Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts.
The combination of febrile illness-induced encephalopathy and rhabdomyolysis has thus far only been described in disorders that affect cellular energy status. In the absence of specific metabolic abnormalities, diagnosis can be challenging. The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented clinically with a similar phenotype that included neurodevelopmental delay, febrile illness-induced encephalopathy and episodes of rhabdomyolysis, followed by developmental arrest, epilepsy and tetraplegia. Whole exome sequencing was used to identify pathogenic variants in the two individuals. Biochemical and cell biological analyses were performed on fibroblasts from these individuals and a yeast two-hybrid analysis was used to assess protein-protein interactions. Probands shared a homozygous TRAPPC2L variant (c.109G>T) resulting in a p.Asp37Tyr missense variant. TRAPPC2L is a component of transport protein particle (TRAPP), a group of multisubunit complexes that function in membrane traffic and autophagy. Studies in patient fibroblasts as well as in a yeast system showed that the p.Asp37Tyr protein was present but not functional and resulted in specific membrane trafficking delays. The human missense mutation and the analogous mutation in the yeast homologue Tca17 ablated the interaction between TRAPPC2L and TRAPPC10/Trs130, a component of the TRAPP II complex. Since TRAPP II activates the GTPase RAB11, we examined the activation state of this protein and found increased levels of the active RAB, correlating with changes in its cellular morphology. Our study implicates a RAB11 pathway in the aetiology of the TRAPPC2L disorder and has implications for other TRAPP-related disorders with similar phenotypes.


Functional connectivity MR imaging of the language network in patients with drug-resistant epilepsy.
Subtle linguistic dysfunction and reorganization of the language network were described in patients with epilepsy, suggesting the occurrence of plasticity changes. We used resting state FC-MRI to investigate the effects induced by chronic epilepsy on the connectivity of the language-related brain regions and correlated it with language performance. FC-MRI was evaluated in 22 right-handed patients with drug-resistant epilepsy (11 with LE and 11 with RE) and in 12 healthy volunteers. Neuropsychological assessment of verbal IQ was performed. Patients and controls underwent BOLD fMRI with a verb-generation task, and language function was lateralized by an LI. Intrinsic activity fluctuations for FC analysis were extracted from data collected during the task. Six seeding cortical regions for speech in both hemispheres were selected to obtain a measure of the connectivity pattern among the language networks. Patients with LE presented atypical language lateralization and an overall reduced connectivity of the language network with respect to controls. In patients with both LE and RE, the mean FC was significantly reduced within the left (dominant) hemisphere and between the 2 hemispheres. In patients with LE, there was a positive correlation between verbal IQ scores and the left intrahemispheric FC. In patients with intractable epilepsy, FC-MRI revealed an overall reduction and reorganization of the connectivity pattern within the language network. FC was reduced in the left hemisphere regardless of the epileptogenic focus side and was positively correlated with linguistic performance only in patients with LE.


Fast evolution from precast bricks: genomics of young freshwater populations of threespine stickleback Gasterosteus aculeatus.
Adaptation is driven by natural selection; however, many adaptations are caused by weak selection acting over large timescales, complicating its study. Therefore, it is rarely possible to study selection comprehensively in natural environments. The threespine stickleback (Gasterosteus aculeatus) is a well-studied model organism with a short generation time, small genome size, and many genetic and genomic tools available. Within this originally marine species, populations have recurrently adapted to freshwater all over its range. This evolution involved extensive parallelism: pre-existing alleles that adapt sticklebacks to freshwater habitats, but are also present at low frequencies in marine populations, have been recruited repeatedly. While a number of genomic regions responsible for this adaptation have been identified, the details of selection remain poorly understood. Using whole-genome resequencing, we compare pooled genomic samples from marine and freshwater populations of the White Sea basin, and identify 19 short genomic regions that are highly divergent between them, including three known inversions. 17 of these regions overlap protein-coding genes, including a number of genes with predicted functions that are relevant for adaptation to the freshwater environment. We then analyze four additional independently derived young freshwater populations of known ages, two natural and two artificially established, and use the observed shifts of allelic frequencies to estimate the strength of positive selection. Adaptation turns out to be quite rapid, indicating strong selection acting simultaneously at multiple regions of the genome, with selection coefficients of up to 0.27. High divergence between marine and freshwater genotypes, lack of reduction in polymorphism in regions responsible for adaptation, and high frequencies of freshwater alleles observed even in young freshwater populations are all consistent with rapid assembly of G. aculeatus freshwater genotypes from pre-existing genomic regions of adaptive variation, with strong selection that favors this assembly acting simultaneously at multiple loci.


Support From Parents, Peers, and Teachers Is Differently Associated With Middle School Students' Well-Being.
Parents, peers, and teachers provide a powerful context for school students' well-being. However, a detailed and systematic analysis of how parental, peer, and teacher support relate to students' well-being, measured by the dimensions self-worth, psychological and physical well-being, is still missing. To address this research gap, the following study investigates 733 adolescent German students from grades 7 and 8 (M age = 13.97, SD = 0.41, 52% girls) with respect to their perceived supportive relationships at home and within the school context. The study considers gender, socioeconomic status, and school form as potential confounders. The results of the structural equation model, analyzed with the statistical software R, indicate that perceived teacher support was positively related to students' self-worth and physical well-being, while peer support was related to psychological well-being. Students who perceived their parents as supportive reported higher well-being with respect to all three dimensions investigated.


Distinct startle responses are associated with neuroanatomical differences in pufferfishes.
Despite the key function of the Mauthner cells (M-cells) in initiating escape responses and thereby promoting survival, there are multiple examples of M-cell loss across the teleost phylogeny. Only a few studies have directly considered the behavioral consequences of naturally occurring M-cell variation across species. We chose to examine this issue in pufferfishes, as previous research suggested that there might be variability in M-cell anatomy in this group of fish. We characterized the M-cell anatomy and fast-start responses of two pufferfish species, Tetraodon nigroviridis and Diodon holocanthus. T. nigroviridis showed robust fast-starts to both tactile and acoustic startling stimuli. These fast-starts occurred with a latency typical of M-cell initiation in other fish, and retrograde labeling of spinal-projection neurons revealed that T. nigroviridis does have M-cells. By contrast, D. holocanthus only rarely exhibited fast-start-like behavior, and these responses were at a substantially longer latency and were much less extensive than those of T. nigroviridis. Using three complementary anatomical techniques we were unable to identify obvious M-cell candidates in D. holocanthus. These results provide a clear correlation between M-cell presence or absence and dramatic differences in fast-start behavior. The rich diversity within the pufferfish clade should allow future studies investigating the factors that contribute to this correlated anatomical and behavioral variation.


SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health-care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with preexisting pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomatology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we envisage could maintain a close interplay with SARS-CoV and COVID-19 mortality rates, despite a current lack of research directly determining how. Taken together, we present the current state of the field regarding SARS-CoV-2 research and illuminate where research is needed to better define the role both estrogen and metabolic comorbidities have in the COVID-19 disease state, which can be key in screening potential therapeutic options as the search for effective treatments continue.


Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications.
Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the self-assembly and toxicity of amyloidogenic proteins using a unique mechanism. They destroy viral membranes and inhibit infection by enveloped viruses, such as HIV-1 and SARS-CoV-2, by mechanisms unrelated to their action on protein self-assembly. They also disrupt biofilm of Gram-positive bacteria. The efficacy and safety of MTs have been demonstrated in vitro, in cell culture, and in vivo, suggesting that these versatile compounds are attractive therapeutic candidates for various diseases, infections, and injuries. A lead compound called CLR01 has been shown to inhibit the aggregation of various amyloidogenic proteins, facilitate their clearance in vivo, prevent infection by multiple viruses, display potent anti-biofilm activity, and have a high safety margin in animal models. The inhibitory effect of CLR01 against amyloidogenic proteins is highly specific to abnormal self-assembly of amyloidogenic proteins with no disruption of normal mammalian biologic processes at the doses needed for inhibition. Therapeutic effects of CLR01 have been demonstrated in animal models of proteinopathies, lysosomal-storage diseases, and spinal-cord injury. Here we review the activity and mechanisms of action of these intriguing compounds and discuss future research directions. SIGNIFICANCE STATEMENT: Molecular tweezers are supramolecular host molecules with broad biological applications, including inhibition of abnormal protein aggregation, facilitation of lysosomal clearance of toxic aggregates, disruption of viral membranes, and interference of biofilm formation by Gram-positive bacteria. This review discusses the molecular and cellular mechanisms of action of the molecular tweezers, including the discovery of distinct mechanisms acting in vitro and in vivo, and the application of these compounds in multiple preclinical disease models.


Anaerobic biofilm reactors for dark fermentative hydrogen production from wastewater: A review.
Dark fermentation is a bioprocess driven by anaerobic bacteria that can produce hydrogen (H2) from organic waste and wastewater. This review analyses a relevant number of recent studies that have investigated dark fermentative H2 production from wastewater using two different types of anaerobic biofilm reactors: anaerobic packed bed reactor (APBR) and anaerobic fluidized bed reactor (AFBR). The effect of various parameters, including temperature, pH, carrier material, inoculum pretreatment, hydraulic retention time, substrate type and concentration, on reactor performances was investigated by a critical discussion of the results published in the literature. Also, this review presents an in-depth study on the influence of the main operating parameters on the metabolic pathways. The aim of this review is to provide to researchers and practitioners in the field of H2 production key elements for the best operation of the reactors. Finally, some perspectives and technical challenges to improve H2 production were proposed.


Clinical trials in traumatic brain injury. What can we learn from previous studies?
Many compounds have now been tested that were expected to ameliorate the secondary ischemic brain damage after severe head injury. Thus far, none of these have been clearly successful. This review is an attempt to identify factors that could be responsible for some of these failures. Recommendations are made that could help to avoid these pitfalls in the future. The usefulness and criteria for use of animal models for traumatic brain injury to depict human head injury are discussed. Clearly, it has now become widely accepted that mechanism-driven trials, in which individual pathophysiological mechanisms are targeted, are preferable in this heterogeneous patient population. Other factors, such as the effect of brain penetration, safety and tolerability of the compound, and the interface between the pharmaceutical industry and academics are a major influence in the success of these trials. Furthermore, different ways of analyzing trials such as sequential analysis and newer, alternative end points should be considered. Pharmacological agents will never be the "magic bullet" for a process as heterogenous in pathophysiological mechanisms as traumatic brain injury. This does not imply that the role of neuroprotective compounds will not be important in the future. New approaches in developing, conducting and analyzing these expensive clinical trials must be devised in the future.


Fentanyl sparing effects of combined ketorolac and acetaminophen for outpatient inguinal hernia repair in children.
In this prospective, randomized, double-blinded study we sought to evaluate the efficacy and safety of combined use of intravenous ketorolac and acetaminophen in small children undergoing outpatient inguinal hernia repair. We studied 55 children 1 to 5 years old who were undergoing elective repair of unilateral inguinal hernia. After induction of general anesthesia children in the experimental group (28 patients) received 1 mg/kg ketorolac and 20 mg/kg acetaminophen intravenously. In the control group (27 patients) the same volume of saline was administered. All patients received 1 microg/kg fentanyl intravenously before incision. We also evaluated the number of patients requiring postoperative rescue fentanyl, total fentanyl consumption, pain scores and side effects. Significantly fewer patients receiving ketorolac-acetaminophen received postoperative rescue fentanyl compared to controls (28.6% vs 81.5%). A significantly lower total dose of fentanyl was administered to patients receiving ketorolac-acetaminophen compared to controls (0.54 vs 1.37 microg/kg). Pain scores were significantly higher in the control group immediately postoperatively but eventually decreased. The incidences of sedation use (55.6% vs 25.0%) and vomiting (33.3% vs 10.7%) were significantly higher in controls. Preoperative intravenous coadministration of ketorolac and acetaminophen is a simple, safe and effective method for relieving postoperative pain, and demonstrates highly significant fentanyl sparing effects in small children after outpatient inguinal hernia repair.


Chondrocyte miRNAs 221 and 483-5p respond to loss of matrix interaction by modulating proliferation and matrix synthesis.
The purpose of this study was to identify the microRNAs that regulate the response of chondrocytes to loss of matrix interaction. MicroRNA and gene expression was compared in bovine cartilage and isolated chondrocytes using array analysis. Those microRNAs showing more than three-fold change in expression were verified by quantitative PCR after a stem-loop reverse transcription in bovine and human cartilage, and chondrocytes. Their function was investigated using target gene reporter construct expression, quantification of cell proliferation, and analysis of gene expression and matrix synthesis after transfection with microRNA mimics. Only four microRNAs were confirmed to have a greater than three-fold change in expression after isolation of bovine or human chondrocytes from their extracellular matrix; miRs-221, -222 and -21 showed increased expression and miR-483-5p showed decreased expression. Transfection with a miR-221 mimic was shown to suppress expression of the cyclin-dependent kinase inhibitor p27 leading to the stimulation of chondrocyte proliferation. Transfection of chondrocytes with a miR-483-5p mimic was shown to suppress several members of the mitogen activated protein kinase (MAPK) pathway; a likely explanation of the increased matrix production observed. microRNAs 221 and 483-5p respond to the loss of chondrocyte matrix interaction by respectively stimulating proliferation by suppression of inhibitors of cell division and suppression of matrix production possibly by release of inhibition of the MAPK pathway.


Academy of Nutrition and Dietetics: Revised 2020 Standards of Professional Performance for Registered Dietitian Nutritionists (Competent, Proficient, and Expert) in Sustainable, Resilient, and Healthy Food and Water Systems.
Current systems of food production and consumption are challenged by factors such as natural resource constraints, relative unaffordability of nutrient-dense foods, persistent social inequities, and high rates of diet-related disease. Registered dietitian nutritionists (RDNs) play a critical role in protecting the health of current and future populations by advancing sustainable, resilient, and healthy food and water systems. By definition, such systems can meet current dietary needs without jeopardizing the ability to meet the needs of future generations; can withstand or adapt to disturbances over time; and can equitably facilitate disease prevention and well-being for all individuals. This area of practice within nutrition and dietetics requires recognition of the complex interrelationships among indiviudal health and economic, environmental, and social domains of food and nutrition, and allows RDNs to bring unique expertise to diverse interprofessional teams. The Revised 2020 Standards of Professional Performance for RDNs (Competent, Proficient, and Expert) in Sustainable, Resilient, and Healthy Food and Water Systems update the 2014 standards and cover the following 6 standards of professional performance: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Within each standard, specific indicators provide measurable action statements that illustrate how the RDN can apply the principles of sustainable food systems to a variety of practice settings. The indicators describe 3 skill levels (ie, competent, proficient, and expert) for RDNs in this focus area.


[Theodor Emil Kocher, modern surgery pioneer].
Theodore Kocher was awarded the Nobel Prize in 1909 for his work on the physiology, pathology and surgery of the thyroid gland. He was the first Swiss citizen and the first surgeon to ever receive such a distinction. He was a pioneer and a world leader in the surgical revolution of the end of the nineteenth century. After graduation in 1865, he traveled in Germany, England, France and Austria to observe the work of Langenbeck, Paget, Wells, Nelaton, Billroth.... In 1866, he returned to Bern and was appointed assistant in the surgical clinic of Lücke. In 1872 he applied for the succession of Lücke. After a lively debate, he was appointed by the Board of Regents against the recommendation of the faculty who wished to nominate a German surgeon, König. It proved to be a good choice, as, over a period of 45 years, Kocher developed a considerable activity in various fields of surgery leading to world-wide acclaim and renown. Kocher's most significant contribution to medicine concerned the thyroid gland. He considerably improved thyroid surgery. His anatomical knowledge, precise operating technic and respect of the aseptic principles defined by Lister, whom he had met in Glasgow, contributed to a reduction of mortality from 13% to 0.18%. He described postoperative hypothyroidism, which he called cachexia strumipriva and concluded that total thyroidectomy was not indicated in benign diseases. When he died, more than 7,000 thyroidectomies had been performed in his clinic. Kocher was also interested in orthopedics, abdominal and genitourinary surgery, surgical oncology, neurosurgery (Cushing conducted experimental research with him). He developed or modified many surgical instruments. He conducted a large number of experimental studies and published 249 articles and books.


Metastatic Colorectal Cancer Treatment Response Evaluation by Ultra-Deep Sequencing of Cell-Free DNA and Matched White Blood Cells.
Circulating tumor DNA (ctDNA) has the potential to guide therapy selection and monitor treatment response in patients with metastatic cancer. However, germline and clonal hematopoiesis-associated alterations can confound identification of tumor-specific mutations in cell-free DNA (cfDNA), often requiring additional sequencing of tumor tissue. The current study assessed whether ctDNA-based treatment response monitoring could be performed in a tumor tissue-independent manner by combining ultra-deep targeted sequencing analyses of cfDNA with patient-matched white blood cell (WBC)-derived DNA. In total, 183 cfDNA and 49 WBC samples, along with 28 tissue samples, from 52 patients with metastatic colorectal cancer participating in the prospective phase III CAIRO5 clinical trial were analyzed using an ultra-deep targeted sequencing liquid biopsy assay. The combined cfDNA and WBC analysis prevented false-positives due to germline or hematopoietic variants in 40% of patients. Patient-matched tumor tissue sequencing did not provide additional information. Longitudinal analyses of ctDNA were more predictive of overall survival than standard-of-care radiological response evaluation. ctDNA mutations related to primary or acquired resistance to panitumumab were identified in 42% of patients. Accurate calling of ctDNA mutations for treatment response monitoring is feasible in a tumor tissue-independent manner by combined cfDNA and patient-matched WBC genomic DNA analysis. This tissue biopsy-independent approach simplifies sample logistics and facilitates the application of liquid biopsy ctDNA testing for evaluation of emerging therapy resistance, opening new avenues for early adaptation of treatment regimens.


Antithrombotic therapy for ischemic stroke: guidelines translated for the clinician.
Acute ischemic stroke is the result of abrupt interruption of focal cerebral blood flow. The majority of ischemic strokes are caused by embolic or thrombotic arterial occlusions. Acute stroke management is complex, in part because of the varying etiologies of stroke and the very brief window of time for reperfusion therapy. Efforts to optimize stroke care have also encountered barriers including low public awareness of stroke symptoms. As initiatives move forward to improve stroke care worldwide, health care providers and institutions are being called onto deliver the most current evidence-based care. Updated versions of three major guidelines were published in 2008 by the American College of Chest Physicians, the American Heart Association, and the European Stroke Organization. This article presents a concise overview of current recommendations for the use of fibrinolytic therapy for acute ischemic stroke and antithrombotic therapy for secondary prevention. Future directions are also reviewed, with particular emphasis on improving therapeutic options early after stroke onset.


A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke.
Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (-2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.


Evidence for a role of metformin in preventing olfactory dysfunction among older adults.
Olfactory dysfunction (OD) is increasingly recognized as a hallmark of unhealthy aging and is intimately associated with mortality, but therapies remain elusive. Recognizing the increased prevalence of OD in individuals with diabetes, and the potential anti-aging effects of metformin, we studied the association of metformin use with OD. Cross-temporal study of participants from Waves 2 (2010-11) and 3 (2015-16) of the National Social Life, Health, and Aging Project (NSHAP), a nationally representative cohort study of community-dwelling older adults. We included participants with diabetes who had complete data on olfaction and relevant covariates at Wave 2 and were not lost to follow-up at Wave 3. Olfactory identification (OI), the ability to identify the odorant, and olfactory sensitivity (OS), the ability to detect the presence of an odorant, were tested. Weighted multivariable logistic regression was used to study the association between metformin use at Wave 2 (baseline) and odds of having impaired OI/OS at Wave 3, adjusted for age, sex, race/ethnicity, education, smoking, BMI, HbA1c, years since diabetes diagnosis, and insulin use. Among 228 participants with diabetes (mean age=70 years, 53% female, 21% Black), 112 (49%) used metformin at baseline. Relative to nonusers, users had 58% lower odds of impaired OI and 67% lower odds of impaired OS at Wave 3. Among participants with normal baseline OS (N=62), users had 97% lower odds of impaired OS at Wave 3. Metformin use is associated with lower odds of OD among individuals with diabetes, suggesting a potential protective effect on olfaction. Future work including a larger sample and additional information on metformin use is needed to establish whether these findings are independent of diabetic control.


The activity of cefotiam on beta-lactamase-producing bacteria in an in-vitro model.
The activity of cefotiam was tested in an in-vitro model simulating human serum pharmacokinetics. Bacterial strains used for inoculation either produced a penicillinase or a cephalosporinase. The rate of hydrolysis and the MICs of cefotiam were determined in comparison with those of ampicillin and cephalothin. The influence of these beta-lactamases on the killing kinetics and the degradation of cefotiam in the in-vitro model were then measured. Although all beta-lactamases hydrolyzed cefotiam, only the chromosomal cephalosporinases, especially those from Enterobacter and Klebsiella, reduced the elimination of the bacteria by degradation of the drug. A rough correlation between the hydrolytic activity and MIC could be demonstrated for cefotiam but not for ampicillin, while a correlation between killing ability and MIC only existed for strains with cefotiam MICs higher than 16 mg/l.


Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation.
The glycogen synthase kinase-3beta (GSK3beta) pathway plays an important role in mediating neuronal fate and synaptic plasticity. In Alzheimer's disease (AD), abnormal activation of this pathway might play an important role in neurodegeneration, and compounds such as lithium that modulate GSK3beta activity have been shown to reduce amyloid production and tau phosphorylation in amyloid precursor protein (APP) transgenic (tg) mice. However, it is unclear whether regulation of GSK3beta is neuroprotective in APP tg mice. In this context, the main objective of the present study was to determine whether pharmacological or genetic manipulations that block the GSK3beta pathway might ameliorate the neurodegenerative alterations in APP tg mice and to better understand the mechanisms involved. For this purpose, two sets of experiments were performed. First, tg mice expressing mutant human APP under the Thy1 promoter (hAPP tg) were treated with either lithium chloride or saline alone. Second, hAPP tg mice were crossed with GSK3beta tg mice, in which overexpression of this signaling molecule results in a dominant-negative (DN) effect with inhibition of activity. hAPP tg mice that were treated with lithium or that were crossed with DN-GSK3beta tg mice displayed improved performance in the water maze, preservation of the dendritic structure in the frontal cortex and hippocampus, and decreased tau phosphorylation. Moreover, reduced activation of GSK3beta was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-beta production. In conclusion, the present study showed that modulation of the GSK3beta signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3beta might be a suitable target for the treatment of AD.


Radiographic bone damage in chronic gout is negatively associated with the inflammatory cytokines soluble interleukin 6 receptor and osteoprotegerin.
We investigated the risk factors for radiographic bone damage to foot joints in patients with chronic gout among various patient characteristics and serum inflammatory cytokines such as interleukin 1ß (IL-1ß), IL-6, soluble IL-6 receptor (sIL-6R), osteoprotegerin (OPG), and receptor activator of nuclear factor-κB ligand (RANKL). Fifty consecutive male patients with gout and 54 age-matched healthy male controls were enrolled. Serum levels of cytokines including IL-1ß, IL-6, sIL-6R, OPG, and RANKL were measured using ELISA. Radiographic damage indices including erosion scores, narrowing scores, and total scores for foot joints were assessed according to a modified Sharp-van der Heijde system. There were significant differences in serum IL-1ß, IL-6, sIL-6R, OPG, and RANKL levels between patients with gout and the controls, after adjustment for confounding factors such as age, body mass index, blood urea nitrogen, creatinine, triglyceride, and fasting blood glucose (p = 0.034 for IL-1ß, p < 0.001 for IL-6, p = 0.040 for sIL-6R, p = 0.002 for OPG, and p = 0.018 for RANKL). Radiographic damage indices (erosion, narrowing, and total scores) were negatively associated with serum sIL-6R and OPG levels in multivariable-adjusted regression analysis. Serum sIL-6R levels in patients without radiographic damage were higher than in those with damage (p = 0.006). Radiographic damage in patients with chronic gouty arthritis was negatively associated with serum sIL-6R and OPG. Further study on the role of inflammatory cytokines in the pathogenesis of radiographic damage in gout is needed.


The monomer state of beta-amyloid: where the Alzheimer's disease protein meets physiology.
One hundred years of study have identified beta-Amyloid (A beta) as the most interesting feature of Alzheimer's disease (AD). Since the discovery of A beta as the principal component of amyloid plaques, the central challenge in AD research has been the understanding of A beta involvement in the neurodegenerative process of the disease. The ability of A beta to undergo conformational changes and subsequent aggregation has always been a limiting factor in finding out the activities of the peptide. Extensive research has been carried out to study the molecular mechanisms of amyloid self-assembly. The finding that soluble Abeta concentrations in the brain are correlated with the severity of AD, whereas fibrillar density is not /40,42/, has pointed attention toward the oligomeric forms of Abeta, which are generally considered the most toxic and, therefore, the most important species to be addressed. Despite great efforts in basic AD research, none of the currently available treatments is able to treat the devastating effects of the disease, leading to the consideration that there is more to reason than just A beta production and aggregation. Here we summarize the emerging evidence for the physiological functions of A beta, including our recent demonstration that A beta monomers are endowed with neuroprotective activity, and propose that A beta aggregation might contribute to AD pathology through a "loss-of-function" process. Finally, we discuss the current therapeutics targeting the cerebral load of A beta and possible new ones aimed at preserving the biological functions of A beta.


Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration.
Myosins are motor proteins that use chemical energy to produce mechanical forces driving actin cytoskeletal dynamics. In the brain, the conventional non-muscle myosin II (NMII) regulates actin filament cytoskeletal assembly and contractile forces during structural remodeling of axons and dendrites, contributing to morphology, polarization, and migration of neurons during brain development. NMII isoforms also participate in neurotransmission and synaptic plasticity by driving actin cytoskeletal dynamics during synaptic vesicle release and retrieval, and formation, maturation, and remodeling of dendritic spines. NMIIs are expressed differentially in cerebral non-neuronal cells, such as microglia, astrocytes, and endothelial cells, wherein they play key functions in inflammation, myelination, and repair. Besides major efforts to understand the physiological functions and regulatory mechanisms of NMIIs in the nervous system, their contributions to brain pathologies are still largely unclear. Nonetheless, genetic mutations or deregulation of NMII and its regulatory effectors are linked to autism, schizophrenia, intellectual disability, and neurodegeneration, indicating non-conventional roles of NMIIs in cellular mechanisms underlying neurodevelopmental and neurodegenerative disorders. Here, we summarize the emerging biological roles of NMIIs in the brain, and discuss how actomyosin signaling contributes to dysfunction of neurons and glial cells in the context of neurological disorders. This knowledge is relevant for a deep understanding of NMIIs on the pathogenesis and therapeutics of neuropsychiatric and neurodegenerative diseases.


Ionotrophic 5-hydroxytryptamine type 3 receptor activates the protein kinase C-dependent phospholipase D pathway in human T-cells.
The present study was undertaken to investigate the role of the 5-hydroxytryptamine (5-HT) ionotrophic receptor 5-HT(3) in the activation of human Jurkat T-cells. 5-HT and 2-methyl-5-HT (2Me-5-HT), an agonist of the 5-HT(3) receptor, induced increases in intracellular free Na(+) concentrations, [Na(+)](i), via opening of the ionotrophic receptor in these cells. These two serotonergic (5-hydroxytryptaminergic) agents potentiated phytohaemagglutinin (PHA)-induced T-cell activation. However, they failed to potentiate dioctanoglycerol-plus-ionomycin-stimulated T-cell blastogenesis. Interestingly, an inhibitor of protein kinase C (PKC), GF 109203X, curtailed significantly 5-HT and 2Me-5-HT-potentiated T-cell activation. These results demonstrate that the opening of the 5-HT(3) ionotrophic receptor is implicated in T-cell activation via the PKC pathway. Furthermore, 5-HT and 2Me-5-HT stimulated phospholipase D (PLD) activity, as measured by the production of phosphatidylethanol and phosphatidylbutanol at the expense of phosphatidic acid (PA). GF 109203X significantly curtailed the 5-HT- and 2Me-5-HT-induced PLD activity and T-cell activation. The PLD/PA pathway stimulated by these two serotonergic agents resulted in the production of 1,2-diacylglycerol (DAG) mass in Jurkat T-cells. These results altogether suggest that 5-HT and 2Me-5-HT potentiate T-cell activation via increases in [Na(+)](i) and the activation of the PKC-dependent PLD pathway.


Loop 7 of E2 enzymes: an ancestral conserved functional motif involved in the E2-mediated steps of the ubiquitination cascade.
The ubiquitin (Ub) system controls almost every aspect of eukaryotic cell biology. Protein ubiquitination depends on the sequential action of three classes of enzymes (E1, E2 and E3). E2 Ub-conjugating enzymes have a central role in the ubiquitination pathway, interacting with both E1 and E3, and influencing the ultimate fate of the substrates. Several E2s are characterized by an extended acidic insertion in loop 7 (L7), which if mutated is known to impair the proper E2-related functions. In the present contribution, we show that acidic loop is a conserved ancestral motif in E2s, relying on the presence of alternate hydrophobic and acidic residues. Moreover, the dynamic properties of a subset of family 3 E2s, as well as their binary and ternary complexes with Ub and the cognate E3, have been investigated. Here we provide a model of L7 role in the different steps of the ubiquitination cascade of family 3 E2s. The L7 hydrophobic residues turned out to be the main determinant for the stabilization of the E2 inactive conformations by a tight network of interactions in the catalytic cleft. Moreover, phosphorylation is known from previous studies to promote E2 competent conformations for Ub charging, inducing electrostatic repulsion and acting on the L7 acidic residues. Here we show that these active conformations are stabilized by a network of hydrophobic interactions between L7 and L4, the latter being a conserved interface for E3-recruitment in several E2s. In the successive steps, L7 conserved acidic residues also provide an interaction interface for both Ub and the Rbx1 RING subdomain of the cognate E3. Our data therefore suggest a crucial role for L7 of family 3 E2s in all the E2-mediated steps of the ubiquitination cascade. Its different functions are exploited thank to its conserved hydrophobic and acidic residues in a finely orchestrate mechanism.


Organization of somatosensory cortex in the laboratory rat (Rattus norvegicus): Evidence for two lateral areas joined at the representation of the teeth.
Lateral somatosensory areas have not been explored in detail in rats, and theories on the organization of this region are based largely on anatomical tracing experiments. We investigated the topography of this region by using microelectrode recordings, which were related to flattened cortical sections processed for cytochrome oxidase (CO). Two lateral somatosensory areas were identified, each containing a complete representation of the body. A larger, more medial representation formed a mirror image of S1 along the rostrocaudal axis of the head region corresponding to the previously identified secondary somatosensory area (S2). A smaller, more lateral representation formed a mirror image of S2 along the rostrocaudal axis of the forelimb and hindlimb regions and likely corresponds to the parietal ventral area (PV) identified in other mammals. We also investigated the representation of the dentition and identified regions of cortex responsive to tooth stimulation. The lower incisor representation was rostral to the lower lip region of S1, and the upper incisor representation was lateral to the buccal pad region of S1. The upper and lower incisors flanked the tongue representation. An additional large region of far lateral cortex responded to both incisors. Finally, five CO-dense modules were consistently identified rostral and lateral to the S1 face representation, which we refer to as OM1, OM2, OM3, FM, and HM. These modules closely correspond to the physiologically identified areas representing the lower incisor (OM1) and tongue (OM2) regions of S1 and the mixed tooth (OM3), forelimb (FM1), and hindlimb (HM) representations of S2 and PV.


Foreign-gas broadening of nitrous oxide absorption lines.
We have measured the foreign-gas broadening coefficients for collisional broadening of lines in the v(3) fundamental of N(2)O by He, Ne, Ar, Kr, Xe, H(2), D(2), and CH(4). These coefficients, which give the ratio of the line-broadening ability of these gases to the line-broadening ability of N(2), can be used with recent measurements and calculations of N(2) broadening to obtain optical collision cross sections.


Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis.
The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments. In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1-2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18. Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p<0·0001) in all patients, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. Humoral and cell-mediated immune responses persisted above baseline until month 13 in all strata and, as expected, vaccine was more reactogenic than placebo (within 7 days after vaccination pain was reported by 221 [79·5%] of 278 vaccine group participants and 45 [16·4%] of 274 placebo group participants; fatigue was reported by 162 [58·3%] of 278 vaccine group participants and 102 [37·2%] of 274 placebo group participants). Incidences of unsolicited or serious adverse events, potential immune-mediated diseases, disease-related events, and fatal serious adverse events were similar between the groups. The immunocompromised adult population with haematological malignancies is at high risk for herpes zoster. The adjuvanted recombinant zoster vaccine, which is currently licensed in certain countries for adults aged 50 years and older, is likely to benefit this population. GlaxoSmithKline Biologicals SA.


Complete Genome Sequences of Four Salmonella enterica Strains (Including Those of Serotypes Montevideo, Mbandaka, and Lubbock) Isolated from Peripheral Lymph Nodes of Healthy Cattle.
Salmonella enterica serotype Lubbock emerged most likely from a Salmonella enterica serotype Mbandaka ancestor that acquired by recombination the fliC operon from Salmonella enterica serotype Montevideo. Here, we report the complete genome sequence of two S. Lubbock, one S. Montevideo, and one S. Mbandaka strain isolated from bovine lymph nodes.


How diversification of products impact emissions in China: a provincial perspective.
Currently, global warming and air pollution are the world's most urgent issues partly caused by carbon dioxide (CO2) and sulfur dioxide (SO2) emissions, and prompt actions are needed to address these global concerns. Sustainable development cannot be attained until we reverse the negative impact of economic factors on the quality of the environment. It is noteworthy to offer a new indication on whether and how the empirical liaison between product diversification and environmental degradation evolved in China from 2008 to 2019. Product diversification (PD) is a remedy for reducing environmental degradation (ED). It is a crucial component of energy demand, which a significant impact on reducing energy consumption and ED. The purpose of this study is to investigate the impact of PD on ED in China using the provincial panel dataset. Employing the fixed effects-Driscoll-Kraay standard errors (FE-DKSE) and feasible generalized least squares (FGLS) methods, we discover an inverted U-shaped link between PD and ED. The control variable urbanization (URB) and technological innovation (TI) reduce ED significantly. However, industry value added (IVA) and energy consumption (EC) promote ED. Our results are robust with the addition of various controls in all models. The policy implication from our findings is that, to achieve a target of carbon neutrality, countries should adopt the product diversification strategy.


The problem of 'thick in status, thin in content' in Beauchamp and Childress' principlism.
For many, Thomas Beauchamp and James Childress have elaborated moral reasoning by using the four principles whereby all substantive problems of medical ethics (and of ethics more generally) can be properly analysed and cogent philosophical solutions for the problems can be found. It seems that their 'principlism' gets updated, with better features being added during the course of the six editions of Principles of Biomedical Ethics. Nonetheless, Beauchamp and Childress seem to have been losing their way when it comes to the common-morality justification, which is the epistemological (and perhaps metaphysical) backbone of their method, and this is shown more vividly in their most recent (2009) edition of Principles of Biomedical Ethics. The author points out what he calls the problem of 'thick in status, thin in content' in principlism. The problem exists because principlism cannot adequately explain how the prescriptive sense of common morality it supports is consistent with the existence of what Beauchamp and Childress call the 'legitimate moral diversity in the world'. Because of this problem, first, the practical end that principlism allegedly accomplishes (ie, providing practical moral guidelines in a relatively 'thick' content, based on common morality) is frustrated, and, second, principlism makes itself the method of common morality de jure and of moral pluralism de facto.


The characteristics of decision making, potential to take risks, and personality of college students with Internet addiction.
This study aimed to identify risk factors involved in Internet addiction. A total of 216 college students (132 males and 84 females) were given the following: (a) the diagnostic interview for Internet addiction, (b) the Iowa gambling test for decision-making deficits, (c) the Balloon Analog Risk Test (BART) to assess risk-taking tendencies, and (d) the Tridimensional Personality Questionnaire (TPQ) for personality characteristics. The results revealed the following: (a) 49% of males and 17% of females were addicted, (b) the addicted students tended to select more advantageous cards in the last 40 cards of the Iowa test, indicating better decision making, (c) no difference was found for the BART, indicating that addicted subjects were not more likely to engage in risk-taking behaviors and (d) TPQ scores showed lower reward dependence (RD) and higher novelty seeking (NS) for the addicts. Their higher performance on the Iowa gambling test differentiates the Internet addiction group from the substance use and pathologic gambling groups that have been shown to be deficient in decision making on the Iowa test. Thus, students that fit these characteristics should be closely monitored to prevent Internet addiction.


Morphological and ultrastructural characterization of sea urchin immune cells.
The free circulating coelomocytes in the coelomic cavity of echinoderms are considered to be immune effectors by phagocytosis, encapsulation, cytotoxicity, and by the production of antimicrobial agents. Although echinoderms (especially sea urchin embryo) have been used as a model organisms in biology, no uniform criteria exist for classification of coelomocytes in echinoderms, and few studies have reported about the biological functions of their coelomocytes. Hence, we study the coelomocytes in the echinoid sea urchin, Paracentrotus lividus, and describe their morphological and ultrastructural features using light and transmission electron microscopes. We classify the coelomocytes of P. lividus into red spherule and colorless spherule cells, small cells, vibratile cells, and phagocytic cells; petaloid and filopodial cells. To our knowledge, this is the first report describing ultrastructural details of the coelomocytes of P. lividus.


HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism.
Plasmacytoid DCs (pDCs) have been implicated as crucial cells in antiviral immune responses. On recognizing HIV, they become activated, secreting large amounts of IFN-alpha and inflammatory cytokines, thereby potentiating innate and adaptive antiviral immune responses. Here, we have shown that HIV-stimulated human pDCs can also induce the differentiation of naive CD4+ T cells into Tregs with suppressive function. This differentiation was independent of pDC production of IFN-alpha and primarily dependent on pDC expression of indoleamine 2,3-dioxygenase, which was induced through the TLR/MyD88 pathway, following binding of HIV to CD4 and triggering of TLR7 by HIV genomic RNA. Functionally, the Tregs induced by pDCs were shown to inhibit the maturation of bystander conventional DCs. This study therefore reveals what we believe to be a novel mechanism by which pDC may regulate and potentially limit anti-HIV immune responses.


Increased expression of calbindin D28k via herpes simplex virus amplicon vector decreases calcium ion mobilization and enhances neuronal survival after hypoglycemic challenge.
Disruption of Ca2+ homeostasis often leads to neuron death. Recently, the function of calcium-binding proteins as neuronal Ca2+ buffers has been debated. We tested whether calbindin D28k functions as an intracellular Ca2+ buffer by constructing bicistronic herpes simplex virus vectors to deliver rat calbindin cDNA to hippocampal neurons in vitro. Neurons were infected with vectors delivering calbindin or a negative control or were mock-infected. After 12 or 24 h of hypoglycemia, infected cells were made aglycemic during fura-2 calcium ratiometric imaging. In response to this challenge, neuronal overexpressing calbindin had less Ca2+ mobilized as compared with negative controls or mock-infected cells. Cells were assayed for survival after 12- or 24-h hypoglycemia or aglycemia. The calbindin vector decreased neuronal death due to hypoglycemia but not aglycemia. Here we demonstrate, in response to hypoglycemic challenge, both decreased Ca2+ mobilization and increased survival of cells infected with the calbindin vector.


Impact of computational methods and spectral models on the retrieval of optical properties via spectral optimization.
Spectral optimization algorithm (SOA) is a well-accepted scheme for the retrieval of water constituents from the measurement of ocean color radiometry. It defines an error function between the input and output remote sensing reflectance spectrum, with the latter modeled with a few variables that represent the optically active properties, while the variables are solved numerically by minimizing the error function. In this paper, with data from numerical simulations and field measurements as input, we evaluate four computational methods for minimization (optimization) for their efficiency and accuracy on solutions, and illustrate impact of bio-optical models on the retrievals. The four optimization routines are the Levenberg-Marquardt (LM), the Generalized Reduced Gradient (GRG), the Downhill Simplex Method (Amoeba), and the Simulated Annealing-Downhill Simplex (i.e. SA + Amoeba, hereafter abbreviated as SAA). The Garver-Siegel-Maritorena SOA model is used as a base to test these computational methods. It is observed that 1) LM is the fastest method, but SAA has the largest number of valid retrievals; 2) the quality of final solutions are strongly influenced by the forms of spectral models (or eigen functions); and 3) dynamically-varying eigen functions are necessary to obtain smaller errors for both reflectance spectrum and retrievals. Results of this study provide helpful guidance for the selection of a computational method and spectral models if an SOA scheme is to be used to process ocean color images.


T cell cytokines and the risk of blood stream infection in extremely low birth weight infants.
Cytokines mediate the host immune response to infectious micro-organisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6, and IL-10) and inflammatory cytokines (Interferon-γ [INF-γ], tumor necrosis factor-β [TNF-β], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the five sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (p=0.01), and higher levels of the regulatory cytokines, IL-6 (p=0.01) and IL-10 (p<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population.


Anti-human von willebrand factor monoclonal antibody AJvW-2 prevents thrombus deposition and neointima formation after balloon injury in guinea pigs.
Immediately after angioplasty, platelet adhesion to the injured arterial wall and subsequent release of various mitogens may contribute to neointima formation. The purpose of this study was to evaluate the inhibitory effect of AJvW-2, a monoclonal antibody against human von Willebrand factor (vWF), on neointima formation in a guinea pig model. The carotid artery was injured with a balloon catheter, and AJvW-2 was administered by a single bolus injection. AJvW-2 dose-dependently prevented neointima formation 14 days after injury. Significant inhibition was observed at 1.8 mg/kg, at which dose significant inhibition of platelet aggregation was achieved for 2 days. By elastic-Masson staining, organized thrombi were observed in the neointimal lesion on day 14. The thrombus area was significantly correlated with neointimal thickness. Furthermore, thrombus deposition, immunostained for vWF and fibrin(ogen), was observed on the media immediately after balloon injury. AJvW-2 significantly reduced the deposition of both adhesive proteins and reduced the incidence of organized thrombus formation, which might affect subsequent neointima formation. However, the proliferation of cultured smooth muscle cells was not affected by AJvW-2. These results suggest that AJvW-2 prevents neointima formation by inhibition of initial platelet-mediated thrombus formation rather than by direct inhibition of smooth muscle cell proliferation.


Testing an AAC system that transforms pictograms into natural language with persons with cerebral palsy.
In this article, we describe a compansion system that transforms the telegraphic language that comes from the use of pictogram-based augmentative and alternative communication (AAC) into natural language. The system was tested with four participants with severe cerebral palsy and ranging degrees of linguistic competence and intellectual disabilities. Participants had used pictogram-based AAC at least for the past 30 years each and presented a stable linguistic profile. During tests, which consisted of a total of 40 sessions, participants were able to learn new linguistic skills, such as the use of basic verb tenses, while using the compansion system, which proved a source of motivation. The system can be adapted to the linguistic competence of each person and required no learning curve during tests when none of its special features, like gender, number, verb tense, or sentence type modifiers, were used. Furthermore, qualitative and quantitative results showed a mean communication rate increase of 41.59%, compared to the same communication device without the compansion system, and an overall improvement in the communication experience when the output is in natural language. Tests were conducted in Catalan and Spanish.


[The dynamics of endogenic intoxication in patients with extensive burns].
The sampling consisted of 22 patients with extensive burns with total affected area from 20% to 84% of body surface and with deep burns area from 10% to 40%. The suppurative complications in the form of sepsis were diagnosed in 10 and the transitory bacteremia in 12 victims. The total and effective concentration of albumin, the content of medium molecular peptides in dynamics at 1-3, 7, 14 and 21 days from the moment of trauma were detected to objectively evaluate the endogenic intoxication. The degree of intensity of endogenic intoxication was studied using such integral indicator as effective utilization factor In patients with extensive burns the endogenic intoxication was diagnosed on the basis of total and effective concentration of albumin and increase of content of medium molecular peptides. However the detection of endogenic intoxication of the basis of effective utilization factor is a more informative as compared with the analysis of these indicators separately and, hence, it promote the prescription of more appropriate disintoxication therapy its effectiveness evaluation including.


Exploration of barriers to breast-self examination among urban women in Shah Alam, Malaysia: a cross sectional study.
Breast cancer is the most common cancer among women in Malaysia. Barriers for practicing breast self examination (BSE) await exploration. To assess the practice of BSE and its correlated factors and particularly barriers amongst urban women in Malaysia. This cross-sectional study was conducted with 222 Malaysian women using a self-administered questionnaire. The mean (SD) age was 28.5 (±9.2) years, 59.0% were university graduates. Of the total, 81.1% were aware of breast cancer and 55% practiced BSE. Amongst 45% of respondents who did not practice BSE, 79.8% did not know how to do it, 60.6% feared being diagnosed with breast cancer, 59.6% were worried about detecting breast cancer, 22% reported that they should not touch their bodies, 44% and 28% reported BSE is embarrassing or unpleasant, 29% time consuming, 22% thought they would never have breast cancer or it is ineffective and finally 20% perceived BSE as unimportant. Logistic regression modeling showed that respondents aged ≥45 years, being Malay, married and having a high education level were more likely to practice BSE (p<0.05). In this study sample, a significant proportion of respondents was aware of breast cancer but did not practice BSE. Knowledge, psychological, cultural, perception and environmental factors were identified as barriers. BSE practice was associated significantly with socio-demographic factors and socioeconomic status.


Ayurvedic Management of Systemic Lupus Erythematosus overlap Vasculitis.
Systemic Lupus erythematosus is the classic prototype of multisystem disease of autoimmune origin. SLE may be associated Vasculitis as an overlap syndrome. In this paper, a patient diagnosed as SLE with Vasculitis, which was managed successfully by Ayurveda treatment was discussed. A 39-year-old female patient came to hospital with complaint of severe pain and burning sensation in both the legs for two months, associated with ulceration and gangrene of toes of both the legs for the last 15 days. She was diagnosed as SLE overlap vasculitis from a higher medical centre with relevant investigations and advised to go for amputation. As patient was not willing for surgery, alternatively opted for Ayurveda treatment. The condition was diagnosed as disease Vatarakta according to Ayurveda and treatment was planned accordingly. Treatment was planned by selecting suitable oral medicines, suitable panchakarma procedures along with the ulcer management. Tinospora cordifolia was the main drug of choice. Treatment was successful and able to save the limb. Patient was followed up for more than a year without any complications and relapses.


[Fracture of the pisiform bone in inline skating].
During the last years inline-skating became one of the most familiar kind of sports with more than 12 million inline-skaters. The danger of injuring is often underestimated. Protectors and technique are important for an effective prophylaxis of injury. The upper extremity is mainly endangered. But despite effective protectors there is still the danger of injury. In particular protectors of the hand can shift the force when falling and result in a fracture of the Os pisiforme. This fracture can be missed in standard x-rays and only be diagnosed with special x-rays.


Recurrence Following Endoscopic Laser Wedge Excision and Triple Medical Therapy for Idiopathic Subglottic Stenosis.
We present the outcomes for patients with idiopathic subglottic stenosis (iSGS) following their first carbon dioxide laser wedge excision (LWE) procedure, additionally examining the effect of compliance with adjuvant medical therapy (triple therapy) after the operation. Retrospective chart review. Tertiary center. A retrospective review was performed on 183 patients with iSGS following their first LWE and their compliance to adjuvant medical therapy (inhaled corticosteroid, proton pump inhibitor, trimethoprim-sulfamethoxazole) following the operation, with all reviewed to December 31, 2020. The primary outcome variable was median time to recurrence (MTR). Patients were stratified by whether the LWE was their first operation (LWE primary or secondary), by compliance to triple therapy, and by compliance with trimethoprim-sulfamethoxazole. Kaplan-Meier analysis and Cox proportional hazards were used to evaluate the MTR across the stratifications. An overall 113 patients underwent their first LWE, while 70 received the procedure after having undergone 1 to 13 procedures. The MTR between LWE primary and secondary was 4.6 and 2.9 years, respectively. Adjusted Cox proportional hazards comparing these 2 groups revealed the number of prior operations to be a confounding variable. A statistically increased MTR was demonstrated with greater degrees of medical compliance. LWE conferred an MTR of 4.1 years in the iSGS cohort. The number of prior procedures preceding LWE behaved as a confounding variable. Patients who were completely or partially compliant to triple therapy appear to demonstrate increased intervals prior to recurrence.


Improving immunization in Afghanistan: results from a cross-sectional community-based survey to assess routine immunization coverage.
Despite progress in recent years, Afghanistan is lagging behind in realizing the full potential of immunization. The country is still endemic for polio transmission and measles outbreaks continue to occur. In spite of significant reductions over the past decade, the mortality rate of children under 5 years of age continues to remain high at 91 per 1000 live births. The study was a descriptive community-based cross sectional household survey. The survey aimed to estimate the levels of immunization coverage at national and province levels. Specific objectives are to: establish valid baseline information to monitor progress of the immunization program; identify reasons why children are not immunized; and make recommendations to enhance access and quality of immunization services in Afghanistan. The survey was carried out in all 34 provinces of the country, with a sample of 6125 mothers of children aged 12-23 months. Nationally, 51% of children participating in the survey received all doses of each antigen irrespective of the recommended date of immunization or recommended interval between doses. About 31% of children were found to be partially vaccinated. Reasons for partial vaccination included: place to vaccinate child too far (23%), not aware of the need of vaccination (17%), no faith in vaccination (16%), mother was too busy (15%), and fear of side effects (11%). The innovative mechanism of contracting out delivery of primary health care services in Afghanistan, including immunization, to non-governmental organizations is showing some positive results in quickly increasing coverage of essential interventions, including routine immunization. Much ground still needs to be covered with proper planning and management of resources in order to improve the immunization coverage in Afghanistan and increase survival and health status of its children.


The best possible intentions testing prophylactic approaches on humans in developing countries.
Debates on human experiments in developing countries focus on ethical principles such as informed consent, accountability, involvement of the concerned communities, and the improvement of local health services. Public health specialists who conducted human experiments in Rio de Janeiro (1902-1905) and in Guatemala (1947-1948) believed, however, that they were acting in the best interests of local populations, were aware of the importance of informed consent, were closely collaborating with local health professionals, and were contributing to the development of local health structures. Nevertheless, their investigations went dramatically wrong. An initial desire to conduct ethically and scientifically sound studies was undermined by pressure to obtain results and to save the researchers' initial investment, the possibility of freely using hospitalized patients as experimental participants, uncritical help from local professional elites, and structural pitfalls of experimenting with severely deprived people. These elements can still be found in trials of preventive methods in the Global South.


Ornithobacterium rhinotracheale in nestling falcons.
This case report describes a severe outbreak of airsacculitis caused by Ornithobacterium rhinotracheale (ORT) in a large falcon breeding farm. Forty young falcons hatched from artificially incubated hatching eggs and were raised by hand for 5-8 days after hatch. Afterwards they were placed back with the parents. Three days after being with the parents, the stock breeder observed that the young falcons stopped begging for food, their crops were empty, and approximately 20% of the young demonstrated respiratory distress. However, all adult falcons and the older young birds appeared to be healthy. Two young falcons died and were submitted for laboratory investigations. A postmortem examination on the two dead falcons and ten 4-wk-old cockerels and baby rats used as feed for the falcons was performed. ORT of serotype A was isolated from lungs and air sacs of both falcons. Samples of the cockerels were positive by ORT PCR. Samples of the baby rats were negative. All young falcons were treated with a long-acting tetracycline (100 mg/kg i.m. followed by a second injection 3 days later). The falcons improved within the next 2 days, and only one additional chick died. According to the available literature, this is the first report of ORT in falcons causing severe clinical disease and outbreak in a breeding farm.


Risk Factors for Development of Rectal Neuroendocrine Tumors Longer Than 9 mm: Retrospective Cohort.
Rectal neuroendocrine tumors (R-NET) represent the most frequent of gastroenteropancreatic neuroendocrine neoplasms (NEN-GEP) according to the United States Surveillance, Epidemiology, and End Results database. With an annual percentage of occurrence increasing to 8.2% of all rectal neoplasms, R-NET affect less than 2% and are reported in only 0.05% to 0.07% of patients undergoing colorectal cancer (CRC) screening. The primary objective of this study was to assess the risk factors associated with R-NET greater than 10 mm. As a secondary objective, it was also aimed to evaluate the response to endoscopic treatment. This was a retrospective study, using data collected through the analysis of medical records of colonoscopies performed from January 2008 to December 2014. Records of polypectomies were identified, and the results were searched for pathological findings of R-NET. We also gathered epidemiological data and outcomes as risk factors for lesions greater than or equal to 10 mm, with local and distant recurrence. During the study period, 18 218 colonoscopies were performed and 10 865 polypoid lesions were detected and removed, 20 with R-NET anatomopathology. The detection rate was 0.1%. The risk factors associated with major lesions were Japanese ethnicity, the lack of previous cancer diagnosis, and a Ki67 index > 2%. The mean follow-up was 56.6 months, and there was no local lymph node recurrence or distant relapse. This study concludes that endoscopic resection is a good and effective method for treatment of Grade 1 rectal NET smaller than 11 mm, with high cure rates and low rates of local or distant relapse.


The diagnostic problem in asthma.
Differences in the types of asthma are due to differences in the cause of the condition. As determination of the type is important with regard to treatment and prognosis, "etiologic diagnosis" is a principal problem. Observers in various parts of the country may disagree sharply as to the relative incidence of one type and another, a disagreement which may be based on differences in the environments in which they make their observations. Reaching agreement on the interpretation of symptoms would be of great value. It must come from further careful, unbiased observation.


An adaptive scaling and biasing scheme for OFDM-based visible light communication systems.
Orthogonal frequency-division multiplexing (OFDM) has been widely used in visible light communication systems to achieve high-rate data transmission. Due to the nonlinear transfer characteristics of light emitting diodes (LEDs) and owing the high peak-to-average-power ratio of OFDM signals, the transmitted signal has to be scaled and biased before modulating the LEDs. In this contribution, an adaptive scaling and biasing scheme is proposed for OFDM-based visible light communication systems, which fully exploits the dynamic range of the LEDs and improves the achievable system performance. Specifically, the proposed scheme calculates near-optimal scaling and biasing factors for each specific OFDM symbol according to the distribution of the signals, which strikes an attractive trade-off between the effective signal power and the clipping-distortion power. Our simulation results demonstrate that the proposed scheme significantly improves the performance without changing the LED's emitted power, while maintaining the same receiver structure.


Successful NBCA embolization of a T2 aneurysmal bone cyst.
Surgically accessible aneurysmal bone cysts (ABC) have traditionally been treated with curettage. Selective arterial embolization was initially proposed as a preoperative adjuvant to reduce peroperative bleeding. Currently, the role of embolization has been extended to the definitive treatment of aneurysmal bone cyst of the spine in children, as well as to other locations in the skeleton. The authors describe the technique in a 15-year-old girl with a T2 aneurysmal bone cyst. Digital subtraction angiography was performed for tumor vascular mapping, followed by selective arterial embolization with N-butyl 2 cyanoacrylate (NBCA). Because of persistent local pain, repeat embolization was done at 8 months. Pain relief and progressive ossification of the lesion were now observed. At 4-year follow-up, the patient was asymptomatic, with complete ossification of the lesion. Selective arterial embolization (SAE) is a minimally invasive, safe and effective procedure for the permanent occlusion of the pathological feeding vessels of spinal ABC. It should be considered as the treatment of choice for lesions difficult to access with surgery, especially in young patients. Careful pre-embolization vascular mapping of the lesion, operator's experience and use of NBCA are the keys to success.


The Regina Elena National Cancer Institute process of accreditation according to the standards of the Organisation of European Cancer Institutes.
The accreditation process is, on the one hand, a tool used to homogenize procedures, rendering comparable and standardized processes of care, and on the other, a methodology employed to develop a culture of quality improvement. Although not yet proven by evidence-based studies that health outcomes improve as a result of an accreditation to excellence, it is undeniable that better control of healthcare processes results in better quality and safety of diagnostic and therapeutic pathways. The Regina Elena National Cancer Institute underwent the accreditation process in accordance with the standards criteria set by the Organisation of European Cancer Institutes (OECI), and it has recently completed the process, acquiring its designation as a Comprehensive Cancer Center (CCC). This was an invaluable opportunity for the Regina Elena Institute to create a more cohesive environment, to widely establish a culture of quality, to implement an institutional information system, and to accelerate the process of patient involvement in strategic decisions. The steps of the process allowed us to evaluate the performance and the organization of the institute and put amendments in place designed to be adopted through 26 improvement actions. These actions regarded several aspects of the institute, including quality culture, information communication technology system, care, clinical trials unit, disease management team, nursing, and patient empowerment and involvement. Each area has a timeline. We chose to present the following 3 improvement actions: clinical trial center, computerized ambulatory medical record, and centrality of patient and humanization of clinical pathway.


Adaptive Genetic Robustness of Escherichia coli Metabolic Fluxes.
Genetic robustness refers to phenotypic invariance in the face of mutation and is a common characteristic of life, but its evolutionary origin is highly controversial. Genetic robustness could be an intrinsic property of biological systems, a result of direct natural selection, or a byproduct of selection for environmental robustness. To differentiate among these hypotheses, we analyze the metabolic network of Escherichia coli and comparable functional random networks. Treating the flux of each reaction as a trait and computationally predicting trait values upon mutations or environmental shifts, we discover that 1) genetic robustness is greater for the actual network than the random networks, 2) the genetic robustness of a trait increases with trait importance and this correlation is stronger in the actual network than in the random networks, and 3) the above result holds even after the control of environmental robustness. These findings demonstrate an adaptive origin of genetic robustness, consistent with the theoretical prediction that, under certain conditions, direct selection is sufficiently powerful to promote genetic robustness in cellular organisms.


Protein (multi-)location prediction: utilizing interdependencies via a generative model.
Proteins are responsible for a multitude of vital tasks in all living organisms. Given that a protein's function and role are strongly related to its subcellular location, protein location prediction is an important research area. While proteins move from one location to another and can localize to multiple locations, most existing location prediction systems assign only a single location per protein. A few recent systems attempt to predict multiple locations for proteins, however, their performance leaves much room for improvement. Moreover, such systems do not capture dependencies among locations and usually consider locations as independent. We hypothesize that a multi-location predictor that captures location inter-dependencies can improve location predictions for proteins. We introduce a probabilistic generative model for protein localization, and develop a system based on it-which we call MDLoc-that utilizes inter-dependencies among locations to predict multiple locations for proteins. The model captures location inter-dependencies using Bayesian networks and represents dependency between features and locations using a mixture model. We use iterative processes for learning model parameters and for estimating protein locations. We evaluate our classifier MDLoc, on a dataset of single- and multi-localized proteins derived from the DBMLoc dataset, which is the most comprehensive protein multi-localization dataset currently available. Our results, obtained by using MDLoc, significantly improve upon results obtained by an initial simpler classifier, as well as on results reported by other top systems. MDLoc is available at: http://www.eecis.udel.edu/∼compbio/mdloc.


Methods for using Bing's AI-powered search engine for data extraction for a systematic review.
Data extraction is a time-consuming and resource-intensive task in the systematic review process. Natural language processing (NLP) artificial intelligence (AI) techniques have the potential to automate data extraction saving time and resources, accelerating the review process, and enhancing the quality and reliability of extracted data. In this paper, we propose a method for using Bing AI and Microsoft Edge as a second reviewer to verify and enhance data items first extracted by a single human reviewer. We describe a worked example of the steps involved in instructing the Bing AI Chat tool to extract study characteristics as data items from a PDF document into a table so that they can be compared with data extracted manually. We show that this technique may provide an additional verification process for data extraction where there are limited resources available or for novice reviewers. However, it should not be seen as a replacement to already established and validated double independent data extraction methods without further evaluation and verification. Use of AI techniques for data extraction in systematic reviews should be transparently and accurately described in reports. Future research should focus on the accuracy, efficiency, completeness, and user experience of using Bing AI for data extraction compared with traditional methods using two or more reviewers independently.


Reducing the Global Burden of Alcohol-Associated Liver Disease: A Blueprint for Action.
Alcohol-associated liver disease (ALD) is a major driver of global liver related morbidity and mortality. There are 2.4 billion drinkers (950 million heavy drinkers) and the lifetime prevalence of any alcohol use disorder (AUD) is 5.1%-8.6%. In 2017, global prevalence of alcohol-associated compensated and decompensated cirrhosis was 23.6 million and 2.5 million, respectively. Combined, alcohol-associated cirrhosis and liver cancer account for 1% of all deaths worldwide with this burden expected to increase. Solutions for this growing epidemic must be multi-faceted and focused on both population and patient-level interventions. Reductions in ALD-related morbidity and mortality require solutions that focus on early identification and intervention, reducing alcohol consumption at the population level (taxation, reduced availability and restricted promotion), and solutions tailored to local socioeconomic realities (unrecorded alcohol consumption, focused youth education). Simple screening tools and algorithms can be applied at the population level to identify alcohol misuse, diagnose ALD using non-invasive serum and imaging markers, and risk-stratify higher-risk ALD/AUD patients. Novel methods of healthcare delivery and platforms are needed (telehealth, outreach, use of non-healthcare providers, partnerships between primary and specialty care/tertiary hospitals) to proactively mitigate the global burden of ALD. An integrated approach that combines medical and AUD treatment is needed at the individual level to have the highest impact. Future needs include (1) improving quality of ALD data and standardizing care, (2) supporting innovative healthcare delivery platforms that can treat both ALD and AUD, (3) stronger and concerted advocacy by professional hepatology organizations, and (4) advancing implementation of digital interventions.


En-face OCT and OCT angiography analysis of macular choroidal macrovessel.
To analyze en-face optical coherence tomography (OCT) and decorrelation signals on OCT angiography (OCTA) in two cases of macular choroidal macrovessel (MCM). Case report. Both the 64-year-old and 71-year-old females presented for a routine evaluation, and multimodal imaging analysis, including color fundus photography, indocyanine green angiography (ICG), spectral-domain optical coherence tomography (SD-OCT) and OCTA, was performed to diagnose a MCM. En-face OCT, en-face OCTA and decorrelation signals were analyzed through the MCM. In both reported cases, color fundus photograph revealed a serpiginoid lesion in the temporal macula. Red-free imaging enhanced the appearance of this lesion resembling a dilated choroidal vessel. Cross-sectional OCT showed an enlarged choroidal vessel causing elevation of the retinal pigment epithelium (RPE) within the fovea. En-face OCTA with segmentation below the choriocapillaris enhanced the MCM delineation. En-face OCT with segmentation below the choriocapillaris showed MCM with a greater distinctness than the en-face OCTA imaging. Decorrelation signals were not observed within MCM on cross-sectional OCTA. En-face OCT and decorrelation signals on OCTA may have diagnostic value in distinguishing macular choroidal macrovessel from other choroidal vascular diseases.


Mouse monoclonal antibodies to chicken VH idiotypic determinants reactivity with B and T cells.
We have prepared mouse monoclonal antibodies against idiotypic (Id) determinants on chicken antibodies to N-acetylglucosamine (NAGA) and p-aminobenzoic acid (PABA) made by inbred line EL 6(3) birds. The monoclonal anti-NAGA Id antibody, termed CId-1, reacted with affinity purified antibodies to NAGA, but not with antibodies specific for PABA, arsanilic acid (Ars), phosphorylcholine (PC), or with normal chicken IgG and IgM. The monoclonal anti-PABA ID antibody, termed CId-2, reacted with anti-PABA antibodies and to a lesser extent with anti-Ars antibodies, but not with anti-NAGA, anti-PC, and normal IgG and IgM. The Id determinants were found among antibodies to NAGA and PABA made by outbred and inbred lines of White Leghorn chickens. The binding of the CId-1 and CId-2 antibodies to intact homologous anti-NAGA and anti-PABA antibodies, respectively, was not hapten-inhibitable in either case. Both anti-Id antibodies reacted specifically with isolated homologous heavy chains, suggesting VH Id specificities. The monoclonal CId-1 and CId-2 antibodies were reactive by immunofluorescence with approximately 0.9 and 0.2%, respectively, of the circulating lymphocytes and with approximately 0.4 and 0.15 of plasma cells. CId-1+ and CId-2+ bursal cells were first detected on the 16th and 14th days of incubation, respectively; both reached maximal frequencies by the 17th day of incubation. The CId-2 antibody reacted exclusively with immunoglobulin-positive cells. The CId-1 antibody also reacted with a subpopulation (0.4%) of immunoglobulin-negative lymphocytes from normal and agammaglobulinemic chickens, and thus would appear to recognize an idiotypic determinant expressed by certain clones of B and T cells.


Study of cluster headache: A hospital-based study.
Cluster headache (CH) is uncommon and most painful of all primary headaches, and continues to be managed suboptimally because of wrong diagnosis. It needs to be diagnosed correctly and specifically treated. There are few studies and none from this region on CH. To study the detailed clinical profile of CH patients and to compare them among both the genders. Study was conducted at Mahatma Gandhi hospital, Jodhpur (from January 2011to December 2013). Study comprises 30 CH patients diagnosed according to International Headache Society guidelines (ICHD-II). Routine investigations and MRI brain was done in all patients. All measurements were reported as mean ± SD. Categorical variables were compared using the Chi-square test, and continuous variables were compared using Student's t-test. SPSS for Windows, Version 16.0, was used for statistical analyses with the significance level set at P = 0.05. M: F ratio was 9:1. Age at presentation was from 22-60 years (mean - 38 years). Latency before diagnosis was 3 months-12 years (mean - 3.5 years). All suffered from episodic CH and aura was found in none. Pain was strictly unilateral (right-19, left-11), predominantly over temporal region-18 (60%). Pain intensity was severe in 27 (90%) and moderate in 3 (10%). Pain quality was throbbing in 12 (40%). Peak intensity was reached in 5 minutes-30 minutes and attack duration varied from 30 minutes to 3 hours (mean - 2.45 hours). Among autonomic features, conjunctival injection-23 (76.6%) and lacrimation-25 (83.3%) were most common. Restlessness during episode was found in 80%. CH duration varied from 10 days to 12 weeks. Circadian periodicity for attacks was noted in 24 (80%). Results are consistent with other studies on many accounts, but is different from Western studies with respect to low frequency of family history, chronic CH, restlessness and aura preceeding the attack. Detailed elicitation of history is paramount as misdiagnosis is common.


Epitope analysis of the F4 (K88) fimbrial antigen complex of enterotoxigenic Escherichia coli by using monoclonal antibodies.
So far, three subtypes of the F4 (K88) fimbrial antigen of porcine enterotoxigenic Escherichia coli, F4ab, F4ac, and F4ad, have been distinguished by using polyclonal antisera in agglutination and precipitation tests. The a factor represents one or more common epitopes, whereas each of the b, c, and d factors represents one or more subtype-specific epitopes. We further characterized the F4 antigen complex by using a panel of 40 F4-specific monoclonal antibodies (MAbs). The specificity of all MAbs was proven by enzyme-linked immunosorbent assays, agglutination and radioimmunoprecipitation tests, and immunoelectron microscopy. The MAbs either reacted with all F4 subtypes, reacted with two subtypes, or were subtype specific. Epitope analysis by competition enzyme-linked immunosorbent assays revealed at least 11 epitope clusters on the F4 antigen complex, designated a1 to a7, b1, b2, c, and d. The following antigenic formulas were found for the F4 subtypes: F4ab, a1a2a3a4a5a6b1b2; F4ac, a1a2a3(a4)a5a6a7c; and F4ad, a1a2a3a4a7d. All MAbs were directed against conformational epitopes located on the 27,500-dalton major fimbrial subunits. Consequences for the replacement of polyclonal antisera by MAbs in diagnostic tests are discussed.


Functional salivary gland regeneration by transplantation of a bioengineered organ germ.
Salivary gland hypofunction, also known as xerostomia, occurs as a result of radiation therapy for head cancer, Sjögren's syndrome or aging, and can cause a variety of critical oral health issues, including dental decay, bacterial infection, mastication dysfunction, swallowing dysfunction and reduced quality of life. Here we demonstrate the full functional regeneration of a salivary gland that reproduces the morphogenesis induced by reciprocal epithelial and mesenchymal interactions through the orthotopic transplantation of a bioengineered salivary gland germ as a regenerative organ replacement therapy. The bioengineered germ develops into a mature gland through acinar formations with a myoepithelium and innervation. The bioengineered submandibular gland produces saliva in response to the administration of pilocarpine and gustatory stimulation by citrate, protects against oral bacterial infection and restores normal swallowing in a salivary gland-defective mouse model. This study thus provides a proof-of-concept for bioengineered salivary gland regeneration as a potential treatment of xerostomia.


Phosphate effects on cadmium(II) sorption to ferrihydrite.
Phosphate influences the sorption of metals to iron (hydr)oxides. An enhanced formation of inner-sphere complexes on the (hydr)oxide surface can be attributed to electrostatic interactions and/or to changes in metal coordination on the iron (hydr)oxide surface. Phosphate was expected to increase cadmium(II) sorption on ferrihydrite. It should be possible to identify changes in cadmium(II) coordination upon phosphate addition by Extended X-ray absorption fine structure (EXAFS) spectroscopy and implement the identified complexes in a surface complexation model (SCM). The effect of phosphate addition on cadmium(II) sorption to ferrihydrite was studied by a series of batch experiments covering the pH range from 4 to 8. EXAFS spectroscopy was performed on ferrihydrite from the batch experiments at the cadmium K edge. The identified surface complexes were incorporated in the Charge distribution multisite complexation (CD-MUSIC) model, and new surface complexation constants were optimized. Without phosphate addition cadmium(II) formed inner-sphere bidentate complexes on the ferrihydrite surface. With phosphate there was an increased cadmium(II) sorption that could not be explained by electrostatic interactions alone. The enhancement was best explained by the formation of a ternary complex including cadmium(II), phosphate and ferrihydrite surface groups.


[New classification and standards in treatment of migraine].
Diagnosis of migraine is performed according to the International Classification of Headache Disorders (ICHD). A current version is ICHD-2004 (2 ed.). A new addition of ICHD beta-version has been published in 2013. This article reviews the structure of the new classification and main criteria of different types of headache. Main treatment approaches and features of some drugs for treatment of headache and migraine are considered. Special attention is focused on xefocam, a nonsteroidal anti-inflammatory drug.


[Preperitoneal suprainguinal access with prosthesis of the anterior abdominal wall in treatment of complex forms of incarcerated inguinal hernias].
The article describes a non-typical access to treatment of gigantic incarcerated inguinal hernias. Preperitoneal suprainguinal access allows solution of the main task of operative aid in this pathology: inspection of the strangulated organs, safe dissection of the incarcerating ring and prosthesis of the anterior abdominal wall. This method in many aspects is comparable with traditional methods of hernioplasty, but the postoperative quality of life is much better.


Tibial Component Subsidence in a Total Ankle System Comparing Standard Technique Versus a Hybrid Technique.
Total ankle arthroplasty (TAA) is a viable treatment option for end-stage ankle arthritis. However, implant survivorship remains an important consideration. Concerns regarding early component loosening with the low-profile tibial tray utilized by fourth-generation TAA systems have been raised in the literature. We have previously described our preliminary outcomes of a hybrid technique combining a stemmed intramedullary tibial component with a chamfer-cut talar component for TAA. A retrospective study comparing short-term outcomes of the tibial component between a standard fourth-generation TAA system versus our hybrid technique was performed. 46 patients with a minimum of 1-year follow up were included in the analyses. There were 25 subjects in the standard implant cohort utilizing a low-profile tibial tray, and 21 subjects in the hybrid group utilizing a stemmed intramedullary tibial component. No statistically significant difference between the demographics of each group was found. The rate of tibial component subsidence was 8% (n = 2) in the standard implant group, and 0% (n = 0) in the hybrid group, though this did not meet statistical significance (p = .49). Mean time to subsidence was 6 months, and revision rate due to tibial component subsidence was 2.1% (n = 1). Periprosthetic lucency was present on most recent follow-up radiographs in 32% and 9.5% of ankles in the standard and hybrid groups, respectively (p = .08). Despite prior concerns for tibial component subsidence with the standard fourth-generation system, we demonstrated low rates in both implant groups. Additional studies are needed to further explore factors that may predispose patients to early tibial component subsidence and resulting implant failure.


Drug Resistance Pattern of M. tuberculosis Complex in Oromia Region of Ethiopia.
Multidrug resistant tuberculosis is an emerging problem in many parts of the world. The aim of this study was to determine the drug resistance pattern of Mycobacterium tuberculosis complex in Oromia Region of Ethiopia. A cross-sectional study was conducted from Jan 2017 to June 2018 on 450 pulmonary tuberculosis patients who visited health facilities in nine administrative zones of Oromia Region. Socio-demographic characteristics and relevant clinical information were obtained using a structured questionnaire. Line Probe Assay for first and second line drugs was used to assess the pattern of drug resistance. SPSS version 20 was used for statistical analysis. Median age was 26 years and 240 (53.3%) patients were males. About 24% of them were previously treated for tuberculosis. Thirty-four (7.6%) were HIV co-infected. Line Probe Assay interpretable results were obtained for 387 isolates. Thirty (7.8%) were resistant to rifampicin and isoniazid and thus were multidrug resistant isolates. Among the multidrug resistant samples, three were found to be extensively drug resistant and one was pre-extensively drug resistant. Previous treatment history (AOR 9.94 (95% CI 3.73-26.51), P < 0.001) and nutritional status below normal (AOR 3.15 (95% CI 1.13-8.81), P < 0.029) were found to be associated with multidrug resistance. The chi-square tests have shown that there was a significant difference between the BCG vaccinated and the non-vaccinated in developing multidrug resistant tuberculosis at P = 0.027. The proportion of multidrug resistance is above the WHO estimate for the country, Ethiopia, and the fact that some zones were at risk of transmission of extensively drug resistant tuberculosis warrant great attention of the control program holders even though it has to be verified through the conventional method.