Molecular mechanisms of interaction between the neuroprotective substance riluzole and GABA(A)-receptors.
The antiepileptic drug riluzole is used as a therapeutic agent in amyotrophic lateral sclerosis due to its neuroprotective effects. Besides presynaptic inhibition of GABAergic and preferentially glutamatergic transmission, it also potentiates postsynaptic GABA(A)-receptor function. We investigated the postsynaptic effects of riluzole on GABA(A)-receptor channels by use of the patch-clamp technique. Recombinant alpha1beta2gamma(2s) and alpha1beta2 GABA(A) receptors were expressed in HEK 293 cells by transient transfection. Pulses of GABA were applied in combination with different concentrations of riluzole to whole cell or outside-out patches with either alpha1beta2gamma(2s) or alpha1beta2 GABA(A)-receptor channels. Co-application of riluzole led to a slight decrease of absolute peak current amplitudes and steady-state currents in prolonged presence of GABA at saturating concentrations. In the presence of riluzole, enhancement of current amplitudes was observed with lower concentrations of GABA at alpha1beta2gamma(2s) receptors and to a lower extent also at alpha1beta2 receptors. Thus, the potentiating effect of riluzole was shown to be not abolished in the absence of the gamma(2s)-subunit. A further prominent effect of riluzole was a highly significant acceleration of the time course of current decay, most probably pointing to an open-channel block-like mechanism of action. As both receptor subtypes were affected similarly by the block, it could be concluded that the respective binding sites should be assumed within a region of high sequence homology like it is given for the channel-lining M2 domain of GABA(A)-receptor subunits. In conclusion, three different molecular mechanisms of interaction of the neuroprotective compound riluzole were observed at two different subtypes of GABA(A) receptor channels. The results further point to the impact of the inhibitory as well as the excitatory synaptic activity as a pharmacological target to counteract chronic excitotoxicity and reveal molecular mechanisms of action of the only one neuroprotective drug in current clinical use in patients suffering from amyotrophic lateral sclerosis.


Effect of Peer Mentors in Diabetes Self-management vs Usual Care on Outcomes in US Veterans With Type 2 Diabetes: A Randomized Clinical Trial.
Diabetes is a substantial public health issue. Peer mentoring is a low-cost intervention for improving glycemic control in patients with diabetes. However, long-term effects of peer mentoring and creation of sustainable models are not well studied. Assess the effects of a peer support intervention for improving glycemic control in patients with diabetes and evaluate a model in which former mentees serve as mentors. A randomized clinical trial was conducted from September 27, 2012, to March 21, 2018, at the Corporal Michael J. Crescenz Medical Center. US veterans with type 2 diabetes aged 30 to 75 years with hemoglobin A1C (HbA1c) greater than 8% received support over 6 months from peers with prior poor glycemic control but who had achieved HbA1c less than or equal to 7.5% (phase 1). Phase 1 mentees were then randomized to become a mentor or not to new randomly assigned participants in phase 2. Outcomes were assessed at 6 and 12 months. Data were analyzed from October 5, 2016, to September 4, 2018. Mentors who received an initial training session and monthly reinforcement training were assigned 1 mentee and given $20 for each month they contacted their mentee at least weekly. Primary outcome was HbA1c change at 6 months. Secondary outcomes included HbA1c change at 12 months and change in low-density lipoprotein, blood pressure, diabetes quality of life, and depression symptoms at 6 and 12 months. The study enrolled 365 participants into phase 1 and 122 participants into phase 2. Most participants were Black (341 [66%]) and male (454 [96%]), with a mean (SD) age of 60 (7.5) years. Mean phase 1 HbA1c change at 6 months for usual care was -0.20% (95% CI, -0.46% to 0.06%) vs -0.52% (95% CI, -0.76% to -0.29%) for mentees (P = .06). Mean phase 2 HbA1c change at 6 months for usual care was -0.46% (95% CI, -1.02% to 0.10%) vs 0.08% (95% CI, -0.42% to 0.57%) for mentees (P = .16). There were no differences in secondary outcomes or HbA1c levels at 12 months. There was no benefit to past mentees who became mentors. In this randomized clinical trial, a peer mentor intervention did not improve 6-month HbA1c levels and did not have sustained benefits. ClinicalTrials.gov Identifier: NCT01651117.


Mycotoxin production by isolates of Fusarium lactis from greenhouse sweet pepper (Capsicum annuum).
Internal fruit rot, caused by Fusarium lactis, is an important disease of sweet pepper (Capsicum annuum) in Canadian greenhouses. Production of the mycotoxins fumonisin B₁ (FB₁), moniliformin (MON) and beauvericin (BEA) by F. lactis (17 isolates) and the related species F. proliferatum (three isolates) and F. verticillioides (one isolate), which are also associated with internal fruit rot, was evaluated on rice medium. All 21 isolates examined were found to produce BEA, at concentrations ranging from 13.28 to 1674.60 ppm, while 13 of 17 F. lactis isolates and two of three F. proliferatum isolates produced MON (0.23 to 181.85 ppm). Only one isolate of F. lactis produced detectable levels of FB₁ in culture, whereas all three F. proliferatum isolates and the F. verticilloides isolate produced this mycotoxin (0.28 to 314 ppm). Production of FB₁, MON and BEA was also evaluated in inoculated pepper fruits showing mild or severe symptoms of infection. FB₁ could be detected in both lightly and heavily diseased fruit tissue after inoculation with F. lactis, F. proliferatum or F. verticilloides, at concentrations ranging from 0.61 to 8.04 ppm. BEA was also detected in lightly and heavily diseased fruit tissue inoculated with F. lactis, as well as in heavily diseased tissue inoculated with F. proliferatum (3.00 to 19.43 ppm), but not in tissue inoculated with F. verticilloides. MON was detected in all tissues inoculated with F. proliferatum or F. verticilloides, and in heavily diseased tissue inoculated with F. lactis (0.03 to 0.27 ppm). The three mycotoxins were also found in naturally infected sweet pepper fruits exhibiting symptoms of internal fruit rot and collected from a commercial greenhouse. The production of MON, BEA and FB₁ alone or in combination by isolates of F. lactis suggests that development of internal fruit rot of sweet pepper is an important food safety concern, and that every effort should be made to cull infected fruit before it makes it to market.


Pleomorphic lipoma: a tumour simulating liposarcoma.
Pleomorphic lipoma or giant-cell lipoma is a recently recognized entity affecting predominantly elderly and middle-aged men. The neck, shoulder region and back are the sites of predilection. The clinical setting is similar to that seen with spindle-cell lipoma. The lesion is characterized by an intricate mixture of mature fibrous tissue, adipose tissue and myxoid tissue interspersed with cellular foci. Most characteristic of the latter are a variety of giant cells and especially the 'floret' giant-cells, so named because of the arrangement of their nuclei which is reminiscent of the petals of a flower. The pleomorphism of the lesion frequently leads to misdiagnosis as liposarcoma. Criteria for the differentiation from the various types of liposarcoma are discussed. The possible relationship of pleomorphic lipoma to some of the 'atypical lipomas' described in the recent literature is analysed. The pleomorphic lipoma is a benign lesion of subcutaneous tissue which must be sharply differentiated from sarcomas. Some of the liposarcomas alleged in the literature to have originated within a pre-existing lipoma possibly represented pleomorphic lipomas. Pleomorphic lipoma is an entity which must be added to the growing number of pseudosarcomatous lesions of soft tissue.


Expression of Immunomodulatory Checkpoint Molecules in Drug-Resistant Neuroblastoma: An Exploratory Study.
Neuroblastoma is a common childhood cancer with poor prognosis when at its advanced stage. Checkpoint molecule inhibition is successful in treating multiple advanced adult cancers. We investigated PD-L1 and other checkpoint molecule expression to determine their roles in drug resistance and usefulness as targets for drug therapy. We developed three doxorubicin-resistant (DoxR) cell lines from parental cell lines. Matrigel in vitro invasion assays were used to compare invasiveness. Western blot assays were used to compare PD-L1 expression. Immuno-oncology checkpoint protein panels were used to compare concentrations of 17 checkpoint molecules both cellular and soluble. PD-L1 and 12 other checkpoint molecules were present in all cell lysates of each cell line without significantly different levels. Three were solubilized in the media of each cell line. PD-L1 is expressed in all DoxR and parental neuroblastoma cells and may be a potential target for drug therapy although its role in drug resistance remains unclear. Benchmarking checkpoint molecules provides the basis for future studies identifying targets for directed therapy and biomarkers for cancer detection or prognosis.


Overexpression of Orange Gene (OsOr-R115H) Enhances Heat Tolerance and Defense-Related Gene Expression in Rice (Oryza sativa L.).
In plants, the orange (Or) gene plays roles in regulating carotenoid biosynthesis and responses to environmental stress. The present study investigated whether the expression of rice Or (OsOr) gene could enhance rice tolerance to heat stress conditions. The OsOr gene was cloned and constructed with OsOr or OsOr-R115H (leading to Arg to His substitution at position 115 on the OsOr protein), and transformed into rice plants. The chlorophyll contents and proline contents of transgenic lines were significantly higher than those of non-transgenic (NT) plants under heat stress conditions. However, we found that the levels of electrolyte leakage and malondialdehyde in transgenic lines were significantly reduced compared to NT plants under heat stress conditions. In addition, the levels of expression of four genes related to reactive oxygen species (ROS) scavenging enzymes (OsAPX2, OsCATA, OsCATB, OsSOD-Cu/Zn) and five genes (OsLEA3, OsDREB2A, OsDREB1A, OsP5CS, SNAC1) responded to abiotic stress was showed significantly higher in the transgenic lines than NT plants under heat stress conditions. Therefore, OsOr-R115H could be exploited as a promising strategy for developing new rice cultivars with improved heat stress tolerance.


Observations on the marginal ruffles of an established fibroblast-like cell line.
LW13K2 cells, a clone of a spontaneously in vitro transformed derivative of embryonic Lewis rat fibroblastic cells, were studied by phase contrast cine-light microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The ruffles found at the advancing edge of cells grown on glass substrates in vitro form and recede in a period of less than one min if they do not make an attachment of the substrate. If they fail to make an attachment they may form pinocytotic channels near the leading edge as described by Price (1972) and/or collapse, generally backwards, towards the cell body. The "spines" which appear to reinforce the membranous ruffles are the last structures to disappear, and accumulate in an irregular array behind the ruffling edge; this area is behind that in which pinocytosis occurs. In comparison with the sparse numbers of ribosomes found in the trailing edge, they are present in notable concentrations near the leading, ruffling edge of the cell. No membrane vesicles have been found in or near the ruffling edges at the ruffle-spine concentration zone.


Separation of 2-arylpropionic acids on a cellulose based chiral stationary phase by RP-HPLC.
The enantiomers of eight 2-arylpropionic acids, a group of chiral non steroidal antiinflammatory drugs, were resolved as their benzylamide derivatives on a high-performance liquid chromatographic chiral stationary phase consisting of a covalently bound tris (4-methylbenzoate) cellulose layer on silica gel. The column was used under reversed-phase conditions using methanol as the main mobile phase component, with a perchlorate buffer pH 2.0. A compromise for derivatization with a water soluble carbodiimide and 1-hydroxybenzotriazole of a group of eight analytes was obtained. The derivatives were identified by IR- and MS-spectroscopy.


Comments on vaccines, August 1987.
Because of latency and infectious recurrences, eradication of herpes simplex and herpes zoster from the world by vaccines is likely to be much more difficult to accomplish than eradication of smallpox. For some time we may have to settle for control of these diseases rather than their eradication. The live, attenuated varicella vaccine protects immunocompromised and normal persons against clinical chickenpox but it does not completely prevent subsequent infection with natural chickenpox virus or latency. With herpes simplex vaccines we may have to be satisfied with amelioration or control of clinical infections and diminution of latency and recurrent disease. Varicella zoster immune globulin plays a useful role in attenuation of varicella in immunocompromised or special-risk persons exposed to varicella zoster virus. Passive immunization for herpes simplex (herpes simplex immune globulin or other antibody preparations) has been studied very little. Maybe passive immunization will have a place in future therapies, especially for serious herpes simplex virus infections in immunocompromised hosts.


Dynamic changes of timing precision in timed actions during a behavioural task in guinea pigs.
Temporal precision is a determinant of performance in various motor activities. Although the accuracy and precision of timing in activities have been previously measured and quantified, temporal dynamics with flexible precision have not been considered. Here, we examined the temporal dynamics in timed motor activities (timed actions) using a guinea pig model in a behavioural task requiring an animal to control action timing to obtain a water reward. In well-trained animals, momentary variations in timing precision were extracted from the temporal distribution of the timed actions measured over daily 12-h sessions. The resampling of the observed time of action in each session demonstrated significant changes of timing precision within a session. Periods with higher timing precision appeared indiscriminately during the same session, and such periods lasted ~ 20 min on average. We conclude that the timing precision in trained actions is flexible and changes dynamically in guinea pigs. By elucidating the brain mechanisms involved in flexibility and dynamics with an animal model, future studies should establish more effective methods to actively enhance timing precision in our motor activities, such as sports.


L-arginine pathway in neonates with meconium-stained amniotic fluid.
To study the arginase, nitric oxide synthase and nitric oxide pathways associated with passage of meconium. Cord blood samples were collected from 20 newborns with meconium-stained amniotic fluid (MSAF) and from 23 newborns with clear amniotic fluid. Cord blood pH, arginase, nitric oxide synthase and nitric oxide levels were compared between the groups. The differences between the arginase and nitric oxide measurements of the newborns with MSAF and those with clear amniotic fluid were significant. In the MSAF group arginase levels were significantly lower (p=0.007) and nitric oxide levels were significantly higher (p=0.032) than the clear amniotic fluid group. Hypoxia may be involved in the pathogenesis of meconium passage due to decreased arginase and increased nitric oxide levels.


Optimising a multi-strategy implementation intervention to improve the delivery of a school physical activity policy at scale: findings from a randomised noninferiority trial.
To maximise their potential health benefits, school-based physical activity policies need to be implemented at scale. This paper describes the third in a sequence of trials that sought to optimise an effective strategy (PACE) to assist schools' implementation of a physical activity policy. Specifically, it aimed to determine the probability that a multi-strategy intervention adapted to reduce in-person contact (Adapted PACE) was "as good as" the original intervention (PACE) in increasing the weekly minutes of structured physical activity implemented by classroom teachers. A noninferiority cluster randomised controlled trial was undertaken with 48 primary schools in New South Wales, Australia. Schools were randomised to receive PACE or a model with adaptations made to the delivery modes (Adapted PACE). Teachers' scheduled minutes of weekly physical activity was assessed at baseline (Oct 2018-Feb 2019) and 12-month follow-up (Oct-Dec 2019). The noninferiority margin was set at - 16.4 minutes based on previous data and decision panel consensus. A linear mixed model analysed within a Bayesian framework was used to explore noninferiority between the two PACE models. A cost minimisation analysis was conducted from the health service provider perspective, using the Australian dollar (AUD). The posterior estimate for the between group difference at follow-up was - 2.3 minutes (95% credible interval = - 18.02, 14.45 minutes). There was an estimated 96% probability of Adapted PACE being considered noninferior (only 4% of the posterior samples crossed the noninferiority margin of - 16.4 minutes). That is, the minutes of physical activity implemented by teachers at Adapted PACE schools was not meaningfully less than the minutes of physical activity implemented by teachers at PACE schools. The mean total cost was AUD$25,375 (95% uncertainty interval = $21,499, $29,106) for PACE and AUD$16,421 (95% uncertainty interval = $13,974, $19,656) for Adapted PACE; an estimated reduction of AUD$373 (95% uncertainty interval = $173, $560) per school. It is highly probable that Adapted PACE is noninferior to the original model. It is a cost-efficient alternative also likely to be a more suitable approach to supporting large scale implementation of school physical activity policies. Retrospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619001229167).


Erratum: An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder [Corrigendum].
[This corrects the article DOI: 10.2147/NDT.S313840.].


Ultrasonographic diaphragm thickness correlates with compound muscle action potential amplitude and forced vital capacity.
Noninvasive evaluation of respiratory function in patients with various neuromuscular disorders is important for predicting life expectancy. We performed B-mode ultrasonography (USG) and nerve conduction studies in 37 patients (16 had amyotrophic lateral sclerosis; 11, myopathy; and 10, neuropathy) and 10 controls. USG of the diaphragm was performed in the supine position using a linear probe over the intercostal space at the anterior axillary line. Diaphragm muscle thickness was measured at end-expiration. The amplitude of diaphragm compound muscle action potentials (CMAP) was obtained by phrenic nerve stimulation with a surface electrode. Respiratory function was measured with standard pulmonary function tests including forced vital capacity (FVC). Diaphragm thickness was significantly correlated with FVC (r = 0.74) and CMAP amplitude (r = 0.53). Diaphragm USG is useful for objective evaluation of pulmonary function in neuromuscular disorders without requiring undue patient effort or cooperation.


Primary colorectal diffuse large B-cell lymphoma: A report of eighteen cases in a tertiary care center.
Primary colorectal diffuse large B-cell lymphoma (DLBCL) is very rare colon malignancy. It is important to know the main demographic and clinical characteristics of these patients. We conducted a retrospective analysis of 18 patients diagnosed with primary colorectal DLBCL during a 17-year period at the National Cancer Institute of Brazil (INCA) between 2000 and 2018. Demographic characteristics, tumor localization, HIV status, lactate dehydrogenase (LDH) levels, treatment modality and follow-up status were obtained from medical records. Survival was estimated from the date of diagnosis until death. There were 11 male and seven female patients in our cohort, the median age at diagnosis was 59.5 years and four patients were HIV positive. Tumor was mainly localized in the right colon. Patients were treated with chemotherapy (CT) and/or surgical resection. Eleven patients died during a median follow-up of 59 months and the median survival time was 10 months. Six or more cycles of CT (HR=0.19; CI 95% 0.054-0.660, p = 0.009), LDH levels below 350 U/L (HR=0.229; CI 95% 0.060-0.876, p = 0.031) and surgical resection (HR=0.23; CI 95% 0.065-0.828, p = 0.030) were associated with reduced risk of death in univariate analysis. Patient's age and DLBCL right colon localization should be considered at diagnosis to distinguish between DLBCL and other diseases for differential diagnosis. Six cycles of CT, LDH levels below 350 U/L and surgical resection were associated with better survival. Our results are consistent with previous publications and address the importance of correct colorectal DLBCL diagnosis and treatment.


The Gln-Arg 191 polymorphism of the human paraoxonase gene is not associated with the risk of coronary artery disease among Chinese in Taiwan.
Paraoxonase (PON1) is a high density lipoprotein-associated enzyme capable of hydrolyzing lipid peroxides, and thus, might protect lipoproteins from oxidation. A common polymorphism due to an amino acid substitution (Gln-Arg) at codon 191 is considered to be a major determinant of variation in serum PON1 activity. Recent studies have suggested that the PON1-191 polymorphism is an independent risk factor for coronary atherosclerosis in patients with or without diabetes mellitus. The association of PON1-191 polymorphism genotypes and coronary artery disease (CAD) among Chinese subjects in Taiwan was examined. The genotype of 218 angiographically documented CAD patients and the same number of age- and sex-matched control subjects was determined. Genotypes AA, AB and BB were present in 25 (11%), 102 (47%) and 91 (42%) of control subjects, respectively, and in 30 (14%), 96 (44%) and 92 (42%) of CAD patients, respectively (chi2 = 0.57, P = 0.75 between groups). The frequency of the A allele was 0.36 for the control group and 0.35 for CAD patients (P = 0.94). No significant differences in the PON1-191 genotype frequencies could be found between groups when multivariate logistic regression analysis was performed, or different subgroups of age, sex or risk factors were analyzed. Among control subjects, there was also no significant difference between genotypes of the PON1-191 polymorphism and various clinical and lipid variables. In conclusion, our data suggest that there is no association between the Gln-Arg 191 polymorphism of the human PON1 gene and CAD among Chinese subjects in Taiwan.


Clinical risk scores predict procedural complications of primary percutaneous coronary intervention.
The predictive value of five risk score models containing clinical (PAMI-PMS, GRACE-GRS, and modified ACEF-ACEFm-scores), angiographic SYNTAX score (SXS) and combined Clinical SYNTAX score (CSS) variables were evaluated for the incidence of three procedural complications of primary percutaneous coronary intervention (pPCI): iatrogenic coronary artery dissection, angiographically visible distal embolization and angiographic no-reflow phenomenon. The mentioned scores and the incidence of procedural complications were retrospectively analyzed in 399 consecutive patients with acute ST-elevation myocardial infarction who underwent pPCI. Coronary dissection, distal embolization and no-reflow occurred in 39 (9.77%), 71 (17.79%), and 108 (27.07%) subjects, respectively. Coronary dissections were significantly associated with higher GRS, ACEFm, and CSS values (all p<0.05). PMS, GRS, ACEFm, and CSS were significantly higher in patients with no-reflow (all p<0.05), while distal embolization was not predicted by any of the calculated scores. In multiple logistic regression models, GRS and ACEFm remained independent predictors of both coronary dissections (OR 3.20, 95% CI 1.56-6.54, p<0.01 and OR 2.87, 95% CI 1.27-6.45, p=0.01, respectively) and no-reflow (OR 1.71, 95% CI 1.04-2.82, p=0.03 and OR 1.86, 95% CI 1.10-3.14, p=0.01, respectively). Whereas SXS failed to predict procedural complications related to pPCI, two simple, noninvasive risk models, GRS and ACEFm, independently predicted coronary dissections and no-reflow. Pre-interventional assessment of these scores may help the interventional cardiologist to prepare for procedural complications during pPCI.


Technique to display topographical evolution of EEG events.
We have developed a system to generate from 16 channels of the EEG 3-dimensional sequential topographical displays that facilitate the analysis of the propagation and field distribution of paroxysmal discharges. The ease and flexibility of data storage and analysis is as important as the concept of representing the EEG field potentials in a comprehensible fashion.


Percutaneous balloon kyphoplasty for the vertebral compression osteoporotic and pathological fracture: one-year retrospective study of 112 patients.
The aim of the study was to look for the effectiveness of percutaneous balloon kyphoplasty in the management of vertebral compression osteoporotic and pathological fracture. A retrospective analysis of 112 patients with 198 symptomatic wedge vertebral compression fractures who were treated by percutaneous balloon kyphoplasty was done. Visual Analogue pain (VAP) scale, Oswestry Disability index (ODI) and Short Form (SF-36) were used to look for the outcome. Pre-operative median VAS score was (8.0, IQR 2.0) which decreased to (4.0, IQR 3.0) at 12 months. Pre-operative median ODI score was (66, IQR 22) which at 12 months follow up decreased to (28, IQR 31). Short-form 36 showed improvement in all quality of life sub-domains. The physical component summary (PCS) improved from 33.0 ± 5.0 to 37.4 ± 6.1. The Mental component summary (MCS) improved from 17.1 ± 8.6 to 23.5 ± 18.9. The results were statistically significant (p < 0.001). Percutaneous balloon kyphoplasty alleviates pain and improves function, disability, and quality of life in osteoporotic and pathological fracture.


[Relationship of patients with multiple sclerosis to vaccination against COVID-19].
To study the attitude of patients with multiple sclerosis (MS) to vaccination as a method of preventing infectious diseases, in particular, COVID-19. The data of a survey of 408 patients with MS in the Sverdlovsk region in relation to vaccination against COVID-19, conducted using the original questionnaire, were analyzed. According to the survey data, 266 (65.2%) patients with MS are positive about vaccination. 222 (54.4%) patients with MS refused vaccination. The most common reasons for refusal were - fear that the vaccine could worsen the state of health - 44.1%, coronavirus infection in the last 6 months - 14.85%, «I was always told that I should not be vaccinated» - 14.4%, a combination of the above answers - 16.65%. The accumulated world experience and our observations demonstrate the important role of vaccination of patients with MS from COVID-19. It is necessary to rise the awareness of vaccination among patients with MS, since until recently this has been given insufficient attention.


A 13-Year-Old Male Patient With Severe Multifocal Pneumonia and Bronchiectasis That Required Extracorporeal Membrane Oxygenation.
A 13-year-old male patient with intermittent asthma and joint hypermobility presented to the ED in acute hypoxemic respiratory distress. He reported experiencing cough, increased work of breathing, and worsening chest pain for 3 days before presentation. He also reported fatigue and decreased appetite for 2 weeks. He had no known fever, myalgias, or recent weight loss. His medical history included two hospitalizations during early childhood for viral respiratory illnesses, one of which required intubation at 8 months of age. He had a gastrostomy tube placed shortly after his hospitalization because of failure to thrive secondary to aspiration based on a swallow study. His weight gain and growth improved with adequate nutrition, and his gastrostomy tube was removed at 2 years of age. His newborn screen, which included immunoreactive trypsinogen, was normal. He was noted to have hypermobile joints on physical examination at a clinic visit in childhood, but his examination results were not concerning for a hypermobility syndrome, and further diagnosis was not pursued. His parents endorsed that he has been a "healthy child" overall other than the occasional cough, which was attributed to asthma. His lifestyle was described as sedentary; he did not play any sports or have any unusual hobbies. He did not take any daily medications and no environmental exposures were reported. There was no family history of pulmonary, autoimmune, or connective tissue disease.


Pitch deviancy and intelligibility of deaf speech.
The relationship between pitch deviancy and other aspects of speech production that affect intelligibiliyy of deaf speech was investigated. The speech skills assessed included the following: ratings of pitch deviancy, ratings of overall intelligibility, production of the prosodic features--stress, intonation, and pause, and production of phonemes. Children who could not sustain phonation had speech that was consistently judged unintelligible. This group of children also had pure tone averages greater than 90 dB. For the remaining children, the relationship among pitch deviancy, intelligibility, and hearing level was variable. The highest intercorrelations were among prosodic feature production, phoneme production, and intelligibility.


Dental students' and staff perceptions of the impact of learning environment disruption on their learning and teaching experiences.
This project is a qualitative investigation into student and staff experiences of the effect of a major building redevelopment on their Dental School learning and teaching environments. Currently, there is little research exploring the impact of disruptions to the learning environment on students' learning and staff teaching experiences. Data were collected in 2016 using an online survey, semi-structured interviews and focus groups with students and staff. Data were analysed using a general inductive approach. Four broad themes emerged as follows: (i) students valued having a space for personal and collaborative work within the Dental School; (ii) both staff and students positioned staff contributions to learning experiences above the role of the physical learning environment; (iii) the majority of staff and students not feel that the physical environment limited their clinical training; and (iv) staff and students were able to adapt to the impact of building redevelopment through resilience and organisation. Results of this research have informed the provision of collegial spaces at the School, both as the building redevelopment continues, and in planning for the completed building.


Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms.
A population-based case-control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m(-2) at five years before diagnosis,, was associated with an increased risk of NHL (OR = 1.5, 95% CI 1.1-2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR = 1.9, 95% CI 1.3-2.8). Genetic variants in the leptin (LEP 19G > A, LEP -2548G > A) and leptin receptor genes (LEPR 223Q > R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR = 0.7, 95% CI 0.5-1.0) and increased with LEP -2548GA (OR = 1.3, 95% CI 1.0-1.7) and -2548AA (OR = 1.4, 95% CI 1.0-1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women.


Cardiomyopathy: appearances on ECG-gated 64-detector row computed tomography.
Multi-detector row cardiac computed tomography (MDCT) with its high spatial and temporal resolution now has an established clinical role in cardiac imaging. The present review illustrates the MDCT appearances of cardiomyopathy, with reference to the normal myocardium, using multi-planar, near-isotropic imaging, three-dimensional volume rendering, and ECG-gated multi-phasic functional imaging software capabilities of 64-MDCT. MRI and echocardiographic correlations are also provided where appropriate.


A scoring system to predict recurrence in patients with differentiated thyroid cancer.
Though predictive models have been constructed to determine the risk of recurrence in differentiated thyroid carcinoma, various aspects of these models are inadequate. Therefore, we aimed to construct, internally validate and implement on a mobile application a scoring system to determine this risk within 10 years. A retrospective cohort study in 1984-2016. A Spanish region. We enrolled 200 patients with differentiated thyroid carcinoma without distant metastasis at diagnosis. Time-to-recurrence. A risk table was constructed based on the sum of points to estimate the likelihood of recurrence. The model was internally validated and implemented as a mobile application for Android. Predictive factors were follicular histology, T, N and multifocality. This risk table had a C-statistic of 0.723. The calibration was satisfactory. This study provides an instrument able to predict rapidly and very simply which patients with differentiated thyroid carcinoma have a greater risk of recurrence.


Population pharmacokinetics and exposure-safety of lipophilic conjugates prodrug DP-VPA in healthy Chinese subjects for dose regime exploring.
Phospholipid-valproic acid (DP-VPA)is a prodrug for treating epilepsy. The present study explored the pharmacokinetics (PK) and exposure safety of DP-VPA to provide a basis for future studies exploring the safe dosage and therapeutic strategies for epilepsy. The study included a randomized placebo-controlled dose-escalation tolerance evaluation trial and a randomized triple crossover food-effect trial in healthy Chinese volunteers. A population pharmacokinetic (PopPK) model was established to analyze the PK of DP-VPA and active metabolite VPA. The exposure safety was assessed with the adverse drug reaction (ADR) in CNS. The PopPK of DP-VPA and metabolite VPA fitted a two-compartment model coupling one-compartment with Michaelis-Menten metabolite kinetics and first-order elimination. The absorption processes after single oral administration of DP-VPA tablet demonstrated nonlinear characteristics, including 0-order kinetic phase and time-dependent phase fitting Weibull distribution. The final model indicated that the DP-VPA PK was significantly affected by dosage and food. The exposure-safety relationship demonstrated a generalized linear regression; mild/moderate ADRs occurred in some subjects with 600 mg and all subjects with 1500 mg of DP-VPA, and no severe ADRs were reported up to 2400 mg. In conclusion, the study established a PopPK model describing the processing of DP-VPA and VPA in healthy Chinese subjects. DP-VPA showed good tolerance after a single dose of 600-2400 mg with nonlinear PK and was affected by dosage and food. Based on the association between neurological ADRs and higher exposure to DP-VPA by exposure-safety analysis, 900-1200 mg was recommended for subsequent study of safety and clinical effectiveness.


Western Cape local authority compliance with tuberculosis policy, 1984.
Local authority compliance with the national tuberculosis regimen in 1984 was examined in 29 of the 32 largest local authorities in the western Cape. The variability in management practices was especially evident with respect to children. The effects of the relative lack of uniformity and deviations from recommended policy need to be determined.


Ozanimod differentially preserves human cerebrovascular endothelial barrier proteins and attenuates matrix metalloproteinase-9 activity following in vitro acute ischemic injury.
Endothelial integrity is critical in mitigating a vicious cascade of secondary injuries following acute ischemic stroke (AIS). Matrix metalloproteinase-9 (MMP-9), a contributor to endothelial integrity loss, is elevated during stroke and is associated with worsened stroke outcome. We investigated the FDA-approved selective sphingosine-1-phosphate receptor 1 (S1PR1) ligand, ozanimod, on the regulation/activity of MMP-9 as well as endothelial barrier components [platelet endothelial cell adhesion molecule 1 (PECAM-1), claudin-5, and zonula occludens 1 (ZO-1)] in human brain microvascular endothelial cells (HBMECs) following hypoxia plus glucose deprivation (HGD). We previously reported that S1PR1 activation improves HBMEC integrity; however, mechanisms underlying S1PR1 involvement in endothelial cell barrier integrity have not been clearly elucidated. We hypothesized that ozanimod would attenuate an HGD-induced increase in MMP-9 activity that would concomitantly attenuate the loss of integral barrier components. Male HBMECs were treated with ozanimod or vehicle and exposed to 3 h of normoxia (21% O2) or HGD (1% O2). Immunoblotting, zymography, qRT-PCR, and immunocytochemical labeling techniques assessed processes related to MMP-9 and barrier markers. We observed that HGD acutely increased MMP-9 activity and reduced claudin-5 and PECAM-1 levels, and ozanimod attenuated these responses. In situ analysis, via PROSPER, suggested that attenuation of MMP-9 activity may be a primary factor in maintaining these integral barrier proteins. We also observed that HGD increased intracellular mechanisms associated with augmented MMP-9 activation; however, ozanimod had no effect on these select factors. Thus, we conclude that ozanimod has the potential to attenuate HGD-mediated decreases in HBMEC integrity in part by decreasing MMP-9 activity as well as preserving barrier properties.NEW & NOTEWORTHY We have identified a potential novel mechanism by which ozanimod, a selective sphingosine-1-phosphate receptor 1 (S1PR1) agonist, attenuates hypoxia plus glucose deprivation (HGD)-induced matrix metalloproteinase-9 (MMP-9) activity and disruptions in integral human brain endothelial cell barrier proteins. Our results suggest that ischemic-like injury elicits increased MMP-9 activity and alterations of barrier integrity proteins in human brain microvascular endothelial cells (HBMECs) and that ozanimod via S1PR1 attenuates these HGD-induced responses, adding to its therapeutic potential in cerebrovascular protection during the acute phase of ischemic stroke.


Role of corrosion in Harrington and Luque rods failure.
Ten in-vivo failed spinal instrumentation systems, i.e. six Harrington distraction rods with sublaminar hooks, one Harrington distraction rod with segmental wiring and three Luque rods with sublaminar wires, were fractographically analysed. In both Harrington and Luque rods corrosion fatigue was the predominant mechanism resulting in the failure. Five Harrington rods fractured at the first ratchet junction; fractures of the Luque rods were initiated by fretting of sublaminar wire with the rod surface in the presence of spinal non-union. Fretting and crevice corrosion were found to play an important role in compromising the segmental spinal instrumentation. The susceptibility of the 316 L CW austenitic stainless steel to pitting and relative resistance to crevice corrosion were measured by cyclic anodic polarization tests. The oxide inclusions have been found to play a significant role in the pitting of the alloy.


Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2.
Tandutinib is a novel inhibitor of tyrosine kinases FLT3, PDGFR and KIT. Our study was to explore the capability of tandutinib to reverse ABC transporter-mediated multidrug resistance. Tandutinib reversed ABCG2-mediated drug resistance in ABCG2-482-R2, ABCG2-482-G2, ABCG2-482-T7 and S1-M1-80 cells and increased the accumulation of doxorubicin, rhodamine 123 and [H(3)] mitoxantrone in ABCG2-overexpressing cells. Importantly, tandutinib selectively sensitized side population cells to mitoxantrone. Taken together, our results advocate the potency of tandutinib as an ABCG2 modulator and stem-like cells targeted agent to increase efficiency of anticancer drugs.


The influence of pH and temperature on the aqueous geochemistry of neodymium in near surface conditions.
Geochemical calculations were employed for the solubility and speciation of neodymium in a model soil solution as a function of pH. The calculations were based on the recently determined stability constants for Nd and solubility product for the Nd end-member of mineral monazite (NdPO(4)). Simulations were carried out at near neutral pH (pH 6.0 to pH 7.5) and 25 degrees C at the atmospheric CO(2) partial pressure. Additional calculations were also performed to assess Nd mobility at the extreme temperature conditions (300 degrees C) at neutral pH. Our results suggest that relatively dilute (Ionic Strength, I = 0.1), low-temperature waters may transport very small quantities of rare earth elements and actinides to the surficial environment at near neutral pH conditions. Evidently, higher temperature or extreme fluid composition may have a greater potential for mobilization of these elements. The results are pertinent to researchers interested in engineering applications for the precipitation of Nd and surrogate actinides from aqueous nuclear wastes.


Has changing diagnostic preference been responsible for the recent fall in incidence of sudden infant death syndrome in South Australia?
An apparent decrease in deaths attributed to sudden infant death syndrome (SIDS) has been noted in a number of diverse geographical areas during the past several years. At the same time the definition of SIDS has been in a state of flux and some observers have raised the possibility that the fall in SIDS deaths is due to diagnostic transfer rather than to a genuine decrease in numbers. The present study was undertaken to investigate this possibility. All sudden and unexpected deaths in infants under 1 year of age in South Australia during a 10 year period from 1984 to 1993 were reviewed. The number of deaths due to SIDS fell from 40 in 1984 to 17 in 1993, with a maximum of 52 cases per year in 1987. In contrast, the number of cases of sudden death not due to SIDS remained under 10 per year. The overall infant death rate also fell, while the total number of births per year remained relatively unchanged. The lack of major change in sudden infant death rates from other causes, combined with the fall in SIDS deaths, is not supportive of diagnostic transfer being a major determinant of the declining SIDS death rate. Therefore, other factors are likely to be responsible for the falling SIDS rate in this population.


Unraveling the structure and function of bacterioferritin in Candidatus Kuenenia stuttgartiensis: Iron storage sites maintain cellular iron homeostasis.
Anammox bacteria rely heavily on iron and have many iron storage sites. However, the biological significance of these iron storage sites has not been clearly defined. In this study, we explored the properties and location of iron storage sites to better understand their cellular function. To do this, the Candidatus Kuenenia stuttgartiensis iron storage protein, bacterioferritin (K.S Bfr), was successfully expressed and purified. In vitro, correctly assembled globulins were observed by transmission electron microscopy. The self-assembled K.S Bfr has active redox and can bind Fe2+ and mineralize it in the protein cavity. In vivo, engineered bacteria with K.S Bfr showed good adaptability to Fe2+, with a survival rate of 78.9% when exposed to 5 mM Fe2+, compared with only 66.0% for wild-type bacteria lacking K.S Bfr. A potential iron regulatory strategy similar to that of Anammox was identified in transcriptomic analysis of engineered bacteria. This system may be controlled by the iron uptake regulator Furto transport Fe2+ via FeoB and store excess Fe2+ in K.S Bfr to maintain cellular homeostasis. K.S Bfr has superior iron storage capacity both intracellularly and in vitro. The discovery of K.S Bfr reveals the storage location of iron-rich nanoparticles, increases our understanding of the adaptability of iron-dependent bacteria to Fe2+, and suggests possible iron regulation strategies in Anammox bacteria.


Induction of immunological tolerance in chickens inoculated with xenogeneic antigens at an early stage of embryonic development.
To induce immunotolerance, laboratory chicken embryos were inoculated with casein via embryonic blood vessel microinjection or with bovine serum albumin (BSA) by either embryonic blood vessel or yolk sac injection. All hatched chickens were challenged with the same protein four times at 10-day intervals beginning at 3 weeks old. Serum anti-casein and anti-BSA antibodies were analyzed by enzyme-linked immunosorbent assay (ELISA). Significantly reduced serum specific antibody, demonstrating immunotolerance, was observed in 53.8% of chickens exposed to casein in embryo by microinjection at 65-70 h of incubation; and in 62.5% (inoculating at 65-67 h of incubation) and 33.33% (inoculating at 67-70 h of incubation) of chickens exposed to BSA. Tolerant chickens presented in those groups inoculated with BSA at 5-7 days of embryogenesis by in ovo injection. The results showed tolerance could be induced by injecting xenogeneic protein into early developing embryo by both inoculation methods.


An NBD-based fluorescent and colorimetric chemosensor for detecting S2-: Practical application to zebrafish and water samples.
A novel 7-nitro-1,2,3-benzoxadiazole (NBD)-based chemosensor BOP ((5-bromopyridin-2-yl)(4-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)piperazin-1-yl)methanone) was synthesized. BOP could detect S2- through fluorescent quenching and colorimetric change. The detection limit was calculated to be 10.9 µM through fluorescence titration. The reaction mechanism of BOP towards S2- was estimated to be thiolysis of NBD amine, producing the cleavage products, NBD-S- and BP ((5-bromopyridin-2-yl)(piperazin-1-yl)methanone). The thiolysis was demonstrated by 1H NMR titrations, ESI-mass analysis and theoretical calculations. Importantly, BOP was able to successfully monitor S2- in zebrafish and water samples. Additionally, test strips coated with BOP were applied to the in-the-field measurements of S2-.


The anterior tympanomeatal angle in tympanoplasty: surgical techniques for the prevention of blunting.
The surgical repair of the anterior tympanic membrane with reconstruction of the vibrating anterior tympanomeatal angle is particularly difficult because of problems with graft separation, recurrent perforations, scar formation and blunting. The multilayer tympanoplasty technique anchors the structural layer of the drum to the annulus, by fixing the underlay fascial graft to the overlay graft, and reduces scar formation and blunting by immediate epithelial coverage of the vibrating anterior tympanomeatal angle. The purpose of this paper is to describe the multilayer sandwich graft tympanoplasty technique that has been effective in reconstructing the anterior tympanic membrane with preservation of the vibrating anterior tympanomeatal angle.


Isolation and analysis of nuclear bodies from estrogen-stimulated chick liver.
The target cells of most steroid hormones contain prominent structures termed nuclear bodies (NB). Estrogen (ES) responsive tissues have very distinctive NB, whose development has been associated with both the level of ES receptors and their retention times in nuclei. It has been suggested that these NB may be large-scale ES binding centers at transcriptionally hyperstimulated sites. We examined the formation of NB in ES-stimulated rooster liver, after primary induction of vitellogenesis and during subsequent decay of this response. Distinct NB appear 6 h postinduction, initially as compact spheroids with ring-like profiles and later on as more complex morphotypes. Nuclei average 15-17 NB each at peak induction (24-48 h), but this declines again gradually as the hormonal response abates. This transient pattern is paralleled closely by the [3H]ES binding capacity of nuclei in vitro and the calculated number of specific hormone receptors present. There is no direct numerical correspondence, however, between the NB and the ES receptors, either on a one-to-one basis or as some simple ratio. Hence any links between ES binding activity in nuclei and the NB must be both complex and indirect. Nuclear bodies were isolated following lysis of nuclei by sonication and separation of subfractions on discontinuous sucrose gradients. The resultant NB-enriched fraction consisted primarily of protein, with traces of DNA and RNA. Analysis of proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a complex pattern of polypeptides, some apparently unique and probably NB-derived.


Tail-pinch stress increases extracellular DOPAC levels (as measured by in vivo voltammetry) in the rat nucleus accumbens but not frontal cortex: antagonism by diazepam and zolpidem.
The effect of a tail-pinch stress on dopamine metabolism in the nucleus accumbens and frontal cortex was investigated in the awake unrestrained rat by measuring extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) levels through the use of in vivo differential pulse voltammetry. Mild tail pressure for 8 min caused a large (maximal effect + 70%) and sustained (more than 2 h) increase in the amplitude of the DOPAC oxidation peak in the nucleus accumbens but not in the prefrontal cortex. A similar increase in DOPAC levels was observed in the nucleus accumbens postmortem 1 h after tail-pinch stress. The tail-pinch induced increase in extracellular DOPAC levels in the nucleus accumbens was antagonized by pretreatment with diazepam (5 mg/kg i.p.) or zolpidem (5 mg/kg i.p.), a novel non-benzodiazepine hypnotic possessing anxiolytic properties. These results suggest that in contrast to other stressors, tail-pinch selectively activates dopaminergic systems projecting to the nucleus accumbens.


Treatment of refractory autoimmune diseases with ablative immunotherapy.
Immunological manipulations are the basis of modern therapy for refractory autoimmune diseases (AID). Ablative chemotherapy with stem cell support (autotransplant) as well as targeted immunotherapy using specific monoclonal antibodies, such as rituximab and campath 1-H have become acceptable second line therapy for severe refractory AID. Until now, more than 500 autotransplants have been performed worldwide for various autoimmune disorders, including multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) with encouraging results, although transplant related mortality (TRM) in the range between 2 and 17% still remains one of the major limitations of the procedure. Immunotherapy is a relatively safe approach associating with sustained remissions in a considerable proportion of treated patients. Better selection of patients and earlier immunotherapy, preceded an irreversible organ damage might further improve the clinical outcome of patients with AID.


Repetitive head impacts do not affect postural control following a competitive athletic season.
Evidence suggests that Repetitive Head Impacts (RHI) directly influence the brain over the course of a single contact collision season yet do not significantly impact a player's performance on the standard clinical concussion assessment battery. The purpose of this study was to investigate changes in static postural control after a season of RHI in Division I football athletes using more sensitive measures of postural control as compared to a non-head contact sports. Fourteen Division I football players (CON) (age=20.4±1.12years) and fourteen non-contact athletes (NON) (2 male, 11 female; age=19.85±1.21years) completed a single trial of two minutes of eyes open quiet upright stance on a force platform (1000Hz) prior to athletic participation (PRE) and at the end of the athletic season (POST). All CON athletes wore helmets outfitted with Head Impact Telemetry (HIT) sensors and total number of RHI and linear accelerations forces of each RHI were recorded. Center of pressure root mean square (RMS), peak excursion velocity (PEV), and sample entropy (SampEn) in the anteroposterior (AP) and mediolateral (ML) directions were calculated. CON group experienced 649.5±496.8 mean number of impacts, 27.1±3.0 mean linear accelerations, with ≈1% of total player impacts exceeded 98g over the course of the season. There were no significant interactions for group x time RMS in the AP (p=0.434) and ML (p=0.114) directions, PEV in the AP (p=0.262) and ML (p=0.977) directions, and SampEn in the AP (p=0.499) and ML (p=0.984) directions. In addition, no significant interactions for group were observed for RMS in the AP (p=0.105) and ML (p=0.272) directions, PEV in the AP (p=0.081) and ML (p=0.143) directions, and SampEn in the AP (p=0.583) and ML (p=0.129) directions. These results suggest that over the course of a single competitive season, RHI do not negatively impact postural control even when measured with sensitive non-linear metrics.


Chondroitinase improves midbrain pathway reconstruction by transplanted dopamine progenitors in Parkinsonian mice.
Within the adult central nervous system the lack of guidance cues together with the presence of inhibitory molecules produces an environment that is restrictive to axonal growth following injury. Consequently, while clinical trials in Parkinson's disease (PD) patients have demonstrated the capacity of fetal-derived dopamine neurons to survive, integrate and alleviate symptoms, the non-permissive host environment has contributed to the incomplete re-innervation of the target tissue by ectopic grafts, and even more noticeable, the poor reconstruction of the midbrain dopamine pathways following homotopic midbrain grafting. One such inhibitory molecule is the chondroitin sulfate proteoglycan (CSPG), a protein that has been shown to impede axonal growth during development and after injury. Digestion of CSPGs, by delivery of the bacterial enzyme chondroitinase ABC (ChABC), can improve axonal regrowth following a number of neural injuries. Here we examined whether ChABC could similarly improve axonal growth of transplanted dopamine neurons in an animal model of PD. Acute delivery of ChABC, into the medial forebrain bundle, degraded CSPGs along the nigrostriatal pathway. Simultaneous homotopic transplantation of dopaminergic progenitors, into the ventral midbrain of ChABC treated PD mice, had no effect on graft survival but resulted in enhanced axonal growth along the nigrostriatal pathway and reinnervation of the striatum, compared to control grafted mice. This study demonstrates that removal of axonal growth inhibitory molecules could significantly enhance dopaminergic graft integration, thereby holding implications for future approaches in the development of cell replacement therapies for Parkinsonian patients.


Mesenchymal-epithelial interaction techniques.
This paper reviews the importance of mesenchymal-epithelial interactions in development and gives detailed technical protocols for investigating these interactions. Successful analysis of mesenchymal-epithelial interactions requires knowing the ages in which embryonic, neonatal and adult organs can be separated into mesenchymal and epithelial tissues. Methods for separation of mesenchymal and epithelial tissues and preparation of tissue recombinants are described.


Detection and Management of Intraocular Inflammation after Brolucizumab Treatment for Neovascular Age-Related Macular Degeneration.
To present interim descriptive insights from the OCTOPUS and SWIFT studies on incidence, clinical features, management, and outcomes of intraocular inflammation (IOI), vasculitis, and occlusive vasculitis with brolucizumab treatment (Beovu, Novartis) in patients with neovascular age-related macular degeneration (nAMD) who were anti-VEGF naive or pretreated with anti-VEGFs (ranibizumab or aflibercept). OCTOPUS (NCT04239027) and SWIFT (NCT04264819) studies are prospective phase IIIb single-arm, open-label, multicenter studies assessing brolucizumab. Anti-VEGF naive (OCTOPUS) and pretreated (SWIFT) patients with nAMD. Interim prespecified analysis on the efficacy end point provided an opportunity to analyze IOI-related safety. Reports of IOI-related adverse events (AEs) were reviewed, and AE images and clinical features and outcomes of each case were analyzed by a review committee. Of 505 brolucizumab-treated eyes/patients with median brolucizumab treatment of 8.8 months, 53 eyes demonstrated at least 1 IOI-related AE. The incidence of overall IOI-related AEs was 10.5%; among these events, the incidence was 7.1% for IOI only without retinal involvement and 3.4% for IOI with retinal involvement (2.0% with vasculitis, 1.4% with vascular occlusion with or without vasculitis). Incidence was similar in naive and pretreated patients. Before the onset of the first IOI-related AE, eyes received a median of 2 brolucizumab injections; 81.1% of IOI-related AEs occurred during the loading phase (median, 25.0 days from the last brolucizumab injection). At AE onset, most frequently reported symptoms were floaters (52.8%) and blurred or decreased vision (37.8%). Of the 86.8% of AEs that were treated, most were treated with topical corticosteroids (75.5%), 28.3% by systemic corticosteroids, and 26.8% by intraocular corticosteroids. No severe vision loss was reported for the 7 nontreated AEs. Overall, the median best-corrected visual acuity (BCVA) change at IOI-related AEs resolution from baseline was 1 letter (range, -74 to +32 letters), and 2 patients with occlusive vasculitis had BCVA loss ≥ 15 letters due to IOI-related AEs. All eyes permanently discontinued brolucizumab after the first IOI-related AE. This analysis highlights the need for monitoring and education of patients to report any signs of IOI-related events immediately when being treated with brolucizumab. IOI should be treated promptly and intensely with corticosteroids. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Induction of peroxisomal beta-oxidation in 7800 C1 Morris hepatoma cells in steady state by fatty acids and fatty acid analogues.
(1) The activities of peroxisomal beta-oxidation and palmitoyl-CoA hydrolase in Morris hepatoma 7800 C1 cells were studied. The cells were grown until they reached steady state (constant DNA content per dish) and then were cultured in the presence of fatty acids or alkylthioacetic acids, i.e., S-substituted fatty acid analogues. (2) The fatty acid analogues increased the activity of the cyanide-insensitive palmitoyl-CoA oxidase several-fold. The effect was dose-dependent; 5 microM tetradecylthioacetic acid (TTA) was sufficient to give a significant induction. With 20 microM TTA, the increase in enzyme activity was discernable after 3 h and reached a maximum after 3 days. The inducing effect of the alkylthioacetic acids increased with the length of the hydrophobic alkyl end of the analogue. The inducing ability disappeared when the fatty acid analogue was omega-oxidized to the corresponding dicarboxylic acid. Oxidation of the sulfur atom resulted in inhibited cellular uptake and abolished enzyme induction. (3) At higher concentrations (0.5-1 mM), normal fatty acids also induced cyanide-insensitive palmitoyl-CoA oxidation. Myristic acid was the most potent inducer, whereas fatty acids with shorter as well as longer carbon chains were less efficient. The inducing effect increased with the number of double bounds in the fatty acid. (4) The normal fatty acids as well as the fatty acid analogues also induced palmitoyl-CoA hydrolase, but the relative changes were much less pronounced than with the palmitoyl-CoA oxidase.


Relationship between cellular accumulation of rhodamine 123 (R123) and cytotoxicity in B16 melanoma cells.
Rhodamine 123 (R123) is a mitochondria-specific prototype anticancer agent because its target is the energy-producing mechanism of the cell. The goal of this study was to investigate the relationship between intracellular R123 accumulation and cytotoxicity in a R123-sensitive cell line (RS) and a R123-resistant subline (RR) that we developed. Cytotoxicity after exposure to R123 (0-60 micrograms/ml) was assessed using the clonogenic assay. Intracellular R123 was extracted with acid-alcohol and measured by fluorimetry. The rate of R123 accumulation over 1 hr was significantly higher (P less than 0.0001) for RS cells (4.65 +/- 0.39 micrograms/min/10(6) cells) than for RR cells (1.29 +/- 0.24 micrograms/min/10(6) cells). R123 accumulation in RS cells was strongly correlated (r = 0.80; P less than 0.0001) with cytotoxicity. Treatment of RR cells with verapamil (100 microM) reversed R123 resistance. The resulting dose-survival curve was identical to the dose-response curve of RS cells treated with R123 alone. Cellular content of R123 in RR cells treated with verapamil increased to a level similar to that of RS cells and correlated with cytotoxicity. These data suggest that cytotoxicity of R123 in B16 cells results from increased cellular accumulation of R123.


Background rates of adverse events of special interest for COVID-19 vaccine safety monitoring in the United States, 2019-2020.
The U.S. Food and Drug Administration (FDA) Biologics Effectiveness and Safety (BEST) Initiative conducts active surveillance of adverse events of special interest (AESI) after COVID-19 vaccination. Historical incidence rates (IRs) of AESI are comparators to evaluate safety. We estimated IRs of 17 AESI in six administrative claims databases from January 1, 2019, to December 11, 2020: Medicare claims for adults ≥ 65 years and commercial claims (Blue Health Intelligence®, CVS Health, HealthCore Integrated Research Database, IBM® MarketScan® Commercial Database, Optum pre-adjudicated claims) for adults < 65 years. IRs were estimated by sex, age, race/ethnicity (Medicare), and nursing home residency (Medicare) in 2019 and for specific periods in 2020. The study included >100 million enrollees annually. In 2019, rates of most AESI increased with age. However, compared with commercially insured adults, Medicare enrollees had lower IRs of anaphylaxis (11 vs 12-19 per 100,000 person-years), appendicitis (80 vs 117-155), and narcolepsy (38 vs 41-53). Rates were higher in males than females for most AESI across databases and varied by race/ethnicity and nursing home status (Medicare). Acute myocardial infarction (Medicare) and anaphylaxis (all databases) IRs varied by season. IRs of most AESI were lower during March-May 2020 compared with March-May 2019 but returned to pre-pandemic levels after May 2020. However, rates of Bell's palsy, Guillain-Barré syndrome, narcolepsy, and hemorrhagic/non-hemorrhagic stroke remained lower in multiple databases after May 2020, whereas some AESI (e.g., disseminated intravascular coagulation) exhibited higher rates after May 2020 compared with 2019. AESI background rates varied by database and demographics and fluctuated in March-December 2020, but most returned to pre-pandemic levels after May 2020. It is critical to standardize demographics and consider seasonal and other trends when comparing historical rates with post-vaccination AESI rates in the same database to evaluate COVID-19 vaccine safety.


Toward the synthesis of spirastrellolide a: construction of a tetracyclic C26-C40 subunit containing the DEF-bis-spiroacetal.
[reaction: see text] A stereo-controlled synthesis of the fully elaborated C26-C40 tricyclic [5,6,6]-bis-spiroacetal of spirastrellolide A containing the C28 chlorine substituent is reported, exploiting asymmetric Sharpless dihydroxylation and boron-mediated allylation methodology.


Clinical effects of insulin glargine combined with repaglinide in the treatment of type 2 diabetes.
To analyze the clinical effects of insulin glargine combined with repaglinide on the treatment of type 2 diabetes (T2D). One hundred and twelve T2D patients were divided into two groups based on the treatment strategy, the control group (N=56) receiving insulin glargine and the experimental group (N=56) receiving insulin glargine combined with repaglinide. Clinical effects were analyzed and compared between the two groups. After treatment, the levels of fasting blood glucose (FBG), 2h-postprandial blood glucose (2h-PBG), and glycosylated hemoglobin of the experimental group were significantly lower than those of the control group (P<0.05). The levels of fasting C-peptide (FCP) and 2h-postprandial C-peptide (2h-PCP) of the experimental group were significantly higher than those of the control group (P<0.05) after treatment. Compared with the control group, the therapeutic efficacy was significantly higher (P<0.05), the time to normal blood glucose was notably shorter (P<0.05), and the insulin dosage was considerably lower in the experimental group (P<0.05). The incidence of adverse effects of the experimental group was significantly lower than that of the control group (P<0.05), and the treatment satisfaction of the experimental group was significantly higher than that of the control group (P<0.05). Insulin glargine combined with repaglinide is an effective and safe regimen in clinical practice, which can effectively control the blood glucose level, lower insulin dosage, and reduce adverse effects of T2D.


Using participatory action research to co-design perinatal support strategies for Aboriginal and Torres Strait Islander parents experiencing complex trauma.
Support is important for all parents but critical for those experiencing complex trauma. The The Healing the Past by Nurturing the Future project uses participatory action research to co-design effective perinatal support for Aboriginal and Torres Strait Islander parents. This research aims to identify and refine culturally appropriate support strategies for Aboriginal and Torres Strait Islander parents experiencing complex trauma. We presented our synthesised eight parent support goals and 60 strategies, collated from Elder and parent focus groups, previous participatory workshops, and evidence reviews, for discussion at a stakeholder workshop. Stakeholder perspectives were captured using a three-point agreement activity and, self- and scribe-recorded comments. Aboriginal and non-Aboriginal researchers analysised the qualitative data, to identify core factors which might facilitate or help enact the parenting related goals. Overall, stakeholders (n = 37) strongly endorsed all eight goals. Workshop attendees (57% Aboriginal) represented multiple stakeholder roles including Elder, parent and service provider. Four core factors were identified as crucial for supporting parents to heal from complex trauma: Culture (cultural traditions, practices and strengths), Relationality (family, individual, community and services), Safety (frameworks, choice and control) and Timing (the right time socio-emotionally and stage of parenting). Context-specific support tailored to the Culture, Relationality, Safety, and Timing needs of parents is essential. These four factors are important elements to help enact or facilitate parenting support strategies. Further work is now required to develop practical resources for parents, and to implement and evaluate these strategies in perinatal care to address cumulative and compounding cycles of intergenerational trauma.


Changes in sleep schedule and chronotype due to COVID-19 restrictions and home office.
In this study, we researched the effects of the COVID-19 restriction measures on the sleep health of N = 681 German residents (mean age: 28.63 years, SD: 10.49 years). The data were collected with an anonymous online survey composed of validated questionnaires and additional questions to quantify changed circumstances during the pandemic. Data were collected from May 18 to June 17, 2020, while governmental restrictions were imposed in Germany. We exclusively analysed participants working in home office during this time. Participants woke up about 1 hour later during the COVID-19 restriction phase, while going to bed at almost the same time as before. During the week, participants slept about an hour longer, while sleep at weekends did not differ significantly. Social jetlag decreased from 1:39 ± 1:00 to 0:49 ± 0:42 min in our sample. The number of children in the household was a significant factor predicting sleep timing. Participants with children living in the same household slept longer and sleep onset was later. In terms of sleep behaviour and, consequently, sleep health, participants benefited from the transition to home office. They were able to adapt their waking and working hours better to their biological rhythm, which reduced social jetlag.


Transcription factor MafB may play an important role in secondary hyperparathyroidism.
The transcription factor MafB is essential for development of the parathyroid glands, the expression of which persists after morphogenesis and in adult parathyroid glands. However, the function of MafB in adult parathyroid tissue is unclear. To investigate this, we induced chronic kidney disease (CKD) in wild-type and MafB heterozygote (MafB+/-) mice by feeding them an adenine-supplemented diet, leading to secondary hyperparathyroidism. The elevated serum creatinine and blood urea nitrogen levels in heterozygous and wild-type mice fed the adenine-supplemented diet were similar. Interestingly, secondary hyperparathyroidism, characterized by serum parathyroid hormone elevation and enlargement of parathyroid glands, was suppressed in MafB+/- mice fed the adenine-supplemented diet compared to similarly fed wild-type littermates. Quantitative RT-PCR and immunohistochemical analyses showed that the increased expression of parathyroid hormone and cyclin D2 in mice with CKD was suppressed in the parathyroid glands of heterozygous CKD mice. A reporter assay indicated that MafB directly regulated parathyroid hormone and cyclin D2 expression. To exclude an effect of a developmental anomaly in MafB+/- mice, we analyzed MafB tamoxifen-induced global knockout mice. Hypocalcemia-stimulated parathyroid hormone secretion was significantly impaired in MafB knockout mice. RNA-sequencing analysis indicated PTH, Gata3 and Gcm2 depletion in the parathyroid glands of MafB knockout mice. Thus, MafB appears to play an important role in secondary hyperparathyroidism by regulation of parathyroid hormone and cyclin D2 expression. Hence, MafB may represent a new therapeutic target in secondary hyperparathyroidism.


Design, synthesis, and evaluation of a novel class of 2,3-disubstituted-tetrahydro-β-carboline derivatives.
Several novel tetrahydro-β-carboline derivatives with amino acid residues at the 2-position and a glucosamine group at the 3-position of the tetrahydro-β-carboline nucleus were synthesized from a readily available starting material, tryptophane, and were evaluated for their anti-inflammatory activity in the present study. Our results showed that all of the derivatives tested exhibited a significant inhibition of xylene-induced inflammation in mice.


A comparison between quality assurance and action research.
Superficially, action research and audit, or quality assurance, initiatives have much in common. However, a closer examination reveals some fundamental differences in the background, goals, processes, data collection, motivation and funding of these approaches ( Fig.1 ).


Thymol and eugenol against Rhipicephalus sanguineus sensu lato engorged females: Biological, histopathological and bioinformatic analysis.
The aim of this study was to evaluate the reproductive biology and histopathology of the ovaries of engorged females of Rhipicephalus sanguineus sensu lato exposed to combinations of thymol and eugenol, as well as to evaluate in silico the possible interactions of thymol and eugenol in tick cell membranes. To evaluate the tick reproductive biology, the adult immersion test (AIT) was performed, in which the engorged females were immersed in solutions of thymol and eugenol, combined or alone, at concentrations of 2.5 and 5.0 mg/mL. Two control groups (water and 3% DMSO) were also performed. The ticks were kept in a controlled chamber (B.O.D - 27 ± 1 °C and 80% ± 5% RH) to evaluate egg production and viability. To perform the ovaries histopathological evaluation, females were immersed in combination of thymol and eugenol (each at 2.5 and 5.0 mg/mL) and control (water and 3% DMSO) solutions. After immersion, the females were kept in B.O.D (27 ± 1 °C and RH of 80% ± 5%) for four days, they were dissected and the ovaries processed for histological analysis. In addition, an in silico analysis was performed using PASS online® software to predict probability activity (PA) of thymol and eugenol in cell membranes. The treatment with the combination of thymol and eugenol (each at 5.0 mg/mL) caused a reduction (p < 0.01) in oviposition, while the treatments with thymol (5.0 mg/mL) and combination of thymol and eugenol (5.0 mg/mL) reduced (p < 0.05) the egg viability. The treatment with combination of thymol and eugenol (5.0 mg/mL) resulted in a control percentage of 99.9%, while in the other treatments, control percentages below 56% were observed. Oocytes from the females exposed to the combinations of thymol and eugenol (each compound at 2.5 mg/mL) showed histopathological changes, except on oocyte V, while those treated with these compounds alone at 2.5 mg/mL, did not reveal any change. Changes in the shape of the oocyte, presence of vacuoles in the cytoplasm and germinal vesicle, reduction and fusion of yolk granules and rupture of some oocytes were observed. In silico analysis, showed that these compounds can act as membrane permeability inhibitors, membrane permeability agonists, membrane integrity antagonists and apoptosis agonists. We conclude that the combination of thymol and eugenol causes changes in the reproductive biology and morphophysiology of engorged females oocytes. The in silico analysis using thymol and eugenol revealed the possibility of disorganization in the cell membranes, a fact that may explain the histopathological alterations observed.


Impact of PLA/Mg films degradation on surface physical properties and biofilm survival.
New biocompatible and bioabsorbable materials are currently being developed for bone regeneration. These serve as scaffolding for controlled drug release and prevent bacterial infections. Films of polylactic acid (PLA) polymers that are Mg-reinforced have demonstrated they have suitable properties and bioactive behavior for promoting the osseointegration process. However little attention has been paid to studying whether the degradation process can alter the adhesive physical properties of the biodegradable film and whether this can modify the biofilm formation capacity of pathogens. Moreover, considering that the concentration of Mg and other corrosion products may not be constant during the degradation process, the question that arises is whether these changes can have negative consequences in terms of the bacterial colonization of surfaces. Bacteria are able to react differently to the same compound, depending on its concentration in the medium and can even become stronger when threatened. In this context, physical surface parameters such as hydrophobicity, surface tension and zeta potential of PLA films reinforced with 10% Mg have been determined before and after degradation, as well as the biofilm formation capacity of Staphylococcus epidermidis. The addition of Mg to the films makes them less hydrophobic and the degradation also reduces the hydrophobicity and increases the negative charge of the surface, especially over long periods of time. Early biofilm formation at 8 h is consistent with the physical properties of the films, where we can observe a reduction in the bacterial biofilm formation. However, after 24 h of incubation, the biofilm formation increases significantly on the PLA/Mg films with respect to PLA control. The explosive release of Mg ions and other corrosion products within the first hours were not enough to prevent a greater biofilm formation after this initial time. Consequently, the Mg addition to the polymer matrix had a bacteriostatic effect but not a bactericidal one. Future works should aim to optimize the design and biofunctionality of these promising bioabsorbable composites for a degradation period suitable for the intended application.


Pharmacognostic standardization of Rhododendron afghanicum through scanning electron microscopy and analytical techniques.
The aim of this study was to assess and compare the pharmacognostic and microscopic features of the selected parts of Rhododendron afghanicum Aitch. & Hemsl. It is a perennial and shrub. Anatomy of stem and leaves depicted dicot structure. It will provide knowledge about standardization, authentication, and adulteration with its co-species. The macroscopic examination reveals that fresh leaves are green, pleasant odor with a bitter taste. The leaf is oblong-elliptic in shape and sub-acute at apex; rounded at the base with entire margin. Stem is irregular and the outer surface is light brown, rough with fissures and ridges. Microscopic examination indicated the presence of xylem, phloem, peltate trichome, epidermal cells, collenchymas cells, paracytic stomata, and reticulate vessels. Stem microscopy reveals epidermis, hypodermis, cortex, sclerenchymatous sheath, phloem, xylem, and pith. It will be helpful in identification and quality control. Micro-morphological features were observed through SEM. EDX spectroscopy were carried out and revealed the presence of calcium, silicon, and potassium. Phytochemical analysis revealed the presence of tannins, saponins, phenols, protein, flavonoids, glycosides, and alkaloids. Ethyl acetate for leaf and stem demonstrate the highest extractive values (18% and 13%), respectively. XRD peaks appeared at 30.21, 28.73, 205.73, 200.73, 380.07, 390.24, 490.11, and 450.33ο . This will be helpful to identify the ownership of herbal drugs by the diffraction peaks through crystal structures and atomic spacing. These parameters are crucial for drug identification, standardization, authentication, and drug designing. These studies also provided knowledge regarding therapeutic and nutraceutical importance of this plant. RESEARCH HIGHLIGHTS: The current pharmacognostic studies carried out on Rhododendron afghanicum can serve as a basis for compiling keys for finding the taxonomic identification and authentication of the said species by morphological, anatomical, and physicochemical features.


Management of distal rectal cancer: results from a national survey.
Owing to the complexity of distal rectal cancer its management requires a multidisciplinary approach. The diagnosis and the response after neoadjuvant chemoradiotherapy are not easy to assess and therefore the surgical approach is heterogeneous. The purpose of this survey is to evaluate the experiences of members of the Italian Society of Surgery in diagnosis and treatment strategies for rectal cancer and compare it with international practice. A questionnaire was devised comprising 18 questions with 11 sub-items making a total of 29 questions and submitted online to all the 2,500 members of the SIC starting from July 2010. The survey was completed in June 2011. The overall response rate was 17.8 % (444). The majority of the Italian surgeons' responses were in line with the international consensus reflecting the complex management of distal rectal cancer. Other opinions, especially those on staging, diverge from the common view of MRI being the gold standard in the assessment of loco-regional diffusion of the disease and on the superiority of FDG PET-CT versus CT for systemic staging. The timing for the re-staging and for surgery following neoadjuvant chemoradiotherapy does not reflect the international opinion. Italian surgeons are also exposed to the common difficulties encountered internationally in the management of distal rectal cancer. Probably, the implementation of an Italian rectal cancer registry and of many national and international multicentre studies may improve the management of rectal cancer in Italy.


Omega-3 and -6 fatty acids allocate somatic and germline lipids to ensure fitness during nutrient and oxidative stress in Caenorhabditis elegans.
Animals in nature are continually challenged by periods of feast and famine as resources inevitably fluctuate, and must allocate somatic reserves for reproduction to abate evolutionary pressures. We identify an age-dependent lipid homeostasis pathway in Caenorhabditis elegans that regulates the mobilization of lipids from the soma to the germline, which supports fecundity but at the cost of survival in nutrient-poor and oxidative stress environments. This trade-off is responsive to the levels of dietary carbohydrates and organismal oleic acid and is coupled to activation of the cytoprotective transcription factor SKN-1 in both laboratory-derived and natural isolates of C. elegans. The homeostatic balance of lipid stores between the somatic and germ cells is mediated by arachidonic acid (omega-6) and eicosapentaenoic acid (omega-3) precursors of eicosanoid signaling molecules. Our results describe a mechanism for resource reallocation within intact animals that influences reproductive fitness at the cost of somatic resilience.


High-throughput calculation screening for new silicon allotropes with monoclinic symmetry.
A total of 87 new monoclinic silicon allotropes are systematically scanned by a random strategy combined with group and graph theory and high-throughput calculations. The new allotropes include 13 with a direct or quasi-direct band gap and 12 with metallic characteristics, and the rest are indirect band gap semiconductors. More than 30 of these novel monoclinic Si allotropes show bulk moduli greater than or equal to 80 GPa, and three of them show even greater bulk moduli than diamond Si. Only two of the new Si allotropes show a greater shear modulus than diamond Si. The crystal structures, stability (elastic constants, phonon spectra), mechanical properties, electronic properties, effective carrier masses and optical properties of all 87 Si monoclinic allotropes are studied in detail. The electron effective masses ml of five of the new allotropes are smaller than that of diamond Si. All of these novel monoclinic Si allotropes show strong absorption in the visible spectral region. Taken together with their electronic band gap structures, this makes them promising materials for photovoltaic applications. These investigations greatly enrich the current knowledge of the structure and electronic properties of silicon allotropes.


[Dimensions and interpretative patterns of aging: attitudes about aging, being old and ways of living in old age].
Attitudes about older people and being old develop in the early and middle phases of life and influence the subsequent aging process. Because aging processes vary across different domains of life and functioning, one cannot assume unanimously negative or positive attitudes towards old age and aging. Thus, in the psychological part of the project Zones of Transition ("Zonen des Übergangs"), age stereotypes and views of the self in old age were assessed in different life domains and for different age groups, and their relation to well-being and the self-concept was investigated. The project also focused on the analysis of attitudes towards one's personal way of living in old age. A questionnaire was developed that assesses those attitudes on the basis of the dimensions "active commitment" and "pleasure and leisure". Our results support a multidimensional conception of attitudes towards aging and way of living in old age as well as of their influence on development across the lifespan.


Prediction of production facility priorities using Back Propagation Neural Network for bus body building industries: a post pandemic research article.
The pandemic recession has caused enormous disturbances in many industrialized countries. The massive disruption of the supply chain of production is affecting manufacturing companies operating in and around India. Particularly the medium-sized bus body building works have been reduced, due to its compound anomalies. The integrated view of the production facility priorities is not an easy task. Since it is difficult for available labour to conduct an entire project, the completion of a production process is delayed. But still, the dilemma remains as to how production managers can correctly interpret the priorities of the facility. Indeed, this is a problem missing from the previous study. Fortunately, in the current competitive environment, it is essentially needed. This study has been used Back Propagation Neural Network (BPNN) approach for predicting production facility priorities. The experimental results confirm the suitability of the model for predicting priorities. A real-world problem is taken into account in making use of the model output. In this sense, this total solution facilitates production managers in assessing and enhancing the production facilities. The findings emphasize the priority of "equipment effectiveness, labour scheduling and communication" in order to strengthen the post-pandemic production facility.


From 'Nerve Fiber Regeneration' to 'Functional Changes' in the Human Brain-On the Paradigm-Shifting Work of the Experimental Physiologist Albrecht Bethe (1872-1954) in Frankfurt am Main.
Until the beginning 1930's the traditional dogma that the human central nervous system (CNS) did not possess any abilities to adapt functionally to degenerative processes and external injuries loomed large in the field of the brain sciences (Hirnforschung). Cutting-edge neuroanatomists, such as the luminary Wilhelm Waldeyer (1836-1921) in Germany or the Nobel Prize laureate Santiago Ramón y Cajal (1852-1934) in Spain, debated any regenerative and thus "plastic" properties in the human brain. A renewed interest arose in the scientific community to investigate the pathologies and the healing processes in the human CNS after the return of the high number of brain injured war veterans from the fronts during and after the First World War (1914-1918). A leading research center in this area was the "Institute for the Scientific Study of the Effects of Brain Injuries," which the neurologist Ludwig Edinger (1855-1918) had founded shortly before the war. This article specifically deals with the physiological research on nerve fiber plasticity by Albrecht Bethe (1872-1954) at the respective institute of the University of Frankfurt am Main. Bethe conducted here his paradigmatic experimental studies on the pathophysiological and clinical phenomena of peripheral and CNS regeneration.


Bacterial virulence factors are associated with occurrence of acute pyelonephritis but not renal scarring.
We evaluated the influence of patient factors and virulence factors of uropathogenic Escherichia coli on the occurrence of acute pyelonephritis and subsequent renal parenchymal scarring. We evaluated 80 boys and 45 girls 1 to 180 months old with febrile urinary tract infections who underwent renal scan to diagnose acute pyelonephritis and followup dimercapto-succinic acid scintigraphy at least 6 months later. Urinalysis, white blood cell count, uropathogenic E. coli genotype and vesicoureteral reflux were measured. Voiding cystourethrogram was investigated after acute pyelonephritis was confirmed by renal scan and acute inflammation subsided, about 2 to 4 weeks later. Acute pyelonephritis was significantly more likely to develop in children with urinary tract infections and persistent fever before and after hospitalization, elevated C-reactive protein or positive renal ultrasound findings. E. coli strains with the papG II and iha genes were significantly more likely to occur in patients with acute pyelonephritis. Patients with a fever for more than 3 days and C-reactive protein levels greater than 90.8 mg/l were significantly more likely to have renal scarring. Age was not an independent predictor of acute pyelonephritis, but modified the effect of virulence factors on the development of acute pyelonephritis. Bacterial virulence factors and host factors are associated with the occurrence of acute pyelonephritis. Host factors such as patient age and vesicoureteral reflux severity modify the influence of virulence factors, although only host factors are associated with the occurrence of renal scarring.


Recommendations Concerning the First-Line Treatment of Children with Tuberculosis.
This document describes the recommendations of a group of scientific societies concerning the first-line therapeutic approach to paediatric tuberculosis (TB). The treatment of pulmonary TB should be based on the existence of parenchymal involvement and the risk of antibiotic resistance. The treatment of extra-pulmonary TB is based on the regimens used for severe pulmonary TB. The administration of corticosteroids is recommended only in cases of miliary TB, tuberculous meningitis and tuberculous pericarditis. Vitamin B6 may be indicated in the case of isoniazid-treated TB in breastfeeding infants, severely malnourished subjects, or patients with other diseases at high risk of vitamin deficiency. Once having started treatment, children with TB should be carefully followed up in order to evaluate compliance, the response to treatment, the need for treatment changes, and the presence of drug-related adverse events. Primary care paediatricians can support reference centres in providing family healthcare education and encouraging treatment compliance.


Chondrocalcinosis and haemophilia.
Chondrocalcinosis has been found in a wide variety of diseases. Cartilage calcification is commonly noted in patients with haemochromatosis, but it has not been previously reported in haemophilia, although increased levels of iron are present in the joints in both these conditions. The radiographic demonstration of chondrocalcinosis in patients with advanced joint changes due to haemophilia is precluded by the extensive joint narrowing and cartilage damage associated with the repeated haemarthroses. Cartilage calcification in less severely damaged joints of three patients with Factor VII, AHG-deficient haemophilia is described. Inhibition of pyrophosphatase activity by divalent cations as a cause of calcium pyrophosphate dihydrate (CPPD) deposition in cartilage is reviewed. The biomechanics of articular cartilage and the effects of divalent cations on normal cartilage elasticity are discussed. The possibility that both the development of the degenerative joint changes and the associated chondrocalcinosis may occur simultaneously due to the presence of abnormal divalent cations is suggested.


DCIS treated with excision alone using the National Comprehensive Cancer Network (NCCN) guidelines.
In 2008, the NCCN published guidelines allowing low-risk DCIS patients to be treated by excision alone. The goal of this study was to determine local and distant recurrence and breast-cancer specific survival in patients with DCIS that meet NCCN criteria and are treated with excision alone. A prospective, single institution database was analyzed for patients with the following: pure ductal carcinoma in situ (no microinvasion), tumor extent 20 mm or less, age ≥50 years, margin width ≥2 mm, and nuclear grade 1 or 2 (non-high grade). Patients were treated with excision alone. Kaplan-Meier analysis was used to determine recurrence and survival rates. A total of 205 patients were treated with excision alone. The median age was 59 years. The median time of follow-up was 51 months. The median extent of disease was 8 mm. There were a total of nine local recurrences. The 6-year probability of local recurrence was 6.6 %. The 12-year probability of local recurrence was 7.8 %. The 12-year breast cancer-specific survival probability was 100 %. The 12-year local recurrence rate for DCIS patients in NSABP Protocol B-17 treated with excision alone was 32 %, and for excision plus radiation therapy, it was 16 %. In this study, retrospectively applying the NCCN Guidelines to our patients, the 12-year local recurrence rate for excision alone was 7.8 %. Patients with a low risk of local recurrence, if treated by excision alone, can be safely selected using the NCCN Guidelines.


On the elasticity of cytoskeletal networks.
Models relating to the gelation and elasticity of complex cytoskeletal networks are formulated and investigated. Kinetic equations for reversible elongation of nucleated actin filaments are analyzed when the filaments are acted upon by capping proteins and cross-linking factors. Analytical expressions are obtained that relate the low frequency elastic shear modulus of a network, G, to chain growth kinetics, the number of nucleation sites, monomer concentration, and the amount of capping and cross-linking protein. Elasticity curves that relate G to such factors as the association constant for cross-linking are derived and then used to determine solation-gelation phase contours.


Extraction and Purification of Single Nuclei from Frozen Human Brain Tissue.
Resolving the complexity of the human brain at the level of single cells is essential to gaining an understanding of the immense diversity of cell types and functional states in both healthy and diseased brains. To exploit fully the technologies available for such studies, one must extract and isolate pure nuclei from unfixed postmortem tissue while preserving the molecules to be interrogated. Currently, nuclei are necessary substitutes for individual brain cells, since myriad cell types/sub-types constituting the human brain are embedded within the neuropil-a complex milieu of interconnected cells, processes, and synapses-which precludes intact and selective isolation of single brain cells. Here, we describe a protocol for the extraction and purification of intact single nuclei from frozen human brain tissue along with modifications to accommodate numerous downstream analyses, particularly for transcriptomic applications.


Characterization of the expression of macrophage inflammatory protein-1α (MIP-1α) and C-C chemokine receptor 5 (CCR5) after kainic acid-induced status epilepticus (SE) in juvenile rats.
To identify the potential role of macrophage inflammatory protein-1α (MIP-1α) with its C-C chemokine receptor 5 (CCR5) in epileptogenic brain injury, we examined their expression in juvenile rat hippocampus and explored the potential link between MIP-1α, CCR5 and neuropathological alterations after status epilepticus (SE) induced by intracerebroventricular (i.c.v.) kainic acid (KA) injection. Based on the determination of the development of spontaneous seizures initiated by SE in developing rat brain, we firstly examined hippocampal neurone damage through Nissl and Fluoro-Jade B staining, and evaluated microglial reaction during the early phase following KA-induced SE in 21-day-old rats. MIP-1α and CCR5 protein were quantified by ELISA and Western blot respectively following mRNA by real-time PCR. We also mapped MIP-1α and CCR5 expression in the hippocampus by immunohistochemistry and identified their cellular sources using double-labelling immunofluorescence. In juvenile rats, KA caused characteristic neurone damage in the hippocampal subfields, with accompanying microglial accumulation. In parallel with mRNA expression, MIP-1α protein in hippocampus was transiently increased after KA treatment, and peaked from 16 to 72 h. Double-labelling immunofluorescence revealed that MIP-1α was localized to microglia. Up-regulated CCR5 remained prominent at 24 and 72 h and was mainly localized to activated microglia. Further immunohistochemistry revealed that MIP-1α and CCR5 expression were closely consistent with microglial accumulation in corresponding hippocampal subfields undergoing degenerative changes. Our data indicated that MIP-1α as a regulator, linking with the CCR5 receptor, may be involved within the early stages of the epileptogenic process following SE by i.c.v. KA injection.


Effect of BBX-B8 overexpression on development, body weight, silk protein synthesis and egg diapause of Bombyx mori.
Bombyxin (BBX) is an insulin-like peptide exists in the silkworm Bombyx mori. Our previous studies on the effects of inhibiting BBX-B8 expression found that BBX-B8 is important for the development of organ, reproduction and trehalose metabolism in the silkworms. In this paper, we investigated the expression profile of the BBX-B8 gene and effect of BBX-B8 overexpression on the development, body weight, silk protein synthesis and egg diapause of B. mori to further understand BBX-B8 functions. BBX-B8 gene expression could be detected in the brains, midguts, anterior silkglands, ovaries, testes, fat bodies, hemolymph, malpighian tubules and embryos by RT-PCR, however it was mainly expressed in the brain. Western blots showed that the change in BBX-B8 expression was not obvious in the brain of 1- to 4-day-old larvae of fifth instar silkworms, but expression increased substantially at 5- to 6-day-old larvae of fifth instar silkworms. Transgenic silkworms overexpressing BBX-B8 were obtained by introducing non-transposon transgenic vector pIZT-B8 containing a BBX-B8 gene driven by Orgyia pseudotsugata nucleopolyhedrovirus IE2 promoter into the genome. Development duration of the transgenic silkworms was delayed by 2.5-3.5 days. Cocoon shell weight of transgenic silkworms was reduced by 4.79 % in females and 7.44 % in males, pupal weight of transgenic silkworms was reduced 6.75 % in females and 13.83 % in males compared to non-transgenic silkworms, and 5.56-14.29 % of transgenic moths laid nondiapausing eggs. All results indicated that BBX-B8 plays an important role in the development, silk protein synthesis and egg diapause of silkworm.


Muscle fatigue: general understanding and treatment.
Muscle fatigue is a common complaint in clinical practice. In humans, muscle fatigue can be defined as exercise-induced decrease in the ability to produce force. Here, to provide a general understanding and describe potential therapies for muscle fatigue, we summarize studies on muscle fatigue, including topics such as the sequence of events observed during force production, in vivo fatigue-site evaluation techniques, diagnostic markers and non-specific but effective treatments.