Differential cytotoxicity of trace metals in cisplatin-sensitive and -resistant human ovarian cancer cells.
Cellular resistance of cisplatin is related to various factors such as membrane transformations, changes in cellular transport systems, and an increased efflux of cisplatin by the tumor cells. Deficiencies of one or more trace metals can affect normal physiological functions, leading to altered enzymatic activities and a reduction in immune responses. This in vitro investigation was undertaken to study and determine the differential cytotoxicity of certain trace metals in human ovarian cancer cells that were sensitive and resistant to cisplatin. Standard cytotoxicity assays were performed using the neutral red assay. In general, the cisplatin-resistant cells exhibited an increased resistance to the externally supplied trace metals. For both cell lines the rank order of cytotoxicity from greatest to least with the non-essential metals was Cd2+ > Bi3+, and for the macrometals, Ca2+ > K+ > Mg2+. The transition metals and selenium exhibited a slight difference between the two cell lines with respect to the order of cytotoxicity. The cisplatin-sensitive cells had a rank order of V5+ > Se6+ > Cu2+ > Zn2+ > Fe3+, from greatest to least toxicity. The cisplatin-resistant cells had a rank order of Cu2+ > V5+ > Se6+ > Zn2+ > Fe3+. Since trace metals have various functions in maintaining normal health, these results provide key baseline cytotoxicity data and show that, in general, cytotoxic resistance to the trace metals tested followed a pattern similar to cellular cisplatin resistance.


Processing from LVF, RVF and BILATERAL presentations: examinations of metacontrol and interhemispheric interaction.
Observers indicated whether two successively presented drawings of faces were identical or differed in one feature (hair, eyes, mouth, jaw). The first face of each pair was presented at the fixation point and the second was presented to the left visual field-right hemisphere (LVF-RH), right visual field-left hemisphere (RVF-LH), or to both visual fields simultaneously (BILATERAL). On DIFFERENT trials the RT of correct responses depended on which feature differed and the pattern of feature location effects was significantly different on LVF-RH and RVF-LH trials. On BILATERAL trials the feature location effect was identical to that obtained on RVF-LH trials and significantly different from that obtained on LVF-RH trials. In addition, the percentage of errors and RT of correct responses were both higher on BILATERAL trials than on unilateral trials. Implications of these results are considered for the concept of "metacontrol" in neurologically normal humans and for models of interhemispheric interaction.


Immunohistologic dissection of the human kidney using monoclonal antibodies.
Nine murine monoclonal antibodies which detect differentiation antigens of the human kidney are described. Immunofluorescence and immunoperoxidase studies demonstrate that these antigens are expressed by different cell types comprising the nephron. Monoclonal antibody MA99 detects a glycoprotein complex of the glomerular basement membrane. Monoclonal antibody S4 detects a glycoprotein of 160,000 daltons (gp160) expressed by glomerular and proximal tubular epithelial cells. Monoclonal antibodies S23, S27 and S6 immunoprecipitate a glycoprotein of 120,000 daltons (gp120) found on cells of the proximal tubule and portions of Henle's loop. Monoclonal antibody C26 identifies a glycoprotein of 40,000 daltons (gp40) expressed by cells of the distal and collecting tubules. Monoclonal antibodies M2 and S8 are specific for A and B blood group antigens, respectively, found on cells of the collecting tubule in individuals of the respective blood type. This panel of antibodies is useful in the study of normal renal embryogenesis, microanatomy and physiology as well as pathological processes including tumors.


[Arthroplasty registers as post-marketing surveillance systems: the Catalan Arthroplasty Register].
The aim is to present the functioning and results of the Catalan Arthroplasty Registry (RACat). The RACat arose by the initiative of the Catalan Society of Orthopaedic Surgery and Traumatology, the Catalan Health Service (CHS) and the Catalan Agency for Health Information Assessment and Quality. Publicly funded hospitals sent information through the Internet (CHS Applications website) on knee and hip arthroplasties: patient identification, hospital, joint (hip/knee), type (primary/revision), side of operation, date of surgery and prosthesis (manufacturer's name and reference number). The quality of the data is analysed regularly. We estimate the risk of replacement by the Kaplan-Meier method. A total of 52 hospitals out of 62 send data to RACat, and information on 36,951 knee and 26,477 hip arthroplasties is available. Data quality improved between 2005 and 2010. In 2010 coverage exceeded 70%, with side of operation 97%, and prostheses identification of 80%. The risk of replacement at three years was 3.3% (95% CI:3.1-3.6) for knee, 2.9% (95% CI:2.5-3.3) for total hip, and 2.5% (95% CI:2.0-3.1) for partial hip. Risk of replacement is higher than that observed in other registers, although data quality and its improvement over time should be taken into account. The information available in the RACat will help to establish a standard that will enable hospitals to compare results.


The direct measurement of temperature changes within freeze-fracture specimens during rapid quenching in liquid coolants.
We have evaluated the cooling rates of specimens mounted in a variety of freeze-fracture holders when plunged into a series of liquid coolants. these rates were measured using miniature thermocouples placed within the mounted specimens. The most rapid cooling rates were obtained using propane at 83 K as the coolant. When mounted on a newly devised 'copper sandwich' holder, specimen cooling rates in excess of 4500 K/s have been recorded. A simple guillotine-like device for quenching freeze-fracture specimens under reproducible conditions is presented.


Mitochondrial permeability transition pore contributes to mitochondrial dysfunction in fibroblasts of patients with sporadic Alzheimer's disease.
In the last few decades, many reports have suggested that mitochondrial function impairment is a hallmark of Alzheimer's disease (AD). Although AD is a neurodegenerative disorder, mitochondrial damage is also present in patients' peripheral tissues, suggesting a target to develop new biomarkers. Our previous findings indicate that AD fibroblasts show specific defects in mitochondrial dynamics and bioenergetics, which affects the generation of adenosine triphosphate (ATP). Therefore, we explored the possible mechanisms involved in this mitochondrial failure. We found that compared with normal fibroblasts, AD fibroblasts had mitochondrial calcium dysregulation. Further, AD fibroblasts showed a persistent activation of the non-specific mitochondrial calcium channel, the mitochondrial permeability transition pore (mPTP). Moreover, the pharmacological blockage of mPTP with Cyclosporine A (CsA) prevented the increase of mitochondrial superoxide levels, and significantly improved mitochondrial and cytosolic calcium dysregulation in AD fibroblasts. Finally, despite the failure of CsA to improve ATP levels, the inhibition of mitochondrial calcium uptake by the mitochondrial calcium uniporter increased ATP production in AD fibroblasts, indicating that these two mechanisms may contribute to mitochondrial failure in AD fibroblasts. These findings suggest that peripheral cells present similar signs of mitochondrial dysfunction observed in the brain of AD patients. Therefore, our work creates possibilities of new targets to study for early diagnosis of the AD.


Synthesis, structure activity relationships and biological activity evaluation of novel spirocyclic thiazolidin-4-ones as potential anti-breast cancer and epidermal growth factor receptor inhibitors.
A series of triazaspiro[4.5]dec-8-ene benzylidine derivatives containing thiazolidinone ring system (6-18) have been designed, synthesized and their biological activities evaluated as potential epidermal growth factor receptor inhibitors. Among them, 9-amino-2-(4-nitrobenzylidene)-3-oxo-4-phenyl-7-thioxo-1-thia-4,6,8-triazaspiro[4.5]dec-8-ene-10-carbonitrile (18) displayed the most potent inhibitory activity (IC50=6.355 µM). Antiproliferative assay results indicated that compound 18 exhibited moderate antiproliferative activity against MCF-7 cell line in vitro; with GI50 value of 30.6 µM. In addition, compounds 7 and 15 displayed the highest antiproliferative activity at a common GI50 value of 10.8 µM. Docking simulation was performed to determine the probable binding model and to pursuit information regarding the activity of compound 18. Based on the preliminary results, compound 18 could be used as an attractive building block for designing potential epidermal growth factor receptor inhibitors.


Maltose modified poly(propylene imine) dendrimers as potential carriers of nucleoside analog 5'-triphosphates.
Poly(propylene imine) (PPI) dendrimers contained surface maltose modification are proposed as drug carriers for nucleoside analog (NA) 5'-triphosphates. The aim of this study was to investigate the interactions between PPI dendrimers of 3rd (G3) or 4th (G4) generation and cytidine-5'-triphosphate (CTP) by Isothermal Titration Calorimetry method. CTP was used as a model molecule of pyrimidine nucleoside analog-cytarabine (ara-CTP) commonly used in leukemia treatment. Complexes of PPI dendrimers with NAs may help to overcome severe limitations of NAs associated with their low solubility and stability or resistance in cancer cells. In the present work, we evaluated stoichiometry and a mechanism of forming complexes between dendrimers and the nucleotide. Moreover, we examined the efficiency of complex formation in relation to dendrimer generations, a type of dendrimer modification with maltose residues and a type of solvent. It was observed that PPI dendrimers create complexes with CTP with high efficiency that makes them promising candidates for a drug delivery system.


Characterization of the complete chloroplast genome of Astragalus galactites (Fabaceae).
Astragalus galactites is a medicinal plant. The total plastome length of A. galactites is 126,117 bp. It contains a large single-copy region of 69,805 bp, two inverted repeat regions of 20,638 bp, and a small single-copy region of 15,036 bp. The cp genome contains 110 complete genes, including 75 protein-coding genes (75 PCGs), 4 ribosomal RNA genes (4 rRNAs), and 30 tRNA genes (30 tRNAs). The overall GC content of cp DNA is 33.9%, the corresponding values of the LSC, SSC, and IR regions are 33.0%, 30.4%, and 43.3% respectively. The phylogenetic tree shows that A. galactites has the closest relationship with A. laxmannii.


Treatment of osteoarthritis with autologous, micro-fragmented adipose tissue: a study protocol for a randomized controlled trial.
Osteoarthritis is a destructive joint disease that leads to degeneration of cartilage and other morphological changes in the joint. No medical treatment currently exists that can reverse these morphological changes. Intra-articular injection with autologous, micro-fragmented adipose tissue has been suggested to relieve symptoms. The study is a blinded randomized controlled trial with patients allocated in a 1:1 ratio to 2 parallel groups. Patients suffering from pain and functional impairment due to osteoarthritis Kellgren-Lawrence grades 2-3 in the tibiofemoral joint are eligible for inclusion. The intervention group is treated with an intra-articular injection with autologous, micro-fragmented adipose tissue prepared using the Lipogems® system. The control group receives an intra-articular injection with isotonic saline. In total, 120 patients are to be included. The primary outcome is The Knee injury and Osteoarthritis Outcome Score (KOOS4) evaluated at 6 months. Secondary outcomes are KOOS at 3, 12 and 24 months; the Tegner activity score; treatment failure; and work status of the patient. The analysis will be conducted both as intention-to-treat and per-protocol analysis. This trial is the first to investigate the efficacy of autologous, micro-fragmented adipose tissue in a randomized controlled trial. The study uses the patient-reported outcome measure Knee Injury and Osteoarthritis Outcome Score (KOOS4) after 6 months as the primary outcome, as it is believed to be a valid measure to assess the patient's opinion about their knee and associated problems when suffering from osteoarthritis.


Protective effect of a Chinese Medicine formula He-Ying-Qing-Re Formula on diabetic retinopathy.
He-Ying-Qing-Re Formula (HF) is a formula modified from "Si-Miao-Yong-An Decoction", a traditional Chinese medical classic emerged in the Qing dynasty and has been reported for treatment of vascular diseases. HF, containing 8 herbs, has been used in local hospital for decades as a complementary method for diabetic retinopathy (DR) with retinal vascular dysfunction. Clinical reports revealed HF could ameliorate vision defects, microaneurysms, hemorrhages and macular edema. The aim of this study is to investigate the anti-DR action of HF and its underlying mechanism experimentally. Chromatographic fingerprinting of HF and rodent model of DR were established; hypoglycemic effect of HF was measured by fasting, random blood glucose and glucose tolerance test; vascular degeneration was measured by retinal digestion; blood-retina-barrier (BRB) permeability was assessed with Evans Blue leakage assay. Advanced glycation end products (AGEs) were measured in vitro and in vivo level; Migration of retinal vascular endothelial cells were determined by wound healing and transwell chamber assays; permeability of endothelial monolayer was monitored with dextran transport. AGEs-related proteins and signaling were measured with immunoblotting and immunohistochemistry. Chlorogenic acid, ferulic acid and arctin were identified as major components in HF; HF suppresses retinal vasculature degeneration and BRB permeability damage without significant inhibition on hyperglycemia; HF reduces in vitro and in vivo formation of AGEs and AGEs-induced migration as well as permeability of retinal vascular endothelial cells. Expression of tight junction proteins Zo-1 and Claudin-1 was increased while activation of AGEs receptor and downstream signaling Akt were suppressed upon HF treatment. HF exhibits protective effect against diabetic retinopathy, which may be associated with inhibition on AGEs and recovery on endothelial dysfunction via modulation of tight junction and AGEs downstream signaling.


The impact of tumour location on the histological subtype of renal cortical tumours.
To determine whether the location of renal cortical tumours (RCTs) is a possible factor affecting tumour behaviour, by investigating whether exophytic vs a central location is associated with a difference in histological subtype distribution, as recognized prognostic factors for RCTs include size, stage, grade, and histological subtype. Between 1 January 1996 and 1 June 2003, we evaluated 485 consecutive RCTs in 469 patients who had renal imaging studies and underwent either partial or radical nephrectomy at our institution. A radiologist and a urologist independently reviewed the imaging studies of all patients to determine exophytic vs central location. An exophytic lesion was defined as one that clearly both pushed out the renal contour and did not extend into the collecting system, hilum, or renal sinus. A lesion that did not meet these criteria was defined as a central lesion. Logistic regression analysis was used to determine if either type of lesion had a greater representation of any histological subtype. A two-tailed P < or = 0.05 was considered to indicate significance. Of the 485 RCTs, 171 (35%) were exophytic and 314 (65%) were central, while 308 (64%) were clear cell and 177 (36%) were non-clear cell tumour histology. Of the exophytic lesions, 52.0% were clear cell, while 69.7% of central lesions were clear cell (P < 0.001). Conversely, 71.1% of clear cell tumours were central, while 53.7% of non-clear cell tumours were central (P = 0.003). After controlling for size and stage, tumour location remained associated with histological subtype (P = 0.003). Exophytic lesions are significantly more likely than central lesions to be non-clear cell tumours, and clear cell tumours are significantly more likely than non-clear cell tumours to be central. As studies indicate that the clear cell histological subtype portends a worse prognosis than the non-clear cell subtype, our results imply that tumour location affects the prognosis in RCTs, with exophytic lesions having a better prognosis than central lesions. This result may have important implications for physicians and patients when planning partial vs radical nephrectomy by either open or minimally invasive techniques.


Energetic stress: The reciprocal relationship between energy availability and the stress response.
The worldwide epidemic of metabolic syndromes and the recognized burden of mental health disorders have driven increased research into the relationship between the two. A maladaptive stress response is implicated in both mental health disorders and metabolic disorders, implicating the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of this relationship. This review explores how an altered energetic state, such as hyper- or hypoglycemia, as may be manifested in obesity or diabetes, affects the stress response and the HPA axis in particular. We propose that changes in energetic state or energetic demands can result in "energetic stress" that can, if prolonged, lead to a dysfunctional stress response. In this review, we summarize the role of the hypothalamus in modulating energy homeostasis and then briefly discuss the relationship between metabolism and stress-induced activation of the HPA axis. Next, we examine seven mechanisms whereby energetic stress interacts with neuroendocrine stress response systems, including by glucocorticoid signaling both within and beyond the HPA axis; by nutrient-induced changes in glucocorticoid signaling; by impacting the sympathetic nervous system; through changes in other neuroendocrine factors; by inducing inflammatory changes; and by altering the gut-brain axis. Recognizing these effects of energetic stress can drive novel therapies and prevention strategies for mental health disorders, including dietary intervention, probiotics, and even fecal transplant.


Paraventricular nucleus projections to the nucleus tractus solitarii are essential for full expression of hypoxia-induced peripheral chemoreflex responses.
The hypothalamic paraventricular nucleus (PVN) is essential to peripheral chemoreflex neurocircuitry, but the specific efferent pathways utilized are not well defined. The PVN sends dense projections to the nucleus tractus solitarii (nTS), which exhibits neuronal activation following a hypoxic challenge. We hypothesized that nTS-projecting PVN (PVN-nTS) neurons contribute to hypoxia-induced nTS neuronal activation and cardiorespiratory responses. To selectively target PVN-nTS neurons, rats underwent bilateral nTS nanoinjection of retrogradely transported adeno-associated virus (AAV) driving Cre recombinase expression. We then nanoinjected into PVN AAVs driving Cre-dependent expression of Gq or Gi designer receptors exclusively activated by designer drugs (DREADDs) to test the degree that selective activation or inhibition, respectively, of the PVN-nTS pathway affects the hypoxic ventilatory response (HVR) of conscious rats. We used immunohistochemistry for Fos and extracellular recordings to examine how DREADD activation influences PVN-nTS neuronal activation by hypoxia. Pathway activation enhanced the HVR at moderate hypoxic intensities and increased PVN and nTS Fos immunoreactivity in normoxia and hypoxia. In contrast, PVN-nTS inhibition reduced both the HVR and PVN and nTS neuronal activation following hypoxia. To further confirm selective pathway effects on central cardiorespiratory output, rats underwent hypoxia before and after bilateral nTS nanoinjections of C21 to activate or inhibit PVN-nTS terminals. PVN terminal activation within the nTS enhanced tachycardic, sympathetic and phrenic (PhrNA) nerve activity responses to hypoxia whereas inhibition attenuated hypoxia-induced increases in nTS neuronal action potential discharge and PhrNA. The results demonstrate the PVN-nTS pathway enhances nTS neuronal activation and is necessary for full cardiorespiratory responses to hypoxia. KEY POINTS: The hypothalamic paraventricular nucleus (PVN) contributes to peripheral chemoreflex cardiorespiratory responses, but specific PVN efferent pathways are not known. The nucleus tractus solitarii (nTS) is the first integration site of the peripheral chemoreflex, and the nTS receives dense projections from the PVN. Selective GqDREADD activation of the PVN-nTS pathway was shown to enhance ventilatory responses to hypoxia and activation (Fos immunoreactivity (IR)) of nTS neurons in conscious rats, augmenting the sympathetic and phrenic nerve activity (SSNA and PhrNA) responses to hypoxia in anaesthetized rats. Selective GiDREADD inhibition of PVN-nTS neurons attenuates ventilatory responses, nTS neuronal Fos-IR, action potential discharge and PhrNA responses to hypoxia. These results demonstrate that a projection from the PVN to the nTS is critical for full chemoreflex responses to hypoxia.


Non-associative defensive responses of rats to ferret odor.
Predators and their odors offer an ethologically valid model to study learning processes. The present series of experiments assessed the ability of ferret odor to serve as an unconditioned stimulus and examined behavioral and endocrine changes in male Sprague-Dawley rats with single or repeated exposures in a defensive withdrawal paradigm or in their home cages. Rats exposed to ferret odor avoided the ferret odor stimulus more, exhibited greater risk assessment and displayed higher adrenocorticotropin hormone (ACTH) and corticosterone release compared with control odor exposed rats and these measures did not significantly habituate over repeated exposures. Ferret odor exposure did not show associative conditioning effects during extinction trials. However, rats that were pre-exposed to ferret odor only once, as compared to control and repeatedly exposed rats, displayed a sensitized ACTH and corticosterone response to an additional ferret odor exposure in small cages. These experiments suggest that ferret odor is a highly potent unconditioned stimulus that has long lasting effects on behavior and endocrine responses, and further suggests the independence of habituation and sensitization processes.


Longitudinal evaluation of pharmacy students' metacognition in interpretation of evidence-based medicine.
Metacognition is one's ability to "think about thinking" and to understand what knowledge and skills one has. Pharmacy professionals are required to have high metacognitive skills to ensure they are aware of what information they know and when to utilize resources. This longitudinal evaluation of pharmacy students' metacognitive ability was conducted via analysis of students' knowledge and confidence in evidence-based medicine (EBM) skills. A survey was administered to the graduating classes of 2017 and 2018 four times, from the beginning of the second-year drug literature evaluation course (baseline) through graduation. The surveys included seven self-confidence questions for which a corresponding knowledge question was asked. Students' metacognition was evaluated on the basis of whether the level of confidence was a "match" or a "mismatch" to their corresponding level of knowledge of each question. The proportion of matches over time was determined. Fifty-eight students (22%) completed all four surveys. The mean proportion of matches at baseline was 40% and increased over time until graduation when the proportion of matches was 74%. The proportion of matches at baseline for all seven questions were ranged from 33% to 57%. An improvement in meta-cognition was seen in 5 out 7 questions. This evaluation provides evidence that as students learned material and revisited concepts, their confidence, knowledge, and potentially metacognition regarding EBM concepts increased. However, as 26% of items measured were not a match at graduation, interventions need to be designed and tested to improve student metacognition.


New 2-(2'-phenyl-9'-benzyl-8'-azapurin-6'-ylamino)-carboxylic acid methylesters as ligands for A1 adenosine receptors.
Synthesis of a series of new 2-phenyl-9-benzyl-8-azaadenines bearing on N6 an alkyl or aralkyl chain having a carbonyloxymethyl group on the carbon bound to N6 were reported. The ester group could assure to the molecule a better water-solubility than the 8-azaadenines 2, 6 and 9 substituted with lipophilic groups synthesised in the past. Compounds synthesised demonstrated only little capability of binding A1 adenosine receptors.


The association of APOC4 polymorphisms with premature coronary artery disease in a Chinese Han population.
Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤ 60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD. Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤ 60 years old) using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with premature CAD was performed with SPSS software. Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33). Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.


Cerebrolysin Alleviating Effect on Glutamate-Mediated Neuroinflammation Via Glutamate Transporters and Oxidative Stress.
Glutamate, one of the most important excitatory neurotransmitters, acts as a signal transducer in peripheral tissues and endocrine cells. Excessive glutamate secretion has been shown to cause excitotoxicity and neurodegenerative disease. Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain including neurotrophic factors, like brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF). The present study investigated the protective effects of cerebrolysin on glutamate transporters (EAAT 1, EAAT 2) and cytokines (IL-1β and IL-10) activity in glutamate-mediated neurotoxicity. Primary cortex neuron culture was exposed to glutamate and successively treated with various cerebrolysin concentrations for 24 and 48 h. Our data showed that cerebrolysin primarily protects neurons by decreasing glutamate concentration in the synaptic cleft. In addition, Cerebrolysin can decrease oxidative stress and neuron cell damage by increasing antioxidant activity and decreasing inflammation cytokine levels.


16,16-Dimethyl prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats. Possible role of the increased mucosal vascular permeability.
Histamine dihydrochloride (40 or 80 mg/kg, dissolved in 10% gelatin) subcutaneously administered to fasted rats induced few lesions in the gastric mucosa within 4 h. Pretreatment with subcutaneously administered 16,16-dimethyl prostaglandin E2 (dmPGE2; greater than or equal to 10 micrograms/kg) dose-dependently worsened mucosal injury induced by histamine, mostly with severe hemorrhage in the corpus mucosa along the greater curvature, although dmPGE2 alone did not induce any macroscopic damage. The mucosal vascular permeability as measured using Evans blue was slightly but significantly augmented by either dmPGE2 (30 micrograms/kg) or histamine (80 mg/kg) alone, but was markedly increased by histamine in the presence of dmPGE2. The increased vascular permeability occurred within 2 h, and preceded the appearance of hemorrhagic mucosal injury. Both the mucosal injury and the increased vascular permeability caused by histamine (80 mg/kg) in the presence of dmPGE2 (30 micrograms/kg) were significantly reduced by pretreatment with tripelennamine (30 mg/kg) and prednisolone (3 mg/kg), but not affected by atropine sulfate, cimetidine, methysergide, or indomethacin. The stimulation of acid secretion caused by histamine was significantly inhibited by dmPGE2 (30 micrograms/kg). Repeated administration of histamine (40 or 80 mg/kg) in the same area of the stomach in the presence of dmPGE2 (30 micrograms/kg), once or twice daily for 4 days to fed rats, induced more pronounced damage than single-dose treatment. These results suggest that dmPGE2 may aggravate gastric mucosal injury induced by histamine in rats probably due to potentiation of the increased vascular permeability caused by histamine through stimulation of H1-receptors.


Controllable Synthesis of Multicompartmental Particles Using 3D Microfluidics.
A microfluidic assembly method based on a microfluidic chip and capillary device was developed to create multicompartmental particles. The microfluidic chip design endows the particles with regulable internal structure. By adjusting the microstructure of the chip, the diameter of the capillary, the gap length between the two microfluidic components, and the flow rates, the size of the particles and the number or the ratio of different regions within the particle could be widely varied. As a proof of concept, we have produced some complicated particles that even contain 20 compartments. Furthermore, the potential applications of the anisotropic particles are explored by encapsulating magnetic beads, fluorescent nanoparticles, and the cells into different compartments of the microparticles. We believe that this method will open new avenues for the design and application of multicompartmental particles.


Switching to nonacog beta pegol in hemophilia B: Outcomes from a Canadian real-world, multicenter, retrospective study.
The Canadian Bleeding Disorders Registry (CBDR) captures data from 24 hemophilia treatment centers and patients directly. Nonacog beta pegol (N9-GP) was approved in Canada in 2018. To assess treatment outcomes following switching to N9-GP in a real-world setting. CBDR data for Canadian male patients (aged 7-72 years) with hemophilia B receiving prophylactic N9-GP for ≥6 months as of March 31, 2021, were included. To allow comparison with the previously used products, only patients for whom data were available in the CBDR for at least 6 months before the switch to N9-GP were included in this retrospective analysis. Forty-two patients were included in the analysis (total observation period: 148.0 patient-years). The distribution of disease severity was 62% severe, 36% moderate, 2% mild, with 62% of patients previously receiving recombinant factor IX-Fc-fusion protein (rFIXFc) and 38% previously receiving standard half-life (SHL) recombinant factor IX (rFIX). During a median follow-up period of 2.3 years on N9-GP prophylaxis, 232 bleeds were reported in 30 patients, 29% of patients reported zero bleeds. The median overall annualized bleeding rate on N9-GP was 0.73 for patients switching from rFIXFc (previously 1.44) and 2.10 for patients switching from SHL rFIX (previously 6.06). Median total annualized factor consumption (IU/kg) was lower with N9-GP than with previous SHL rFIX (2152 vs 3018) and previous rFIXFc (1766 vs 2278). Results from this first real-world study of N9-GP in patients with hemophilia B suggest optimal bleeding control with low factor consumption after switching to N9-GP, irrespective of the previous product.


Analytic consistency and neural correlates of peak alpha frequency in the study of pain.
Several studies have found evidence of reduced resting-state peak alpha frequency (PAF) in populations with pain. However, the stability of PAF from different analytic pipelines used to study pain has not been determined and underlying neural correlates of PAF have not been validated in humans. For the first time we compare analytic pipelines and the relationship of PAF to activity in the whole brain and thalamus, a hypothesized generator of PAF. We collected resting-state functional magnetic resonance imaging (rs-fMRI) data and subsequently 64 channel resting-state electroencephalographic (EEG) from 47 healthy men, controls from an ongoing study of chronic prostatitis (a pain condition affecting men). We identified important variations in EEG processing for PAF from a review of 17 papers investigating the relationship between pain and PAF. We tested three progressively complex pre-processing pipelines and varied four postprocessing variables (epoch length, alpha band, calculation method, and region-of-interest [ROI]) that were inconsistent across the literature. We found a single principal component, well-represented by the average PAF across all electrodes (grand-average PAF), explained > 95% of the variance across participants. We also found the grand-average PAF was highly correlated among the pre-processing pipelines and primarily impacted by calculation method and ROI. Across methods, interindividual differences in PAF were correlated with rs-fMRI-estimated activity in the thalamus, insula, cingulate, and sensory cortices. These results suggest PAF is a relatively stable marker with respect to common pre and post-processing methods used in pain research and reflects interindividual differences in thalamic and salience network function.


A Practice in Maturation: Current Perspectives on the Transition from Pediatric to Adult Care for Young Adults with Diabetes.
This review of available literature and resources highlights the challenges in transition from pediatric to adult care for young adults with diabetes, summarizes practical recommendations for facilitating the process, and identifies areas for improvement in current transition practice. Observational studies highlight suboptimal transition preparation counseling, gaps between pediatric and adult care, and increased post-transition hemoglobin A1c and acute care utilization. Studies showing improved outcomes with later age at transition allows for an extended focus on transition preparation with an eye toward developmental maturity. Interventional studies suggest varying benefits of transition coordinators and support programs. The period of transition from pediatric to adult care is a time of in which patients are at high risk for adverse outcomes and loss to follow-up; however, careful attention to planning the process and tracking patient readiness along with skilled care coordination can contribute to transition success. The durability of interventional models, as well as generalizability to varied clinical settings, must be further tested.


Circling and consumatory behavior induced by striatal and neocortical spreading depression.
Single waves of spreading depression (SD) were induced in freely moving Sprague Dawley rats by microinjection of KCl solution into either neocortex or caudate nucleus. DC recordings of slow potential changes (SPC) revealed that a wave of SD propagates from the neocortex to the caudate nucleus in only a very few cases (12.5% of trials, involving 4.3% of the SPC waves). This result contrasts with earlier reported higher incidences of neocortical-striatal transmission of SD, and suggests that such transmission may vary across rat strains. Invasion of the caudate nucleus by a wave of neocortical SD was accompanied by contralateral circling in 50% of the cases. Similarly, SD induced by injection of KCl into the striatum was accompanied by circling in 43% of trials. It was also found that neocortical SD-induced feeding generally occurred only upon recovery of neocortex from the slow potential negativity, and that invasion of the caudate nucleus by SD is not involved in the elicited feeding phenomenon.


Unwinding of a skyrmion lattice by magnetic monopoles.
Skyrmion crystals are regular arrangements of magnetic whirls that exist in a wide range of chiral magnets. Because of their topology, they cannot be created or destroyed by smooth rearrangements of the direction of the local magnetization. Using magnetic force microscopy, we tracked the destruction of the skyrmion lattice on the surface of a bulk crystal of Fe(1-x)Co(x)Si (x = 0.5). Our study revealed that skyrmions vanish by a coalescence, forming elongated structures. Numerical simulations showed that changes of topology are controlled by singular magnetic point defects. They can be viewed as quantized magnetic monopoles and antimonopoles, which provide sources and sinks of one flux quantum of emergent magnetic flux, respectively.


Comparison of computerised tomography with other neuroradiological methods. A plea for a different kind of analysis.
Two different types of retrospective study of the value of CT have been contrasted. In one, the patients were chosen because of the way they presented (with posterior fossa signs of symptoms) or because they were found to have posterior fossa disease; in the other, all were reported as having, or found to have, gliomas or metastases. The first type of study provides a better basis for evaluation of neuroradiological procedures.


Tumor length as a prognostic factor in esophageal malignancy: univariate and multivariate survival analyses.
Gastrointestinal specialists generally feel that long esophageal tumors carry a worse prognosis and are likely to be more advanced than shorter lesions. Our aim was to investigate the relationship between histologically determined tumor length and aspects of tumor pathology and survival for patients with resected esophageal malignancy. Three hundred and nine patients who underwent esophageal resection with curative intent in our unit between 1994 and 2003 were retrospectively analyzed. Pathological details such as TNM stage, differentiation, completeness of surgical resection, and overall stage were collected. Survival data were obtained for each patient and univariate and multivariate analyses were performed. Overall survival was used as the primary endpoint. There were 225 adenocarcinomas, 72 squamous cell carcinomas, and 12 other tumor types with a median tumor length of 3.5 cm (range 0.5-14 cm). Tumor length greater than 3.5 cm was associated with increasing T stage (P = 0.0001), N stage (P = 0.032), overall stage (P = 0.003), and involvement of the longitudinal resection margins (P = 0.02). Univariate analysis found tumor length greater than 3.5 cm was associated with worse overall survival compared with shorter tumors (P = 0.0002). Tumor length remained a significant prognostic factor on multivariate analysis (P = 0.04). Other prognostic factors on multivariate analysis were age, tumor differentiation, nodal involvement, and resection margin status. Tumor length greater than 3.5 cm (as determined histologically) is associated with worse disease stage and poor overall patient survival. If preoperative endoscopic tumor length bears a similar relationship, this could assist in patient selection for appropriate treatments.


Effects of Dietary Administration of Shewanella xiamenensis A-1, Aeromonas veronii A-7, and Bacillus subtilis, Single or Combined, on the Grass Carp (Ctenopharyngodon idella) Intestinal Microbiota.
Gut microbiota of grass carp plays an important role in host. However, detailed information regarding the changes of microbiota after probiotics administration in relation to the gastrointestinal microbiota is absent. In the present study, dietary administration of putative probiotics Shewanella xiamenensis A-1, Aeromonas veronii A-7, and Bacillus subtilisstrains was conducted in grass carp to investigate if there is a discernible alteration in intestinal microbiota and whether the alteration is associated with previous study about the immunity regulation in grass carp. Bacterial 16S rRNA gene sequence-based comparisons of the bacterial communities in the grass carp intestine were detected after 28 days feeding by five diets, and results demonstrated the changes of microbial community composition at genus level. The abundance of Cetobacterium genus with potential immunity function increased. Potential pathogens and probiotics are important constitutions of the intestinal microbiota. Orally taken probiotics considerably reduced the abundance of the potential pathogenic bacteria (e.g., Pseudomonas and Flavobacterium genus) in the intestine. Meanwhile, putative probiotics used in this study were favorable to the reproduction of potential probiotics in THE intestine of grass carp (e.g., Vibrio, Streptococcus, and Enterococcus genus). Moreover, modulation of intestinal environment by the probiotics could impact the abundance of cellulose-degrading bacteria (e.g., Citrobacter genus). Those results suggested that oral probiotics administration can positively improve the composition of intestinal microbial community in grass carp, and this was associated with regulation of immunity in grass carp. Probiotics-induced alteration of microbiota may potentially lower the risk of disease outbreaks during cultivation stage of grass carp.


The oral health-related quality of life in edentulous patients treated with conventional complete dentures.
To compare the oral health-related quality of life (OHRQoL) between patients with both maxillary and mandibular complete denture and those with either the maxillary or the mandibular complete denture. Satisfaction of denture wearers can be estimated using the OHRQoL questionnaires like the OHIP-EDENT and the Geriatric Oral Health Assessment Index (GOHAI). Two questionnaires were used to compare the OHRQoL between edentulous patients who had conventional removable complete denture on both jaws and those who had on either one of the jaws. The age of the participants ranged from 42 to 75 years, with the mean age of 58 ± 8.12 years. The mean OHIP-EDENT scores were significantly high among those who wore conventional dentures in both jaws (54.12 ± 5.21), compared with the participants who only had denture either on upper or lower jaw (46.52 ± 7.35). It was noticed that the mean GOHAI score was significantly lower (p < 0.05) among participants who had conventional denture on both upper and lower jaw (28.25 ± 3.67), as compared to those who had conventional denture only on one arch (35.12 ± 2.11). Patients with complete dentures in both jaw (Group I) were less satisfied than patients with single complete denture (Group II). The result obtained in this study shows dissatisfaction with conventional dentures among edentulous patients.


The effect of Tai Chi on functional mobility, balance and falls in Parkinson's disease: A systematic review and meta-analysis of systematic reviews.
The aim of the study was to evaluate the effect of Tai Chi on functional mobility, balance and falls in Parkinson's disease. A comprehensive literature search was conducted to identify the systematic reviews and meta-analyses up to the end of October 2021. 601 studies were identified, and 16 of them were included in our study. According to our meta-analysis; there was a significant effect of Tai Chi on balance (SMD, -0.777 95% CI -0.921 to -0.633; p = 0.000), functional mobility (SMD, -0.719 95% CI -0.944 to -0.494; p = 0.000), and falls (SMD, -0.456 95% CI -0.668 to -0.245; p = 0.000) in PD. Our systematic review and meta-analysis found significant effects of Tai Chi on functional mobility, balance and falls in patients with PD.


Structure guided approaches toward exploiting and manipulating nonribosomal peptide and polyketide biosynthetic pathways.
Nonribosomal peptide and polyketide natural products are structurally diverse small molecules synthesized on complex enzyme assemblies. The ability to rationally engineer secondary metabolic pathways is a promising approach to novel therapeutics. Atomic resolution structures of biosynthetic enzymes provide information on active site architecture and macromolecular assembly that can aid in the engineering of new compounds. This review surveys recent applications toward biosynthetic engineering of natural products guided by structural biology.


Invasions in heterogeneous habitats in the presence of advection.
We investigate invasions from a biological reservoir to an initially empty, heterogeneous habitat in the presence of advection. The habitat consists of a periodic alternation of favorable and unfavorable patches. In the latter the population dies at fixed rate. In the former it grows either with the logistic or with an Allee effect type dynamics, where the population has to overcome a threshold to grow. We study the conditions for successful invasions and the speed of the invasion process, which is numerically and analytically investigated in several limits. Generically advection enhances the downstream invasion speed but decreases the population size of the invading species, and can even inhibit the invasion process. Remarkably, however, the rate of population increase, which quantifies the invasion efficiency, is maximized by an optimal advection velocity. In models with Allee effect, differently from the logistic case, above a critical unfavorable patch size the population localizes in a favorable patch, being unable to invade the habitat. However, we show that advection, when intense enough, may activate the invasion process.


Fractures of the tibial shaft treated in a patellar-tendon-bearing cast.
A retrospective review of fractures of the tibial shaft treated in patellar-tendon bearing (PTB) casts shows that a high rate of union, in respect of both time required and numbers, and a low morbidity can be expected. The method is easy to apply. In those patients who had the casts applied early, once swelling had settled down, the fractures united more quickly.


Malaria endemicity and co-infection with tissue-dwelling parasites in Sub-Saharan Africa: a review.
Mechanisms and outcomes of host-parasite interactions during malaria co-infections with gastrointestinal helminths are reasonably understood. In contrast, very little is known about such mechanisms in cases of malaria co-infections with tissue-dwelling parasites. This is lack of knowledge is exacerbated by misdiagnosis, lack of pathognomonic clinical signs and the chronic nature of tissue-dwelling helminthic infections. A good understanding of the implications of tissue-dwelling parasitic co-infections with malaria will contribute towards the improvement of the control and management of such co-infections in endemic areas. This review summarises and discusses current information available and gaps in research on malaria co-infection with gastro-intestinal helminths and tissue-dwelling parasites with emphasis on helminthic infections, in terms of the effects of migrating larval stages and intra and extracellular localisations of protozoan parasites and helminths in organs, tissues, and vascular and lymphatic circulations.


Left atrial strain for predicting recurrence in patients with non-valvular atrial fibrillation after catheter ablation: a single-center two-dimensional speckle tracking retrospective study.
Although catheter ablation (CA) is an effective treatment for non-valvular atrial fibrillation (AF), a good many of patients still have a recurrence following post-operation. Prediction of AF recurrence by evaluating left atrial (LA) phase function with speckle tracking echocardiography (STE) may be helpful for risk stratification and clinical management for AF patients. Therefore, the current study aimed to assess the prognostic value of LA strains in non-valvular AF patients after CA. A total of 95 non-valvular AF patients (70.5% paroxysmal AF, 56.8% males, mean age 63.2 ± 9.7 years) were included in this retrospective study between October 2019 and August 2020. Transthoracic echocardiography was performed in all the subjects and STE was used to analyze the LA reservoir strain (LASr), LA conduit strain (LAScd) and LA contractile strain (LASct) during different phases before CA. Patients were followed up with until January 2022. The endpoint was AF recurrence. Over a median follow-up period of 26.0 months (interquartile range, 24.7-26.7 months), 26 patients experienced recurrence and 69 stayed in sinus rhythm. Compared with no-recurrence group, maximum volume of LA (LAVmax), minimum volume of LA (LAVmin) and LA volume index (LAVI) were increased in the recurrence group, while LAEF, LASr and LASct were worsened (P < 0.05). Multivariable logistic regression analysis revealed that LASct was an independent predictor of AF recurrence (odds ratio, 0.89; 95% confidence interval (CI), 0.82-0.97; P = 0.007) and receiver operating characteristic (ROC) curve analysis showed an area under the curve of LASct<8% was 0.70 (95% CI, 0.59-0.79; P = 0.0008). LASct was of independent predictive value of AF recurrence. LA function assessed by STE may contribute to the risk stratification for AF patients and selection of suitable patients for CA.


RNA nucleation by MSL2 induces selective X chromosome compartmentalization.
Confinement of the X chromosome to a territory for dosage compensation is a prime example of how subnuclear compartmentalization is used to regulate transcription at the megabase scale. In Drosophila melanogaster, two sex-specific non-coding RNAs (roX1 and roX2) are transcribed from the X chromosome. They associate with the male-specific lethal (MSL) complex1, which acetylates histone H4 lysine 16 and thereby induces an approximately twofold increase in expression of male X-linked genes2,3. Current models suggest that X-over-autosome specificity is achieved by the recognition of cis-regulatory DNA high-affinity sites (HAS) by the MSL2 subunit4,5. However, HAS motifs are also found on autosomes, indicating that additional factors must stabilize the association of the MSL complex with the X chromosome. Here we show that the low-complexity C-terminal domain (CTD) of MSL2 renders its recruitment to the X chromosome sensitive to roX non-coding RNAs. roX non-coding RNAs and the MSL2 CTD form a stably condensed state, and functional analyses in Drosophila and mammalian cells show that their interactions are crucial for dosage compensation in vivo. Replacing the CTD of mammalian MSL2 with that from Drosophila and expressing roX in cis is sufficient to nucleate ectopic dosage compensation in mammalian cells. Thus, the condensing nature of roX-MSL2CTD is the primary determinant for specific compartmentalization of the X chromosome in Drosophila.


Detection of Carbapenemase Production in a Collection of Enterobacteriaceae with Characterized Resistance Mechanisms from Clinical and Environmental Origins by Use of Both Carba NP and Blue-Carba Tests.
Rapid-screening methods to confirm the presence of resistance mechanisms in multidrug-resistant bacteria are currently recommended. Carba NP and Blue-Carba tests were evaluated in carbapenemase-producing Enterobacteriaceae from hospital (n = 102) and environmental (n = 57) origins for detecting the different molecular classes among them. Both methods showed to be fast and cost-effective, with high sensitivity (98% to 100%) and specificity (100%), and may be easily introduced in the routine laboratory.


Photoelectrocatalytic Degradation of Paraquat by Pt Loaded TiO₂ Nanotubes on Ti Anodes.
Nanotube structured TiO₂ on Ti surface were prepared in ethylene glycol (Ti/TiO₂NTEG) medium by anodic oxidation method with different times and then the plates were calcinated at different temperatures. Non-nanotube structured Ti/TiO₂, prepared by thermal oxidation method, and nanotube structured TiO₂ on Ti plate in hydrogen fluoride solution were also prepared for comparison. Pt loaded Ti/TiO₂NTEG photoanodes were also prepared by cyclic voltammetry method with different cycles and the optimum loaded Pt amount was determined. Photoanodes were characterized by using X-ray Diffraction (XRD), Scanning Electron Microscopy-Energy-Dispersive X-ray Analysis (SEM-EDX), and photocurrent methods. XRD analyses proved that almost all TiO₂ is in anatase phase. SEM analyses show that nanotubes and Pt nanoparticles on nanotube surface are dispersed quite homogeneously. The longest nanotubes were obtained in the ethylene glycol medium and the nanotube length increased by increasing applied anodic oxidation time. In addition, a linear correlation between nanotube length and XRD peak intensity was found. Moreover, SEM-EDX and XRD analyses evidence that Pt nanoparticles on nanotube surface are metallic and in cubic structure. Photoelectrocatalytic degradation of paraquat was performed using the prepared photoanodes. Moreover, electrocatalytic and photocatalytic degradations of paraquat were also investigated for comparison, however lower activities were observed. These results evidence that the photoanodes show a significant synergy for photoelectrocatalytic activity.


Disorders of heart rate and rhythm.
The clinical approach to a child with a disorder of the heart beat is still that of a careful history, physical examination, and an ECG with a long rhythm strip. A diagnostic approach is presented which is based on rate, rhythm, and mechanism. Newer diagnostic methods are presented as well as advances in the basic cellular electrophysiology. Disorders of automaticity, triggerable cells, and re-entry are analyzed. Finally, therapy is revised for conventional drugs, and new and nonapproved drugs are listed. Indications and limitations for cardioversion, electrical pacing, and surgery are presented.


Effects of thread depth, taper shape, and taper length on the mechanical properties of mini-implants.
The primary stability of a mini-implant is critical, since most orthodontic mini-implant failures occur at an early stage. As orthodontic mini-implants have restrictions in diameter and length, an optimal design of the shape is important for sufficient primary stability. The purpose of this study was to investigate the influence of various mini-implants design factors, including thread depth, degree of taper, and taper length on insertion torque, pullout strength, stiffness, and screw displacement before failure. Finite element analyses were conducted first for identification of optimal design parameters. Four types of mini-implants with different design parameters were then custom manufactured and tested mechanically. All mechanical tests were performed in artificial bone with homogenous density to remove the variability associated with bone. Finite element results showed that, for mini-implants with a fixed external diameter of 2 mm, a thread length of 9.82 mm, and a pitch of 0.75 mm, those with greater thread depths, smaller taper degrees, and shorter taper lengths generated higher maximum stresses on the bone and thread elements. These mini-implants also had larger relative displacements. Maximum pullout resistance was attained with a core/external diameter ratio of 0.68. All mechanical results were compatible with the findings in the finite element analyses. Modification of the mini-implant design can substantially affect the mechanical properties. The finite element method is an effective tool to identify optimal design parameters and allow for improved mini-implant designs.


Crystal lattice as biological phenotype for insect viruses.
Many insect viruses survive for long periods by occlusion within robust crystalline polyhedra composed primarily of a single polyhedrin protein. We show that two different virus families form polyhedra which, despite lack of sequence similarity in the virally encoded polyhedrin protein, have identical cell constants and a body-centered cubic lattice. It is almost inconceivable that this could have arisen by chance, suggesting that the crystal lattice has been preserved because it is particularly well-suited to its function of packaging and protecting viruses.


Chloroplast-based DNA barcode analysis indicates high discriminatory potential of matK locus in Himalayan temperate bamboos.
The study was conducted to evaluate the discriminatory potential of selected chloroplast-based DNA barcode regions for identifying and resolving phylogeny of the Indian bamboos. Among 11 chloroplast markers screened, only four, namely matK, rbcL, psbK-I and rps16-trnQ showed successful amplification in 88 genotypes of 30 Indian bamboo taxa under Bambuseae and Arundinarieae tribes. A total of 244 sequences were generated for the four chloroplast regions. Tree-based analysis demonstrated that none of the tested regions successfully discriminated the taxa under Bambuseae tribe. Importantly, our highly concerned Himalayan temperate bamboo species under Arundinarieae tribe, were successfully discriminated by matK locus with high bootstrap support (>60%). Sequence comparisons revealed that the discriminatory power demonstrated by matK region actually lies in the few unique fixed nucleotides (UFNs) despite the overall DNA polymorphism. Although, rps16-trnQ region was found to be the most polymorphic and revealed high genetic divergence among different taxonomic levels, it could not successfully discriminated the taxa with strong statistical support. In a taxonomically difficult plant group like bamboos, whose genome is relatively more complex and has a slow rate of molecular evolution, it is difficult to get a universal marker. Further, highly variable barcode regions utilized in other species may not be informative, and thus, the development of DNA barcodes for different taxonomic levels, such as lineages or tribes could be a viable approach.


Kinetics of angiopoietin-2 in serum of multi-trauma patients: correlation with patient severity.
Angiopoietin-2 (Ang-2) is considered a proinflammatory mediator promoting vascular leakage. Its participation in the inflammatory process following multiple injuries was investigated. Blood was sampled on consecutive days from 54 patients with multiple injuries and six healthy volunteers. Ang-2 was estimated in serum by an enzyme immunoassay. From the enrolled patients, 10 did not develop any complication; 17 developed systemic inflammatory response syndrome (SIRS); 16 developed sepsis and 11 severe sepsis. Among those who did not develop any complication, all survived. Ang-2 was increased on days 4 and 7 of follow-up in patients with SIRS. Ang-2 was highly increased upon advent of sepsis and of severe sepsis. Patients with serum levels below 15,200 pg/ml survived longer compared to those with levels above 15,200 pg/ml (p=0.015). OR for death with serum Ang-2 above 15,200 pg/ml was 4.00 (p=0.037). Serum levels of Ang-2 in multi-trauma patients are increased upon advent of septic complications and they are connected with bad prognosis. Its exact role in the process of multiple trauma remains to be defined.


Complete Genome Assembly of a Multidrug-Resistant New Delhi Metallo-β-Lactamase 1 (NDM-1)-Producing Escherichia coli Human Isolate from a New Zealand Hospital.
We report the complete genome of a multidrug-resistant Escherichia coli strain isolated from a New Zealand patient with a history of hospitalization in India. The strain, carrying eight plasmids, harbors chromosome-encoded nfsA and nfsB mutations, which cause nitrofuran resistance, and class C β-lactamase (bla EC) and plasmid-encoded bla NDM-1, bla CTX-M-15, and bla CMY-6, as well as other antibiotic resistance genes.


A comparative study of floral and electrophoretic variation with life history variation in Limnanthes alba (Limnanthaceae).
Plants derived from ten representative Limnanthes alba populations in Northern California, grown in a common environment, showed significant among-population genetic variation of certain floral and life history characters. Variation of these two sets of characters also correlated with the geographic distribution of populations, suggesting the influence either of common ancestry of neighboring populations, or of gradients of natural selection. In contrast, allozyme variation at eleven polymorphic loci showed little pattern. This suggests, if allozyme variants are assumed to accurately measure co-ancestry and each character set is assumed to give adequate and similar statistical power, that selection may have predominated over certain neutral processes during the evolution of some floral and life history characters.Life history characters, being closely tied to fitness, are particularly relevant to the postulated selection gradient. Studies of three representative populations in nature revealed significant differences in the sizes of dormant seed banks and several reproductive characters. These differences correlated with some field measures of soil and biotic variables, and were compared with certain predictions from reproductive strategy models in an attempt to identify any agents of selection. Alternative sets of life history characters were discernable corresponding to varieties identified on the basis of floral morphology, but these sets did not match those predicted the by r and k selection dichotomy; instead alternative selection regimes that may also favor some "bethedging" adaptations are postulated, although we emphasize our measures of habitat and climatic factors are too preliminary to clearly distinguish selective environmental factors.


New flavonoids and methylchromone isolated from the aerial parts of Baeckea frutescens and their inhibitory activities against cyclooxygenases-1 and -2.
In the present study, we carried out a phytochemical investigation of the ethanol extract of the aerial parts of Baeckea frutescens, which resulted in the isolation of two new flavonoid glycosides, myricetin 3-O-(5″-O-galloyl)-α-L-arabinofuranoside (1), 6-methylquercetin 7-O-β-D-glucopyranoside (2), one new methylchromone glycoside, 7-O-(4', 6'-digalloyl)-β-D-glucopyranosyl-5-hydroxy-2-methylchromone (3), together with three known compounds (4-6). The structures of these isolated compounds were established on the basis of 1D and 2D NMR techniques and chemical methods. The anti-inflammatory activities of the compounds 1-6 were evaluated for their inhibitory effects against cyclooxygenases-1 and -2 in vitro. Compounds 1-6 showed potent COX-1 and COX-2 inhibiting activities in vitro with IC50 values ranging from 1.95 to 5.54 μmol·L-1 and ranging from 1.01 to 2.27 μmol·L-1, respectively.


The enantiomers of carbocyclic 5'-norguanosine: activity towards Epstein-Barr virus.
(-)-5'-noraristeromycin (1) has shown antiviral activity towards, particularly cytomegalovirus, vaccinia virus and measles while its (+)-enantiomer (2) is effective towards hepatitis B virus. To determine if the antiviral characteristics of 1 and 2 extended to the guanine analogues (3 and 4), these enantiomers were prepared and evaluated against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6), human herpes virus type 8 (HHV-8), vaccinia virus (VV), cowpox virus (CV), vesicular stomatitis virus (VSV), respiratory syncytial virus (RSV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The only activity found for 3 was for Epstein-Barr virus in VCA Elisa (EC50 0.78 microg/mL), immunofluorescence assay for VCA or gp 350/250 (1.8-4.0 microg/mL) and DNA hybridization (EC50 0.82 microg/mL) assays with no accompanying toxicity seen in the host Daudi cells. No activity was noted for 4.


Climate change and the surgeon: what is the problem? Why is it so hard? What can be done?
We know very well what causes climate change, and in general terms, what the dangers are. This is a new kind of environmental problem, it is not like taking lead out of petrol, and it is important to understand why responding to climate change is so challenging. But that is no reason to give up: in fact there are many opportunities to intervene, including actions that can be taken by surgeons and other health professionals.


Clinical relevance of polymerase chain reaction (PCR) assays and antigen-driven immunoblots for the diagnosis of neurological infectious diseases.
Polymerase chain reaction assays are a powerful tool for detecting the presence of infectious genomes in the cerebrospinal fluid. Positive results always mean a current or pending infection of the central nervous system. Subacute (>7 days) or chronic infections induce an intrathecal humoral immune response and the appearance of oligoclonal IgG antibodies directed against the causal infectious agent. This local synthesis may be observed even in cases of severe systemic immunodeficiency. The use of polymerase chain reactions in combination with the detection of a specific intrathecal immune response should represent the most reliable strategy for the diagnosis of viral and chronic infections of the central nervous system. The authors describe their experience, using this approach, in herpetic encephalitis, acute and recurrent herpetic meningitis, varicella zoster-induced neurological diseases, cytomegalovirus encephalitis, progressive multifocal leukoencephalitis and tuberculous meningitis.


Insecticidal and repellent effects of tea tree (Melaleuca alternifolia) oil against Lucilia cuprina.
Laboratory studies were conducted to assess the effect of tea tree oil (TTO) from Melaleuca alternifolia (terpinen-4-ol chemotype) against different stages of the Australian sheep blowfly Lucilia cuprina. When applied to wool, 3% TTO formulation repelled gravid female L. cuprina and prevented oviposition for six weeks. Formulations containing 1% TTO caused 100% mortality of L. cuprina eggs and 1st instar larvae and 2.5% TTO caused mortality of most second and third instar larvae in agar feeding assays. In experiments where third instar larvae were dipped in TTO formulations for 60s, concentrations of up to 50% TTO gave less than 50% kill. TTO at concentrations of 0.5%, 2% and 5% was strongly repellent to third instar larvae and caused them to evacuate treated areas. Inclusion of TTO in formulations with diazinon, ivermectin and boric acid reduced mortality in comparison with the larvicides used alone, at least partially because of avoidance behaviour stimulated by the TTO. Addition of TTO to wound treatments may aid in wound protection and myiasis resolution by preventing oviposition by L. cuprina adults, insecticidal action against L. cuprina eggs and larvae, stimulating larvae to leave the wound and through antimicrobial and anti-inflammatory properties that aid in wound healing.


Application of the seven-factor model of personality to early childhood.
The seven-factor model of personality developed by Cloninger and colleagues describes personality as a function of developmental aspects of character superimposed on heritable dimensions of temperament. The objective of this study was to determine whether this model could be applied to early childhood. We tested a preschool version of the Temperament and Character Inventory (the preschool TCI) in 305 children aged 2-5 years. Exploratory factor analysis provided support for the presence of distinct domains of temperament (comprising four factors) and character (comprising three factors). The preschool TCI demonstrated high internal consistency for each of the seven factors (Cronbach's alpha values: 0.70-0.93). Inter-individual differences in novelty seeking, reward dependence and cooperativeness were highly preserved (Pearson's r values 0.75, 0.64 and 0.80, respectively) in 29 subjects who were studied over a 3-year period from toddlerhood to early school age. Future studies are warranted to test the extent to which early childhood measurements of the seven factors might predict the development of personality disorders.


The impact of in vitro embryo production on placental and umbilical cord vascularization is minimized by the addition of reproductive fluids.
Animals born from in-vitro-produced (IVP) embryos show changes in the placenta and umbilical cord vascularization. This study compares the placental and umbilical vascular morphometry in pigs (n = 19) born through artificial insemination (AI group) or after transfer of IVP embryos cultured with (RF-IVP group) or without (C-IVP group) reproductive fluids. The relationship between vascular parameters and animal growth during the first year of life was also analyzed. Samples were collected at birth, fixed, paraffin-embedded, cut in sections, stained, and photographed for vascular and morphometric analysis with ImageJ® and Slide Viewer®. The average daily weight gain was individually scored from birth to the first year of life. No differences were found in placental vascular morphometry among groups, except for the vascular area of small vessels (arterioles, venules, and small vessels) that was higher in the C-IVP group. Regarding the umbilical cord, the values for perimeter (AI: 26.40 ± 3.93 mm; IVP: 30.51 ± 4.74 mm), diameter (AI: 8.35 ± 1.01 mm; IVP: 10.26 ± 1.85 mm), area (AI: 43.18 ± 12.87; IVP: 56.61 ± 14.89 mm2), and Wharton's jelly area (AI: 36.86 ± 12.04 mm2; IVP 48.88 ± 12.80 mm2) were higher in IVP-derived than AI-derived animals, whereas arterial and venous morphometric data were similar between groups. A correlation study showed that placental and umbilical cord vascular phenotypes affect the further growth of pigs. In conclusion, assisted reproductive technologies impact small caliber vessels in the placenta and morphometric parameters in the umbilical cord. The addition of reproductive fluids in IVP-embryo contributes to reduce the differences with in vivo-derived animals.


Influence of krummholz mat microclimate on needle physiology and survival.
Microclimate and photosynthesis of krummholz mat growth forms of Picea engelmanii (Parry) and Abies lasiocarpa [Hook.] Nutt. were investigated to determine structural features which may aid survival in alpine environments. The structure of krummholz mats was described in terms of the vertical distribution of leaf area index and leaf area density, which exceeded 50 m-1 (based on total leaf surface area) near the canopy surface and approached zero below 30 cm from the surface in both species. Photosynthetic photon flux density (PPFD, 0.4-0.7 μm wavelengths) and wind decreased by an average of 6 and 50-fold, respectively, between 1 m above and 10 cm below mat surfaces in both species. Needle temperatures on a P. engelmannii krummholz mat during July averaged about 2°C above air temperature during the day, with a maximum overtemperature of greater than 20°C above T air during one sunlit period. At night, needle temperatures averaged 3-4°C below T air.Net photosynthesis in year-old P. engelmannii shoots reached a maximum at 15-20°C during July and August. Surface shoots were light saturated at near 1200 μmoles m-2s-1 PPFD, and had higher photosynthetic rates than subsurface, predominantly shaded shoots above 800 μmoles m-2s-1. Shade shoots had higher photosynthetic rates when PPFD was below 600 μmoles m-2s-1, and at 250 μmoles m-2s-1 shade shoots maintained about 50% of the net photosynthetic rate of sun shoots at light saturation. Shade shoots appeared capable of benefitting photosynthetically from elevated temperatures within krummholz mats despite relatively low light levels. Especially rapid photosynthesis may occur when canopy needles are illuminated by sunflecks and needle temperatures rise by 10° C or more.Snow cover appears crucial for the survival of needles during winter. Snow accumulated within krummholz needle canopies before the sub-canopy zone of unfoliated branches became filled. The concentrated needle growth in the krummholz canopy captured snow in early autumn without support from ground-level snowpack. Early snow cover in both species prevented cuticle abrasion and resulted in high winter needle water contents and viabilities for subsurface compared to surface needles which became abraded, severely dehydrated, and had high mortality between December and February, especially on windward sides of shoots.Extremely high concentrations of needles within krummholz mat canopies created an aerodynamic structure which elevated needle temperatures to more optimal photosynthetic levels in summer and resulted in more efficient snow accumulation in winter. These factors appear crucial for winter needle survival. Thus, krummholz mats appear to be an important adaptation in growth form which provides survival benefits in both summer and winter.


Special Considerations for the Management of Disorders of Gut-Brain Interaction in Older Adults.
The world's population is aging rapidly, with 40% of patients seen in US gastroenterology (GI) clinics being 60 years or older. Many gastrointestinal problems are more common or unique to the older adult because of progressive damage to the structure and function of the GI tract. Until recently, the epidemiology of disorders of gut-brain interaction (such as irritable bowel syndrome and functional dyspepsia) was not well-characterized. Forty percent of persons worldwide have disorders of gut-brain interaction (DGBI), with varying global patterns of incidence in older adults. There are multiple first-line approaches to managing DGBI which can also be combined including pharmacologic (e.g., neuromodulators) and nonpharmacologic approaches including dietary therapies and brain-gut behavioral therapies. However, there are considerations clinicians must account for when offering each approach related to unique biopsychosocial factors in the older adult population. In this review, we aim to critically review recent literature on the pathophysiology, epidemiology, and special considerations for diagnosing and managing DGBI in the older adult population. There have been many advances in the management of DGBI over the past decades. Given the increase in the number of older adults in the USA and worldwide, there is an urgent need for evidence-based guidance to help providers guide comprehensive care for specifically our aging patient population with respect to DGBI.


A Dementia mortality rates dataset in Italy (2012-2019).
Dementia is on the rise in the world population and has been defined by the World Health Organization as a global public health priority. In Italy, according to demographic projections, in 2051 there will be 280 elderly people for every 100 young people, with an increase in all age-related chronic diseases, including dementia. Currently the total number of patients with dementia is estimated to be over 1 million (mainly with Alzheimer's disease (AD) and Parkinson's disease (PD)). In-depth studies of the etiology and physiology of dementia are complicated due to the complexity of these diseases and their long duration. In this work we present a dataset on mortality rates (in the form of Standardized Mortality Ratios, SMR) for AD e PD in Italy at provincial level over a period of 8 years (2012-2019). Access to long-term, spatially detailed and ready-to-use data could favor both health monitoring and the research of new treatments and new drugs as well as innovative methodologies for early diagnosis of dementia.


Building a community network for behavioral health care.
Mental health and substance abuse patients often have nowhere to go but the ED. Hospitals can help create a more appropriate alternative.


False-positive ketone tests: a bedside measure of urinary mesna.
The sulfhydryl mesna is increasingly used to protect the bladder and kidney from effects of chemotherapy with ifosfamide and cyclophosphamide. Mesna reacts with reagents on urinary test strips designed to detect ketones. Test-strip results were correlated to sulfhydryl concentrations in 931 urine specimens obtained after infusions of mesna. These data may be used to estimate urinary mesna concentrations at the bedside or to test compliance in outpatients given oral mesna therapy.


Increased Colorectal Neoplasia Risk in Patients with Inflammatory Bowel Disease and Serrated Polyps with Dysplasia.
The impact of serrated polyps on the advanced colorectal neoplasia (CRN) risk in inflammatory bowel disease (IBD) patients is unknown. Serrated polyps are histologically categorized as hyperplastic polyps (HPs), sessile serrated lesions (SSLs), and traditional serrated adenomas (TSAs). We aimed (1) to characterize the serrated polyps in IBD patients, (2) to identify factors associated with the presence of serrated polyps in IBD, and (3) to assess the CRN risk in IBD patients with serrated polyps. We established a retrospective cohort of IBD patients with and without colonic serrated polyps. Cox-regression analysis with time-dependent variables was used to compare advanced CRN risk in IBD patients with and without serrated polyps. Of the 621 enrolled IBD patients, 198 had a serrated polyp (92 HPs, 88 SSLs without dysplasia, 13 SSLs with dysplasia, and 5 TSAs). Independent factors associated with serrated polyps were ulcerative colitis (UC) (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.19-2.62, p = 0.005), male gender (OR 1.63, 95% CI 1.11-2.40, p = 0.013), and older age (per year increase, OR 1.06, 95%CI 1.05-1.08, p < 0.001). TSAs and SSLs with dysplasia were risk factors for subsequent advanced CRN (HR 13.51, 95% CI 3.11-58.68, p < 0.001), while HPs (HR 1.98, 95% CI 0.46-8.60, p = 0.36) and SSLs without dysplasia (HR 0.87, 95% CI 0.11-6.88, p-0.89) did not impact the subsequent advanced CRN risk. UC, male gender and older age were associated with the presence of serrated polyps. The majority of serrated polyps (91%) were HPs and SSL without dysplasia and did not affect the CRC risk. However TSAs and SSLs with dysplasia, representing a small subgroup of serrated polyps (9%), were associated with subsequent advanced CRN.


Arachidonic acid release from mammalian cells transfected with human groups IIA and X secreted phospholipase A(2) occurs predominantly during the secretory process and with the involvement of cytosolic phospholipase A(2)-alpha.
Stable expression of human groups IIA and X secreted phospholipases A(2) (hGIIA and hGX) in CHO-K1 and HEK293 cells leads to serum- and interleukin-1beta-promoted arachidonate release. Using mutant CHO-K1 cell lines, it is shown that this arachidonate release does not require heparan sulfate proteoglycan- or glycosylphosphatidylinositol-anchored proteins. It is shown that the potent secreted phospholipase A(2) inhibitor Me-Indoxam is cell-impermeable. By use of Me-Indoxam and the cell-impermeable, secreted phospholipase A(2) trapping agent heparin, it is shown that hGIIA liberates free arachidonate prior to secretion from the cell. With hGX-transfected CHO-K1 cells, arachidonate release occurs before and after enzyme secretion, whereas all of the arachidonate release from HEK293 cells occurs prior to enzyme secretion. Immunocytochemical studies by confocal laser and electron microscopies show localization of hGIIA to the cell surface and Golgi compartment. Additional results show that the interleukin-1beta-dependent release of arachidonate is promoted by secreted phospholipase A(2) expression and is completely dependent on cytosolic (group IVA) phospholipase A(2). These results along with additional data resolve the paradox that efficient arachidonic acid release occurs with hGIIA-transfected cells, and yet exogenously added hGIIA is poorly able to liberate arachidonic acid from mammalian cells.


The DWEYS peptide in systemic lupus erythematosus.
Current therapies for treating systemic lupus erythematosus (SLE) mainly rely upon nonspecific and toxic immunosuppression by corticosteroids and cytotoxics. Although biologics hold promise, many agents have yet to prove clinical efficiency in controlled trials, with further limitations related to safety and cost. The primary self-specificity in SLE is double-stranded (ds) DNA. Studying anti-dsDNA antibodies in animal models of lupus and SLE patients identified a neurotoxic and nephrotoxic subset, including the nephritogenic mouse monoclonal anti-dsDNA antibody R4 that crossreacts with a sequence present in subunits of the N-methyl-d-aspartate receptor. In this review, anti-dsDNA antibodies as a pathogenic factor in SLE and recent efforts for the creation of highly specific, nontoxic therapeutics against an extremely pathogenic subset of such antibodies is discussed.


Possible involvement of prostaglandins in increases in rat plasma adrenocorticotropic hormone and corticosterone levels induced by radiation and interleukin-1 alpha alone or combined.
Exposing rats to 1-10 Gy of ionizing radiation increased plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels. In both irradiated and nonirradiated rats, recombinant human interleukin-1 alpha (rhIL-1 alpha; 1 hr before radiation/sham exposure) enhanced plasma ACTH and CORT levels. Indomethacin, a cyclooxygenase inhibitor, attenuated plasma ACTH and CORT levels induced by radiation. Indomethacin also attenuated ACTH and CORT levels induced by radiation and interleukin-1 alpha alone or combined. These results suggest that prostaglandins are involved in the increase in plasma ACTH and CORT levels induced by radiation and rhIL-1 alpha alone or combined.


Application of a Deep Machine Learning Model for Automatic Measurement of EZ Width in SD-OCT Images of RP.
We applied a deep convolutional neural network model for automatic identification of ellipsoid zone (EZ) in spectral domain optical coherence tomography B-scans of retinitis pigmentosa (RP). Midline B-scans having visible EZ from 220 patients with RP and 20 normal subjects were manually segmented for inner limiting membrane, inner nuclear layer, EZ, retinal pigment epithelium, and Bruch's membrane. A total of 2.87 million labeled image patches (33 × 33 pixels) extracted from 480 B-scans were used for training a convolutional neural network model implemented in MATLAB. B-scans from a separate group of 80 patients with RP were used for testing the model. A local connected area searching algorithm was developed to process the model output for reconstructing layer boundaries. Correlation and Bland-Altman analyses were conducted to compare EZ width measured by the model to those by manual segmentation. The accuracy of the trained model to identify inner limiting membrane, inner nuclear layer, EZ, retinal pigment epithelium, and Bruch's membrane patches in the test dataset was 98%, 89%, 91%, 94%, and 96%, respectively. The EZ width measured by the model was highly correlated with that by two graders (r = 0.97; P < 0.0001). Bland-Altman analysis revealed a mean EZ width difference of 0.30 mm (coefficient of repeatability = 0.9 mm) between the model and the graders, comparable to the mean difference of 0.34mm (coefficient of repeatability = 0.8 mm) between two graders. The results demonstrated the capability of a deep machine learning-based method for automatic identification of EZ in RP, suggesting that the method can be used to quantify structural deficits in RP for detecting disease progression and for evaluating treatment effect. A deep machine learning model has the potential to replace humans for grading spectral domain optical coherence tomography images in RP.


MRI of the breast in patients with DCIS to exclude the presence of invasive disease.
Core biopsy underestimates invasion in more than 20% of patients with preoperatively diagnosed ductal carcinoma in situ (DCIS) without evidence of invasion (pure DCIS). The aim of the current study was to evaluate the efficacy of preoperative magnetic resonance imaging (MRI) to discriminate between patients with DCIS who are at high risk of invasive breast cancer and patients at low risk. One hundred and twenty-five patients, preoperatively diagnosed with pure DCIS (128 lesions; 3 bilateral) by core-needle biopsy, were prospectively included. Clinical, mammographic, histological (core biopsy) and MRI features were assessed. All patients underwent breast surgery. Analyses were performed to identify features associated with presence of invasion. Eighteen lesions (14.1%) showed invasion on final histology. Seventy-three lesions (57%) showed suspicious enhancement on MRI with a type 1 (n = 12, 16.4%), type 2 (n = 19, 26.0%) or type 3 curve, respectively (n = 42, 57.5%). At multivariate analysis, the most predictive features for excluding presence of invasive disease were absence of enhancement or a type 1 curve on MRI (negative predictive value 98.5%; A(Z) 0.80, P = 0.00006). Contrast medium uptake kinetics at MRI provide high negative predictive value to exclude presence of invasion and may be useful in primary surgical planning in patients with a preoperative diagnosis of pure DCIS. It is important to determine invasion in breast DCIS. • MRI contrast medium uptake kinetics can help exclude the presence of invasion. • However, the positive predictive value for the presence of invasion is limited. • MRI features were more accurate at predicting invasion than mammographic features alone.


[The expertise of quality assessment of obstetric-gynecologic and neonatal care at different stages of its delivery].
The results of sociologic survey of obstetrician-gynecologists in various medical organizations of Penzenskaya oblast are discussed. The issues of delivering medical care to pregnant women, parturient women, gynecologic patients and newborns are considered. The expertise is made concerning the quality of secondary medical care at every stage of its delivering. The study demonstrated that obstetric-gynecologic and neonatal care of higher quality is delivered in perinatal center.


Evidence of neurotoxicity in working children in Lebanon.
The potential for exposure to neurotoxicants in Lebanon is high, especially in the absence of strict control and regulatory measures in workplaces. Children working in mechanical and other trade workshops are at significant risk of exposure to organic solvents and as a result at significant risk to develop clinical and subclinical signs of neurotoxicity. This study investigated the association between exposure to solvents and neurobehavioral performance of 10-17 years old working children in comparison to groups of non-exposed working children and non-exposed children at school. A convenience cross-sectional sample of 100 working children (10-17 years) exposed to organic solvents at work, a positive control of 100 non-solvent exposed working children, and a negative control of 100 non-working, non-exposed school children were recruited to the study. The exposed and non-exposed groups were, as far as possible, frequency matched on geographic location of residence and on age. Neurotoxic effects were assessed through a questionnaire and the child's performance on a battery of neurobehavioral tests, which were specifically selected for a non-English speaking population and were tailored to assess the specific modalities of the central nervous system commonly known to be affected by the neurotoxicants identified. Children in the non-exposed groups (working and non-working) performed better than the working exposed group on reaction speed for the choice reaction time, symbol-digit and dual task tracking tests, but accuracy of performance was not affected on these tests. Children in the working exposed group also complained of more headaches, loss of concentration, memory deficits and higher irritability. This study identifies an association between exposure to solvents and lower neurobehavioral performance. Response speed appears to be particularly affected in solvent exposed working children.


NTRK gene aberrations in triple-negative breast cancer: detection challenges using IHC, FISH, RT-PCR, and NGS.
Triple-negative breast cancer (TNBC) is usually an aggressive disease with a poor prognosis and limited treatment options. The neurotrophic tyrosine receptor kinase (NTRK) gene fusions are cancer type-agnostic emerging biomarkers approved by the Food and Drug Administration (FDA), USA, for the selection of patients for targeted therapy. The main aim of our study was to investigate the frequency of NTRK aberrations, i.e. fusions, gene copy number gain, and amplification, in a series of TNBC using different methods. A total of 83 TNBCs were analyzed using pan-TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR), and RNA-based next-generation sequencing (NGS). Of 83 cases, 16 showed pan-TRK positivity although no cases had NTRK-fusions. Indeed, FISH showed four cases carrying an atypical NTRK1 pattern consisting of one fusion signal and one/more single green signals, but all cases were negative for fusion by NGS and RT-PCR testing. In addition, FISH analysis showed six cases with NTRK1 amplification, one case with NTRK2 copy number gain, and five cases with NTRK3 copy number gain, all negative for pan-TRK IHC. Our data demonstrate that IHC has a high false-positive rate for the detection of fusions and molecular testing is mandatory; there is no need to perform additional molecular tests in cases negativity for NTRK by IHC. In conclusion, the NTRK genes are not involved in fusions in TNBC, but both copy number gain and amplification are frequent events, suggesting a possible predictive role for other NTRK aberrations.


Chaetonigrisins A-L, a group of 3-Indole-1,2-Propanediol derived alkaloids from Chaetomium nigricolor YT-2.
Thirteen new alkaloids (1-13) as well as ten known compounds were isolated from the solid-state fermented rice medium of the fungus Chaetomium nigricolor YT-2. Their structures were elucidated on the basis of spectroscopic data, quantum calculations, and single crystal X-ray crystallographic analysis. Chaetonigrisin A (1) represents an unprecedented carbon skeleton featuring a polycyclic 1H-pyrano[3,2:3,4-]furo[2,3-b]indole. Chaetonigrisin B (2) displays a unique carbon skeleton with a 1,3‑dioxolane bridged-ring. Chaetonigrisin C (3) is a spirocyclic indole alkaloid. Chaetonigrisins D-H (4-8) are a group of asymmetric dimers, formed with two 3-indol-3yl-1,2-propanediol (4-6) or with a 3-indol-3yl-1,2-propanediol and a 3-indol-2yl-1,2-propanediol (7-8) by a pyran ring. Chaetonigrisins I-L (9-12) each contains a 3-indol-3yl-1,2-propanediol or 3-indol-2yl-1,2-propanediol substructure. Chaetonigrisin M (13) is a new quinoline alkaloid. The neuroprotective activity assay showed that at the concentration of 40 μM, compounds (4-7, 11, and 12) improved the cell viability of PC12 cells were 49.26 %, 74.69 %, 74.76 %, 86.63 %, 66.89 %, and 69.92 %, respectively induced by 6-OHDA, compound 7 showed significant neuroprotective activity via upregulation of SOD1 mRNA and Bcl-2 mRNA.


Leptin receptor (Lepr) is a negative modulator of bone mechanosensitivity and genetic variations in Lepr may contribute to the differential osteogenic response to mechanical stimulation in the C57BL/6J and C3H/HeJ pair of mouse strains.
This study investigated the role of leptin receptor (Lepr) signaling in determining the bone mechanosensitivity and also evaluated whether differences in the Lepr signaling may contribute to the differential osteogenic response of the C57BL/6J (B6) and C3H/HeJ (C3H) pair of mouse strains to mechanical stimuli. This study shows that a loading strain of ∼2,500 με, which was insufficient to produce a bone formation response in B6 mice, significantly increased bone formation parameters in leptin-deficient ob(-)/ob(-) mice and that a loading strain of ∼3,000 με also yielded greater osteogenic responses in Lepr-deficient db(-)/db(-) mice than in wild-type littermates. In vitro, a 30-min steady shear stress increased [(3)H]thymidine incorporation and Erk1/2 phosphorylation in ob(-)/ob(-) osteoblasts and db(-)/db(-) osteoblasts much greater than those in corresponding wild-type osteoblasts. The siRNA-mediated suppression of Lepr expression in B6 osteoblasts enhanced (but in osteoblasts of C3H (the mouse strain with poor bone mechanosensitivity) restored) their anabolic responses to shear stress. The Lepr signaling (leptin-induced Jak2/Stat3 phosphorylation) in C3H osteoblasts was higher than that in B6 osteoblasts. One of the three single nucleotide polymorphisms in the C3H Lepr coding region yielded an I359V substitution near the leptin binding region, suggesting that genetic variation of Lepr may contribute to a dysfunctional Lepr signaling in C3H osteoblasts. In conclusion, Lepr signaling is a negative modulator of bone mechanosensitivity. Genetic variations in Lepr, which result in a dysfunctional Lepr signaling in C3H mice, may contribute to the poor osteogenic response to loading in C3H mice.


Method for the Determination of 2'-Fucosyllactose (2'-FL), 3-Fucosyllactose (3-FL), 6'-Sialyllactose (6'-SL), 3'-Sialyllactose (3'-SL), Lacto-N-Tetraose (LNT), and Lacto-N-neoTetraose (LNnT) by High-Performance Anion-Exchange Chromatography With Pulsed Amperometric Detection (HPAEC-PAD): First Action 2022.04.
A method for simultaneous determination of six human milk oligosaccharides (HMOs) is described. The HMOs include 2'-fucosyllactose (2'-FL, CAS number 41263-94-9), 3-fucosyllactose (3-FL, CAS number 41312-47-4), 6'-sialyllactose (6'-SL, CAS number 35890-39-2), 3'-sialyllactose (3'-SL, CAS number 35890-38-1), lacto-N-tetraose (LNT, CAS number 14116-68-8), and lacto-N-neotetraose (LNnT, CAS number 13007-32-4). The method was designed to comply with the respective Standard Method Performance Requirements (SMPR®; seeTable 1), respectively. The method is valid for six HMOs in infant formula and adult nutritional matrixes, including samples with intact protein, protein hydrolysates, elemental formulations free of intact protein, and rice flour over the ranges defined in the SMPR (seeTable 2). The method is not valid for determination of difucosyllactose (DFL/DiFL). For most samples, reconstitution with water followed by filtration. For products containing interferences (fructans and maltodextrins), hydrolysis with enzymes is used. After preparation, samples are analyzed using high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). The method provides for separation of six HMOs and other carbohydrates commonly found in infant formula and adult nutritional products (e.g., lactose, sucrose, and GOS). This study includes data from multiple matrixes evaluated by multiple laboratories globally. RSDr ranged from 0.0068 to 4.8% RSDr, and spike recovery results ranged from 89.4 to 109%. Calibration fit optimal with a quadratic curve; alternately linear fit showed no statistically significant impact to data (when correlation passes). This method was reviewed by the AOAC SPIFAN Expert Review Panel (ERP) and determined to meet the SMPRs for the six noted HMOs. The method was granted First Action Official MethodsSM status.


Extinction of Ig genes expression in myeloma x fibroblast somatic cell hybrids is accompanied by repression of the oct-2 gene encoding a B-cell specific transcription factor.
In most instances, fusion of differentiated cell types with fibroblasts has resulted in the extinction of differentiation-specific traits of the nonfibroblast parental cell. To explore the genetic basis of this phenomenon, we have used a series of somatic cell hybrids between myeloma cells and fibroblasts. Previous findings show that in these hybrids expression of the immunoglobulin (Ig) genes was extinguished at the transcriptional level. Our present results show that NF-kappa B transcription factor, known to be critical for kappa-chain enhancer activity, is present although in a lower amount, in the nucleus and in the cytosolic fraction of most of these hybrids (probably attached to the previously postulated I-kappa B inhibitor). In contrast, the expression of the NF-A2/OTF-2 transcription factor encoded by the oct-2 gene, which binds to the octameric motif located in the Ig promoters and heavy chain gene enhancer, is extinguished at the transcriptional level. Our data thus suggest that extinction of Ig genes expression occurs via an indirect mechanism in which a fibroblast factor suppresses transcription factor(s) which are critical for Ig transcription.


Infections of the Spine.
Pyogenic infections of the bony spinal column and the intervertebral discs are on a steady rise in an aging western population. Despite advanced medical imaging, this clinical entity of devastating consequences if missed, still presents a diagnostic conundrum and is plagued by an unacceptably long diagnostic delay. The aim of this article is to raise awareness of the heterogeneity of spinal infections paralleling the complex structure of the spinal column and neighboring soft tissues. Emphasis is placed on the clinical presentation and management of septic facet joints and psoas muscle abscesses associated with lumbar spondylodiscitis.


Intraspecific Aggression in Giant Honey Bees (Apis dorsata).
We investigated intraspecific aggression in experimental nests (expN₁, expN₂) of the giant honey bee Apis dorsata in Chitwan (Nepal), focusing on interactions between surface bees and two other groups of bees approaching the nest: (1) homing "nestmate" foragers landing on the bee curtain remained unmolested by guards; and (2) supposed "non-nestmate" bees, which were identified by their erratic flight patterns in front of the nest, such as hovering or sideways scanning and splaying their legs from their body, and were promptly attacked by the surface bees after landing. These supposed non-nestmate bees only occurred immediately before and after migration swarms, which had arrived in close vicinity (and were most likely scouting for a nesting site). In total, 231 of the "nestmate" foragers (fb) and 102 approaches of such purported "non-nestmate" scouts (sc) were analysed (total observation time expN₁: 5.43 min) regarding the evocation of shimmering waves (sh). During their landing the "nestmate" foragers provoked less shimmering waves (relnsh[fb] = 23/231 = 0.0996, relnsh[sc] = 75/102 = 0.7353; p <0.001, χ²-test) with shorter duration (Dsh[fb] = 197 ± 17 ms, Dsh[sc] = 488 ± 16 ms; p <0.001; t-test) than "non-nestmates". Moreover, after having landed on the nest surface, the "non-nestmates" were attacked by the surface bees (expN₁, expN₂: observation time >18 min) quite similarly to the defensive response against predatory wasps. Hence, the surface members of settled colonies respond differently to individual giant honey bees approaching the nest, depending on whether erratic flight patterns are displayed or not.