% carried the homozygous FXII:46T genotype. The 2.5-fold lower prevalence of the FXII:46T genotype in patients with ACS could indicate a protective effect on the development of ACS (odds ratio = 0.4, 95% CI 0.1-0.9) in patients with pre-existing CAD.


Contrast-enhanced FLAIR in the early diagnosis of infectious meningitis.
We investigated the accuracy of MRI in the early diagnosis of infectious meningitis with emphasis on the value of gadolinium-enhanced fluid-attenuated inversion recovery (FLAIR) sequence. Twenty-seven patients with clinical suspicion of infectious meningitis were included. MRI was performed within 3 h of clinical evaluation. For all patients, T1-weighted spin-echo, dual-echo T2-weighted fast-spin-echo and FLAIR sequences were performed, followed by gadolinium-enhanced T1-weighted spin-echo and FLAIR sequences. Final diagnosis was based on the clinical findings and the analysis of cerebrospinal fluid, obtained by lumbar puncture after the MRI. Infectious meningitis was confirmed in 12 patients. In all of these patients of the plain studies, FLAIR was positive in only four patients. MRI gadolinium-enhanced FLAIR showed abnormal meningeal enhancement in all 12 patients, while gadolinium-enhanced T1-weighted spin-echo was positive only in six cases. There were no false-positive or false-negative results. It is concluded that MRI could have an important role in the early screening for infectious meningitis, provided a gadolinium-enhanced FLAIR sequence is used.


The oncomodulin receptor ArmC10 enables axon regeneration in mice after nerve injury and neurite outgrowth in human iPSC-derived sensory neurons.
Oncomodulin (Ocm) is a myeloid cell-derived growth factor that enables axon regeneration in mice and rats after optic nerve injury or peripheral nerve injury, yet the mechanisms underlying its activity are unknown. Using proximity biotinylation, coimmunoprecipitation, surface plasmon resonance, and ectopic expression, we have identified armadillo-repeat protein C10 (ArmC10) as a high-affinity receptor for Ocm. ArmC10 deletion suppressed inflammation-induced axon regeneration in the injured optic nerves of mice. ArmC10 deletion also suppressed the ability of lesioned sensory neurons to regenerate peripheral axons rapidly after a second injury and to regenerate their central axons after spinal cord injury in mice (the conditioning lesion effect). Conversely, Ocm acted through ArmC10 to accelerate optic nerve and peripheral nerve regeneration and to enable spinal cord axon regeneration in these mouse nerve injury models. We showed that ArmC10 is highly expressed in human-induced pluripotent stem cell-derived sensory neurons and that exposure to Ocm altered gene expression and enhanced neurite outgrowth. ArmC10 was also expressed in human monocytes, and Ocm increased the expression of immune modulatory genes in these cells. These findings suggest that Ocm acting through its receptor ArmC10 may be a useful therapeutic target for nerve repair and immune modulation.


A new alpha 1-antitrypsin allele PI Poki: isoelectric focusing with immobilized pH gradients as a tool for identification for PI variants.
A new rare genetic variant PI Poki in the protease inhibitor system found in two Japanese subjects, was compared with some PI P variants using several electrophoresis systems. Although this variant was slightly anodal to P by separator isoelectric focusing, it could be readily distinguished by isoelectric focusing with immobilized pH gradients: the mobility of Poki became cathodal to P. This method proved to be a powerful tool for identification of PI variants.


Detection of MHC class II expression on human basophils is dependent on antibody specificity but independent of atopic disposition.
A debate has recently arisen as to whether murine basophils can function as antigen presenting cells in allergic inflammation. However, mouse and human basophils differ considerably, and the expression of MHC class II on human basophils has been investigated as a proxy for their capability of antigen presentation but conflicting results have emerged. In this technical note, we show that an antibody specific for all three MHC class II subtypes (HLA-DR, -DP, and -DQ), leads to a significantly higher amount of MHC class II+ basophils compared to antibodies specific for HLA-DR only. A significant difference was also observed between the HLA-DR specific antibodies, indicating that the choice of antibody is crucial. Furthermore, critical compensation was essential to avoid false HLA-DR+ basophils. Finally, we found that detection of MHC class II on human basophils was independent of atopic disposition.


Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.
Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.


[Whether or not to perform an early endoscopy following ingestion of potentially caustic agents - a retrospective longterm analysis in a tertiary referral institution].
The optimal clinical management of patients following ingestion of potentially caustic lesions is still undetermined. In particular, the indication for early upper GI endoscopy in this context remains unclear. To draft recommendations regarding the use of early upper GI endoscopy following hospital admissions of patients after ingestion of potentially caustic agents. For this purpose, a retrospective cohort study of patients treated for ingestion of potentially caustic substances during a 13 year-period at the university hospital of Berne was performed. In total, 61 patients with acute ingestion of potentially caustic substances were identified. Overall mortality was 5 %. 11/61 patients had to be admitted to the intensive care unit. Most ingestions were performed in suicidal intention (62 %). In 53 % of these patients, a combined ingestion of several substances occurred. In 33 % of patients, an early upper GI endoscopy was performed within 24 hours after ingestion. The degree of burn depended upon the hazard potential of the respective substance. In patients with ingestion of low risk substances, upper GI endoscopy was only performed when additional risk factors were present. Based upon the results of the present study, ingestion of potentially caustic agents requires an individualized strategy whether or not to perform early endoscopy.


Expression analysis of the tylosin-biosynthetic gene cluster: pivotal regulatory role of the tylQ product.
Expression analysis by RT-PCR, applied to the entire tyl cluster, revealed that the pattern of transcription is more complex than expected. For example, the five tylG polyketide synthase genes are not necessarily cotranscribed or even coregulated. Among the regulatory genes, tylQ has emerged as a key factor. Although several genes (including the positive regulator, tylS) were possibly expressed constitutively, only tylQ was silent during secondary metabolism. Analysis of engineered strains, in which tylQ was disrupted or overexpressed, showed that the TylQ protein is a transcriptional repressor that blocks tylosin biosynthesis by controlling expression of the activator, tylR. Before tylosin production can be triggered, tylQ must be switched off, or at least downregulated.


Analysis of telomeres and telomerase.
The terminal chromatin structures at the ends of eukaryotic chromosomes, the telomeres, are a focus of intensive research due to their importance for the maintenance of chromosome integrity. Their shortening due to incomplete replication functions as a molecular clock counting the number of cell divisions, and ultimately results in cell-cycle arrest and cellular senescence. Telomere shortening can be compensated by the nucleoprotein enzyme complex called telomerase, which is able to extend shortened telomeres. In humans, only embryonic and germ cells show telomerase activity that is sufficient for telomere length stability and cellular immortality. Unfortunately, telomerase is activated in cancer cells, which, thus, achieve unlimited growth and a malignant phenotype. Even if there were no any other links of telomere biology to other essential processes in the cell nucleus such as DNA repair, chromosome positioning, and nuclear architecture in mitosis and meiosis, the close connection of telomere biology to aging and cancer makes telomeres and techniques for their analysis important enough from the point of view of us, mortal and disease-prone people. In this chapter, we describe the most common types of analyses used in telomere biology: screening for typical and variant telomeric sequences, determination of telomere lengths, and measurement of telomerase activity.


Prognostic Role of Lymph Node Sampling in Adolescent and Young Adults With Fibrolamellar Carcinoma.
Hepatocellular carcinoma (HCC) is rare among adolescent and young adult (AYA) patients, and resection or transplant remains the only curative therapy. The role of lymph node (LN) sampling is not well-defined. The aim of this study was to describe practice patterns, as well as investigate the impact of LN sampling on survival outcomes in this population. A retrospective cohort study using the 2004-2018 National Cancer Database (NCDB) was performed. Patients ≤21 y old with nonmetastatic HCC who underwent liver resection or transplant were evaluated. Clinical features of patients who underwent LN sampling were compared to those who did not, and univariable and multivariable logistic regression was performed to evaluate independent predictive factors of node positivity. Survival analysis was performed using Kaplan-Meier methods and Cox Proportional Hazard Survival Regression. A total of 262 AYA patients with HCC were identified, of whom 137 (52%) underwent LN sampling, 44 patients had positive nodes, 40 (95%) of them had tumors >5 cm; 87 (64%) of patients with sampled nodes had fibrolamellar carcinoma (FLC), which was an independent risk factor for predicting positive nodes (P = 0.001). There was no difference in overall survival between patients who underwent LN sampling and those who did not; however, 5-y overall survival for node-positive patients was 40% versus 79% for node-negative patients (P < 0.0001). In AYA patients with HCC, LN sampling was not associated with an independent survival benefit. However, FLC was an independent risk factor for LN positivity, suggesting a role for routine LN sampling in these patients.


Novel Adjuvants and Immunomodulators for Veterinary Vaccines.
Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the vaccine is becoming a reality with our increased understanding of innate and adaptive immune activation. This will allow future vaccines to induce immune reactivity having adequate specificity as well as protective and recallable immune effector mechanisms in appropriate body compartments, including mucosal surfaces. Here we describe these new developments and, when possible, relate new immunological knowledge to the many years of experience with traditional, empirical adjuvants. Finally, some protocols are given for production of emulsion (oil-based) and liposome-based adjuvant/antigen formulations.


COVID-19 outbreak improves attractiveness of medical careers in Chinese senior high school students.
The shortage of healthcare workers is becoming a serious global problem. The underlying reasons may be specific to the healthcare system in each country. Over the past decade, medicine has become an increasingly unpopular profession in China due to the heavy workload, long-term training, and inherent risks. The ongoing COVID-19 pandemic has placed the life-saving roles of healthcare professionals under the spotlight. This public health crisis may have a profound impact on career choices in Chinese population. We conducted a questionnaire-based online survey among 21,085 senior high school students and 21,009 parents from 24 provinces (or municipalities) of China. We investigated the change of interest in medical study due to the outbreak of COVID-19 and the potential motivational factors based on the expectancy-value theory framework. Pearson correlation analysis was used to assess the correlation of static or dynamic interest in medical career pursuit with the reported number of COVID-19 cases. Logistic regression model was adopted to analyze the main factors associated with students' choices. We observed an increased preference for medical study post the outbreak of COVID-19 in both students (17.5 to 29.6%) and parents (37.1 to 47.3%). Attainment value was found to be the main reason for the choice among students, with the contribution to society rated as the top motivation. On the other hand, the predominant demotivation in high school students was lack of interest, followed by concerns regarding violence against doctors, heavy workload, long-term training and heavy responsibility as a doctor. Additionally, students who were female, in the resit of final year, had highly educated parents and outside of Hubei province were significantly associated with a keen interest in pursuing medical study. This is the first multi-center cross-sectional study exploring the positive change and motivations of students' preferences in medical study due to the outbreak of COVID-19. Our results may help medical educators, researchers and policymakers to restructure medical education to make it more appealing to high school students, particularly, to develop a more supportive social and working environment for medical professionals to maintain the observed enhanced enthusiasm.


A histochemical technique for evaluation of progesterone receptors in breast cancer.
A histochemical method for the detection and localization of progesterone receptors in human breast cancer has been developed employing a fluorescein labeled conjugate of bovine serum albumin linked to a progestin as the binding hormone. Considerable tumor cell receptor heterogeneity was apparent and nuclear binding was frequently noted. The results of the new assay correlated with those obtained by dextran-coated charcoal assay in 91 per cent of specimens.


Regulation of Slug transcription in embryonic ectoderm by beta-catenin-Lef/Tcf and BMP-Smad signaling.
Neural crest is formed at the boundary of epidermal and neural ectoderm. To understand the molecular mechanism of neural crest formation, we focused on the transcriptional regulation of the Slug gene. In the upstream sequence of the chicken Slug gene, we have identified potential binding sites for transcription factors, such as Lef/Tcf and Smad1. Transgenic mouse embryos carrying the chicken Slug promoter-reporter gene showed a crest-specific activation of the reporter, suggesting the isolated sequence included the cis-regulatory elements to receive Slug-inducing signals in the mouse neural crest. While these potential cis-regulatory elements could be recognized and activated by corresponding transcription factors, such as Lef1 and Smad1, Wnt-Lef-beta-catenin signal failed to induce endogenous Slug expression in quail neural plate tissue prepared from forebrain and midbrain levels. In contrast, Slug expression and subsequent epithelial-mesenchymal transition were effectively induced by BMP4. Consistently, while we could detect phosphorylation of Smad1 in the ectoderm including the neural plate and the neural fold region, the activation of a reporter gene for a detection of canonical Wnt signal activation was below the level of detection at the forebrain and midbrain levels. These observations indicated that in the anterior ectoderm BMP signal has a predominant role for Slug expression.


Toll-like receptor 9 gene expression in the post-thrombotic syndrome, residual thrombosis and recurrent deep venous thrombosis: A case-control study.
Animal models suggest that toll-like receptor 9 (TLR9) promotes thrombus resolution after acute deep venous thrombosis (DVT). We hypothesized that TLR9 expression is lower in patients with post-thrombotic syndrome (PTS) and investigated the role of TLR9 in residual thrombosis (RT) and recurrence. Patients with a history of DVT with PTS (cases, n=30) and without PTS after minimal 24 months follow-up (controls, n=30) were selected. Healthy individuals (HI, n=29) without DVT were included as reference. TLR9 mRNA expression in leukocytes was determined by qPCR and normalized to the housekeeping succinate dehydrogenase subunit A gene using the ΔCt method. Sub analyses were performed to explore the TLR9 expression in patients with and without RT and multiple DVT episodes. The median TLR9 expression was 0.45 (interquartile range 0.31 to 0.93), 0.39 (0.25 to 0.69) and 0.62 (0.32 to 0.75) in cases, controls and HI respectively (p=0.61). The median TLR9 expression was 0.39 (0.26 to 0.51) in patients with RT compared to 0.55 (0.30 to 0.86, p=0.13) in those without. The median TLR9 expression was significantly lower in patients who had one DVT compared to patients with recurrent DVT, 0.37 (0.23 to 0.63) versus 0.55 (0.43 to 0.96) respectively (p<0.01). No significant difference in TLR9 expression was found between cases, controls and HI. However TLR9 expression seems lower in individuals with DVT and RT, albeit not significant. Interestingly, TLR9 might play a role in recurrent DVT, as the TLR9 expression was significantly higher in patients with recurrent DVT.


PEPRs spice up plant immunity.
Some pattern recognition receptors (PRRs) in plants, such as PEPRs, sense endogenous, damage-associated molecular patterns (DAMPs) that are released during pathogen infection. In this issue of The EMBO Journal, Yamada and colleagues show that genetic or pathogen-induced depletion of Arabidopsis BAK1, a co-receptor for multiple PRRs, primes immune activation through PEPRs. The work illustrates a link between pathogen-induced perturbation of BAK1 and DAMP signaling.


Organization of the boar spermatozoan plasma membrane: evidence for separate domains (subdomains) of integral membrane proteins in the plasma membrane overlying the principal segment of the acrosome.
Indirect immunofluorescence microscopy and freeze-fracture have been used to identify overlapping subdomains at the peripheral rim of the sperm-head plasma membrane (PM) and the margin of the outer acrosomal membrane (OAM) comprising the principal segment of the acrosome of the boar spermatozoon. An array of ridge-like structures (spaced 12-16 nm centre-to-centre), originally observed on the OAM by Aguas & Pinto da Silva, lies just beneath an area of the PM that is sparsely populated with large intramembranous particles compared to that of other regions of the head PM. This region has a high specificity for the lectin arachis hypogaea (peanut agglutinin). We suggest that the OAM at the rim of the sperm head may be rich in acidic phospholipids and that the close apposition of this membrane with a region of the PM relatively poor in integral membrane proteins may provide sites for initiating the acrosome reaction.


Outcomes following potentially curative therapies for older patients with metastatic colorectal cancer.
Older age represents a major risk factor for developing colorectal cancer and the disease disproportionately affects patients older than 60 years of age. However, knowledge regarding the optimal management of older patients with metastatic colorectal cancer (mCRC) remains limited. The challenge of treating older patients arises in tailoring treatments to a heterogeneous cohort whilst adjusting for individuals with a wide variation of physiological reserve, a reduced tolerance to treatment side-effects and morbidity, and often different priorities as compared with younger patients. Data from the published literature supports the premise that older age alone is not an acceptable determinant of treatment options. In particular, patients aged 65-70 years with mCRC ought to be considered similarly to younger patients and patients aged 70-74 also stand to benefit from both hepatic resection and systemic therapy notwithstanding the higher rates of morbidity and mortality. Patients aged 75-79, and with sufficient physiological reserve ought to be considered for curative treatment options which are proportional to the extent of metastatic disease. Meanwhile, in patients aged ≥80 years, life-extending or life-enhancing benefit ought to be demonstrable prior to embarking upon major surgery as a curative treatment option. Older patients who meet the physiological eligibility criteria to enter clinical trials of systemic chemotherapy appear to gain similar benefit as younger patients and should not be excluded on the basis of age alone. Clinical trials that are specifically designed for older patients are feasible and could yield valuable information to guide clinical practice.


Bariatric surgeons' experiences of working in the first year of the pandemic.
The first year of the Covid-19 pandemic saw drastic changes to bariatric surgical practice, including postponement of procedures, altered patient care and impacting on the role of bariatric surgeons. The consequences of this both personally and professionally amongst bariatric surgeons has not as yet been explored. The aim of this research was to understand bariatric surgeons' perspectives of working during the first year of the pandemic to explore the self-reported personal and professional impact. Using a retrospective, two phased, study design with global participants recruited from closed, bariatric surgical units. The first phase used a qualitative thematic analytic framework to identify salient areas of importance to surgeons. Themes informed the construction of an on-line, confidential survey to test the potential generalizability of the interview findings with a larger representative population from the global bariatric surgical community. Findings of the study revealed that the first year of the pandemic had a detrimental effect on bariatric surgeons both personally and professionally globally. This study has identified the need to build resilience of bariatric surgeons so that the practice of self-care and the encouragement of help-seeking behaviors can potentially be normalized, which will in turn increase levels of mental health and wellbeing.


Poly(vinylidene fluoride)/NH2-Treated Graphene Nanodot/Reduced Graphene Oxide Nanocomposites with Enhanced Dielectric Performance for Ultrahigh Energy Density Capacitor.
This work describes a ternary nanocomposite system, composed of poly(vinylidene fluoride) (PVDF), NH2-treated graphene nanodots (GNDs), and reduced graphene oxides (RGOs), for use in high energy density capacitor. When the RGO sheets were added to PVDF matrix, the β-phase content of PVDF became higher than that of the pristine PVDF. The surface-treatment of GNDs with an ethylenediamine can promote the hydrogen bonding interactions between the GNDs and PVDF, which promote the formation of β-phase PVDF. This finding could be extended to combine the advantages of both RGO and NH2-treated GND for developing an effective and reliable means of preparing PVDF/NH2-treated GND/RGO nanocomposite. Relatively small amounts of NH2-treated GND/RGO cofillers (10 vol %) could make a great impact on the α → β phase transformation, dielectric, and ferroelectric properties of the ternary nanocomposite. The resulting PVDF/NH2-treated GND/RGO nanocomposite exhibited higher dielectric constant (ε' ≈ 60.6) and larger energy density (U(e) ≈ 14.1 J cm(-3)) compared with the pristine PVDF (ε' ≈ 11.6 and U(e) ≈ 1.8 J cm(-3)).


Looking Inside the Matrix: Perineuronal Nets in Plasticity, Maladaptive Plasticity and Neurological Disorders.
The integrity of the central nervous system (CNS) matrix is crucial for its proper function. Loss of the lattice-like structure compromise synaptic stability and can lead to the disruption of the excitatory/inhibitory balance, astrocytosis, maladaptive plasticity and neuronal death. Perineuronal nets (PNNs) in the extracellular matrix (ECM) provide synaptic integration and control the functional wiring between neurons. These nets are significantly modified during CNS disorders, such as neurodegenerative, cerebrovascular and inflammatory diseases. The breakdown or the modification of PNNs could be due to the activity of matrix metalloproteinases (MMPs) or to the deposition of proteoglycans, glycoproteins, and hyaluronic acid. The expression and the activity of ECM-degrading enzymes can be regulated with tissue inhibitors of MMPs or via transcriptional and epigenetic silencing or enhancement (i.e. via histone deacetylases). The identification of molecules and mechanisms able to modify these processes will be essential for a new perspective on brain functioning in health and disease, leading to a target-directed approach with drugs directly interfering with the molecular mechanism underlying neurological disorders.


Spontaneous perforation of the ureter: a rare complication of urolithiasis.
The spontaneous rupture of the ureter is a rare condition. A case of a girl is reported with a spontaneous perforation caused by ureteral and renal calculi. The concomitant urinoma was drained and the ureter splinted with a double-J catheter. The calculi were destroyed by extracorporal piezoelectric lithotripsy without anesthesia.


Real-world evidence analysis of the impact of steroid-eluting implants on healthcare resource use among chronic rhinosinusitis patients undergoing sinus surgery.
To compare healthcare resource use (HCRU) in patients undergoing sinus surgery with or without steroid-eluting sinus implants. A retrospective, observational cohort study using real-world evidence data (OM1, Inc, Boston, MA, USA) was conducted on adult patients with chronic rhinosinusitis (CRS) with or without nasal polyps who underwent endoscopic sinus surgery between 2014 and 2019 and had at least 18 months of data both before and after surgery. Patients receiving implants ("implant cohort") were matched to patients who did not receive implants ("non-implant cohort") based on a propensity score developed using baseline characteristics. Chi-square for binary variables and analysis of variance tests for continuous variables were applied to compare HCRU measures. Comparison of the implant (N = 1983) and non-implant (N = 1983) cohorts during the 18-month follow-up period demonstrated significantly lower HCRU in those receiving implants, including all-cause outpatient visits (94.3% vs. 96.6%, p < .001), all-cause otolaryngologist visits (47.3% vs. 59.6%, p < .001) and all cause ER/urgent care visits (9.2% vs. 11.8%, p = .007), as well as sinus-related endoscopies (39.1% vs. 43.8%, p = .003). Although not statistically significant, fewer patients in the implant cohort had undergone repeat surgeries (4.6% vs. 5.3%, p = .273). Patients with steroid-eluting sinus implants had lower HCRU over a post-operative period of 18 months. These findings support the contention that reductions in HCRU may be achieved using steroid-eluting implants during sinus surgery.What is known on this topicChronic rhinosinusitis (CRS) causes severe symptoms that lead to poor quality of life.Endoscopic sinus surgery (ESS) is 76-98% effective in improving CRS patients' symptoms.Surgical outcomes can be compromised in the immediate post-operative period by scarring, adhesion formation, and early polyp recurrence.Oral and topical corticosteroid therapy has become integral to the maintenance of successful surgical outcomes, the management of post-operative scarring and edema, and the prevention of nasal polyp recurrence.Steroid-eluting sinus implants have been shown in clinical trials to improve postoperative outcomes after ESS by delivering localized, sustained release of corticosteroids directly onto inflamed sinus tissue.What this study addsThis observational study is one of the first to use real-world evidence to assess the effect of steroid-eluting sinus implants on healthcare resource use (HCRU) in patients with chronic rhinosinusitis who underwent sinus surgery with or without implants.Use of implants significantly reduced HCRU, including all-cause outpatient visits (94.3% vs 96.6%, p < .001), all-cause otolaryngologist visits (47.3% vs 59.6%, p < .001), and all-cause ER/urgent care visits (9.2% vs 11.8%, p = .007), as well as sinus endoscopy (39.1% vs 43.8%, p = .003).Use of implants had no significant effect on sinus procedures such as debridement and polypectomy, as well as sinus-related imaging such as CT, MRI, and x-ray.


Systematic review with meta-analysis: endoscopic balloon dilatation for Crohn's disease strictures.
Endoscopic balloon dilatation (EBD) is recognised treatment for symptomatic Crohn's strictures. Several case series report its efficacy. A systematic analysis for overall efficacy can inform the design of future studies. To examine symptomatic (SR) and technical response (TR) and adverse events (AE) of EBD. Stricture characteristics were also explored. A systematic search strategy of COCHRANE, MEDLINE and EMBASE was performed. All original studies reporting outcomes of EBD for Crohn's strictures were included. SR was defined as obstructive symptom-free outcome at the end of follow-up, TR as post-dilatation passage of the endoscope through a stricture, and adverse event as the presence of complication (perforation and/or bleeding). Pooled event rates across studies were expressed with summative statistics. Twenty-five studies included 1089 patients and 2664 dilatations. Pooled event rates for SR, TR, complications and perforations were 70.2% (95% CI: 60-78.8%), 90.6% (95% CI: 87.8-92.8%), 6.4% (95% CI: 5.0-8.2) and 3% (95% CI: 2.2-4.0%) respectively. Cumulative surgery rate at 5 year follow-up was 75%. Pooled unweighted TR, SR, complication, perforation and surgery rates were 84%, 45%, 15%, 9% and 21% for de novo and 84%, 58%, 22%, 5% and 32% for anastomotic strictures. Outcomes between two stricture types were no different on subgroup meta-analysis. Efficacy and complication rates for endoscopic balloon dilatation were higher than previously reported. From the few studies with 5 year follow-up the majority required surgery. Future studies are needed to determine whether endoscopic balloon dilatation has significant long-term benefits.


Electron energy-loss spectroscopy of V₂O₅ nanofibers synthesized by electro-spinning.
The dielectric properties of V₂O₅ nanofibers, synthesized by the electrospinning method, are studied by analyzing the low-loss region of the electron energy loss spectroscopy (EELS) in a transmission electron microscope. A comparison of experimental EELS spectra and ab initio density-functional theory calculations (WIEN2k code) within the Generalized Gradient Approximation (GGA) is presented, having found an excellent agreement between them. Although the experimental EELS has been acquired for the nanoparticles composing the fibers, and numerical calculations were carried out for bulk material, agreement between experimental and calculated results shows that no difference exists between the electronic structure in calculated bulk material and the nanoparticles. Furthermore, our results from EELS confirm that we accomplished the expected crystalline phase. The origins of interband transitions are identified in the electronic band structure by calculating the partial imaginary part of the dielectric function and the partial density of states.


[Oropharyngeal kaposiform hemangioendothelioma].
The kaposiform hemangioendothelioma is a very infrequent tumor proceeding from the endothelial-derived spindle cells, more often found on the limbs, although peritoneal, retroperitoneal and sacrum locations are also prevailing. Head and neck are exceptional locations. The kaposiform hemangioendothelioma is almost exclusively found in children and early adolescents, and it is highly associated with the Kasabach-Merritt syndrome and lymphangiomatosis. The main treatment is the tumor surgical removal, including wide margins, plus supporting therapy when Kasabach-Merritt syndrome is linked. We report an isolated oropharyngeal kaposiform hemangioendothelioma 9-10-year old male case.


Caustic ingestion in children: is endoscopy always indicated? The results of an Italian multicenter observational study.
The ingestion of caustic substances can represent a serious medical problem in children. Whether or not an urgent endoscopy should be performed is still a matter of debate, particularly in asymptomatic patients. We conducted a multicenter observational study to investigate the predictive value of signs and symptoms in detecting severe esophageal lesions. The records of 162 children who presented with accidental caustic substance ingestion were analyzed. Signs and symptoms were divided into minor (oral and/or oropharyngeal lesions and vomiting) and major (dyspnea, dysphagia, drooling, and hematemesis). An endoscopy was performed in all patients within 12 to 24 hours of the substance being ingested. The types of substance ingested, signs and symptoms, age, sex, and severity of esophageal injury were correlated. Mild esophageal lesions were identified in 143 of 162 patients (88.3%), and severe (third degree) esophageal lesions in 19 patients (11.7%). The risk of severe esophageal lesions without signs and/or symptoms was very low (odds ratio [OR] 0.13 [95% CI, 0.02-0.62], P = .002). Indeed, the presence of 3 or more symptoms is an important predictor of severe esophageal lesions (OR 11.97 [95% CI, 3.49-42.04], P = .0001). Multivariate analysis showed that the presence of symptoms is the most significant predictor of severe esophageal lesions (OR 2.3 [95% CI, 1.57-3.38], P = .001). The results demonstrated that the incidence of patients with third-degree lesions without any early symptoms and/or signs is very low, and an endoscopy could be avoided. The risk of severe damage increases proportionally with the number of signs and symptoms, and an endoscopy is always mandatory in symptomatic patients.


Microtubule-associated protein tau in development, degeneration and protection of neurons.
As a principal neuronal microtubule-associated protein, tau has been recognized to play major roles in promoting microtubule assembly and stabilizing the microtubules and to maintain the normal morphology of the neurons. Recent studies suggest that tau, upon alternative mRNA splicing and multiple posttranslational modifications, may participate in the regulations of intracellular signal transduction, development and viability of the neurons. Furthermore, tau gene mutations, aberrant mRNA splicing and abnormal posttranslational modifications, such as hyperphosphorylation, have also been found in a number of neurodegenerative disorders, collectively known as tauopathies. Therefore, changes in expression of the tau gene, alternative splicing of its mRNA and its posttranslational modification can modulate the normal architecture and functions of neurons as well as in a situation of tauopathies, such as Alzheimer's disease. The primary aim of this review is to summarize the latest developments and perspectives in our understanding about the roles of tau, especially hyperphosphorylation, in the development, degeneration and protection of neurons.


Characteristics of T lymphocyte cell lines established from NIH minipigs challenge inoculated with Trichinella spiralis.
MHC restricted, antigen specific, cytokine dependent T-cell lines were established from peripheral blood mononuclear cells (PBMC) of NIH minipigs that were challenge inoculated with Trichinella spiralis. Swine lymphocyte antigen (SLA) inbred NIH minipigs of the SLA a/a (aa) haplotype can be divided into Responder (R) and Non-responder (NR) phenotypes on the basis of their ability to destroy encysted muscle larval (ML) forms of the parasite T. spiralis. When orally inoculated with 300 infectious ML and challenge inoculated with 10,000 ML, R pigs are able to mount an immune attack against encysted ML resident in host muscle cells since the primary inoculation. Because T-lymphocyte mediated mechanisms are likely to be operative in this response, a series of T-lymphocyte cell lines was established from PBMC of ten aa minipigs 10 days after the challenge infection with T. spiralis. These T-lymphocyte lines showed antigen specific, cytokine dependent proliferation in response to T. spiralis antigen stimulation. T-lymphocyte cell lines from R and NR pigs were compared and found to be similar in the magnitude of proliferative responses, in the duration of antigen specificity, and in the alterations in T-lymphocyte subsets and cell surface phenotype after antigen stimulation. In vitro antigen stimulation of T-lymphocyte cell lines and evaluation of small lymphocytes and lymphoblasts by density gradient centrifugation, immunofluorescent staining and flow cytometry, revealed that up to 55% of the cells were lymphoblasts at 4 days after stimulation, and that the majority of the lymphoblast population expressed CD4 and CD8, as well as the interleukin-2 receptor and the Class II alloantigen, SLA-DR (DR+). These results indicate that pig T-lymphocytes of the CD4+CD8+ phenotype may be involved in the anamnestic cell mediated immune response to T. spiralis.


Malignant potential of small oncocytic follicular carcinoma/Hürthle cell carcinoma: an institutional experience.
Oncocytic follicular carcinoma/Hürthle cell carcinoma (OFCA/HCCA) is a rare tumour of the thyroid gland that can be associated with an aggressive clinical course. Most OFCA/HCCAs are large; however, tumours ≤20 mm can occur. The aim of this study was to report our experience with OFCA/HCCA diagnosed at our institution. One hundred and nineteen cases of OFCA/HCCA were included in this study. Data points included age, sex, size of tumour, method of diagnosis, lymph node (LN) status, and clinical follow-up. The cohort included 37 males and 82 females (average age: 55 years). Preoperative fine-needle aspiration (FNA) was performed in 73 (61%) cases. Twenty-five (21%) tumours measured ≤20 mm and 94 (79%) measured >20 mm. Angioinvasion (AI) was present in 48 (40%) cases, and LN metastases (LNMs) in seven (6%) cases; of these, eight (17%) with AI and 1 (2%) with LNMs measured ≤20 mm. Clinical follow-up was available in 74 (62%) cases (range 12-144 months); 13 (17.5%) developed LNMs and six (8%) regional recurrence. Distant metastases (DMs) were seen in 12 (16%) cases. Two cases with DMs and two with LN recurrence measured ≤20 mm. Oncocytic follicular carcinoma/Hürthle cell carcinoma (OFCA/HCCA) can present as small (≤20 mm) tumours, and can be associated with AI, LNM, and DM.


Agreement between event-based and trend-based glaucoma progression analyses.
To evaluate the agreement between event- and trend-based analyses to determine visual field (VF) progression in glaucoma. VFs of 175 glaucoma eyes with ≥5 VFs were analyzed by proprietary software of VF analyzer to determine progression. Agreement (κ) between trend-based analysis of VF index (VFI) and event-based analysis (glaucoma progression analysis, GPA) was evaluated. For eyes progressing by event- and trend-based methods, time to progression by two methods was calculated. Median number of VFs per eye was 7 and follow-up 7.5 years. GPA classified 101 eyes (57.7%) as stable, 30 eyes (17.1%) as possible and 44 eyes (25.2%) as likely progression. Trend-based analysis classified 122 eyes (69.7%) as stable (slope >-1% per year or any slope magnitude with P>0.05), 53 eyes (30.3%) as progressing with slope <-1% per year, P≤0.05 (sensitive criteria), and 37 eyes (21.1%) as progressing with slope <-1% per year, P≤0.01 (specific criteria). κ between sensitive criteria of GPA (possible combined with likely progression) and trend-based analysis was 0.48, and between specific criteria of GPA (possible clubbed with no progression) and trend-based analysis was 0.50. In eyes progressing by sensitive criteria of both methods (42 eyes), median time to progression by GPA (4.9 years) was similar (P=0.30) to trend-based method (5.0 years). This was also similar in eyes progressing by specific criteria of both methods (25 eyes; 5.6 years versus 5.9 years, P=0.23). Agreement between event- and trend-based progression analysis was moderate. GPA seemed to detect progression earlier than trend-based analysis, but this wasn't statistically significant.


Whole genome sequencing across clinical trials identifies rare coding variants in GPR68 associated with chemotherapy-induced peripheral neuropathy.
Dose-limiting toxicities significantly impact the benefit/risk profile of many drugs. Whole genome sequencing (WGS) in patients receiving drugs with dose-limiting toxicities can identify therapeutic hypotheses to prevent these toxicities. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention. We conducted a genetic study of time-to-first peripheral neuropathy event using 30× germline WGS data from whole blood samples from 4900 European-ancestry cancer patients in 14 randomized controlled trials. A substantial number of patients in these trials received taxane and platinum-based chemotherapies as part of their treatment regimen, either standard of care or in combination with the PD-L1 inhibitor atezolizumab. The trials spanned several cancers including renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, and melanoma. We identified a locus consisting of low-frequency variants in intron 13 of GRID2 associated with time-to-onset of first peripheral neuropathy (PN) indexed by rs17020773 (p = 2.03 × 10-8, all patients, p = 6.36 × 10-9, taxane treated). Gene-level burden analysis identified rare coding variants associated with increased PN risk in the C-terminus of GPR68 (p = 1.59 × 10-6, all patients, p = 3.47 × 10-8, taxane treated), a pH-sensitive G-protein coupled receptor (GPCR). The variants driving this signal were found to alter predicted arrestin binding motifs in the C-terminus of GPR68. Analysis of snRNA-seq from human dorsal root ganglia (DRG) indicated that expression of GPR68 was highest in mechano-thermo-sensitive nociceptors. Our genetic study provides insight into the impact of low-frequency and rare coding genetic variation on PN risk and suggests that further study of GPR68 in sensory neurons may yield a therapeutic hypothesis for prevention of CIPN.


PD-1 disrupted CAR-T cells in the treatment of solid tumors: Promises and challenges.
Unprecedented efficacy of chimeric antigen receptor (CAR) T cell therapy in the treatment of hematologic malignancies brings new hope for patients with many cancer types including solid tumors. However, the challenges for CAR-T cell therapy in eradicating solid tumors are immense. To overcome these seemingly intractable hurdles, more "powerful" CAR-T cells with enhanced antitumor efficacy are required. Emerging data support that the anti-tumor activity of CAR-T cells can be enhanced significantly without evident toxicity through simultaneous PD-1 disruption by genome editing. This review focuses on the current progress of PD-1 gene disrupted CAR-T cells in cancer therapy. Here we discuss key rationales for this new combination strategy and summarize the available pre-clinical studies. An update is provided on human clinical studies and available registered cancer clinical trials using CAR-T cells with PD-1 disruption. Future prospects and challenges are also discussed.


Intrathecal Injection of Botulinum Toxin Type A has an Analgesic Effect in Male Rats CCI Model by Inhibiting the Activation of Spinal P2X4R.
Purinergic receptor P2X4 (P2X4R) plays an essential role in neuropathic pain. However, the specific mechanism needs to be clarified. Botulinum toxin type A is a neurotoxin produced by Clostridium botulinum type A. This study found that intrathecal injection of botulinum toxin type A produced an excellent analgesic effect in a rat model of chronic constriction sciatic nerve injury and inhibited the activation of P2X4R, microglia, and astrocytes. The administration of a P2X4R activator can up-regulate the expression of P2X4R and eliminate the analgesic effect of intrathecal injection of botulinum toxin type A. In addition, we found that microglia and astrocytes in the spinal cord of rats injected with botulinum toxin type A were reactivated after administration of the P2X4R activator. Our results suggest that intrathecal injection of botulinum toxin type A has an analgesic effect in a rat model of chronic constriction sciatic nerve injury by inhibiting the activation of P2X4R in the spinal cord.


Effect of breathing pattern on blood pressure and heart rate oscillations in humans.
1. The relationships of respiratory sinus arrhythmia (RSA) and respiratory changes in systolic blood pressure (SBP) to tidal volume (VT) and breathing frequency (BF), were quantified during voluntary control of VT and BF in healthy subjects. 2. Respiration was measured non-invasively with a respiratory inductive plethysmograph, which was calibrated prior to each study while breathing through a pneumotachygraph. Finger arterial blood pressure was measured non-invasively by the Finapres. 3. Heart rate (HR) increased during inspiration, with a nearly fixed time delay for most VT and BF approximating 0.9 s. The magnitude of RSA increased with increases in VT and with decreases in BF. SBP decreased during inspiration, with a time delay which increased as BF decreased, resulting in a phase delay approximating 160 degrees. The magnitude of the inspiratory fall in SBP increased with increases in VT. Increased amplitudes of RSA and SBP variation occurred at the lowest BF, consistent with the possibility of interactions between respiratory-related influences and those due to 'slow waves' of vasomotor tone. 4. The present results are consistent with the conclusion that respiratory effects on SBP are caused by a mechanism other that simply changes in HR.


Overall evaluability of low dose protocol for computed tomography angiography of thoracic aorta using 80 kV and iterative reconstruction algorithm using different concentration contrast media.
Multidetector Computed Tomography Angiography (MDCTA) is presently the imaging modality of choice for aortic disease. However, the effective radiation dose and the risk related to the use of contrast agents associated with MDCTA is an issue of concern. Aim of this study was to assess image quality of a low dose ECG-gated MDCTA of thoracic aorta using different concentration contrast media without tailored injection protocol. Two-hundred patients were randomised into four different scan protocols: Group A (Iodixanol 320 and 80 Kvp tube voltage), Group B (Iodixanol 320 and 100 Kvp tube voltage), Group C (Iomeprol 400 and 80 Kvp tube voltage) and Group D (Iomeprol 400 and 100 Kvp tube voltage). Image quality, noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and effective dose (ED) were compared among groups. No significant differences in image noise, SNR and CNR between groups with the same tube voltage. Significant differences in SNR and CNR were found among groups with 80 kV versus groups using 100 kV but without differences in terms of image quality. ED was significantly lower in groups with 80 kV. Multidetector Computed Tomography Angiography protocols using 80 kV and low concentration contrast media are feasible without need of tailored injection protocols.


One-step synthesis and characterization of core-shell Fe@SiO2 nanocomposite for Cr (VI) reduction.
A facile one-step method was developed to fabricate mono-dispersed Fe nanoparticles (Fe NPs) coated with SiO(2) shell by aqueous reduction method combined with modified Stöber method. Borohydride was acted not only as a reductant for iron salt but also as a catalyst for hydrolysis and polycondensation reaction of tetraethylorthosilicate (TEOS), and more importantly, there was no need to use surface primer for the generation of Fe NPs and catalyst NH(4)OH for SiO(2). Both the Fe NPs agglomeration and SiO(2) shell thickness can be controlled through the synthetic conditions. Lower potassium borohydride (KBH(4)) injection speed was preferable to assemble Fe NPs. The SiO(2) shell thickness increased gradually with the increase of TEOS amount. Under the condition of TEOS amount of 0.1mL and KBH(4) injection speed of 5mL/min, 25nm single Fe NP was coated with SiO(2) shell with thickness of about 9nm. The resulting nanoporous SiO(2) shell was proved to allow reactant to reach the Fe NPs while at the same time protect them from aggregation. The reactivity characterization of the SiO(2)-coated Fe nanoparticles (Fe@SiO(2)) showed that both TEOS concentration and KBH(4) injection speed had effect on Cr (VI) degradation ability. The highest removal capacity of Fe@SiO(2) can reach 467mgCr/gFe at an initial Cr (VI) concentration of 70mg/L under pH 6.0±0.1. XPS and TEM results showed that Cr (VI) was converted to nontoxic Cr (III) and the reaction product was completely adsorbed to SiO(2) shell.


Tracking pesticide fate in conventional banana cultivation in Costa Rica: A disconnect between protecting ecosystems and consumer health.
Conventional banana cultivation in Costa Rica relies on heavy pesticide use. While pesticide residues in exported bananas do not generally represent a safety concern for consumers abroad, ecosystem and human health in producing regions are not likewise protected. In Costa Rica, most studies on pesticide residues in the environment are snapshots, limiting our ability to identify temporal dynamics that can inform risk mitigation strategies. To help bridge this gap, we created a dynamic multimedia model for the Caño Azul River drainage area, which is heavily influenced by banana and pineapple plantations. This model estimates chemical concentrations in water, air, soil, sediments, and banana plants through time, based on pesticide properties and emission patterns and on variable environmental conditions. Case studies for three representative chemicals-the herbicide diuron, the nematicide ethoprofos, and the fungicide epoxiconazole-show that concentrations in fruit remain below EU and US maximum residue limits set to ensure consumer health, while those in the environment are highly variable, reaching peak concentrations in water that can exceed thresholds for ecosystem health. Critical research needs, including incorporating sediment dynamics and the effects of adjuvants on the properties and transport of active ingredients into multimedia models, were identified.


Structural identification and immunostimulating activity of a Laminaria japonica polysaccharide.
In the present study, a new water-soluble polysaccharide (LJP-11) was obtained from Laminaria japonica by anion exchange DEAE-cellulose chromatography and Sephacryl S-500 chromatography. The average molecular weight of this polysaccharide was estimated to be about 2.89×10(6) Da by high performance liquid chromatography system. Gas chromatography showed that LJP-11 was composed of arabinose, mannose and glucose in a molar ratio of 1.0:1.16:6.33. LJP-11 contains a long backbone consisting of (1→4)-β-D-GlcpAc, (1→4)-α-D-Glcp, (1→6)-β-D-Glcp and (1→3,6)-α-D-Manp. The 1-linked β-L-Araf was linked to the C-6 of (1→3)-α-D-Manp and the sulfate group was attached to the C-4 of (1→6)-β-D-Glcp. Pharmacological tests displayed that LJP-11 can stimulate macrophages to release NO, IL-6, TNF-α and IL-10 as well as the up-regulation of their gene expressions, indicating LJP-11 has beneficial effects on immunostimulation. Moreover, LJP-11 exhibited positive effects on the translocation of NF-κB p65 from cytoplasm to nucleus and the phosphorylation of IκBα, ERK1/2, JNK1/2 and P38 in macrophages. These results suggested that the activation of MAPK and NF-κB signaling pathways is one of the mechanisms responsible for the immunostimulating activity of LJP-11.


Location response to a startling noise depends on the preferred grooming site in mice.
The exploratory behavior of adult male Balb/c mice was observed in both a small black box and an open field. The normal exploratory pattern included a strong tendency to groom in a preferred place (G-site); thus, an average of 86% (black box) and 92% (open field) of the total grooming time was spent in a single location, specific for each animal and environment. The response of the animals to a 2-sec, 100 dB auditory stimulus varied according to their location. If the unexpected sound occurred when the mice were in their G-site, they remained there an average of 67% (black box) and 75% (open field) of the trials. If elsewhere, they escaped and ran to their G-site 89% (black box) and 73% (open field) of the times. Mice treated with diazepam (5 mg/kg) showed the normal tendency to groom in a preferred place, but never escaped after the stimulus, even if it occurred when they were outside their G-site, nor did they resume normal exploratory behavior. It seems that the preferred grooming location is the place that serves as a refuge from an aversive noise signal, but only the latter behavior is abolished by diazepam, presumably by reduction of stress.


Pholipomycin, a new member of phosphoglycolipid antibiotics. II. Physico-chemical properties and comparison with other members of this family of antibiotics.
Physico-chemical characterization of pholipomycin revealed that this antibiotic is a new member of phosphoglycolipid antibiotics. Pholipomycin was differentiated from other members by the products formed on acid hydrolysis as follows: the presence of glucosamine, a 257 nm chromophore and moenocinol-type C25 lipids, but the absence of glucose, 6-deoxyglucosamine and glycine.


The essential drugs concept is needed now more than ever.
The debate on access to essential medicines, which was live in the late 1970s and 1980s when strong pressure from public health advocates led the pharmaceutical industry to accept the concept, is now back on the international health policy agenda. Currently, the Essential Drugs List (EDL) forms an integral part of national drug policies in 146 countries, guiding the selection of drugs on the basis of public health relevance, efficacy, safety and cost. The essential medicines debate is back on the agenda as part of the access to medicines debate. The Trade Related Aspects on Intellectual Property Rights agreement has caused concern among public health advocates in terms of its impact on access to essential medicines. This article reviews the concept of essential medicines in the light of the changing political context and recommends that the EDL is supported as a crucial public policy tool in all countries.


Efficacy of stereotactic body radiotherapy for unresectable or recurrent cholangiocarcinoma: a meta-analysis and systematic review.
Non-surgical treatment including stereotactic body radiation therapy (SBRT) have been used practically as alternative modalities for unresectable or recurrent cholangiocarcinoma (CC). We performed a systematic review and meta-analysis to examine the efficacy of SBRT for such patients. Embase, PubMed, MEDLINE, and Cochrane library databases were searched systematically until October 2017. Primary endpoint was 1‑year local control (LC) rate; 1‑year overall survival (OS), response rates, and grade ≥3 toxicities were assessed as secondary endpoints. Eleven studies (226 patients) were included. The prescribed median SBRT dose was 45 (range 30-55) Gy in 3-5 fractions. The pooled 1‑year LC rate was 81.8% (95% confidence interval [CI] 69.4-89.9%) in the studies using an equivalent dose in 2 Gy per fraction (EQD2) ≥71.3 Gy2 and 74.7% (95% CI 57.1-86.7%) in the studies using an EQD2 <71.3 Gy2. The median OS was 13.6 (range 10-35.5) months. The pooled 1‑year OS rate was 53.8% (95% CI 44.9-62.5%) and the pooled 1‑year LC rate was 78.6% (95% CI 69.0-85.8%). Most common toxicity was duodenal ulcer and gastric ulcer in available studies, with the acute incidence of grade ≥3 of less than 10% and the late incidence of 10-20%. SBRT was a feasible treatment option with respect to achieving a high LC for unresectable or recurrent CC. Gastrointestinal toxicity is acceptable, but remains an obstacle related to dose escalation.


Built-in electric field and oxygen absorption synergistically optimized an organic/inorganic heterojunction for high-efficiency photocatalytic hydrogen peroxide production.
The production of hydrogen peroxide (H2O2) from oxygen and water is an attractive route for converting solar energy into chemical energy. In order to achieve high solar-to-H2O2 conversion efficiency, floral inorganic/organic (CdS/TpBpy) composite with strong oxygen absorption and S-scheme heterojunction was synthesized by simple solvothermal-hydrothermal methods. The unique flower-like structure increased the active sites and oxygen absorption. The existence of S-scheme heterojuntion facilitated the charge transfer across the built-in electric field. Without sacrificial reagents or stabilizers, the optimal CdS/TpBpy had a higher H2O2 production (3600 µmol g-1 h-1), which was 2.4 and 25.6 times than those of TpBpy and CdS, respectively. Meanwhile, CdS/TpBpy inhibited the H2O2 decomposition, thus increasing the overall output. Furthermore, a series of experiments and calculations were carried out to verify the photocatalytic mechanism. This work demonstrates a modification method to improve the photocatalytic activity of hybrid composites, and shows potential applications in energy conversion.


Synthetic amyloid-β oligomers drive early pathological progression of Alzheimer's disease in nonhuman primates.
As an insidious and slowly progressive neurodegenerative disorder, Alzheimer's disease (AD) uniquely develops in humans but fails in other species. Therefore, it has been challenged to rebuild human AD in animals, including in non-human primates. Here, we bilaterally delivered synthetic Aβ oligomers (AβOs) into the cerebral parenchyma of cynomolgus monkeys, which rapidly drove the formation of massive Aβ plaques and concomitant neurofibrillary tangles in the cynomolgus brain. The amyloid and tau pathology as well as their co-occurrence in AβO-monkeys were reminiscent of those in patients with AD. In addition, the activated astrocytes and microglia surrounding Aβ plaques indicated the triggered neuroinflammation. The degenerative neurons and synapses around Aβ plaques also emerged in cynomolgus brain. Together, soluble AβOs caused the cascade of pathologic events associated with AD in monkeys as occurred in patients at the early phase, which could facilitate the development of a promising animal model for human AD in non-human primates.


Evidence that steroid 5alpha-reductase isozyme genes are differentially methylated in human lymphocytes.
The synthesis of dihydrotestosterone (DHT) is catalyzed by steroid 5alpha-reductase isozymes 1 and 2, and this function determines the development of the male phenotype during embriogenesis and the growth of androgen sensitive tissues during puberty. The aim of this study was to determine the cytosine methylation status of 5alpha-reductase isozymes types 1 and 2 genes in normal and in 5alpha-reductase deficient men. Genomic DNA was obtained from lymphocytes of both normal subjects and patients with primary 5alpha-reductase deficiency due to point mutations in 5alpha-reductase 2 gene. Southern blot analysis of 5alpha-reductase types 1 and 2 genes from DNA samples digested with HpaII presented a different cytosine methylation pattern compared to that observed with its isoschizomer MspI, indicating that both genes are methylated in CCGG sequences. The analysis of 5alpha-reductase 1 gene from DNA samples digested with Sau3AI and its isoschizomer MboI which recognize methylation in GATC sequences showed an identical methylation pattern. In contrast, 5alpha-reductase 2 gene digested with Sau3AI presented a different methylation pattern to that of the samples digested with MboI, indicating that steroid 5alpha-reductase 2 gene possess methylated cytosines in GATC sequences. Analysis of exon 4 of 5alpha-reductase 2 gene after metabisulfite PCR showed that normal and deficient subjects present a different methylation pattern, being more methylated in patients with 5alpha-reductase 2 mutated gene. The overall results suggest that 5alpha-reductase genes 1 and 2 are differentially methylated in lymphocytes from normal and 5alpha-reductase deficient patients. Moreover, the extensive cytosine methylation pattern observed in exon 4 of 5alpha-reductase 2 gene in deficient patients, points out to an increased rate of mutations in this gene.