Variation in expression of class 1 and class 5 outer membrane proteins during nasopharyngeal carriage of Neisseria meningitidis.
Accidental nasopharyngeal colonization of a laboratory worker by a human disease isolate of Neisseria meningitidis allowed us to examine the variation in expression of outer membrane components and the host humoral response over time. There were quantitative differences in class 1 outer membrane protein expression in nasopharyngeal isolates obtained at different times. Isolates also showed phase variation of all four class 5 outer membrane proteins produced by the colonizing strain. After colonization, we detected new host serum immunoglobulin G antibodies directed against class 1, class 5, and H.8 outer membrane proteins.


Measuring the Power of Food Marketing to Children: a Review of Recent Literature.
This scoping review examines literature from the past 5 years (June 2014 to June 2019) across three databases (PubMed, MEDLINE, and Scopus) to detail how the persuasive power of child-targeted food marketing content is addressed and evaluated in current research, to document trends and gaps in research, and to identify opportunities for future focus. Eighty relevant studies were identified, with varied approaches related to examining food marketing techniques to children (i.e., experimental, survey, meta-analyses, mixed methods, content analyses, focus groups). Few studies specifically defined power, and studies differed in terms of techniques examined. Spokes-characters were the predominant marketing technique measured; television was the platform most analyzed; and dominant messages focused on health/nutrition, taste appeals, and appeals to fun/pleasure. Mapping the current landscape when it comes to the power of food marketing to children reveals concrete details about particular platforms, methods, and strategies, as well as opportunities for future research-particularly with respect to definitions and techniques monitored, digital platforms, qualitative research, and tracking changes in targeted marketing techniques over time.


Role of central glucagon-like peptide-1 in stress regulation.
Glucagon-like peptide 1 (GLP-1) is best known as an incretin hormone, secreted from L cells in the intestine in response to nutrient ingestion to stimulate glucose-dependent insulin secretion. However, GLP-1 is also expressed in neurons, and plays a major role in regulation of homeostatic function within the central nervous system (CNS). This review summarizes our current state of knowledge on the role GLP-1 plays in neural coordination of the organismal stress response. In the brain, the primary locus of GLP-1 production is in the caudal nucleus of the solitary tract (NTS) and the ventrolateral medulla of the hindbrain. GLP-1 immunoreactive fibers directly innervate hypophysiotrophic corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), placing GLP-1 in prime position to integrate hypothalamo-pituitary-adrenocortical responses. Exogenous central GLP-1 activates HPA axis stress responses, and responses to a variety of stressors can be blocked by a GLP-1 receptor (GLP-1R) antagonist, confirming an excitatory role in glucocorticoid secretion. In addition, central infusion of GLP-1R agonist increases heart rate and blood pressure, and activates hypothalamic and brainstem neurons innervating sympathetic preganglionic neurons, suggesting a sympathoexcitatory role of GLP-1 in the CNS. Bioavailability of preproglucagon (PPG) mRNA and GLP-1 peptide is reduced by exogenous or endogenous glucocorticoid secretion, perhaps as a mechanism to reduce GLP-1-mediated stress excitation. Altogether, the data suggest that GLP-1 plays a key role in activation of stress responses, which may be connected with its role in central regulation of energy homeostasis.


A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions.
Proteolysis targeting chimera (PROTAC) is one of the most frequently used technologies for targeted protein degradation. PROTACs are composed of target protein ligand, E3 ligase ligand and a linker between them. Traditional methods for the development of PROTACs involve step-by-step synthesis and are time consuming. Herein, we report a platform for the rapid synthesis of PROTACs (Rapid-TAC) via a traceless coupling reaction between ortho-phthalaldehyde (OPA) motif on the ligand of targeting protein and an amine fucntional group on the commercially available partial PROTAC library that is composed of different E3 ligase ligands and various types and lengths of linkers. Under our optimized miniaturized conditions, the full PROTACs can be synthesized in a high throughput manner and the products can be directly used for screening without any further manipulations including purification. We demonstrated the utility of this platform by quickly identifying active degraders for androgen receptor (AR) and BRD4 with DC50 of 41.9 nM and 8.9 nM, respectively. It is expected that this Rapid-TAC platform can be easily extended to many other targets, thus lowering the barrier to access this novel modelity for small molecule drug discovery and faciliate structure activity relationship studies.


Multimorbidity: a challenge and opportunity for the dental profession.
Multimorbidity (the coexistence of two or more chronic conditions) is common, is likely to be on the increase and has a major impact on quality of life, increased risk of mortality, and significant financial costs to the health and social care system. Multimorbidity is strongly associated with increasing age and is also directly linked to socioeconomic status. A substantial body of scientific evidence has shown an association between specific oral diseases and a range of other health conditions. Less is known, however, about the inter-relationships between oral diseases and multiple other health conditions. As multimorbidity is increasingly becoming the norm, rather than the exception, a profound shift is now needed in the training of oral health professionals, and the practice and delivery of dental care. A more integrated and coordinated approach to training and care is needed, which will require radical system-level reform and redesign of how health and dental services are commissioned, delivered and financed. Truly multidisciplinary teamwork requires system reform to facilitate effective joint working. The pattern of disease in society is changing and the dental profession needs to respond accordingly.


Effects of organic solvents on erythrocyte membrane acetylcholine esterase activity.
In the present study, the effects of several organic solvents on human erythrocyte membrane acetylcholine esterase activity were tested in vitro with the Ellman method. All the organic solvents studied decreased the enzyme activity. The effects of aromatic hydrocarbons were greater than the effects of chlorinated aliphatic hydrocarbons. The effect on membrane ACh-esterase was greater at low temperatures, when tested with toluene (300 ppm) and using incubation temperatures of +5 degrees, +15 degrees, +25 degrees and +37 degrees. The erythrocyte membrane was considered a suitable model for studying the membrane effects of organic solvents. The membrane effects may be associated with the narcotic potency of organic solvents.


Diagnostic stability four years after a first episode of psychosis.
The objective of this study was to determine the stability of a diagnosis of psychosis four years after the first-episode diagnosis. The study was a prospective four-year follow-up study (1995 to 1999) of 147 patients with schizophrenia, affective disorder, and other psychoses who presented with a first episode of psychosis in an epidemiologic catchment area in Ireland. All diagnoses were made on the basis of the Structured Clinical Interview for DSM-IV. One quarter of the patients evidenced a change in diagnosis at follow-up. The most common change was to a diagnosis of schizophrenia. The positive predictive values of schizophrenia and bipolar affective disorder were 97 percent and 80 percent, respectively. Fewer years spent in education, lower levels of initial psychopathology, and presence of comorbid alcohol or substance abuse were associated with change in diagnosis at follow-up. Among the diagnoses studied, schizophrenia was the most stable diagnosis after four years. The greatest instability occurred in the categories of drug-induced psychosis and psychosis not otherwise specified.


County-level social vulnerability and nonfatal drug overdose emergency department visits and hospitalizations, January 2018-December 2020.
Nonfatal drug overdoses (NFODs) are often attributed to individual behaviors and risk factors; however, identifying community-level social determinants of health (SDOH) associated with increased NFOD rates may allow public health and clinical providers to develop more targeted interventions to address substance use and overdose health disparities. CDC's Social Vulnerability Index (SVI), which aggregates social vulnerability data from the American Community Survey to produce ranked county-level vulnerability scores, can help identify community factors associated with NFOD rates. This study aims to describe associations between county-level social vulnerability, urbanicity, and NFOD rates. We analyzed county-level 2018-2020 emergency department (ED) and hospitalization discharge data submitted to CDC's Drug Overdose Surveillance and Epidemiology system. Counties were ranked in vulnerability quartiles based on SVI data. We used crude and adjusted negative binomial regression models, by drug category, to calculate rate ratios and 95% confidence intervals comparing NFOD rates by vulnerability. Generally, as social vulnerability scores increased, ED and hospitalization NFOD rates increased; however, the magnitude of the association varied across drugs, visit type, and urbanicity. SVI-related theme and individual variable analyses highlighted specific community characteristics associated with NFOD rates. The SVI can help identify associations between social vulnerabilities and NFOD rates. Development of an overdose-specific validated index could improve translation of findings to public health action. The development and implementation of overdose prevention strategies should consider a socioecological perspective and address health inequities and structural barriers associated with increased risk of NFODs at all levels of the social ecology.


Genotoxicity profile of erinacine A-enriched Hericium erinaceus mycelium.
Hericium erinaceus (H. erinaceus) has a long history of usage in traditional Chinese medicine for the treatment of gastric disorders. Recently, it has become a well-established candidate in causing positive brain and nerve health-related activities by inducing nerve growth factor (NGF) from its bioactive ingredient, erinacine A. This active compound, which exists only in fermented mycelium but not in its fruiting body, increases NGF levels in astroglial cells in vitro as well as catecholamine and NGF levels in vivo. With increasing recognition of erinacine A in H. erinaceus (EAHE) mycelium improving neurodegenerative diseases, numerous products are being marketed based on these functional claims. To our knowledge, there have been no reports on the mutagenicity of EAHE prior to this paper. Hence, the present study was undertaken to determine the mutagenicity and genotoxicity effects of EAHE mycelium conducted in three standard battery of tests (reverse mutation, chromosomal aberration, and micronuclei tests) according to the latest guidelines in order to meet all international regulatory requirements and provide information on the safety of this new and promising natural remedy. Our results have indicated that EAHE mycelium did not significantly increase the number of revertant colonies in the bacterial reverse mutation test nor induce higher frequency of aberrations in the chromosome aberration test. Moreover, no statistically significant EAHE mycelium-related increase was observed in the incidence of reticulocytes per 1000 red blood cells and micronucleated reticulocytes per 1000 reticulocytes. In conclusion, the three standard battery of tests suggested that EAHE mycelium was devoid of mutagenicity and genotoxicity in the tested doses and experimental conditions.


Reliability and reproducibility of the larval paralysis test as an in vitro method for the detection of anthelmintic resistance of nematodes against levamisole and morantel tartrate.
In order to study the reliability of the larval paralysis test as an in vitro assay for the detection of resistance of nematodes to levamisole and morantel tartrate, the influence of different parameters was evaluated using resistant and susceptible Ostertagia ostertagi strains. The operator, the sample (10% of the larvae present in the suspension), the incubation time (24, 48 or 72 h), the incubation temperature (20 or 25 degrees C) and the observation period of the larvae (5 or 15 s) had no statistically significant influence on the test results. Statistical differences were obtained only when L3 larvae of different ages (1 or 2 months) were used. Reversibility of the paralysis did not occur when concentrations of levamisole of less than or equal to 200 micrograms ml-1 or morantel tartrate of less than 2000 micrograms ml-1 were used. The reproducibility of the test was fairly good, with a mean standard deviation of 21.3% for the LC50 values. Morantel resistance in a strain of O. ostertagi was not confirmed as such by the larval paralysis test. The resistance factor was less than or equal to 1, in spite of an efficacy of morantel of 77.4% as shown in vivo.


Stability of intraoral vertical ramus osteotomies for mandibular setback: a longitudinal study.
This study aimed to investigate the postoperative longitudinal skeletal changes and stability following intraoral vertical ramus osteotomies (IVRO) for orthognathic mandibular setback, and the possible risk factors that might affect the stability. A retrospective cohort study was conducted. Lateral cephalograms were analyzed for the predictor (magnitude of setback and adjunctive procedures) and outcome (stability of vertical and horizontal dimensions) variables at six time points. A total of 152 patients (mean age 24.2 years) were included in the study. Following IVRO, the mandible measured at B-point had moved a mean 0.50mm posteriorly at 1 week after the removal of intermaxillary fixation (7 weeks postoperative); this was followed by progressive small anterior relapse. At 2 years postoperative, the mean relapse of the mandible after IVRO measured at B-point was 0.05mm (standard deviation 1.14mm), representing 0.7% of the mean surgical movement. Large setback (>8mm) showed significantly higher relapse compared to small setback (<4mm) at 2 years after surgery (P=0.021). Patients who underwent adjunctive mandibular surgeries other than IVRO showed no significant differences in relapse compared to those who underwent IVRO alone. In conclusion, IVRO for mandibular setback is a stable procedure in the long term, with small relapse of 0.05mm after 2 years.


Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology.
Familial Alzheimer's disease (FAD) is a complex neurodegenerative disorder for which there are no therapeutics to date. Several mutations in presenilin 1 (PSEN 1), which is the catalytic component of γ-secretase complex, are causal of FAD. Recently, the p.Ile416Thr (I416T) PSEN 1 mutation has been reported in large kindred in Colombia. However, cell and molecular information from I416T mutation is scarce. Here, we demonstrate that menstrual stromal cells (MenSCs)-derived planar (2D) PSEN 1 I416T cholinergic-like cells (ChLNS) and (3D) cerebral spheroids (CSs) reproduce the typical neuropathological markers of FAD in 4 post-transdifferentiating or 11 days of transdifferentiating, respectively. The models produce intracellular aggregation of APPβ fragments (at day 4 and 11) and phosphorylated protein TAU at residue Ser202/Thr205 (at day 11) suggesting that iAPPβ fragments precede p-TAU. Mutant ChLNs and CSs displayed DJ-1 Cys106-SO3 (sulfonic acid), failure of mitochondria membrane potential (ΔΨm), and activation of transcription factor c-JUN and p53, expression of pro-apoptotic protein PUMA, and activation of executer protein caspase 3 (CASP3), all markers of cell death by apoptosis. Moreover, we found that both mutant ChLNs and CSs produced high amounts of extracellular eAβ42. The I416T ChLNs and CSs were irresponsive to acetylcholine induced Ca2+ influx compared to WT. The I416T PSEN 1 mutation might work as dominant-negative PSEN1 mutation. These findings might help to understanding the recurring failures of clinical trials of anti-eAβ42, and support the view that FAD is triggered by the accumulation of other intracellular AβPP metabolites, rather than eAβ42.


How dental team members describe adverse events.
Although some patients experience adverse events (AEs) resulting in harm caused by treatments in dentistry, few published reports have detailed how dental providers describe these events. Understanding how dental treatment professionals view AEs is essential to building a safer environment in dental practice. The authors interviewed dental professionals and domain experts through focus groups and in-depth interviews and asked them to identify the types of AEs that may occur in dental settings. The initial interview and focus group findings yielded 1,514 items that included both causes and AEs. In total, 632 causes were coded into 1 of the 8 categories of the Eindhoven classification, and 882 AEs were coded into 12 categories of a newly developed dental AE classification. Interrater reliability was moderate among coders. The list was reanalyzed, and duplicate items were removed leaving a total of 747 unique AEs and 540 causes. The most frequently identified AE types were "aspiration and ingestion" at 14% (n = 142), "wrong-site, wrong-procedure, wrong-patient errors" at 13%, "hard-tissue damage" at 13%, and "soft-tissue damage" at 12%. Dental providers identified a large and diverse list of AEs. These events ranged from "death due to cardiac arrest" to "jaw fatigue from lengthy procedures." Identifying threats to patient safety is a key element of improving dental patient safety. An inventory of dental AEs underpins efforts to track, prevent, and mitigate these events.


Proteins wriggle.
We propose an algorithmic strategy for improving the efficiency of Monte Carlo searches for the low-energy states of proteins. Our strategy is motivated by a model of how proteins alter their shapes. In our model, when proteins fold under physiological conditions, their backbone dihedral angles change synchronously in groups of four or more to avoid steric clashes and respect the kinematic conservation laws. They wriggle; they do not thrash. We describe a simple algorithm that can be used to incorporate wriggling in Monte Carlo simulations of protein folding. We have tested this wriggling algorithm against a code in which the dihedral angles are varied independently (thrashing). Our standard of success is the average root-mean-square distance (rmsd) between the alpha-carbons of the folding protein and those of its native structure. After 100,000 Monte Carlo sweeps, the relative decrease in the mean rmsd, as one switches from thrashing to wriggling, rises from 11% for the protein 3LZM with 164 amino acids (aa) to 40% for the protein 1A1S with 313 aa and 47% for the protein 16PK with 415 aa. These results suggest that wriggling is useful and that its utility increases with the size of the protein. One may implement wriggling on a parallel computer or a computer farm.


Effect of Virtual Reality Therapy on Balance and Walking in Children with Cerebral Palsy: A Systematic Review.
Aim: To investigate the effect of Virtual Reality Therapy (VRT) on balance and walking in children with cerebral palsy (CP). Method: A systematic search in Pubmed and Embase was performed until the 9th of July 2019. Articles were included if the population consisted of children with CP and data on balance and/or walking were reported. Results were pooled in two meta-analyses. Results: 26 articles were included. For 'balance' 5 and for 'walking' 4 were used for the meta-analyses. The meta-analyses showed a significant result in favor of VRT for balance, SMD 0.89 [95% CI, SD 0.14, 1.63] and for walking, SMD 3.10 [95% Cl, SD 0.78, 5.35]. Interpretation: VRT seems a promising intervention for rehabilitation in children with CP. The meta-analysis confirmed this positive effect. These results must be interpreted with caution due to differences in the interventions used, the lack of randomized-controlled trials, and the relatively small groups.


Sex- and age-based differences in the effect of central serotonin on arterial blood pressure regulation.
Medullary serotonin (5-hydroxytryptamine; 5-HT) neurons project to multiple autonomic nuclei in the central nervous system (CNS). Infant rats lacking 5-HT have low arterial blood pressure (ABP) in quiet sleep, but the role of 5-HT in ABP regulation across vigilance states in adults has not been studied. We hypothesized that in adults, CNS 5-HT deficiency leads to hypotension mainly in quiet wakefulness (QW) and non-rapid eye movement (NREM) sleep, when 5-HT neurons are active. We tested male and female tryptophan hydroxylase 2 knockout rats (TPH2-/-), specifically deficient in CNS 5-HT, and wild-type (TPH2+/+) controls at 2-3, 5-8, and 12-13 mo of age. Compared with TPH2+/+, mean arterial pressure of 5-8- and 12-13-mo-old (middle-aged) male TPH2-/- rats was significantly elevated (∼10 mmHg) in QW and rapid eye movement (REM) sleep. Middle-aged male TPH2-/- rats also had more frequent extreme hypertensive events during prolonged episodes of REM sleep. Female TPH2-/- had normal ABP. The low- and very-low-frequency components of systolic ABP variability were significantly higher in middle-aged male, but not female, TPH2-/- rats compared with in TPH2+/+ rats, suggesting elevated sympathetic vascular tone in male TPH2-/- rats. However, the hypertension of male TPH2-/- rats was not ameliorated by ganglionic blockade. Hearts and lungs of middle-aged male TPH2-/- rats were significantly heavier than those of TPH2+/+ rats. We show that a loss of CNS 5-HT leads to high ABP only in middle-aged males during wakefulness and REM sleep, possibly due to increased vascular tone. It should be investigated whether elevated ventricular afterload associated with CNS 5-HT deficiency initiates cardiac remodeling or alters pulmonary hemodynamics.NEW & NOTEWORTHY The role of serotonin in arterial blood pressure (ABP) regulation across states of vigilance is unknown. We hypothesized that adult rats devoid of CNS serotonin (TPH2-/-) have low ABP in wakefulness and NREM sleep, when serotonin neurons are active. However, TPH2-/- rats experience higher ABP than TPH2+/+ rats in wakefulness and REM only, a phenotype present only in older males and not females. CNS serotonin may be critical for preventing high ABP in males with aging.


Improvement of graft prognosis in penetrating normal-risk keratoplasty by HLA class I and II matching.
Owing to contradictory results, HLA matching in penetrating keratoplasty still is equivocal. Different surgical techniques in multicentre studies, missing risk differentiation in high-risk situations, and faulty HLA typing can be identified as main reasons for these contradictory results. In this monocentre study, the value of HLA class I and II matching (A, B, DR loci) was examined in a homogeneous group of 418 normal-risk keratoplasty patients using serological typing techniques for HLA class I and immunogenetic typing techniques for class II. Penetrating normal-risk keratoplasty was performed in two groups of patients (group I with 0-2, group II with 3-6 mismatches in the A/B/DR loci). All surgery was carried out by three experienced surgeons according to a standardized scheme. Furthermore, postoperative therapy and controls were standardized. There were no statistically significant differences between the two study groups with regard to the number of ABO or H-Y compatibilities, patient age, patient gender, ratio of previous intraocular surgery, ratio of triple procedures, indication for surgery, follow-up period, donor age, donor gender, post-mortem time of the graft, and endothelial cell density of the graft at the end of organ culture. All HLA typing was performed in a quality-controlled laboratory, serologically for HLA class I (A and B loci) and immunogenetically for HLA class II (DR locus). At 4 years postoperatively, the ratio of clear and rejection-free graft survival was 92% in group I and 66% in group II (Kaplan-Meier estimation, log rank test, P=0.03). Monovariate analysis in the Cox model gave no influence of solitary HLA class I or II matching, but only an influence of combined HLA class I and II matching (P=0.03). In this monocentre study with proper typing techniques, the beneficial effect of HLA class I plus II matching on clear and rejection-free graft survival could be demonstrated in a homogeneous group of normal-risk keratoplasty patients.


Ultrasound findings of incidental adnexal and ovarian lesions on emergency CT scans.
A search through 6076 nontraumatic emergency computed tomography (CT) scans of female patients yielded 266 (4.4%) CT scans with an incidentally detected adnexal lesion and ultrasound follow-up within 7days. The population was 87% premenopausal and 13% postmenopausal. Follow-up ultrasound yielded an ultrasound diagnosis 32% of the time. Potentially serious diagnoses included pelvic infection (3%) and suspected malignancy (2%). Benign diagnoses included normal ovaries (16%), hemorrhagic cyst (6%), and benign cyst (5%). The remaining 68% of cases were equivocal, requiring further evaluation.


hTERT expression in colorectal adenocarcinoma: correlations with p21, p53 expressions and clinicopathological features.
The clinicopathological roles and relationships of hTERT, p21 and p53 proteins have not been studied in depth in colorectal cancer. The aim of the present study is to investigate the clinicopathological roles of expression of hTERT protein expression and its relationship with the expression of p21 and p53 proteins in a large cohort of patients with colorectal adenocarcinoma. Expressions of hTERT, p21 and p53 proteins were investigated in 188 patients with colorectal adenocarcinomas by immunohistochemistry. The findings were correlated with the clinicopathological features and survival data of colorectal adenocarcinomas. hTERT, p53 and p21 proteins were detected in 63%, 100% and 62% of the patients with colorectal carcinoma. High level of hTERT protein expression was noted in patients with metastases (p = 0.038) and in patients with rectal cancer (p = 0.046). Loss or low level of p21 protein was often noted in non-mucinous colorectal adenocarcinoma when compared with mucinous adenocarcinoma (p = 0.001). Furthermore, p53 expression was more frequently noted in non-mucinous adenocarcinoma (p = 0.001). The level of expression of p21 protein was positively correlated with expression of level of hTERT protein (p = 0.00001). The survival of the patients was related to staging (p = 0.001) and p53 protein expression (p = 0.038) of the tumours. hTERT protein expression is an indicator of the biological aggressiveness of the cancer. The level of expression of the protein was also related to the distal location and level of p21 expression of the tumours.


B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response.
To assess the relationships between serum B lymphocyte stimulator (BLyS) levels, autoantibody profile and clinical response in patients with systemic lupus erythematosus (SLE) following rituximab-based B cell depletion therapy (BCDT). A total of 25 patients with active refractory SLE were followed for >or=1 year following BCDT. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) system, and serum levels of BLyS and autoantibodies to dsDNA and extractable nuclear antigens (ENA) measured by ELISA. Serum immunoglobulins and anti-dsDNA antibodies were assessed for expression of the 9G4 idiotope (indicating VH4-34 germline gene origin). Following BCDT, all patients depleted in the peripheral blood and improved clinically for >or=3 months. Pre-BCDT BLyS levels were quantifiable (median 1.9 ng/ml) in 18/25 patients and rose in most patients at 3 months post-BCDT (median 4.15 ng/ml). Nine patients, all with quantifiable pre-BCDT serum BLyS, experienced a disease flare within 1 year. This group of patients was more likely to harbour anti-Ro/SSA antibodies (odds ratio 1.76; p = 0.06) with higher serum levels (p = 0.0027; Mann-Whitney U test). Serum levels of anti-ribonucleoprotein (RNP)/Sm were also higher in this group (p<0.05). Expression of VH4-34 by serum immunoglobulins and anti-dsDNA antibodies had no predictive value for the length of clinical response. Patients with SLE with an expanded autoantibody profile and raised BLyS levels at baseline had shorter clinical responses to BCDT. This may reflect a greater propensity to, and degree of, epitope spreading in such patients and suggests that treatment regimens beyond BCDT may be necessary to induce long-lasting clinical remissions in these individuals.


Drastic transitions of excited state and coupling regime in all-inorganic perovskite microcavities characterized by exciton/plasmon hybrid natures.
Lead-halide perovskites are highly promising for various optoelectronic applications, including laser devices. However, fundamental photophysics explaining the coherent-light emission from this material system is so intricate and often the subject of debate. Here, we systematically investigate photoluminescence properties of all-inorganic perovskite microcavity at room temperature and discuss the excited state and the light-matter coupling regime depending on excitation density. Angle-resolved photoluminescence clearly exhibits that the microcavity system shows a transition from weak coupling regime to strong coupling regime, revealing the increase in correlated electron-hole pairs. With pumping fluence above the threshold, the photoluminescence signal shows a lasing behavior with bosonic condensation characteristics, accompanied by long-range phase coherence. The excitation density required for the lasing behavior, however, is found to exceed the Mott density, excluding the exciton as the excited state. These results demonstrate that the polaritonic Bardeen-Cooper-Schrieffer state originates the strong coupling formation and the lasing behavior.


Analysis of dosimetric parameters associated with acute gastrointestinal toxicity and upper gastrointestinal bleeding in locally advanced pancreatic cancer patients treated with gemcitabine-based concurrent chemoradiotherapy.
To identify the dosimetric parameters associated with gastrointestinal (GI) toxicity in patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based chemoradiotherapy. The data from 40 patients were analyzed retrospectively. Chemoradiotherapy consisted of conventional fractionated three-dimensional radiotherapy and weekly gemcitabine. Treatment-related acute GI toxicity and upper GI bleeding (UGB) were graded according to the Common Toxicity Criteria Adverse Events, version 4.0. The dosimetric parameters (mean dose, maximal absolute dose which covers 2 cm(3) of the organ, and absolute volume receiving 10-50 Gy [V(10-50)]) of the stomach, duodenum, small intestine, and a composite structure of the stomach and duodenum (StoDuo) were obtained. The planning target volume was also obtained. Univariate analyses were performed to identify the predictive factors for the risk of grade 2 or greater acute GI toxicity and grade 3 or greater UGB, respectively. The median follow-up period was 15.7 months (range, 4-37). The actual incidence of acute GI toxicity was 33%. The estimated incidence of UGB at 1 year was 20%. Regarding acute GI toxicity, a V(50) of ≥ 16 cm(3) of the stomach was the best predictor, and the actual incidence in patients with V(50) <16 cm(3) of the stomach vs. those with V(50) of ≥ 16 cm(3) was 9% vs. 61%, respectively (p = 0.001). Regarding UGB, V(50) of ≥ 33 cm(3) of the StoDuo was the best predictor, and the estimated incidence at 1 year in patients with V(50) <33 cm(3) of the StoDuo vs. those with V(50) ≥ 33 cm(3) was 0% vs. 44%, respectively (p = 0.002). The dosimetric parameters correlated highly with one another. The irradiated absolute volume of the stomach and duodenum are important for the risk of acute GI toxicity and UGB. These results could be helpful in escalating the radiation doses using novel techniques, such as intensity-modulated radiotherapy, for the treatment of pancreatic cancer.


Lack of correlation between spontaneous fasciculations and double discharges of voluntarily activated motor units.
We have studied the possible correlation between spontaneous fasciculations and double discharges or voluntarily activated motor units in myelopathies and other proximal neuropathies. Though both these phenomena are common in these diseases, they seem to have no correlation in individual muscles. It is concluded that spontaneous fasciculations and doubling of voluntarily activated motor unit potentials have different sites of origin or different mechanism. For example, if doubling reflects a disturbance of firing in the axon hillock, spontaneous fasciculations may originate in a more peripheral part of the motor axon.


The impact of skeletal muscle depletion on older adult patients with head and neck cancer undergoing primary surgery.
Sarcopenia may result in negative outcomes in patients with cancer, but its impact on surgical and oncological outcomes in older adult patients with head and neck squamous cell carcinoma (HNSCC) has not been systematically studied. This study evaluated the clinical impact of sarcopenia on postsurgical and oncological outcomes in older adult patients with HNSCC. This is a prospective study of 190 consecutive HNSCC patients aged ≥65 years who underwent curative surgery at a tertiary referral hospital. Sarcopenia was determined from measurement of the cross-sectional area of skeletal muscles at the level of the third lumbar vertebra on pretreatment images of whole body 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Primary outcomes were early complications and overall survival. Factors of early complications and readmission were identified using binary logistic regression analyses, and factors of overall survival and disease-free survival were identified using univariate and multivariate Cox proportional hazards regression analyses. Pretreatment sarcopenia were found in 64 (33.7%) patients. In multivariate analysis, sarcopenia and N classification were significantly associated with early complications, while sarcopenia and T classification were associated with readmission. Independent factors of overall survival outcomes were age, sarcopenia, and extranodal extension (all P < .005). Sarcopenia was also an independent factor predictive of disease-free survival outcome (P < .001). Sarcopenia was associated with a 3.2-fold increase in the early complication rate and 4.5-fold increase in mortality in older adult surgical patients with HNSCC. Sarcopenia may predict early complications and survival after curative surgery in older adult patients with HNSCC.


Changes in IgE binding capacity, structure, physicochemical properties of peanuts through fermentation with Bacillus natto and Lactobacillus plantarum along with autoclave pretreatment.
This study investigated the immunoglobulin E (IgE) binding capacity, structure, and physicochemical properties of raw crushed peanut (RCP) after fermentation with Lactobacillus plantarum and Bacillus natto along with autoclaved pretreatment. SDS-PAGE showed the disappearance of partial protein (>45 kDa) in autoclaved peanuts (ACP) and fermented autoclaved peanuts with L. plantarum (LP), and of majority protein (>14.4 kDa) in fermented autoclaved peanuts with B. natto (BN) or a mixture of L. plantarum and B. natto (LPBN). Structural analysis revealed protein-aggregation and protein-unfolding in autoclaved and fermented peanuts, respectively. Indirect ELISA demonstrated that the IgE binding capacities in ACP, LP, BN and LPBN were reduced by 11.3%, 20.6%, 78.7% and 90.2%, respectively, compared to RCP. LPBN showed the lowest IgE binding capacity due to the highest masking and destruction of epitopes and exhibited the desirable physicochemical properties simultaneously. Mixed strain fermentation has the potential to produce hypoallergenic peanut products.


Virus-associated neuroendocrine cancers: Pathogenesis and current therapeutics.
Neuroendocrine neoplasms (NENs) comprise malignancies involving neuroendocrine cells that often lead to fatal pathological conditions. Despite escalating global incidences, NENs still have poor prognoses. Interestingly, research indicates an intricate association of tumor viruses with NENs. However, there is a dearth of comprehension of the complete scenario of NEN pathophysiology and its precise connections with the tumor viruses. Interestingly, several cutting-edge experiments became helpful for further screening of NET for the presence of polyomavirus, Human papillomavirus (HPV), Kaposi sarcoma-associated herpesvirus (KSHV), Epstein Barr virus (EBV), etc. Current research on the neuroendocrine tumor (NET) pathogenesis provides new information concerning their molecular mechanisms and therapeutic interventions. Of note, scientists observed that metastatic neuroendocrine tumors still have a poor prognosis with a palliative situation. Different oncolytic vector has already demonstrated excellent efficacies in clinical studies. Therefore, oncolytic virotherapy or virus-based immunotherapy could be an emerging and novel therapeutic intervention. In-depth understanding of all such various aspects will aid in managing, developing early detection assays, and establishing targeted therapeutic interventions for NENs concerning tumor viruses. Hence, this review takes a novel approach to discuss the dual role of tumor viruses in association with NENs' pathophysiology as well as its potential therapeutic interventions.


Expression of rRNA and tRNA genes in Escherichia coli: evidence for feedback regulation by products of rRNA operons.
We have tested a model for global ribosome biosynthesis by examining the effects of increased gene dosage on the synthesis of rRNA. Increasing gene dosage does not lead to a significant increase in total rRNA transcription; i.e., rRNA synthesis from individual rRNA operons is reduced to keep total rRNA production unchanged. In contrast, when the plasmid-encoded rRNA operons used to increase gene dosage contain deletions within the rRNA coding region, rRNA transcription is gene-dosage-dependent; i.e., rRNA regulation is relieved. We find that the syntheses of most, if not all, tRNAs are also subject to the same controls as rRNA transcription. We conclude that the production of functional rRNA is monitored by the regulatory system that controls rRNA and tRNA transcription. We propose that rRNA and tRNA are negatively controlled by products of rRNA operons and discuss evidence suggesting that ribosomes are the key element involved in the postulated feedback regulation.


Long-term radiological findings following reconstruction of the condyle with fibular free flaps.
Fibular bone grafts are considered as one of the best choices for reconstruction of the condyle. However, little data are available on bone remodelling after such reconstruction. The purpose of this study was to evaluate the long-term radiological outcome. Eleven patients underwent condylar reconstruction with a free fibular transplant. In all cases the end of the fibular graft was placed into the glenoid fossa under the intact temporomandibular joint (TMJ) disc. Evaluation consisted of digital width and length measurement of the end of the fibula on panorex studies. Remodelling of the end of the neocondyle was found and consisted of rounding off and narrowing of the end of the transplant. The most likely explanation for these changes is the fact that the TMJ disc was preserved.


Covalent immobilization of tobacco-etch-virus NIa protease: a useful tool for cleavage of the histidine tag of recombinant proteins.
Addition of tags [such as His (histidine) tags] is extremely helpful for the affinity purification of recombinant proteins. In several cases, these tags must be removed before performing functional and structural studies. The enzyme most frequently used to cleave tags of recombinant proteins is the TEV-protease (tobacco-etch-virus NIa protease). The continuous production of this enzyme in soluble form is quite an expensive process and not easily accessible to many laboratories. Thus an interesting alternative is the use of TEV-protease in an immobilized form, which may be reutilized several times. The main objective of the present study was to obtain a TEV-protease in an immobilized form, by covalent immobilization on to solid supports through selective use of different amino acid residues, lysine or cysteine. High protein immobilization yields (75-97%) were obtained with both strategies. The TEV-protease immobilized through its exposed cysteine thiol groups maintained its ability for cleaving a 20 kDa substrate. While the activity of the immobilized TEV-protease maintained only 30% of the activity of the enzyme in soluble form, its stability at 4 degrees C was improved three times. Moreover, this enzyme could be reutilized in at least five cycles of cleavage without loss of performance. The present results indicate that the use of a TEV-protease in an immobilized form is a potentially useful tool for the cleavage of His tags of recombinant proteins and may be useful for reducing the cost of the total process of cleavage.


Cleaning out the Litterbox of Proteomic Scientists' Favorite Pet: Optimized Data Analysis Avoiding Trypsin Artifacts.
Chemically modified trypsin is a standard reagent in proteomics experiments but is usually not considered in database searches. Modification of trypsin is supposed to protect the protease against autolysis and the resulting loss of activity. Here, we show that modified trypsin is still subject to self-digestion, and, as a result, modified trypsin-derived peptides are present in standard digests. We depict that these peptides commonly lead to false-positive assignments even if native trypsin is considered in the database. Moreover, we present an easily implementable method to include modified trypsin in the database search with a minimal increase in search time and search space while efficiently avoiding these false-positive hits.


Giant cell hepatitis in adults.
Giant cell hepatitis is a frequent reaction of the liver to different injuries in newborns and in childhood, but rare in adults. This form of hepatitis is often accompanied by cholestasis and shows fast progression to cirrhosis. In most cases autoimmune, metabolic, toxic or viral origin can be found, but sometimes the etiology remains hidden. This paper introduces two adult giant cell hepatitis cases. Hepatitis C virus infection was the possible origin in the first case and autoimmune disease in the other one.


Virological and clinical implication of core promoter C1752/V1753 and T1764/G1766 mutations in hepatitis B virus genotype D infection in Mongolia.
The aim of the present study was to reveal virological and clinical features of hepatitis B virus (HBV) genotype D infection. One hundred and twenty-two Mongolian chronic liver disease (CLD) patients infected with HBV were subjected for serological HBV-markers screening and HBV-enzyme immunoassay (EIA) genotyping. Nucleotide sequences were analyzed for 48 HBV/D strains (23 isolated from hepatocellular carcinoma (HCC) and 25 from CLD patients). Prevalence of hepatitis B e antigen (HBeAg) positivity was low (25.9%) in young patients (< or =30 years old) indicating early HBeAg seroclearance in HBV/D carriers. The T1764/G1766 double mutation was the most common basal core promoter (BCP) mutation (29.2%) and was frequent in HBeAg-negative patients (39.3%). Patients harboring T1764/G1766 mutants exhibited lower HBV-DNA and HBV core antigen (HBcAg) levels than those with wild-type BCP strains (P = 0.024, 0.049, respectively). C1752 and/or V (not T) 1753 mutation was significantly prevalent in HCC patients (HCC vs CLD; 52.2% vs 20%, P = 0.033). T1762/A1764 mutation was detected in 75.0% of HCC patients with high viral load (> or =5 log copies/mL). Precore stop codon mutation A1896 was detected in (70.8%) of HBV/D-infected patients. In Mongolians infected with HBV/D, C1752 and/or V1753 mutation was associated with HCC.


Ecology of SO2 resistance: I. Effects of fumigations on gas exchange of deciduous and evergreen shrubs.
A unique gas exchange system is described in which photosynthesis, transpiration, and stomatal conductance can be measured on leaves during SO2 fumigations. SO2 concentrations can be continuously monitored and manipulated between 0 and 2.0 ppm. Rates of total SO2 uptake and SO2 absorption through stomates of a fumigated leaf can also be determined.Using this system we compared the effects of SO2 on the gas exchange rates of two shrub species that co-occur in the Califormian chaparral. Diplacus aurantiacus, a deciduous shrub, was more sensitive to SO2 fumigation than Heteromeles arbutifolia, an evergreen shrub. The differences in photosynthetic sensitivity could be attributed, in large part, to differential SO2 absorption rates.


Normative values of polysomnographic parameters in childhood and adolescence: arousal events.
This study focused on differences in arousals during sleep, using the arousal rules of the American Academy of Sleep Medicine, by gender, age, and maturity in healthy children. One-night polysomnography was performed on 209 healthy German children (age 1-18 years) at their habitual bedtimes in 16 laboratories. Subjects were grouped by gender (112 females, 97 males), age, and Tanner stage. Normative values of arousal events in sleep are presented, including indexes of spontaneous and respiratory arousals, total electroencephalogram (EEG) arousals, phasic increase in submental electromyogram (EMG) in stage R, and leg movements. With increasing age, a decrease was seen in: EEG arousal index ≥1-2.9 s, EEG arousal index ≥3 s, index of total EEG arousals, index of respiratory arousals, chin EMG enhancement in stage R ≥1-2.9 and ≥3 s, index of total leg movements, and leg movements with EEG arousals (p<0.05). Only spontaneous arousals showed no association with age. There was a significant negative correlation between Tanner stage and arousals ≥1-2.9 s, respiratory arousals, leg movements, and leg movements with arousals (p<0.05). Only arousals ≥3 s and total leg movements showed gender differences (p<0.05). For the diagnosis of pediatric sleep disturbances, the given arousal data enable estimation of the degree of deviation from normal findings for age and maturity. There is need for further research on, and further discussion of, the arousal rules of the American Academy of Sleep Medicine.


"Nothing About Us, without Us." How Community-Based Participatory Research Methods Were Adapted in an Indigenous End-of-Life Study Using Previously Collected Data.
La recherche en santé autochtone au Canada a été négligée dans le passé et qualifiée de problématique, notamment en raison du manque de collaboration avec les peuples autochtones. L'Énoncé de politique des trois Conseils sur l'éthique de la recherche avec des êtres humains décrit au chapitre 9 la conduite éthique de la recherche axée sur les Premières nations, les Inuits et les Métis. Les principes PCAP® des Premières nations (propriété, contrôle, accès et possession) soulignent l'importance majeure de l'engagement et de la gouvernance autochtones. En vue d'assurer que les buts et les activités de la recherche développée soient réalisés en partenariat complet et significatif avec les peuples et les communautés autochtones, il est possible de faire appel à des méthodes de recherche participative communautaire (RPC) intégrant leur plein engagement. Les recherches utilisant des ensembles de données secondaires, telles que les données administratives sur la santé recueillies en routine, ne devraient plus être exclues de cette approche. Notre objectif était de décrire comment notre équipe de chercheurs universitaires, alliée à un organisme national de santé autochtone, a adapté les méthodes de RPC dans le cadre d'un projet de recherche utilisant des données recueillies antérieurement pour examiner les lacunes dans la prestation de soins de fin de vie aux peuples autochtones en Ontario. Nous décrivons le processus d'élaboration de ce partenariat de recherche et expliquons comment l'intégration des principes de base et des processus de formation du savoir autochtones ont guidé cette collaboration. Notre partenariat de recherche, qui implique l'adaptation de méthodes de RPC, illustre un processus d'engagement qui pourrait guider d'autres chercheurs désirant mener des recherches en santé autochtone à l'aide de données déjà recueillies. Nous faisons aussi état d'une entente de recherche transparente, négociée équitablement entre un organisme national de santé autochtone et des chercheurs, qui pourrait servir de cadre pour des collaborations de recherche similaires. Il est essentiel de s'assurer que les perspectives autochtones soient au cœur des processus de recherche et qu'elles soient reflétées dans ceux-ci lorsque des données administratives sur la santé sont utilisées. Indigenous health research in Canada has a chequered past and has been identified as problematic and lacking in appropriate collaboration with Indigenous people. The Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans, Chapter 9 describes ethical conduct of research regarding First Nations, Inuit, and Métis Peoples. First Nations Ownership, Control, Access, and Possession (OCAP®) Principles highlight the necessity of Indigenous engagement and governance. To ensure that the aims and activities of the research being developed are in full and meaningful partnership with Indigenous peoples and communities, community-based participatory research (CBPR) methods provide a process in which full engagement is possible. Research utilizing secondary data sets, such as routinely collected health administrative data, should no longer be excluded from this approach. Our aim was to describe how our research team of academic researchers and a national Indigenous health organization adapted CBPR methods in a research project using previously collected data to examine end-of-life health care service delivery gaps for Indigenous people in Ontario. We describe the process of how we developed our research partnership and how grounding principles and Indigenous ways of knowing guided our work together. Through the adaptation of CBPR methods, our research partnership illustrates a process of engagement that can guide others hoping to conduct Indigenous health research using previously collected data. We also present a transparent research agreement negotiated equally by a national Indigenous health organization and research scientists, which can also be used as a framework for others wishing to establish similar research partnerships. Ensuring that Indigenous perspectives are central to and reflected in the research process is essential when using health administrative data.


Effects of individualized lower limb isokinetic strengthening in clinical rehabilitation of older post-stroke patients: A retrospective study.
Muscle weakness in the lower limbs is a motor consequence of stroke that causes functional impairment. The aim of this study was to assess the effectiveness of an individualized isokinetic strengthening programme, using the moment-velocity profile, on functional recovery during post-stroke rehabilitation of older patients. A further objective was to describe the effects of the individualized isokinetic strengthening on muscular parameters. Retrospective study. Older post-stroke patients. Using the Barthel Index, functional abilities in basic daily tasks were assessed and retrospectively analysed for 88 patients in a post-stroke rehabilitation unit. Of these, 44 patients received conventional rehabilitation (conventional group) and 44 received individualized isokinetic strengthening in addition to conventional rehabilitation (isokinetic group). A 2-Group (isokinetic, conventional) × 2-Time (before, after intervention) repeated measures analysis of variance (ANOVA) was conducted. For muscular parameters, Student t-tests and Wilcoxon tests were performed. The Barthel Index score increased more in the isokinetic group (61.59 ± 26.34 to 88.18 ± 12.16) than in the conventional group (61.70 ± 26.5 to 76.93 ± 18.12). A significant Time × Group interaction was found (F(1,86) = 5.95, p = 0.02). In the isokinetic group all muscular parameters improved. This retrospective clinical study suggests that lower limb isokinetic strengthening, individualized using the moment-velocity profile, is clinically efficient for functional recovery during post-stroke rehabilitation of older patients. Intragroup effects of isokinetic strengthening also suggest benefits for muscular parameters.


Spontaneous cognition and its relationship to human creativity: A functional connectivity study involving a chain free association task.
Resting-state functional connectivity (RSFC) between various brain regions is thought to be associated with creative abilities. Extensive research correlating RSFC with performance on creativity tasks has revealed some of the RSFC patterns characterizing 'the creative brain'. Yet, our understanding of the neurocognitive processes underlying creative thinking still remains limited. This limitation results, in part, from the fact that standard creativity tasks used in these studies do not distinguish between the different modes of cognitive processing that are critical in creative cognition (e.g., spontaneous cognition vs. controlled cognition). In the present fMRI research we address this limitation by using a chain free association task - a task that we have recently refined and validated for the purpose of isolating measures of spontaneous cognition that are relevant for creative thinking (referred to as associative fluency and associative flexibility). In our study, 27 female participants completed standardized creativity tasks, a chain free association task, and a fMRI scan in which RSFC was measured. Our results indicate that higher scores on associative fluency are associated with stronger positive RSFC within the default mode network (DMN; i.e., between DMN regions). Critically, we provide evidence that the previously-identified relationship between performance on creativity tasks and connectivity within the DMN is partially mediated by associative fluency. Thus, our observations suggest that the heightened DMN connectivity observed in 'the creative brain' can be explained, at least to some extent, by spontaneous cognition. Overall, our study identifies unique RSFC patterns that are related specifically to spontaneous cognitive processes involved in creative ideation, thus shedding new light on mechanisms of creative processing.


Diagnosis and treatment of faecal incontinence: Consensus statement of the Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists.
Faecal incontinence is a common and disturbing condition, which leads to impaired quality of life and huge social and economic costs. Although recent studies have identified novel diagnostic modalities and therapeutic options, the best diagnostic and therapeutic approach is not yet completely known and shared among experts in this field. The Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists selected a pool of experts to constitute a joint committee on the basis of their experience in treating pelvic floor disorders. The aim was to develop a position paper on the diagnostic and therapeutic aspects of faecal incontinence, to provide practical recommendations for a cost-effective diagnostic work-up and a tailored treatment strategy. The recommendations were defined and graded on the basis of levels of evidence in accordance with the criteria of the Oxford Centre for Evidence-Based Medicine, and were based on currently published scientific evidence. Each statement was drafted through constant communication and evaluation conducted both online and during face-to-face working meetings. A brief recommendation at the end of each paragraph allows clinicians to find concise responses to each diagnostic and therapeutic issue.


Stereotactic radiofrequency amygdalohippocampectomy: two years of good neuropsychological outcomes.
To provide two-year seizure and neuropsychological outcomes in patients treated by stereotactic radiofrequency amygdalohippocampectomy (SAHE), an alternative, minimally invasive method for the treatment of mesial temporal lobe epilepsy (MTLE). Thirty-seven MTLE patients treated by SAHE (26 left-sided, 11 right-sided) were included. Patients underwent neuropsychological evaluation by the Wechsler Adult Intelligence Scale-Revised and the Wechsler Memory Scale-Revised preoperatively, 1 year and 2 years after SAHE. Two years after SAHE twenty-eight (75.5%) patients were assessed as Engel Class I and seven (18.9%) patients as Engel Class II. In two patients (5.4%) treatment failed, one of them was classified as Class III and one as Class IV. Irrespective of the laterality of the procedure, the group improved significantly in Global and Verbal Memory Quotients, Attention, Delayed Recall, Semantic Long-term memory subtest and Working Memory. Additionally, increases in Full-scale, Verbal and Visual Intelligence Quotients were detected on the group level. In the present study we report good seizure control and neuropsychological outcomes after SAHE in our patients. We hypothesize that good neuropsychological results were achieved by the incomplete destruction of target structures, sparing the lateral temporal neocortex, and also partially by practice effect. Treatment failures in seizure control may be attributed to larger epileptogenic zones.


Gb3-binding lectins as potential carriers for transcellular drug delivery.
Epithelial cell layers as well as endothelia forming the blood-brain barrier can drastically reduce the efficiency of drug targeting. Our goal was to investigate lectins recognizing the glycosphingolipid globotriaosylceramide (Gb3) for their potential as carriers for transcytotic drug delivery. We utilized an in vitro model based on Madin-Darby canine kidney cells transfected with Gb3 synthase to characterize transcytosis of the Gb3-binding lectins LecA from Pseudomonas aeruginosa and the B-subunit of Shiga toxin (StxB). Both lectins were rapidly transcytosed from the apical to the basolateral plasma membrane and vice versa. Whereas StxB proceeded on retrograde and transcytotic routes, LecA avoided retrograde transport. This differential trafficking could be explained by our observation that LecA and StxB segregated into different domains during endocytosis. Furthermore, inhibiting the small GTPase Rab11a, which organizes trafficking through apical recycling endosomes, blocked basolateral to apical transcytosis of both lectins. Gb3-binding lectins are promising candidates for transcytotic drug delivery. Our findings highlight that LecA and StxB, which both bind Gb3 but exhibit dissimilar valence and molecular structures of their carbohydrate binding sites and can take divergent intracellular trafficking routes. This opens up the possibility of developing tailor-made glycosphingolipid-binding carrier lectins, which take optimized trafficking pathways.


Limitations of randomized clinical trials to recognize possible advantages of combination therapies in rheumatic diseases.
Potential advantages of combination second-line drug therapy in rheumatoid arthritis (RA) may not be detectable in standard randomized controlled clinical trials, despite excellent design and performance. This results from intrinsic limitations of usual clinical studies, such as a short time frame, patient selection, and insufficient numbers of patients. Examples of selected clinical protocols in rheumatic diseases that illustrate these problems are presented. In systemic lupus erythematosus, many well-designed and -performed trials comparing combinations of cytotoxic drugs and corticosteroids with corticosteroids alone were inconclusive. However, combination therapy was superior in three types of studies: a 15-year clinical trial, a pooled analysis of multiple trials, and longitudinal databases of unselected patients. In RA, a 48-week study indicated no differences in results of treatment with auranofin, methotrexate, and the combination of these two drugs. In contrast, a clinical database from 15 rheumatology practices indicates that methotrexate was continued for 5 years by more than 50% of patients, compared with fewer than 10% for auranofin. A subset from the clinical database of courses of second-line drugs over 1 year (rather than 5 years), for only the initial course of a second-line drug (rather than any course), was examined. Using these selected data, which mimic the conditions of the clinical trial, no significant differences were seen in continuation of methotrexate versus auranofin. This observation suggests that intrinsic limitations, including patient selection, insufficient patient numbers, and a short time frame, may render it difficult (or impossible) to document the efficacy of combination therapy in RA using standard randomized controlled clinical trials.


Long-Term Continuous Computer Registration and Analysis of Motor Activity of a Group of Zebrafish Danio rerio.
A new algorithm for long-term continuous computer recording and analysis of motor activity of a group of zebrafish in the home tank has been developed. The movements of a group of Danio rerio during the entire light period and for several days are recorded at a frequency of 1 frame/sec in the form of short (15 min) files. Then these files are analyzed by the unique DanioStudo software, which, using a threshold algorithm and appropriate masks, calculates for each frame the sum of pixels associated with fish (the sum of fish silhouettes), and for two consecutive frames, the sum of altered pixels (the sum of altered fish silhouettes). The following indexes are calculated: the rate of sum of silhouettes alteration as the ratio of the sum of altered silhouettes to the sum of silhouettes (1) and the time spent in the selected area of the home tank as the ratio of the sum of silhouettes in this area to the sum of silhouettes in the entire tank (2). The mean rate of silhouette alteration correlates to the length of the path travelled by the fish and, therefore, serves as a correct measure of the motor activity of a group of fish. Using these algorithms, completely new data were obtained: it was shown that the motor activity of fish remains constant throughout the entire light period, but depends on the size of the home tank. The proposed approach, together with the DanioStudio software, can be effective in studying the dynamics of changes in the behavior of fish under long-term exposure to short daylight, drugs and toxic substances.


Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy.
Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.


Anterior prosthetic knee dislocation with acute vascular injury: A case report.
and Importance: Anterior dislocation of a prosthetic knee is rarely encountered. Acute vascular injury following anterior prosthetic dislocation has only been reported once in the literature with extremely poor outcomes. The authors report the case of a 70-year-old woman who presented with anterior prosthetic knee dislocation after a fall from slipping. After closed reduction, CT angiography found transection and active extravasation of the left popliteal artery. An emergent fasciotomy and popliteal bypass were performed with concurrent external fixation of the joint. Recovery was complicated by bacteremia requiring eventual explant of total knee arthroplasty (TKA). We report the only case of successful vascular repair after acute vascular injury from traumatic anterior prosthetic dislocation. External fixation of the knee allowed for better stabilization of the joint and preservation of the repaired vascular injury; however, it carries a risk for infection, as seen in this case. While there are no clear guidelines for management, we highlight the importance of rapid diagnosis with CT angiography and shared decision making with the vascular surgery team to repair the injury and stabilize the joint.


Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1-3N0 non-small-cell lung cancer: is low incidence of regional failure due to incidental nodal irradiation?
To report the results of high-dose conformal irradiation and examine incidental nodal irradiation and nodal failure in patients with inoperable early-stage non-small-cell lung cancer (NSCLC). This analysis included patients with inoperable CT-staged T1-3N0M0 NSCLC treated on our prospective dose-escalation trial. Patients were treated with radiation alone (total dose, 63-102.9 Gy in 2.1-Gy daily fractions) with a three-dimensional conformal technique without intentional nodal irradiation. Bilateral highest mediastinal and upper/lower paratracheal, prevascular and retrotracheal, sub- and para-aortic, subcarinal, paraesophageal, and ipsilateral hilar regions were delineated individually. Nodal failure and doses of incidental irradiation were studied. The potential median follow-up was 104 months. For patients who completed protocol treatment, median survival was 31 months. The actuarial overall survival rate was 86%, 61%, 43%, and 21% and the cause-specific survival rate was 89%, 70%, 53%, and 35% at 1, 2, 3, and 5 years, respectively. Weight loss (p = 0.008) and radiation dose in Gy (p = 0.013) were significantly associated with overall survival. In only 22% and 13% of patients examined did ipsilateral hilar and paratracheal (and subaortic for left-sided tumor) nodal regions receive a dose of > or = 40 Gy, respectively. Less than 10% of all other nodal regions received a dose of > or = 40 Gy. No patients failed initially at nodal sites. Radiation dose is positively associated with overall survival in patients with medically inoperable T1-3N0 NSCLC, though long-term results remain poor. The nodal failure rate is low and does not seem to be due to high-dose incidental irradiation.


Potential indications for angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease.
Angiotensin-converting enzyme (ACE) inhibitors are well established as first-line therapy for patients with left ventricular dysfunction, diabetic patients with hypertension or renal disease, and patients recovering from myocardial infarction. Angiotensin II and bradykinin regulate cellular proliferation, inflammation, and endothelial function, thus playing an important role in the pathogenesis of atherosclerosis. A large body of experimental evidence reporting that ACE inhibitors limit these effects has formed the rationale for major clinical trials of these drugs in the management of atherosclerotic vascular disease. The first trial to be completed demonstrated that ACE inhibition improves the prognosis of patients who have, or are at risk of, atherosclerotic vascular disease, independent of its effects on left ventricular function and hypertension. Expanding the indications for ACE inhibitors is now evidence driven, although the choice of agent for these new indications remains to be determined by further research.


Left-handedness and life expectancy.
Halpern and Coren recently described an association between left-handedness and a lower life expectancy. This finding is not unexpected because left-handedness has been linked to three leading causes of death in our society--alcoholism, smoking, and breast cancer--as well as to several neurological and immune disorders.


Human papillomavirus genotype detection in recurrent respiratory papillomatosis (RRP) in Colombia.
Knowledge on human papillomavirus (HPV) genotype distribution in recurrent respiratory papillomatosis (RRP) is essential to assess the impact of HPV vaccine. It is provided information for Colombia. In all, 189 RRP primary cases diagnosed between 1985 and 2009 were identified from 5 pathology laboratories of Cali and Medellin, Colombia. HPV DNA testing in 129 cases that fulfilled inclusion criteria (available paraffin blocks, amplifiable DNA, and confirmed histologic diagnosis of RRP) was performed by the SPF-10/LiPA25 assay (version 1). Of all cases 36.1% were juvenile (<12 years old) and a majority of adults were males (p = .09); 95% of cases were HPV positive. HPV 6, 11, and 16 contributed to 69%, 27.1%, and 7.8% of all HPV positive cases. Twelve cases (9.3%) showed multiple infections; 8 of these were HPV 6 or 11 positive. HPV prophylactic vaccine including HPV 6 and 11 may have a major impact against RRP.


Ileal Digestibility and Total Tract Retention of Phosphorus in Inorganic Phosphates Fed to Broiler Chickens Using the Direct Method.
The objective of this study was to determine and compare the phosphorus (P) utilization of inorganic phosphates fed to broiler chickens using the direct method. On day 15 of age, six hundred forty 15-day-old male Ross 308 broiler chickens (initial body weight = 399 ± 38 g) were assigned to five experimental diets with 16 birds per cage in a randomized complete block design. The experimental diets consisted of four semi-purified diets containing monocalcium phosphate, monodicalcium phosphate, dicalcium phosphate, and tricalcium phosphate as the sole P sources. Additionally, a P-free diet was prepared to measure basal endogenous P loss. Chromic oxide was added to the experimental diets as an indigestible index. Excreta were collected per cage on days 17 to 18 of age, and all birds were asphyxiated with carbon dioxide on day 19 of age for ileal digesta collection. The cage was an experimental unit, and the number of replications per each treatment was eight except for the tricalcium phosphate treatment (n = 4). There was no interaction observed between the P source and the collection site (ileal digestibility vs. total tract retention). Phosphorus utilization differed (p < 0.05) among inorganic phosphates and the ileal digestibility of P was greater (p < 0.05) than the total tract retention. In conclusion, the standardized ileal digestibility of P in inorganic phosphates ranged from 56.7% to 89.8% and ileal digestibility was greater than the total tract retention.


Compliance with hygiene guidelines: the effect of a multimodal hygiene intervention and validation of direct observations.
Good compliance with hygiene guidelines is essential to prevent bacterial transmission and health care-associated infections. However, the compliance is usually <50%. A multimodal and multidisciplinary hygiene intervention was launched once the baseline compliance was determined through direct observations in 4 departments of obstetrics and gynecology. Detailed evaluations of the compliance rates were performed at point of stability (at 80%) and follow-up (3 years after hygiene intervention). Validation of direct observations was performed using blinded double appraisal and multiappraisal. At baseline, the compliance with barrier precautions and the dress code at the 4 departments were 39% to 47% and 79% to 98%, respectively. Point of stability was reached approximately 1 year after the hygiene intervention was launched. The compliance with barrier precautions was significantly higher at follow-up compared with baseline in 3 departments. In the validation by double appraisal, 471 of 483 components were judged identical between observers. In the multiappraisal, 95% to 100% of the observers correctly judged the 7 components. It is possible to improve compliance with hygiene guidelines, but, to ensure a long-lasting effect, a continuous focus on barrier precautions is required. Observation is a valid method to monitor compliance.


Integrated microdroplet array platform with temperature controller and micro-stirring for ultra-fast SARS-CoV-2 detection.
The outbreak of COVID-19 has created a huge challenge to global health systems. Experience in fighting the epidemic shows that the development of a rapid and sensitive POCT diagnostic platform for SARS-CoV-2 that can be deployed in situ is crucial to contain the outbreak. Here, we have developed a portable microdroplet detection platform that integrated temperature controller and micro-stirring for high-throughput and ultrafast COVID-19 diagnosis. Such a device uses a p-n junction (PN junction) as the temperature controller to adjust the temperature in a single microdroplet independently and precisely, ensuring the amplification of reverse transcription loop-mediated isothermal amplification (RT-LAMP). Meanwhile, the platform incorporates an ultrasonic micro-stirring unit, greatly increasing the interaction between RT-LAMP molecules and accelerating the amplification. The results show good linearity over a wide linear range (1 to 105 copies/μL) and low LOD (0.48 copy/μL). Our method reports in only 6.1 min for high-viral load samples, and combines with sample preparation, the total detection process could be done within 30 min. Such a portable and fully integrated microdroplet molecular diagnostic platform is a promising tool for point-of-care diagnosis of COVID-19 and other infectious diseases in resource-limited settings.


Inhibition of apoptotic signals in overgrowth of human gingival fibroblasts by cyclosporin A treatment.
Cyclosporin A (CsA), an immunosuppressive drug, has overgrowth effects on human gingival fibroblasts (HGF) in vitro. However, the molecular mechanism responsible for the CsA-induced gingival overgrowth remains still unclear. The present study is aimed to investigate the correlation with the apoptotic signal pathway in CsA-induced overgrowth of HGF. CsA-treated HGF were assessed for cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, for reactive oxygen species (ROS) detection by flow cytometry, for proliferation ability using the 5-bromo-20-deoxyuridine (BrdU), for caspase activities biochemically, for expression of apoptotic signal molecules such as cytochrome c, Fas and Fas-L and Bcl-2 family by Western blotting and VDAC by RT-PCR. CsA increased the cell viability, but not the number of BrdU-positive HGF, indicating that CsA fails to induce the proliferation of HGF. CsA also decreased the intracellular reactive oxygen species level in HGF. This was accompanied by that the antiapoptotic protein Bcl-2 was upregulated whereas the proapoptotic protein Bax was downregulated. Moreover, CsA downregulated VDAC, a mitochondrial transition pore, and decreased the level of cytochrome c released from the mitochondria into the cytosol and activation of caspase-3 and -9 associated with mitochondria-mediated apoptosis. On the other hand, Fas-L level and caspase-8 activation, the major mediator of the death receptor-mediated apoptosis, were diminished in the CsA-treated HGF. CsA inhibits the apoptotic signal molecules such as cytochrome c, caspases and Fas-L with the regulation of Bcl-2 family whereas it has no effect on cell division, which can contribute to overgrowth of HGF. These findings suggest that the decreased apoptosis plays a more important role than the increased cell proliferation in the CsA-induced overgrowth of HGF.


[Brain atrophy in chronic alcoholism. Clinical and computer tomographic study].
Fifty chronic alcoholics (37 men and 13 women, ages 26--55, mean age 39.9 years) with different clinical syndromes (alcoholic psychosis, alcoholic encephalopathies) were studied by computerized cranial tomography. Cerebral atrophy was detected in 96% of all cases. Combined cortical and subcortical signs were encountered in almost all cases. Cortical atrophy seemed to be detectable more easily by CT than by pneumencephalography. The computerized tomographic findings were studied in their relations to age, sex, duration of abuse, clinical syndromes, frequency of relapse (and seizures, too), etc. Cerebral atrophy was correlated primarily with the subjects' age and the duration, and less with the intensity of alcoholism. The most distinct changes were found in delirium syndromes and, in cases with relapse of psychosis, especially in combination with seizures. Wernicke-Korsakow encephalopathies showed the widest third ventricles when combined with repeated syndromes of withdrawal in their case histories. Computerized tomographic examinations of ten patients during acute psychosis as well as 4 weeks later showed identical findings; transitory changes, e.g., cerebral edema, were not detected. Computerized cranial tomography appears to be extremely useful to study the numerous open questions concerning the pathogenetic role of age, duration, and severity of abuse with cerebral atrophy.


Very high frequency oscillations in the heart rate and blood pressure of heart transplant patients.
The authors studied the recently reported very high frequency (VHF) peaks in the heart rate (HR) and blood pressure (BP) power spectra of heart transplant (HT) patients. These VHF peaks appear at frequencies much higher than the respiratory frequency, in addition to the typical low-frequency and high-frequency peaks. Twenty-five recordings obtained from 13 male HT patients (0.5-65 months following surgery) were compared with recordings from 14 normal male subjects. The ECG, continuous BP and respiration were recorded during 45min of supine rest. Eight recordings from HT patients were excluded owing to arrhythmias. Spectral analysis was performed on all other recordings. VHF peaks were found in the spectra of both BP and HR in nine recordings obtained from six HT patients. In some cases, the power in the VHF peaks was markedly higher than that of the high-frequency peak. No VHF peaks were observed in eight recordings obtained from four HT patients or in recording from any of the normal subjects. No correlation was found between the incidence of VHF peaks and time after transplant. It was proved that the VHF peaks were not artifactual, and their significance within the framework of the theory of communication systems is discussed. The presence of those peaks was attributed to vagal denervation.


On the significance of the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus striatum and limbic forebrain.
The effect of various antipsychotic drugs on the blockade of dopaminergic receptors in striatum and limbic forebrain was examined by establishing dose-response curves for the increase in HVA and for the antagonism of d-amphetamine-induced rotation in rats with unilateral lesions of the substantia nigra. A good quantitative correlation was found between dopaminergic blockade in the striatum as reflected by the ED100 for striatal HVA increase and the ED50 for rotational antagonism and the occurrence of extrapyramidal side effects in man. The ED100 for the increase in HVA in the limbic forebrain showed the same rank order of potency as those in the striatum: Haloperidol greater than primozide greater than chlorpromazine greater than thioridazine greater than clozapine. The results thus demonstrate a very good correlation between the degree of dopaminergic blockade and the increase of extrapyramidal side effects in man, but suggest the possibility of a dissociation between dopaminergic blockade and antipsychotic activity.


Mild hypothermia protects synaptic transmission from experimental ischemia through reduction in the function of nucleoside transporters in the mouse hippocampus.
Ischemia, a severe metabolic stress, increases adenosine levels and causes the suppression of synaptic transmission through adenosine A1 receptors. Although temperature also regulates extracellular adenosine levels, the effect of temperature on ischemia-induced activation of adenosine receptors is not yet fully understood. Here we examined the role of adenosine A1 receptors in mild hypothermia-mediated neuroprotection during the acute phase of ischemia. Severe ischemia-induced neurosynaptic impairment was reproduced by oxygen-glucose deprivation at normothermia (36 °C) and assessed with extracellular recordings or whole-cell patch clamp recordings in acute hippocampal slices in mice. Mild hypothermia (32 °C) induced the protection of synaptic transmission by activating adenosine A1 receptors. Stricter hypothermia (28 °C) caused additional neuroprotective effects by extending the onset time to anoxic depolarization; however, this effect was not associated with adenosine A1 receptors. The response of exogenous adenosine-induced inhibition of hippocampal synaptic transmission was increased by lowering the temperature to 32 °C or 28 °C. Hypothermia also reduced the function of dipryidamole-sensitive nucleoside transporters. These findings suggest that an increased response of adenosine A1 receptors, caused by a reduction in the function of nucleoside transporters, is one mechanism by which therapeutic hypothermia (usually used within the mild range) mediates neurosynaptic protection in the acute phase of stroke.


Geriatric spine fractures - Demography, changing trends, challenges and special considerations: A narrative review.
The aim of this manuscript was to summarize the demography and changing trends of geriatric spinal injuries and to enumerate the challenges and special considerations in the care of geriatric spinal injuries. PubMed, Scopus and Embase databases were searched for literature on geriatric spine fractures using MeSH terms 'aged', 'aged, 80 and over', 'elderly', 'spinal fracture/epidemiology', spinal fracture/therapy∗' and keywords pertaining to the same. The search results were screened for appropriate articles and reviewed. There is a high community prevalence of elderly vertebral fractures ranging from 18% to as high as 51%. The proportion of older patients among the spinal injured is rising as well. There is a higher chance of missing spinal injuries in the elderly and clinical guidelines may not be applicable to this patient group. Classification and surgical treatment are different from younger adult counterparts as the elderly osteoporotic spine behaves differently biomechanically. There is a high incidence of respiratory complications both for surgically and conservatively managed groups. Older age generally is associated with a higher complication rate including mortality.


Nurses' behavioral intention in using virtual clinical simulation training: By structural equation modeling.
To examine the relationship between the nurses' behavioral intention to use virtual clinical simulation training and study variables, including perceived usefulness, perceived ease of use, self-efficacy, technology anxiety, perceived enjoyment and personal innovativeness. Little is known about the nurses' behavioral intentions behind using virtual clinical simulation training. A cross-sectional study. A total of 206 registered nurses participated in this survey. Data were collected through online survey from March 20, 2021, to April 2, 2021, since entry into the hospital was strictly controlled due to the COVID-19 outbreak. Structural equation modeling identified that both perceived usefulness and perceived ease of use were the predictors which influenced behavioral intention. Additionally, perceived enjoyment indirectly affected behavioral intention by influencing both perceived usefulness and perceived ease of use. The successful introduction of virtual clinical simulation training depends on nurses' willingness and acceptance of its use. The findings of this study show that virtual clinical simulation training should be perceived as useful, easy to use and enjoyable to be accepted by nurses. Virtual clinical simulation programs may have the potential to help improve nurses' clinical skills and competencies in patient care. This study revealed that the usefulness of its contents, ease of use and enjoyment are important to increase nurses' behavioral intention to use virtual clinical simulation training.


Evaluation of endothelial cell function with anterior segment fluorophotometry in pseudophakic patients.
Determining fluorescein permeability of the endothelial cell layer provides information on the endothelial cell barrier. Following topical application of fluorescein, the time dependent change of its concentration in the corneal stroma and in the aqueous humor yields the transfer coefficient (Kc) of the corneal endothelium. Measurements with a fluorophotometer resulted in a Kc of 0.002 minute to 0.005 minute for normal eyes. Patients with corneal barrier dysfunction (cornea guttata, Fuch's dystrophy) showed an increased Kc of 0.006 minute to 0.013 minute. Up to five years postoperatively, none of the patients investigated after phacoemulsification and posterior chamber lens implantation showed a disturbance in the endothelial cell barrier function.


Sarcopenia and frailty in geriatric patients: implications for training and prevention.
Sarcopenia, the loss of muscle mass and strength, is a constant phenomenon in aging. Physiologic age-dependent changes (drop in growth hormone (GH), IGF-1, menopause/andropause) explain the impaired protein synthesis, the decline of muscle mass, strength, and bone density. Harmful consequences of sarcopenia in old age are loss of muscle strength, inducing itself loss of mobility, neuromuscular impairment, and homeostatic balance failure syndrome with gait and balance disorders. All these sarcopenia-induced disabilities are important factors for an increased rate of falls and fractures in old age. Both falls and fractures cause hospitalisation and immobilisation which again induces sarcopenia. Once the physiological age-dependent decline of protein synthesis has started, some connected "vicious loops" occur in frail elderly patients, forming a typical pattern in geriatric medicine. There is a vicious loop between sarcopenia and immobilisation: sarcopenia --> neuromuscular impairment --> falls and fractures --> immobilisation --> sarcopenia. Another loop is the "nutritional" vicious loop between sarcopenia and malnutrition: sarcopenia --> immobilisation --> decline of nutrition skills ("empty refrigerator") --> malnutrition --> impaired protein synthesis --> sarcopenia. There is also a third "metabolic" vicious loop between sarcopenia and the decline of the protein reserve of the body: sarcopenia --> decline of the protein reserve of the body --> diminished capacity to meet the extra demand of protein synthesis associated with disease and injury --> sarcopenia. Frailty, a term not precisely defined, results from these different "vicious loops" including sarcopenia, neuromuscular impairment, falls and fractures, immobilisation, malnutrition, impaired protein synthesis, and decreased protein reserve of the body. Implications for training: main possibilities for training and prevention (of sarcopenia and frailty) are: a) continuous neuromuscular training (including training of balance) b) mobilisation c) prevention of falls d) training of nutrition skills and improvement of nutrition e) improvement of the impaired protein synthesis (with hormones etc.), and f) avoidance of dangerous drugs (drugs which cause neuromuscular impairment).


Paranasal sinus mucocele: unusual MR manifestations at 1.5 T.
The classic MR appearance of paranasal sinus mucoceles is due to its cystic composition. We present two cases of paranasal sinus mucocele that exhibit atypical signal characteristics. The morphology of this lesion, rather than its signal intensity, is paramount in establishing this diagnosis.


Inhibitory phenomena during NREM sleep related to auditory stimuli and epileptic spikes.
Auditory stimuli induce facilitation of the H reflex during wakefulness (so-called audio-spinal influence). In 5 subjects we found that, during SWS, the same stimuli may provoke phasic losses of muscle tone and H reflex inhibition. Similar losses of tone and H reflex inhibition were related to epileptic spikes in 3 patients.


A novel adaptive droop control strategy for SoC balance in PV-based DC microgrids.
Battery energy storage systems (BESSs) are generally used as a buffer stage for photovoltaic (PV) power generation to tolerate the output power unpredictability in DC microgrids, in which the State-of-Charge (SoC) balance is a necessary and urgent issue to be solved. To this end, an integral feedforward sliding mode controller (SMC) is adopted to replace the traditionally proportional integral (PI) controller such that the voltage response speed of the converter in each BESS can be significantly enhanced. Further, a novel adaptive droop control strategy for SoC balance with three different working modes is proposed, in which all batteries can be cooperated through three different stages corresponding to their different SoC degrees. Compared with most existing SoC balancing approaches, the proposed SoC strategy can improve the transient performance for the BESSs and their robustness against the volatility of PV output powers. The effectiveness of the proposed SoC balancing strategy is verified through a simulation in a DC microgrid network consisting of several PV generators, batteries, and loads utilizing Simulink/SimPower Systems.


Microstructure characterization of Al matrix composite reinforced with Ti-6Al-4V meshes after compression by scanning electron microscope and transmission electron microscope.
Compressive properties of Al matrix composite reinforced with Ti-6Al-4V meshes (TC4(m)/5A06 Al composite) under the strain rates of 10(-3)S(-1) and 1S(-1) at different temperature were measured and microstructure of composites after compression was characterized by scanning electron microscope (SEM) and transmission electron microscope (TEM). Compressive strength decreased with the test temperature increased and the strain-rate sensitivity (R) of composite increased with the increasing temperature. SEM observations showed that grains of Al matrix were elongated severely along 45° direction (angle between axis direction and fracture surface) and TC4 fibres were sheared into several parts in composite compressed under the strain rate of 10(-3)S(-1) at 25°C and 250°C. Besides, amounts of cracks were produced at the interfacial layer between TC4 fibre and Al matrix and in (Fe, Mn)Al(6) phases. With the compressive temperature increasing to 400°C, there was no damage at the interfacial layer between TC4 fibre and Al matrix and in (Fe, Mn)Al(6) phases, while equiaxed recrystal grains with sizes about 10 μm at the original grain boundaries of Al matrix were observed. However, interface separation of TC4 fibres and Al matrix occurred in composite compressed under the strain rate of 1S(-1) at 250°C and 400°C. With the compressive temperature increasing from 25°C to 100°C under the strain rate of 10(-3) S(-1), TEM microstructure in Al matrix exhibited high density dislocations and slipping bands (25°C), polygonized dislocations and dynamic recovery (100°C), equiaxed recrystals with sizes below 500 μm (250°C) and growth of equiaxed recrystals (400°C), respectively.


Duodenal bulb acidity in patients with duodenal ulcer.
Intraluminal pH was measured simultaneously in the human stomach and proximal duodenum with six small glass electrodes tied together at 1.5-cm intervals. Twenty-four healthy control subjects and 44 patients with duodenal ulcer disease were studied under fasting conditions and for 3 h after a standard liquid meal. Mean and median hydrogen ion activity, percentage of time with pH below 2 and 3, and the frequency of pH fluctuations were calculated from digital pH data sampled at a frequency of once per second from each electrode. None of these measurements of acidity differed significantly between the two groups or between subgroups of normosecretor controls and hypersecretor ulcer patients. At the time of pH study 15 of the patients had endoscopically verified active ulcer disease and 13 patients were without disease activity. Gastric as well as duodenal bulb acidity was the same in these two subgroups. We conclude that even though duodenal ulcer patients deliver more acid into the duodenum, this does not cause increased luminal acid aggression.


Effect of cadmium on polyribosome structure and function in mouse liver.
Cadmium chloride injected to mice (20 micronmoles/kg) provokes in the livers a degradation of polyribosomes and diminishes their protein synthetic ability measured in vitro. CdCl2 added in a final concentrations between 30 and 100 micron to the protein synthetic cell-free system derived from livers of control mice inhibits its activity.


Genetic engineering of mammals.
Historically, genetic engineering for mammalian reproductive questions has been accomplished primarily in the mouse. However, all the genetic manipulations that can be done in the mouse can now be accomplished in most domesticated mammals. Random integration of transgenes, homologous recombination and gene editing are now routine for several mammalian species. For livestock, queries related to fertility can be asked directly for the species in question, without a need for a mouse model. For human clinical concerns, the most appropriate model should be selected based on physiology, anatomy, or even size. The mouse will continue to be a useful genetically engineered model. However, other species are now amenable to the full range of genetic manipulations and should be considered as possible models for human conditions when appropriate.


A reproducible evaluation of ANTs similarity metric performance in brain image registration.
The United States National Institutes of Health (NIH) commit significant support to open-source data and software resources in order to foment reproducibility in the biomedical imaging sciences. Here, we report and evaluate a recent product of this commitment: Advanced Neuroimaging Tools (ANTs), which is approaching its 2.0 release. The ANTs open source software library consists of a suite of state-of-the-art image registration, segmentation and template building tools for quantitative morphometric analysis. In this work, we use ANTs to quantify, for the first time, the impact of similarity metrics on the affine and deformable components of a template-based normalization study. We detail the ANTs implementation of three similarity metrics: squared intensity difference, a new and faster cross-correlation, and voxel-wise mutual information. We then use two-fold cross-validation to compare their performance on openly available, manually labeled, T1-weighted MRI brain image data of 40 subjects (UCLA's LPBA40 dataset). We report evaluation results on cortical and whole brain labels for both the affine and deformable components of the registration. Results indicate that the best ANTs methods are competitive with existing brain extraction results (Jaccard=0.958) and cortical labeling approaches. Mutual information affine mapping combined with cross-correlation diffeomorphic mapping gave the best cortical labeling results (Jaccard=0.669±0.022). Furthermore, our two-fold cross-validation allows us to quantify the similarity of templates derived from different subgroups. Our open code, data and evaluation scripts set performance benchmark parameters for this state-of-the-art toolkit. This is the first study to use a consistent transformation framework to provide a reproducible evaluation of the isolated effect of the similarity metric on optimal template construction and brain labeling.