Tissue damage negatively regulates LPS-induced macrophage necroptosis.
Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mφ), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mφ necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mφ necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease Mφ necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.


Design and pilot testing of a 26-gauge impedance-electromyography needle in wild-type and ALS mice.
Needle impedance-electromyography (iEMG) is a diagnostic modality currently under development that combines intramuscular electrical impedance with concentric electromyography (EMG) in a single needle. We designed, manufactured, and tested a prototype iEMG needle in a cohort of wild-type (WT) and SOD1G93A amyotrophic lateral sclerosis (ALS) mice to assess its ability to record impedance and EMG data. A new six-electrode, 26-gauge, iEMG needle was designed, manufactured and tested. Quantitative impedance and qualitative "gestalt" EMG were performed sequentially on bilateral quadriceps of 16-wk-old SOD1G93A ALS (N = 6) and WT (N = 6) mice by connecting the needle first to an impedance analyzer (with the animal at rest) and then to a standard EMG system (with the animal fully under anesthesia to measure spontaneous activity and briefly during awakening to measure voluntary activity). The needle remained in the muscle throughout the measurement period. EMG data were qualitatively similar to that observed with a commercially available concentric EMG needle; fibrillation potentials were observed in 84% of the ALS mice and none of the WT mice; motor unit potentials were also readily identified. Impedance data revealed significant differences in resistance, reactance, and phase values between the two groups, with ALS animals having reduced reactance and resistance values. This work demonstrates the feasibility of a single iEMG needle conforming to standard dimensions of size and function. Further progress of iEMG technology for enhanced neuromuscular diagnosis and quantification of disease status is currently in development.


Intravenous diltiazem in patients with paroxysmal re-entrant supraventricular tachycardia.
The electrophysiologic effects and efficacy of diltiazem were evaluated with programmed electrical stimulation of the heart in 12 patients with supraventricular re-entrant tachycardia (five with atrioventricular nodal tachycardia and seven with circus movement tachycardia the accessory pathway being concealed in 4). Diltiazem was infused over 1 minute at the dose of 0.25 mg/kg and the electrophysiologic parameters were evaluated at 5 and 30 minutes. Diltiazem prolonged the AH interval from 83.5 +/- 58 to 99 +/- 55 msec (P less than 0.05), effective and functional refractory periods of atrioventricular node from 244 +/- 40 to 268 +/- 56 msec (P less than 0.05) and from 432 +/- 124 to 468 +/- 130 msec (P less than 0.005) respectively, lowered the atrial pacing rate inducing second-degree atrioventricular block from 159 +/- 32 to 134 +/- 33 beats/min (P less than 0.005) and decreased systolic and diastolic blood pressure from 143.5 +/- 33 to 132.5 +/- 22 mm Hg (P less than 0.05) and from 90 +/- 15 to 82.5 +/- 9 (P less than 0.05), respectively. Diltiazem prevented the reinduction of the tachycardia in 4 of 5 patients with atrioventricular nodal tachycardia and in 4 of 7 with circus movement tachycardia. The mechanism of action of diltiazem consisted of depression of conduction in atrioventricular node in anterograde fashion while there were no effects on refractoriness of the accessory pathway. The drug was well tolerated with no adverse effects. Diltiazem, therefore, appears an effective and safe drug in the acute treatment of re-entrant supraventricular tachycardia.


New observations on the innervation of striated ducts in submandibular glands of cats, including possible peptidergic nerves.
The presence of hypolemmal axons between striated duct cells in submandibular glands of cats has been established electron microscopically. Axons were found between "light" cells, between "light" and "dark" cells and between "light" and basal cells. Hypolemmal axons were observed most frequently in the junctional region between striated and intercalary ducts. They were often more common in younger animals. "Dark" cells with numerous processes sometimes appeared to have a special relationship with hypolemmal axons. Most of the hypolemmal axons in striated ducts contained characteristic agranular vesicles of the cholinergic type, about 40 nm in diameter; many of these axons also contained large dense cored vesicles of the peptidergic type, about 100 nm in diameter and possessing a more clear outer halo. No adrenergic axons have been observed beneath the basal lamina of striated ducts, even after use of 5-OHDA. The possibility that some of the hypolemmal axons in striated ducts are peptidergic and their possible functions are discussed. Apart from other activities these axons may have a role in supplying special trophic factors to the cells, helping them in their developmental specialisation and maintaining them in normal condition. An absence of such factors after parasympathetic decentralisation may be responsible for the dramatic atrophic changes in striated duct cells, especially since the atrophy in the gland is not solely due to an absence of acetylcholine activation.


Antibiofilm activity of ultra-small gold nanoclusters against Fusobacterium nucleatum in dental plaque biofilms.
Pathogenic dental plaque biofilms are universal and harmful, which can result in oral infections and systemic diseases. Many conventional therapeutic methods have proven insufficient or ineffective against plaque biofilms. Therefore, new strategies are urgently needed. Fusobacterium nucleatum (F. nucleatum), a periodontal pathogen associated with a variety of oral and systemic diseases, is thought to be central to the development and structure of dental plaques. Here, ultra-small gold nanoclusters (AuNCs) were prepared. They exhibited potent antibacterial activity against F. nucleatum through enhanced destruction of bacterial membranes and generation of reactive oxygen species. Furthermore, due to their excellent penetration, the AuNCs could inhibit biofilm formation and destroy mature biofilms in vitro. Their antibiofilm efficacy was further confirmed in a mouse model, where they reduced biofilm accumulation and ameliorated inflammation. Meanwhile, the disruption of oral and gut microbiota caused by colonization of oral F. nucleatum could be partially restored through AuNCs treatment. Therefore, AuNCs could be considered as promising antibiofilm agents and have great potential in the clinical treatment of dental plaque.


Potential inhibitory effect of fish, maize, and whey protein hydrolysates on advanced glycation end-products (AGEs).
Advanced glycation end-products (AGEs) are produced in the final stage of the Maillard reaction. AGEs formation may be inhibited by natural hydrolysates derived from plant or animal sources. The present study aimed to investigate the antiglycation potential of fish, maize, and whey protein hydrolysates. It was carried out in four model systems, Bovine serum albumin (BSA)-Glucose, BSA-Fructose, BSA-Sorbitol, and BSA-HFCS (high fructose corn syrup), by evaluation of fluorescent intensity of AGEs after seven days of reaction at 37°C. The results showed that the highest inhibitory effect belonged to 0.16% of FPH (fish protein hydrolysate, percent inhibition ~99.0%), whereas maize protein hydrolysate (MPH) had lower antiglycation activity in comparison with FPH. Among all hydrolysates, whey protein hydrolysate with the lowest degree of hydrolysis showed the weakest inhibitory activity. Overall, our results indicated that the investigated hydrolysates, particularly FPH, have promising antiglycation potential and can be recommended for the production of functional foods.


Spironolactone and gastrointestinal bleeding: a population based study.
Several medical reports showed an increased risk of stomach and duodenum bleeding associated with the use of spironolactone. The objective of this work is to examine the association between upper gastrointestinal (UGI) bleeding and exposure to spironolactone, using a population-based cohort design. Using the pharmaceutical prescriptions from 2000 to 2006, a cohort was identified of residents in Milan (Italy) with chronic exposure to spironolactone or other diuretic drugs. The main outcome was defined as the hospital admission for UGI bleeding or ulcers. To control for potential bias related to spironolactone use, the propensity score was estimated. Then, each patient treated with spironolactone was randomly matched with one treated with other diuretics and having the same propensity score using the caliper matching method. Proportional hazard models were fitted by computing hazard ratios (HR) and the corresponding 95% confidence intervals (95%CI). A total of 53 550 unexposed and 10 564 exposed to spironolactone were identified. Overall in the study period, 174 patients (3.2%) developed UGI bleeding in the unexposed and 51 (4.8%) in the exposed group. HR for UGI bleeding for the spironolactone exposed group was 1.94 (95%CI 1.42-2.65). The sensitivity analysis based on the matched design using the propensity score showed a statistically significant twofold increase of gastrointestinal bleeding only among subjects exposed to high spironolactone dose (HR 2.50; 95%CI 1.08-5.79). Results from a large population based study confirm that spironolactone increases the risk of UGI bleeding.


Structural basis for recognition of ubiquitinated cargo by Tom1-GAT domain.
Tom1 (Target of Myb1) is suggested to be involved in the transport of ubiquitinated proteins, through the interaction of its GAT (GGA and Tom1) domain with ubiquitin. Here, we demonstrate that the three-helix bundle of Tom1-GAT has two ubiquitin-binding sites recognizing the hydrophobic Ile44 surface of ubiquitin. The complex crystal structure demonstrates that the first site is a hydrophobic patch on helices alpha1 and alpha2. NMR and biochemical data revealed that the N-terminal half of helix alpha3 of Tom1-GAT constitutes the second, stronger binding site. The double-sided ubiquitin binding enhances the efficiency of recognition of ubiquitinated proteins by Tom1.


Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4T-phenyl methoxyalaninyl phosphate derivatives.
d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.


Application of the salutogenic theory in the perinatal period: A systematic mixed studies review.
The pregnancy process has always been medicalized with a focus on the prevention of adverse pregnancy outcomes and a lesser emphasis on enhancing women's wellbeing during the perinatal period. This trend urges healthcare professionals to consider the use of a salutogenic approach throughout the perinatal period. To consolidate and appraise evidence on the use of the salutogenic theory across the perinatal period. A systematic mixed studies review. Four electronic databases (CINAHL, ScienceDirect, PsycINFO, and PubMed) were searched for English studies from each database's inception to November 2018. Thirty-four studies met the inclusion criteria and were appraised for quality by two researchers independently. A narrative synthesis was conducted to consolidate and synthesize results from mixed methodology studies. Four themes emerged from the synthesis: (1) factors affecting sense of coherence (generalized resistance resources), (2) influences of sense of coherence, (3) ways to promote sense of coherence among mothers, and (4) use of salutogenic framework across perinatal healthcare. Sociodemographic background, psychological and birth-related factors, and availability of social support affect sense of coherence among parents, which are positively correlated to quality of relationship, satisfaction of perceived support, psychological wellbeing, and overall birth experience. Sense of coherence also determines mothering orientation and choice of delivery method. Ways to enhance maternal sense of coherence include ensuring continuity of care in the postpartum period, increasing parental involvement, focusing on wellness topics, and having balanced relationships between parents and healthcare providers. Despite consolidating evidence on positive relationships of generalized resistance resources, sense of coherence, and parental outcomes during the perinatal period, the scarcity of literature highlights a need for more in-depth research on the underlying mechanisms of salutogenesis and its components as these insights may underpin future maternal health promotion efforts.


Faecal calprotectin in colonic diverticular disease: a case-control study.
Information about faecal calprotectin (FC) in colonic diverticular disease (DD) are lacking. We assessed FC in colonic DD, comparing it with irritable bowel syndrome (IBS) patients and healthy controls. Moreover, we compared FC levels in different degrees of DD and assessed FC in symptomatic DD before and after treatment. Forty-eight consecutive patients with a new endoscopic diagnosis of DD (16 with asymptomatic diverticulosis, 16 with symptomatic uncomplicated DD, 16 with acute uncomplicated diverticulitis), 16 healthy controls, and 16 IBS patients were studied. FC was assessed by semi-quantitative method and compared with histological inflammation. Moreover, FC was reassessed in symptomatic DD after 8 weeks of treatment. FC was not increased in healthy controls and IBS patients. No difference was found between asymptomatic diverticulosis, healthy controls, and IBS patients (p = n.s.). We found higher FC values in acute uncomplicated diverticulitis (p < 0.0005) and in symptomatic uncomplicated DD (p < 0.005) than in healthy controls and in IBS patients. FC values correlated with inflammatory infiltrate (p < 0.0005). FC decreased after treatment to normal values both in acute uncomplicated diverticulitis (p < 0.0005) and in symptomatic uncomplicated DD (p < 0.005) after treatment. INTERPRETATIONS/CONCLUSIONS: FC may be useful to detect colonic inflammation in DD and in distinguishing symptomatic DD from IBS, as well as in assessing response to therapy in DD.


Evaluation of the efficacy of antimicrobials against pathogens on food contact surfaces using a rapid microbial log reduction detection method.
Microbial contamination of food contact surfaces in food processing industries is a significant health hazard. Evaluating the efficacy of sanitizing agents used during food processing is essential to ensure public health and safety. This study describes an optical screening method using an oCelloScope to quantify the number of surviving bacterial cells, expressed as microbial log reduction (MLR), after antimicrobial treatment. We tested the efficacy of two sanitizing agents, sodium hypochlorite and benzalkonium chloride, against desiccated cells of three pathogens, S. Enteritidis, E. coli O157: H7, and L. monocytogenes that are of concern on food processing surfaces. Stainless steel slides were used to mimic commercial food processing surfaces. Bacterial cells were desiccated at 75% relative humidity (RH) before antimicrobial treatment on stainless steel surfaces, and survivor levels were analyzed via plate counts to calculate MLR. These were compared to MLR values generated using the oCelloScope. For analysis of MLR using the oCelloScope, cells were desiccated at 75% RH on polystyrene microtiter plates, treated with antimicrobials, and surviving cell numbers were analyzed. Our results show that MLR values of treated desiccated cells calculated using the BCA algorithm of the oCelloScope were comparable to the values generated using the traditional plate count assay for the same concentration and treatment duration of the antimicrobials against all the tested pathogens. MLR could not be calculated for a non-lytic antimicrobial (curcumin and UV-A irradiation) against E. coli O157:H7, however, modified growth curves demonstrated an antimicrobial effect of curcumin and irradiation treatment. The results indicate that this method can be used for rapid screening of MLR of lytic antimicrobial compounds. Quantification of MLR using the oCelloScope is an effective tool to rapidly identify appropriate antimicrobial treatments and can be used to study novel antimicrobial compounds in the future.


Human B cell proliferation is stimulated by interleukin 2.
The proliferation of human B cells was studied for response to interleukin 2 (IL-2) produced in Escherichia coli using recombinant DNA technology. The IL-2 was found to be an homogenous preparation by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting using the anti-IL-2 monoclonal antibody DMS-1. IL-2 was found to stimulate B cell proliferation. Activation of the B cells using anti-IgM antibodies increased this response. Resting T cells from the same donors were found to be less reactive to IL-2. The results suggest that human B cell proliferation can be stimulated by IL-2 alone.


Highlighting the Potential Role of Exosomes as the Targeted Nanotherapeutic Carrier in Metastatic Breast Cancer.
Breast cancer, being the second most common type of cancer, is a leading cause of death in the female population. Of all the available treatments existing for breast cancer, exosomes appear as an important medium for the site targeted delivery of the drugs. Exosomes, unlike all the other extracellular vesicles, play a vital role in the transport of numerous biomolecules throughout the body and can easily be detected because of the presence of specific biomarkers. Apart from playing a wide variety of roles in the progression of many diseases, they are also responsible for tumor progression and metastasis in breast cancer. Exosomes and related engineering strategies are being discussed as nano-carrier for the delivery of different drugs in the case of breast cancer. Overall, we have discussed in this review the role of exosomes in breast cancer and the engineering strategies being devised for making them an efficient drug delivery system.


Left atrial strain as a pre-operative prognostic marker for patients with severe mitral regurgitation.
In patients with severe mitral regurgitation (MR), additional echocardiographic indices could be helpful to optimize surgical timing before irreversible left heart myocardial dysfunction has occurred. We investigated the correlation of left atrial (LA) strain by speckle tracking echocardiography with prognosis after mitral surgery for severe MR, and its association with LA fibrosis. 71 patients with primary severe MR undergoing pre-operative echocardiographic assessment were initially enrolled. Exclusion criteria were: other valvular disease>moderate, history of coronary artery disease, heart failure (HF), hypertrophic cardiomyopathy, left bundle branch block, previous pacemaker implantation, heart transplantation, poor acoustic window. The primary endpoint was the occurrence of composite events (HF and mortality); the secondary endpoint was post-operative functional capacity (NYHA and Borg CR10 class). LA fibrosis was assessed by atrial biopsy specimens in a subset of patients. Of 65 eligible patients, the primary endpoint occurred in 30 patients (medium follow-up: 3.7 ± 1 years for event-group, 6.8 ± 1 years for non-event group). After Kaplan-Meier analysis, peak atrial longitudinal strain (PALS) provided good risk stratification (5-year event-free survival:90 ± 5% for PALS≥21% vs 30 ± 9% for PALS<21%, p < 0.0001); it was an independent and incremental predictor of outcome in four multivariate Cox adjusted models. There was also an association between PALS and the secondary endpoint (NYHA: r2 = 0.11, p = 0.04; Borg CR10: r2 = 0.10, p = 0.02) and an inverse correlation between PALS<21% and LA fibrosis (r2 0.80, fibrosis: 76.6 ± 20.7% vs 31.9 ± 20.8%;p < 0.0001). Global PALS emerged as a reliable predictor of outcome and functional capacity for severe primary MR, and as a marker of LA fibrosis.


Control of spindle orientation in Drosophila by the Par-3-related PDZ-domain protein Bazooka.
The orientation of the mitotic spindle influences the asymmetric distribution of cytoplasmic determinants and the positioning of the sibling cell, and therefore has important influences on cell-fate determination and patterning of the embryo. Both the establishment of an axis of polarity and the adjustment of this axis with respect to the coordinates of the embryo have to be controlled. None of the genes identified so far that are involved in these processes seems to have been conserved between flies and nematodes. Here, we show that the bazooka gene encodes a protein with three putative protein-interaction motifs known as PDZ domains and is the first Drosophila representative of the par gene family of Caenorhabditis elegans, members of which are required for establishment of anterior-posterior polarity of the nematode embryo. The bazooka RNA and protein were found to be restricted to the apical cortical cytoplasm of epithelial cells and neuroblasts. Embryos that were mutant for bazooka frequently failed to coordinate the axis of cell polarity with that of the embryo. This was manifested as defective spindle orientation and mispositioning of the daughter cell after division. The Drosophila gene bazooka is likely to be part of a regulatory mechanism required to coordinate the axis of polarity of a cell with that of the embryo. The PDZ domains of Bazooka provide several protein-protein interfaces, which possibly participate in the assembly of a multiprotein complex at the apical pole.


Radiobromine labeled norcholesterol analogs. Synthesis and tissue distribution study in rats of bromine-82 labeled 6beta-bromomethyl-19-norcholest-5(10)-EN-38-OL.
6beta-Bromomethyl-19-norcholest-5(10)-en-3beta-ol (NCL-6-Br) was synthesized directly from cholest-5-ene-3beta,19-diol 19-toluene-p-sulfonate via homoallylic rearrangement with ammonium bromide or sodium bromide in acetonitrile. This method was applied to the radiolabeling of NCL-6-Br with bromine-82. Tissue distribution of bromine-82 labeled NCL-6-Br (NCL-6-Br-82) in rats was determined. The mean percent dose per gram uptake in adrenal at 24 and 120 h was 98 and 80 %/gm, respectively, which indicated a higher adrenal uptake as compared to iodine-131 labeled 19-iodocholest-5-en-3beta-ol (CL-19-I-131), but was at a lower level than that achieved with iodine-131 labeled 6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol (NCL-6-I-131). The ratio of radioactivity in the adrenal-to-liver concentration was also lower than that of CL-19-I-131 or NCL-6-I 131.


The development of empathy in child maltreatment contexts.
Despite robust associations between child maltreatment experiences and emotional development, a paucity of research examines the influence of child maltreatment on empathy development, and still fewer studies differentiate these effects across maltreatment subtypes. The present study examined the development of children's empathy from ages six to eight, as predicted by maltreatment, and as moderated by children's attachment representations. Participants were a community sample of 250 children followed longitudinally and assessed in a laboratory setting with their primary caregivers. Child maltreatment experiences from birth to age six were assessed by semi-structured interviews with caregivers, which were rated according to widely-used child maltreatment coding protocols, and by caregiver and child self-report measures. Child empathy was assessed at ages six and eight by caregiver-report. Attachment representations were observed in children using the MacArthur Story Stem Battery. Child emotional abuse (β = -0.150, p = .012) and child neglect (β = -0.137, p = .016) predicted decreased empathy at age eight, whereas child physical abuse (β = 0.132, p = .027) and child exposure to domestic violence (β = 0.164, p = .004) predicted increased empathy at age eight. Further, children's negative representations of mother figures moderated the positive association between child physical abuse and empathy (β = -0.177, p = .005), such that the association became weaker as negative representations increased. These results highlight the nuanced ways in which child maltreatment experiences of different subtypes contribute to the development of empathy in school-aged children.


6 and 12 month outcomes in patients following COVID-19-related hospitalization: a prospective monocentric study.
The long-term consequences of COVID-19 in those who recover from acute infection requiring hospitalization have not been defined yet. In this study, we aim to describe the long-term symptoms and respiratory outcomes over 12 months in patients hospitalized for severe COVID-19. In this prospective cohort study, patients admitted to hospital for severe COVID-19 were prospectively followed up at 6 and 12 months after discharge from the Hospital of Fermo, Italy. Patients were interviewed for persisting symptoms and underwent physical examination, routine blood test, pulmonary function tests, chest high-resolution CT (HRCT), and 6 min walking test. A total of 64 patients were evaluated and participated in this study. The mean age of participants was 68 years, 41 (64%) were males, and the median body mass index (BMI) was 26 kg/m2. After 6 months, 36% of patients reported persistent dyspnea, 37.5% persistent fatigue, 30.6% hair loss, 14% arthralgia and 11% memory and attention deficits. The rate of these symptoms reduced at the 12 month follow-up. At least 50% of the patients reported anxiety and depression symptoms. At 6 months 57.4% of patients showed reduced DLCO and 21.3% reduced FVC% and improvement at 12 months was noted for FVC but not for DLCO and TLC. Persistent radiographic abnormalities, most commonly ground-glass opacities and interstitial changes, were observed at both timepoints in many patients. Long-term symptoms and pulmonary deficits are common in patients admitted for severe COVID-19. Further studies are needed to assess the clinical significance of long-term consequences of severe COVID-19.


Imaging Polarization in Budding Yeast.
We describe methods for live-cell imaging of yeast cells that we have exploited to image yeast polarity establishment. As a rare event occurring on a fast time-scale, imaging polarization involves a trade-off between spatiotemporal resolution and long-term imaging without excessive phototoxicity. By synchronizing cells in a way that increases resistance to photodamage, we discovered unexpected aspects of polarization including transient intermediates with more than one polarity cluster, oscillatory clustering of polarity factors, and mobile "wandering" polarity sites.


A magnetization transfer imaging study of corpus callosum myelination in young children with autism.
Several lines of evidence suggest that autism may be associated with abnormalities in white matter development. However, inconsistencies remain in the literature regarding the nature and extent of these abnormalities, partly because of the limited types of measurements that have been used. Here, we used magnetization transfer imaging to provide insight into the myelination of the corpus callosum in children with autism. Magnetization transfer imaging scans were obtained in 101 children with autism and 35 typically developing children who did not significantly differ with regard to gender or age. The midsagittal area of the corpus callosum was manually traced and the magnetization transfer ratio (MTR) was calculated for each voxel within the corpus callosum. Mean MTR and height and location of the MTR histogram peak were analyzed. Mean MTR and MTR histogram peak height and location were significantly higher in children with autism than in typically developing children, suggesting abnormal myelination of the corpus callosum in autism. The differences in callosal myelination suggested by these results may reflect an alteration in the normally well-regulated process of myelination of the brain, with broad implications for neuropathology, diagnosis, and treatment of autism.


Association of the rs3077 and rs9277535 polymorphisms in HLA-DP with hepatitis B virus infection and spontaneous clearance: a meta-analysis.
Owing to inconsistent observations in the literature of an association between HLA-DP polymorphisms (rs3077 and rs9277535) and hepatitis B virus (HBV) infection and spontaneous clearance, there is an urgent need for a comprehensive and reliable understanding of this subject. This meta-analysis was performed to quantitatively summarise the evidence for the relevance of these HLA-DP polymorphisms to HBV infection and spontaneous clearance. A meta-analysis was conducted with the data from eight relevant papers published from April 2009 to March 2012, following strict selection. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for alleles, co-dominant, dominant and recessive genotype models of the rs3077 and rs9277535 loci. Our analysis indicated a significant association of rs3077 and rs9277535 in HLA-DP with HBV infection, suggesting that these HLA-DP polymorphisms act beneficially against HBV infection (for rs3077, AG vs. GG: OR = 0.522, 95% CI = 0.485-0.561; AA vs. GG: OR = 0.350, 95% CI = 0.311-0.393; for rs9277535, AG vs. GG: OR = 0.542, 95% CI = 0.506-0.579; AA vs. GG: OR = 0.371, 95% CI = 0.336-0.409). Additionally, these HLA-DP polymorphisms served as protective factors in the spontaneous clearance of HBV (for rs3077, AG vs. GG: OR = 0.600, 95% CI = 0.464-0.775; AA vs. GG: OR = 0.420, 95% CI = 0.299-0.590; for rs9277535, AG vs. GG: OR = 0.623, 95% CI = 0.570-0.681 and AA vs. GG: OR = 0.464, 95% CI = 0.386-0.556) with similar results for both dominant and recessive genotype models. Our results demonstrated that the rs3077 and rs9277535 HLA-DP polymorphisms reduced HBV infection and increased the likelihood of spontaneous viral clearance in some Asian populations.


Surgical Decision-Making and Outcomes in Open Versus Endovascular Repair for Various Vascular Diseases.
Today's vascular surgeon must navigate their practice through a field of ever-advancing technology while maintaining knowledge of open techniques that remain equally important in the care of their patients. In this article, the authors provide insight into the perioperative decision-making that goes into choosing a surgical plan for each patient based on their disease process, anatomy, nonmodifiable risk factors, and other comorbidities.


Potential antitumor agents. 35. Quantitative relationships between antitumor (L1210) potency and DNA binding for 4'-(9-acridinylamino)methanesulfon-m-anisidide analogues.
Factors influencing dose potency of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogues in L1210 assays have been investigated by multiple regression analysis. The dependent variable was D40, the dose to provide 40% life extension in L1210 tests. Independent variables examined were chromatographic Rm values, as a measure of agent lipophilic-hydrophilic balance; Rm2; log K, where K is the agent-DNA association constant for poly[d(A-T)]; log T1/2, the half-life for congener thiolytic cleavage; and agent pKa values. A regression equation containing terms in Rm2 and log K was derived with the latter term accepting the greater proportion of the biological variance. DNA binding, of acridine substituted m-AMSA variants, is the most important factor influencing dose potency. Modeling of log K for 3-substituted derivatives provided an equation in substituent R constants and molar refractivities (MR).


Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children.
Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size. We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting antiretroviral therapy (ART) <6 months of age. Total HIV-1 DNA was measured from 51 long-term suppressed children aged 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression. At ART initiation, children were aged median [IQR] 2.3 [1.2-4.1] months, CD4% 37 [24-45] %, CD8% 28 [18-36] %, log10 plasma viral load (VL) 5.4 [4.4-5.9] copies per milliliter. Time to viral suppression was 7.98 [4.6-19.3] months. After suppression, 13 (25%) children had suboptimal response [≥2 consecutive VL 50-400 followed by VL <50] and/or experienced periods of virological failure [≥2 consecutive VL ≥400 followed by VL <50]. Median total HIV-1 DNA was 43 [6195] copies/10 PBMC. Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, P = 0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, P = 0.0022) and the absence of viral failure/suboptimal response (AC 0.34 for those with fail/suboptimal response, P = 0.0483) were associated with lower total HIV-1 DNA. Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1-infected children minimize the size of viral reservoir.


Perovskite Films Regulation via Hydrogen-Bonded Polymer Network for Efficient and Stable Perovskite Solar Cells.
Perovskite solar cells (PSCs) are considered as a promising photovoltaic technology due to their high efficiency and low cost. However, their long-term stability, mechanical durability, and environmental risks are still unable to meet practical needs. To overcome these issues, we designed a multifunctional elastomer with abundant hydrogen bonds and carbonyl groups. The chemical bonding between polymer and perovskite could increase the growth activation energy of perovskite film and promote the preferential growth of high-quality perovskite film. Owing to the low defect density and gradient energy-level alignment, the corresponding device exhibited a champion efficiency of 23.10 %. Furthermore, due to the formation of the hydrogen-bonded polymer network in the perovskite film, the target devices demonstrated excellent air stability and enhanced flexibility for the flexible PSCs. More importantly, the polymer network could coordinate with Pb2+ ions, immobilizing lead atoms to reduce their release into the environment. This strategy paves the way for the industrialization of high-performance flexible PSCs.


Loss of Complex I activity in the Escherichia coli enzyme results from truncating the C-terminus of subunit K, but not from cross-linking it to subunits N or L.
Complex I is a multi-subunit enzyme of the respiratory chain with seven core subunits in its membrane arm (A, H, J, K, L, M, and N). In the enzyme from Escherichia coli the C-terminal ten amino acids of subunit K lie along the lateral helix of subunit L, and contribute to a junction of subunits K, L and N on the cytoplasmic surface. Using double cysteine mutagenesis, the cross-linking of subunit K (R99C) to either subunit L (K581C) or subunit N (T292C) was attempted. A partial yield of cross-linked product had no effect on the activity of the enzyme, or on proton translocation, suggesting that the C-terminus of subunit K has no dynamic role in function. To further elucidate the role of subunit K genetic deletions were constructed at the C-terminus. Upon the serial deletion of the last 4 residues of the C-terminus of subunit K, various results were obtained. Deletion of one amino acid had little effect on the activity of Complex I, but deletions of 2 or more amino acids led to total loss of enzyme activity and diminished levels of subunits L, M, and N in preparations of membrane vesicles. Together these results suggest that while the C-terminus of subunit K has no dynamic role in energy transduction by Complex I, it is vital for the correct assembly of the enzyme.


Child's Play: Examining the Association Between Time Spent Playing and Child Mental Health.
It is theorised that adventurous play offers learning opportunities that help to prevent mental health problems in children. In this study, data from two samples is used to examine associations between the time that children aged 5-11 years spent playing adventurously and their mental health. For comparison, time spent playing unadventurously and time spent playing outdoors are also examined. Study 1 includes a sample of 417 parents, Study 2 includes data from a nationally representative sample of 1919 parents. Small, significant associations between adventurous play and internalising problems, as well as positive affect during the first UK-wide Covid-19 lockdown, were found; children who spend more time playing adventurously had fewer internalising problems and more positive affect during the Covid-19 lockdown. Study 2 showed that these associations were stronger for children from lower income families than for children from higher income families. The results align with theoretical hypotheses about adventurous play.


Disease Waves of SARS-CoV-2 in Iran Closely Mirror Global Pandemic Trends.
Complete SARS-CoV-2 genome sequencing in the early phase of the outbreak in Iran showed two independent viral entries. Subsequently, as part of a genome surveillance project, we aimed to characterize the genetic diversity of SARS-CoV-2 in Iran over one year after emerging. We provided 319 SARS-CoV-2 whole-genome sequences used to monitor circulating lineages in March 2020-May 2021 time interval. The temporal dynamics of major SARS-CoV-2 clades/lineages circulating in Iran is comparable to the global perspective and represent the 19A clade (B.4) dominating the first disease wave, followed by 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7), leading the second, third and fourth waves, respectively. We observed a mixture of circulating B.1.36, B.1.1.413, B.1.1.7 lineages in winter 2021, paralleled in a fading manner for B.1.36/B.1.1.413 and a growing rise for B.1.1.7, prompting the fourth outbreak. Entry of the Delta variant, leading to the fifth disease wave in summer 2021, was detected in April 2021. This study highlights three lineages as hallmarks of the SARS-CoV-2 outbreak in Iran; B4, dominating early periods of the epidemic, B.1.1.413 (B.1.1 with the combination of [D138Y-S477N-D614G] spike mutations) as a characterizing lineage in Iran, and the co-occurrence of [I100T-L699I] spike mutations in half of B.1.1.7 sequences mediating the fourth peak. It also designates the renowned combination of G and GR clades' mutations as the top recurrent mutations. In brief, we provided a real-time and comprehensive picture of the SARS-CoV-2 genetic diversity in Iran and shed light on the SARS-CoV-2 transmission and circulation on the regional scale.


The efficacy of retroviral herpes simplex virus thymidine kinase gene transfer and ganciclovir treatment on the inhibition of melanoma growth in vitro and in vivo.
One approach to gene therapy of cancer is based on the insertion of a suicide gene into tumor cells and subsequent activation of the suicide mechanism. We used the herpes simplex virus thymidine kinase (HSVtk) gene followed by ganciclovir (GCV) treatment. The goal of our experiments was to determine the effectiveness of HSVtk gene therapy in malignant melanoma. B16BL6 murine melanoma cells retrovirally transduced with the HSVtk gene became sensitive to low concentrations of GCV. Analysis by RT-PCR showed HSVtk expression in transduced B16BL6tk+ cells. Apoptotic cell death was found in B16BL6tk+ cells treated with GCV (20 microM). The sensitivity of B16BL6tk+ cells to GCV was also examined in vivo. Tumors inoculated subcutaneously into C57BL6 mice regressed rapidly when treated with GCV (50 mg/kg twice a day) and disappeared completely after 14 days treatment. The mice remained in remission for 5 months. A bystander effect through which nontransduced B16BL6 cells were also inhibited by GCV administration when cocultured with B16BL6tk+ cells was expected. However, only slight killing of nontransduced cells was observed in vitro. Analysis of the bystander effect in vivo showed complete regression of tumors inoculated with a mixture of cells mostly consisting of B16BL6tk+ cells. A distant bystander effect was also examined. There was no regression of wild-type tumors raised at a distant site from primary B16BL6tk+ tumors. The failure of a more effective bystander effect indicates the need for further investigation of the possible use of combined gene therapy to treat melanoma.


Effect of lowering of the temperature on the tissue levels of cAMP, cGMP, PGE and PGF2 alpha in spontaneously beating rat atria preparation.
Tissue levels of cAMP, cGMP, PGE, and PGF2 alpha were measured in spontaneously beating rat atria preparation at 20C and 37C. At 20C the formation of cAMP increased in correlation with the markedly increased amplitude and reduced frequency. The other biochemical parameters were not significantly affected by the low temperature.


Penetrance of Colorectal Cancer Among Mismatch Repair Gene Mutation Carriers: A Meta-Analysis.
Lynch syndrome, the most common colorectal cancer (CRC) syndrome, is caused by germline mismatch repair (MMR) genes. Precise estimates of age-specific risks are crucial for sound counseling of individuals managing a genetic predisposition to cancer, but published risk estimates vary. The objective of this work is to provide gene-, sex-, and age-specific risk estimates of CRC for MMR mutation carriers that comprehensively reflect the best available data. We conducted a meta-analysis to combine risk information from multiple studies on Lynch syndrome-associated CRC. We used a likelihood-based approach to integrate reported measures of CRC risk and deconvolved aggregated information to estimate gene- and sex-specific risk. Our comprehensive search identified 10 studies (8 on MLH1, 9 on MSH2, and 3 on MSH6). We estimated the cumulative risk of CRC by age and sex in heterozygous mutation carriers. At age 70 years, for male and female carriers, respectively, risks for MLH1 were 43.9% (95% confidence interval [CI] = 39.6% to 46.6%) and 37.3% (95% CI = 32.2% to 40.2%), for MSH2 were 53.9% (95% CI = 49.0% to 56.3%) and 38.6% (95% CI = 34.1% to 42.0%), and for MSH6 were 12.0% (95% CI = 2.4% to 24.6%) and 12.3% (95% CI = 3.5% to 23.2%). Our results provide up-to-date and comprehensive age-specific CRC risk estimates for counseling and risk prediction tools. These will have a direct clinical impact by improving prevention and management strategies for both individuals who are MMR mutation carriers and those considering testing.


Ancient gene duplication and differential gene flow in plastid lineages: the GroEL/Cpn60 example.
Cryptomonads, small biflagellate algae, contain four different genomes. In addition to the nucleus, mitochondrion, and chloroplast is a fourth DNA-containing organelle the nucleomorph. Nucleomorphs result from the successive reduction of the nucleus of an engulfed phototrophic eukaryotic endosymbiont by a secondary eukaryotic host cell. By sequencing the chloroplast genome and the nucleomorph chromosomes, we identified a groEL homologue in the genome of the chloroplast and a related cpn60 in one of the nucleomorph chromosomes. The nucleomorph-encoded Cpn60 and the chloroplast-encoded GroEL correspond in each case to one of the two divergent GroEL homologues in the cyanobacterium Synechocystis sp. PCC6803. The coexistence of divergent groEL/cpn60 genes in different genomes in one cell offers insights into gene transfer from evolving chloroplasts to cell nuclei and convergent gene evolution in chlorophyll a/b versus chlorophyll a/c/phycobilin eukaryotic lineages.


Detection of changes in speed and direction of motion: reaction time analysis.
Observers reacted to the change in the movement of a random-dot field whose initial velocity, V0, was constant for a random period and then switched abruptly to another value, V1. The two movements, both horizontally oriented, were either in the same direction (speed increments or decrements), or in the opposite direction but equal in speed (direction reversals). One of the two velocities, V0 or V1, could be zero (motion onset and offset, respectively). In the range of speeds used, 0-16 deg/sec (dps), the mean reaction time (MRT) for a given value of V0 depended on magnitude of V1-V0 only: MRT approximately r+c(V0)/magnitude of V1-V0 beta, where beta = 2/3, r is a velocity-independent component of MRT, and c(V0) is a parameter whose value is constant for low values of V0 (0-4 dps), and increases beginning with some value of V0 between 4 and 8 dps. These and other data reviewed in the paper are accounted for by a model in which the time-position function of a moving target is encoded by mass activation of a network of Reichardt-type encoders. Motion-onset detection (V0 = 0) is achieved by weighted temporal summation of the outputs of this network, the weights assigned to activated encoders being proportional to their squared spatial spans. By means of a "subtractive normalization," the visual system effectively reduces the detection of velocity changes (a change from V0 to V1) to the detection of motion onset (a change from 0 to V1-V0). Subtractive normalization operates by readjustment of weights: the weights of all encoders are amplified or attenuated depending on their spatial spans, temporal spans, and the initial velocity V0. Assignment of weights and weighted temporal summation are thought of as special-purpose computations performed on the dynamic array of activations in the motion-encoding network, without affecting the activations themselves.


FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis.
Autophagy is a conserved catabolic pathway with emerging functions in mammalian neurodevelopment and human neurodevelopmental diseases. The mechanisms controlling autophagy in neuronal development are not fully understood. Here, we found that conditional deletion of the Forkhead Box O transcription factors FoxO1, FoxO3, and FoxO4 strongly impaired autophagic flux in developing neurons of the adult mouse hippocampus. Moreover, FoxO deficiency led to altered dendritic morphology, increased spine density, and aberrant spine positioning in adult-generated neurons. Strikingly, pharmacological induction of autophagy was sufficient to correct abnormal dendrite and spine development of FoxO-deficient neurons. Collectively, these findings reveal a novel link between FoxO transcription factors, autophagic flux, and maturation of developing neurons.


Deprivation and survival from breast cancer.
We studied the association between deprivation and survival from breast cancer in 29,676 women aged 30 and over who were diagnosed during the period 1980-89 in the area covered by the South Thames Regional Health Authority. The measure of deprivation was the Carstairs Index of the census enumeration district of each woman's residence at diagnosis. We studied the impact of stage at diagnosis, morphology and type of treatment on this association, with the relative survival rate and the hazard ratio as measures of outcome. There was a clear gradient in survival, with better survival for women from more affluent areas. At all ages, women in the most deprived category had a 35% greater hazard of death than women from the most affluent areas after adjustment for stage at diagnosis, morphological type and type of treatment. In younger women (30-64 years), the survival gradient by deprivation category cannot be explained by these prognostic factors. In older women (65-99 years), part of the unadjusted gradient in survival can be explained by differences in the stage of disease: older women in the most deprived category were more often diagnosed with advanced disease. Other factors, so far unidentified, are responsible for the gradient in breast cancer survival by deprivation category. The potential effect on breast cancer mortality of eliminating the gradient in survival by deprivation category is substantial (7.4%). In women aged 30-64 years, 10% of all deaths within 5 years might be avoidable, while in older women this figure is 5.8%.


Oxygen enrichment of bag-valve-mask units during positive-pressure ventilation: a comparison of various techniques.
Bag-mask devices are used frequently to provide patients with positive-pressure-assisted ventilation. To increase the percentage of oxygen delivered (FDO2) from the bag, supplemental oxygen must be provided by way of an oxygen inlet nipple attached to the unit. Using ten medical volunteers and a test lung with oxygen analyzer, we studied the effect of several variables on the FDO2 and determined the most effective reservoir that would provide the highest consistent FDO2 from the ventilating port of the bag. An FDO2 of 1.00 was consistently provided by the 2.5-L bag reservoir and a demand-valve set-up attached to the reservoir port of the ventilating bag. Bag refill time significantly affected the FDO2 when no reservoir or corrugated tube reservoirs were used. Corrugated tube reservoirs were found to be more sensitive to all variations in ventilatory technique and to oxygen flow rates. From our findings we recommend that corrugated tube reservoirs not be used for oxygen supplementation, as they are sensitive to variations in ventilatory technique and cannot alert clinicians to problems with oxygen flow. While both the 2.5-L bag reservoir and demand-valve provide a consistent FDO2 of 1.00, the demand valve has the advantage of audible filling of the ventilating bag as well as being compact and independent of ventilatory technique.


Salmonella poona infection and surveillance in a neonatal nursery.
This article reports the first known outbreak of Salmonella poona infection in a neonatal unit. Three babies had stool cultures positive for the organism. At the same time, S. poona was the cause of a nationwide food-borne outbreak associated with contaminated canteloupe. To minimize the neonatal outbreak, surveys were performed and control measures were instituted. Epidemiologic surveillance included the culture of rectal swabs collected from 48 employees, 18 babies, and four family members of the babies. Control measures used included the placement in cohorts and isolation of infected babies, strict adherence to universal precautions, and the restriction of visitation in the nursery. A total of three babies and one employee in the surveillance were found to have Salmonella sp. An additional two hospitalized adult patients had S. poona. Of all the people included in the surveillance, only the three babies were found to have S. poona. The hospital employee had S. enteritidis. Timely culture results, rapid cohort placement of infected babies, and strict adherence to universal precautions led to the successful eradication of the organism.


Epigenetic connections between autoimmune disorders and haematological malignancies.
Epigenetic deregulation has become a major topic in biomedical research. Most of the information currently available in the field comes from the study of epigenetic alterations in cancer, particularly in haematological malignancies. The recognition of the epigenetic component of autoimmune diseases in conjunction with the existence of common genes underpinning pathways that are crucial to the development of autoimmunity and haematological cancers, facilitates interaction between these two areas of research. Here, we examine what is presently known from epigenetic studies of autoimmune diseases, how epigenetic alterations in haematological malignancies can be used to better understand mechanisms of epigenetic deregulation and how they might be used in epigenetic therapy to treat autoimmune diseases.


Corrugated mucosal pattern in the esophagus associated with progressive systemic sclerosis.
Three cases of unusual corrugated mucosal pattern in the esophagus accompanying the typical motility disturbance of progressive systemic sclerosis (PSS) are reported. The changes were rarely seen in a group of patients with esophageal involvement by PSS.


Bryophytes with asexual reproduction - Their ability to succeed in an industrial area.
The extent to which the distribution of liverwort and moss species in the industrial area around Duisburg (Federal Republic of Germany) is influenced by asexual reproduction is studied using distribution data. The research shows that neither the liverworts nor the mosses - except the genus Plagiothecium - are more successful in the area of concentrated industry when they are capable of asexual reproduction.


Ecophysiological studies of Sonoran Desert plants. VII. Photosynthetic gas exchange of winter ephemerals from sun and shade environments.
A comparison of photosynthetic adaptations of desert ephemerals from sun and shade environments has shown differences in the magnitude and timing of maximum CO2 assimilation. Photosynthetic rates of species from the sun environment were significantly higher, and maximum observed levels occurred both earlier in the day and earlier in the growing season. For plants of both sites the CO2 assimilation rates were relatively low when the soil water content was highest in the winter months. Anatomical modifications of specific leaf weight occurred for species of both environments, but were not correlated with improved water use efficiency. Throughout the growing season the stomatal conductance of most species was higher than 0.30 cm/s and effects a maximization of photosynthesis when water is available, at the expense of water use efficiency.


Distribution and partial characterization of FMRFamide-like peptides in the stomatogastric nervous systems of the rock crab, Cancer borealis, and the spiny lobster, Panulirus interruptus.
The distribution of FMRFamide-like peptides was studied in the complete stomatogastric nervous system [the paired commissural ganglia, single oesophageal ganglion, and the single stomatogastric ganglion (STG)] of two decapod crustacean species, the spiny lobster Panulirus interruptus and the rock crab Cancer borealis, by using immunocytochemical techniques. Antiserum 231 from the O'Donohue laboratory and antiserum 671C (described here) gave essentially the same staining patterns. In the commissural ganglia of both species there were ten to 20 stained neurons and dense neuropilar staining. The oesophageal ganglion of the crab had four stained neurons. Lucifer Yellow backfills followed by immunostaining showed that the two larger stained neurons of the oesophageal ganglion sent processes into the inferior ventricular nerve. The two smaller neurons sent processes into the inferior oesophageal nerves. The oesophageal ganglion of the lobster had two stained neurons that sent processes into the inferior ventricular nerve as well. None of the somata of the STG stained in either species, but in both species stained fibers were seen in the stomatogastric nerve that entered the STGs and ramified profusely throughout the neuropil. In some preparations of the crab, a stained fiber was visible in the dorsal ventricular nerve. The amounts of the FMRFamide-like peptides found in all regions of the nervous system of P. interruptus and C. borealis were determined by radioimmune assay (RIA). Column chromatography and high-performance liquid chromatography suggest that, in both species, much if not all of the RIA-assayable material is accountable for by peptides that are larger and more hydrophobic than FMRFamide.


Distribution patterns and microhabitat segregation in gastrointestinal helminths of Sorex shrews.
We studied the distribution patterns and microhabitat use in gastrointestinal helminths of the shrews Sorex araneus and S. caecutiens in Finland. The distribution of species prevalences was bimodal, and in S. araneus the abundance (mean intensity) was positively associated with commonness (prevalence), as assumed by the core-satellite species hypothesis (Hanski 1982). However, the positive correlation between prevalence and intensity was observed only when the effects of helminth body size and taxonomic group (cestodes vs nematodes) on intensity were controlled for. The nematodes of the genus Longistriata occurred predictably as core species, whereas the identity of the core cestodes was more variable between host species and regions. Helminth body size and taxonomic group were not related to the degree of aggregation in shrew populations, but helminth body size seemed to explain the differences in the distribution patterns of helminths between shrews and voles. The core species did not show more segregation in microhabitat use than randomly selected species. In fact, the two core nematodes showed largely overlapping intestinal distributions. We conclude that linear intestinal space is not a key resource for shrew nematodes, but it may be for shrew cestodes.


[An hereditary hemorrhagic telangiectasia of late revealed by a cerebral venous thrombosis: A case report].
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the triad of nose bleeding, telangiectasia and familial heredity. We report the case of a patient who had idiopathic venous cerebral thrombosis complicated by a cerebral infarction treated with warfarin. In the context of a psoas hematoma by warfarine overdose and immobilization, the patient had deep vein thrombosis of the left lower limb with pulmonary embolism revealing a pulmonary arteriovenous malformation. After a reexamination, the patient clinical phenotype of HHT was confirmed genetically. The patient was treated with rivaroxaban allowing clinical improvement and partial recanalization of all thrombosis after six months. Thrombotic overisk has already been studied in HHT patients but the use of anticoagulants is at higher risk in these patients. However this patient experienced no adverse event with rivaroxaban. This is the first case described of cerebral venous thrombosis treated with rivaroxaban revealing an HHT.


Categorizing national caregiver recommendations to support family caregivers and address unmet needs.
Recognizing family caregivers as vital providers of long-term assistance to loved ones with chronic illness, several national organizations developed recommendations to improve support for family caregivers. This article categorizes these recommendations to advance family-centered nursing practice, develop health policies, and advocate for family caregiver support. Six reports of caregiver recommendations published in the United States from 2016 to 2021 were analyzed using thematic analysis. The 108 recommendations were organized into five categories: policy; caregiver assessment and support; health professional practices; public awareness; advance care planning. Ensuring economic security, establishing a national data collection strategy, addressing caregivers' diverse needs, improving access to health care and support services, and increasing public awareness were highlighted. The recommendations provide a roadmap for nurses at all levels of practice to advocate for a national agenda to develop, fund, and implement inclusive health care policies and interventions to address unmet caregiver needs and maximize support.


A nutrition and physical activity intervention for family child care homes.
Family child care homes (FCCHs) provide child care to 1.9 million children in the U.S., but many do not meet established child care standards for healthy eating and physical activity. To determine the effects of a community-based train-the-trainer intervention on FCCHs policies and practices related to healthy eating and physical activity. Quasi-experimental design with replication in three independent cohorts of FCCHs. Registered FCCHs from 15 counties across Kansas participated in the Healthy Kansas Kids (HKK) program. Resource and referral agencies (RRAs) in each county recruited and enrolled between five and 15 child care providers in their service delivery area to participate in the program. The number of registered FCCHs participating in HKK in Years 1 (2006-2007); 2 (2007-2008); and 3 (2008-2009) of the program were 85, 64, and 87, respectively. A stratified random sample of registered FCCHs operating in Kansas (n=297) served as a normative comparison group. Child care trainers from each RRA completed a series of train-the-trainer workshops related to promotion of healthy eating and physical activity. FCCHs were subsequently guided through a four-step iterative process consisting of (1) self-evaluation; (2) goal setting; (3) developing an action plan; and (4) evaluating progress toward meeting goals. FCCHs also received U.S. Department of Agriculture resources related to healthy eating and physical activity. Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC) self-assessment instrument (NAP SACC-SA). Analyses of outcome measures were conducted between 2008 and 2010. Healthy Kansas Kids FCCHs exhibited significant improvements in healthy eating (Δ=6.9%-7.1%) and physical activity (Δ=15.4%-19.2%) scores (p<0.05). Within each cohort, pre-intervention scores were not significantly different from the state average, whereas post-intervention scores were significantly higher than the state average. Community-based train-the-trainer interventions to promote healthy eating and physical activity in FCCHs are feasible, sustainable, and effective.


The effect of glucocorticoids in the normal cerebral hemisphere of brain tumour patients.
To study the potential effects of glucocorticoids (GC) in normal white matter (WM) of the contralateral cerebral hemisphere in brain tumour patients in a prospective protocol. Using MR relaxation time (RT) imaging (T1 and T2-maps), 190 different scanning sessions were performed on 42 brain tumour patients before and after initiation of GC-treatment. RT imaging correlates closely with in vivo tissue water content (reported estimation accuracy error <4%). Repetitive studies were performed in order to study changes as a function of time. RTs were measured in the contralateral frontal and occipital white matter (WM). The mean change in T1 after initiation of GC treatment was 1.6+/-1.7% (P = 0.24), and 1.8+/-3.8% in T2. The mean coefficient of variation for the pooled data in all patients was 1.4% for both T1 and T2. There were no differences in effect between different histological types of tumours or sex. GC treatment does not influence in vivo cerebral water content expressed as relaxation times of apparently normal WM. The neurological effects in brain tumour patients are normally evident within 24 h, but do not seem to correlate with changes in brain water content. The normal biological variation in RTs (and thereby in vivo tissue water content) in normal WM of brain tumour patients is very small and approaches the expected fluctuations in the MRI measurement technique.


Localization of chondroitin sulfate proteoglycan versican in adult brain with special reference to large projection neurons.
Versican is a chondroitin sulfate proteoglycan belonging to the lectican family. Versican has two glycosaminoglycan attachment regions, named the GAG alpha and GAG beta domains, which are both regulated by alternative splicing and yield four protein isoforms. We have investigated the expression and localization of versican in the developing and adult brain by using anti-versican GAG alpha and GAG beta antibodies. Western analysis revealed that GAG alpha-reactive isoform was dominant in the adult brain. Immunohistochemical study demonstrated that GAG alpha immunoreactivity was detectable from neonatal periods to adulthood, whereas GAG beta immunoreactivity completely disappeared within 3 weeks of birth. In the adult brain, GAG alpha immunoreactivity was seen in the white matter regions and was also localized in the gray matter including somata and dendrites of cortical and hippocampal pyramidal neurons and cerebellar Purkinje cells. In contrast, GAG alpha immunoreactivity was not localized on parvalbumin-positive interneurons and cerebellar stellate cells. Furthermore, GAG alpha immunoreactivity was not co-localized with perineuronal net markers such as Wisteria floribunda agglutinin lectin and phosphacan. Thus, versican was localized on large projection neurons rather than small interneurons. To confirm the binding mechanism of versican to neurons, hyaluronan and chondroitin sulfates were enzymatically removed from brain sections before the immunolabeling of versican. These treatments had no effect on the labeling pattern of versican, suggesting that other versican-interactive molecules are involved in the binding of versican to neurons.


Inactivation of heamolytic complement by house dust allergen in the serum of children with atopic diseases.
Purified house dust allergen has been employed for screening the susceptibility to inactivation of haemolytic complement in the blood serum of atopic children and control subjects. Fluid phase complement in the control group of children was more sensitive to allergen-induced inactivation than observed in a normal adult population. Though the mean complement sensitivity indices in all groups of patients were below the valve for the control group, there was considerable statistical overlap. The serum complement sensitivities were in no way related to the clinical manifestations. The results of the complement test were not correlated to the total IgE levels, the RAST scores nor the skin reactions with house dust allergen. Some evidence for the in vivo involvement of the complement system in childhood atopic allergy was provided: the mean C3 proactivator level was significantly lower in atopic children, than in the control group; the mean C4 level in children with bronchial asthma and in children with atopic dermatitis was significantly depressed. A significant positive correlation between the serum C4 levels and allergen-complement sensitivities in children with both bronchial asthma and atopic dermatitis was observed.


Blinded Comparison between an In-Air Reverberation Method and an Electronic Probe Tester in the Detection of Ultrasound Probe Faults.
The aim of this study was to perform a blinded trial, comparing the results of a visual inspection of the in-air reverberation pattern with the results of an electronic probe tester in detecting ultrasound probe faults. Sixty-two probes were tested. A total of 28 faults were found, 3 only by in-air reverberation assessment and 2 only by the electronic probe tester. The electronic probe tester provided additional information regarding the location of the fault in 74% of the cases in which both methods detected a fault. It is possible to detect the majority of probe faults by visual inspection and in-air reverberation assessment. The latter provides an excellent first-line test, easily performed on a daily basis by equipment users. An electronic probe tester is required if detailed evaluation of faults is necessary.


Comparative phylogeography study reveals introgression and incomplete lineage sorting during rapid diversification of Rhodiola.
Many plant taxa in the Qinghai-Tibetan Plateau (QTP) and the Hengduan Mountains (HM) radiated rapidly during the Quaternary but with frequent secondary contact between diverging populations. Incomplete lineage sorting and introgressive hybridization might be involved during the rapid radiation, but their effects on phylogeography have not been fully determined. We investigated the chloroplast DNA (cpDNA)/internal transcribed spacer (ITS) sequence variations of 611 samples of Rhodiola bupleuroides, R. discolor, R. fastigiata and R. chrysanthemifolia from the QTP and HM to compare the phylogeographic patterns between the four species with different evolutionary histories, geographic ranges and reproductive modes. The divergence times of these species were consistent with the last peak of in situ speciation in the HM. While closely related species exhibited different phylogeographic patterns, they shared several ribotypes and haplotypes in sympatric populations, suggesting introgressive hybridization. A significant phylogenetic discordance between ribotypes and haplotypes was detected in three species, implying incomplete lineage sorting. Rhodiola discolor houses an extraordinary richness of cpDNA haplotypes, and this finding may be attributed to adaptive radiation. In addition to geographic isolation and climate oscillations during the Quaternary, both introgressive hybridization and incomplete lineage sorting play important roles in species that experienced rapid diversification in the QTP and HM.


FGF21 attenuates lipolysis in human adipocytes - a possible link to improved insulin sensitivity.
Fibroblast growth factor 21 (FGF21) is active in murine adipocytes and has beneficial metabolic effects in animal models of type 2 diabetes mellitus. We assessed whether FGF21 influences lipolysis in human adipocytes and 3T3-L1 cells. FGF21 had no short-time effect (h) while a 3-day incubation with FGF21 attenuated hormone-stimulated lipolysis. FGF21 did not influence the mRNA expression of genes involved in regulating lipolysis, but significantly reduced the expression of the lipid droplet-associated phosphoprotein perilipin without affecting differentiation. Via reduced release of fatty acids into the circulation, the anti-lipolytic effect could be a mechanism through which FGF21 promotes insulin sensitivity in man.


Comparative in vivo and in vitro assessment of the percutaneous absorption of local anaesthetics.
The percutaneous absorption of local anaesthetics in a standard formulation has been compared in vitro and in vivo. In vitro data were obtained with a modified Sartorius absorption system and silastic as a lipophilic barrier membrane. With this system the greatest steady-state flux values and permeability coefficients were obtained with amethocaine and lignocaine. These drugs also performed best in an in vivo volunteer trial. However, statistical analysis revealed that amethocaine was significantly better at producing full-depth anaesthesia to the challenge of insertion of a sterile needle. An optimized amethocaine formulation may therefore be expected to meet most closely the ideal profile for a percutaneous local anaesthetic preparation.


Synchrotron-based rotationally resolved high-resolution FTIR spectroscopy of azulene and the unidentified infrared bands of astronomy.
Chasing the unidentified IR bands: The first rotationally resolved high-resolution infrared spectrum of azulene is reported using synchrotron Fourier transform infrared spectroscopy including a rovibrational analysis of the out-of-plane fundamental ν44. Comparison of azulene, naphthalene, indole, and biphenyl infrared bands leads to coincidences with UIR bands at 12.8 μm with naphthalene and at 13.55 and 14.6 μm with biphenyl bands, but excluding azulene as a strong absorber.


Calculated panel-reactive antibody predicts outcomes on the heart transplant waiting list.
Sensitized heart transplant candidates spend more time and have higher mortality on the waiting list. Although the calculated panel-reactive antibody (CPRA) value is used to assign allocation priority to kidney transplant candidates in the United States, the relationship between CPRA and outcomes on the heart transplant waiting list is unknown. A data set of patients listed for heart transplant with unacceptable human leukocyte antigens (HLA) entered was obtained from the United Network for Organ Sharing. The study cohort was composed of 3,855 adult candidates listed for heart transplant between 2006 and 2013 with active waiting time. The cohort was divided into 5 groups by increasing CPRA. Outcomes were assessed using competing risks and sub-hazard regression analyses. In each group of successively higher CPRA, the percentage of candidates who received a transplant decreased, whereas the percentage of those who were still waiting for a transplant increased, as did the percentage of those removed from the waiting list or had died. The group of candidates with a CPRA >80% displayed a markedly decreased incidence of transplantation (hazard ratio 0.37) and an increased risk of removal from the waiting list or death (hazard ratio 2.18) as compared to those with CPRA of ≤10%. Sensitized heart transplant candidates are at high risk of adverse outcomes on the heart transplant waiting list. Clinicians should strive to minimize the CPRA by maximizing specificity in the selection of HLA antigens to exclude. The optimal clinical approach for candidates with high CPRA requires further study.


Patient identification of the symptomatic impact of charcot-marie-tooth disease type 1A.
The burden of Charcot-Marie-Tooth type 1A (CMT1A), the most common inherited peripheral neuropathy, including impact on patient quality of life (QOL) is not well understood. This study aims to qualitatively describe the range of symptoms associated with CMT1A and impact on QOL. We performed qualitative interviews with 16 adult CMT1A patients. Each interview was analyzed using a qualitative framework technique to identify and index symptoms by theme. Sixteen patients provided 656 quotes. One hundred forty-five symptoms of importance were identified representing 20 symptomatic themes. Symptoms associated with difficulty with mobility and ambulation, specific activity impairment, and emotional distress were the most frequently mentioned. Multiple symptoms contribute to CMT1A disease burden, some previously underrecognized. Improved recognition of underrecognized symptoms will optimize patient care and QOL.


Plasma resistant atypical hemolytic uremic syndrome associated with a CFH mutation treated with eculizumab: a case report.
Thrombotic microangiopathies are a group of diseases presenting as microangiopathic hemolytic anemia, thrombocytopenia and end-organ dysfunction. As the role of the complement system was elucidated in atypical hemolytic uremic syndrome pathogenesis, eculizumab was successfully introduced into clinical practice. We present a large pedigree with multiple individuals carrying a functionally significant novel factor H mutation. We describe the proband's presentation following a presumed infectious trigger requiring plasma exchange and hemodialysis. A 32-year-old Caucasian woman presented with pyrexia and headache lasting one week to our Emergency Department. She gave no history of diarrhea or other symptoms to account for her high temperature. She was not taking any medication. She was pyrexial (38°C), tachycardic (110 bpm) and hypertensive (160/110 mmHg). Her fundoscopy revealed grade IV hypertensive retinopathy. She had mild pretibial and periorbital edema, with oliguria (450 mL/day). She had a pregnancy one year previously, during which she had hypertension, proteinuria and edema, with successful delivery at term. Her mother had died in her early 30s with a clinical picture consistent with thrombotic microangiopathy. Her laboratory evaluation showed microangiopathic hemolytic anemia. After 22 sessions of plasma exchange, her lactate dehydrogenase levels started to climb. As a result, she was classified as plasma resistant and eculizumab therapy was instituted. Her lactate dehydrogenase level and platelet count normalized, and her renal function recovered after three months of dialysis. We demonstrate that, even in patients with atypical hemolytic uremic syndrome and prolonged dialysis dependence, recovery of renal function can be seen with eculizumab treatment. We suggest a treatment regime of at least three months prior to evaluation of efficacy.


Synthesis and characterization of magnetic and non-magnetic core-shell polyepoxide micrometer-sized particles of narrow size distribution.
Core polystyrene microspheres of narrow size distribution were prepared by dispersion polymerization of styrene in a mixture of ethanol and 2-methoxy ethanol. Uniform polyglycidyl methacrylate/polystyrene core-shell micrometer-sized particles were prepared by emulsion polymerization at 73 degrees C of glycidyl methacrylate in the presence of the core polystyrene microspheres. Core-shell particles with different properties (size, surface morphology and composition) have been prepared by changing various parameters belonging to the above seeded emulsion polymerization process, e.g., volumes of the monomer glycidyl methacrylate and the crosslinker monomer ethylene glycol dimethacrylate. Magnetic Fe(3)O(4)/polyglycidyl methacrylate/polystyrene micrometer-sized particles were prepared by coating the former core-shell particles with magnetite nanoparticles via a nucleation and growth mechanism. Characterization of the various particles has been accomplished by routine methods such as light microscopy, SEM, FTIR, BET and magnetic measurements.


NUT Is a Driver of p300-Mediated Histone Hyperacetylation: From Spermatogenesis to Cancer.
In maturing sperm cells, a major genome re-organization takes place, which includes a global increase in the acetylation of histones prior to their replacement by protamines, the latter being responsible for the tight packaging of the male genome. Understanding the function of the oncogenic BRD4-NUT fusion protein in NUT carcinoma (NC) cells has proven to be essential in uncovering the mechanisms underlying histone hyperacetylation in spermatogenic cells. Indeed, these studies have revealed the mechanism by which a cooperation between BRD4, a bromodomain factor of the BET family, NUT, a normally testis-specific factor, and the histone acetyltransferase p300, induces the generation of hyperacetylated chromatin domains which are present in NC cells. The generation of Nut ko mice enabled us to demonstrate a genetic interaction between Nut and Brdt, encoding BRDT, a testis-specific BRD4-like factor. Indeed, in spermatogenic cells, NUT and p300 interact, which results in an increased acetylation of histone H4 at both positions K5 and K8. These two positions, when both acetylated, are specifically recognized by the first bromodomain of BRDT, which then mediates the removal of histone and their replacement by protamines. Taken together, these investigations show that the fusion of NUT to BRD4 in NUT Carcinoma cells reconstitutes, in somatic cells, a functional loop, which normally drives histone hyperacetylation and chromatin binding by a BET factor in spermatogenic cells.


Macrophage plasminogen activator: induction by concanavalin A and phorbol myristate acetate.
The synthesis and secretion of plasminogen activator by cultured macrophages can be induced and stimulated by concanavalin A and by phorbol myristate acetate, and inhibited by such agents as glucocorticoids, mitotic inhibitors and compounds affecting cAMP metabolism. By the manipulation of stimulatory and inhibitory influences, enzyme production can be modulated continuously over a 200 fold range. In the same way, the proportion of cells that secrete detectable levels of enzyme can be varied from 1-90%. No comparable modulation of lysozyme or acid hydrolase production is observed under the same conditions. These results suggest that the physiological control of macrophage plasminogen activator production is achieved by the interacting effects of mutually antagonistic stimuli; this emphasizes the utility of this enzyme for the study of regulatory phenomena, including those relating to inflammation.


Regulation of hexose carriers in chicken embryo fibroblasts. Effect of glucose starvation and role of protein synthesis.
Regulation of hexose transport was investigated in chicken embryo fibroblasts (CEF) which develop 4- to 8-fold enhanced hexose transport activity during glucose starvation. The presence of cycloheximide in low (0.5 micrograms/ml) concentrations during starvation largely blocked the enhancement of transport activity. Glucose refeeding of CEF in the starvation state led to a decline in transport to the basal level. This decline was either potentiated or blocked by the presence of cycloheximide in low or high (50 micrograms/ml) concentrations, respectively. Exposure of CEF in the fed state to low concentrations of cycloheximide resulted in a 70% decrease of transport within 6 h, whereas exposure to high concentrations of cycloheximide led to only a modest loss (35% decrease). In the glucose-starved state, CEF had no significant decline of transport when exposed to cycloheximide at either high or low concentrations. The uptake of 3-O-methylglucose by fed, starved, or cycloheximide-treated CEF correlated closely with D-glucose transport activity and [3H]cytochalasin B binding by plasma membranes prepared from CEF exposed to the same conditions. Hexose transport activity of CEF seems to largely depend on the number of functioning carriers in the plasma membrane, which apparently reflect the balance between carrier synthesis and inactivation. These two processes require protein synthesis, but are differentially sensitive to the effects of cycloheximide, such that low concentrations of cycloheximide appear to block primarily synthesis while high concentrations block both processes. Furthermore, during starvation the enhancement of transport appears largely due to decreased carrier inactivation in the face of continued carrier synthesis.


Schistosoma mansoni: a diamidinophenylindole probe for in vitro death of schistosomula.
The following fluorochromes were studied as probes for discrimination between living and dead Schistosoma mansoni schistosomula: ethidium bromide (EB), propidium iodide (PI), diamidinophenylindole (DAPI), and carboxyfluoresceine diacetate (C-FDA). While schistosomula stained with EB, PI, or C-FDA showed leakage of fluorochrome into the medium, this was not the case with DAPI. Dead schistosomula, which were stained with DAPI, showed an intense blue fluorescence, while living schistosomula were not stained even after prolonged incubation. In addition, the low DAPI concentration (1 microgram/ml) in the medium proved not to be toxic to the schistosomula, nor did it cause any background fluorescence. These properties make DAPI an ideal probe: the viability of S. mansoni schistosomula in cytotoxicity tests can be continuously monitored in tissue culture trays, using an inverted microscope with simultaneous transmitted light and incident fluorescent light illumination.


Whole body fat: content and distribution.
Obesity and its co-morbidities, including type II diabetes, insulin resistance and cardiovascular diseases, have become one of the biggest health issues of present times. The impact of obesity goes well beyond the individual and is so far-reaching that, if it continues unabated, it will cause havoc with the economies of most countries. In order to be able to fully understand the relationship between increased adiposity (obesity) and its co-morbidity, it has been necessary to develop proper methodology to accurately and reproducibly determine both body fat content and distribution, including ectopic fat depots. Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) have recently emerged as the gold-standard for accomplishing this task. Here, we will review the use of different MRI techniques currently being used to determine body fat content and distribution. We also discuss the pros and cons of MRS to determine ectopic fat depots in liver, muscle, pancreas and heart and compare these to emerging MRI techniques currently being put forward to create ectopic fat maps. Finally, we will discuss how MRI/MRS techniques are helping in changing the perception of what is healthy and what is normal and desirable body-fat content and distribution.


A deuterated analog of dasatinib disrupts cell cycle progression and displays anti-non-small cell lung cancer activity in vitro and in vivo.
The pan-Src family kinase inhibitor dasatinib has been approved for chronic myeloid leukemia treatment but displays limited activity in lung cancer patients. In this study, we used a deuterium substitution strategy to develop a class of novel chemicals based on dasatinib and found that these compounds maintain inhibition on c-Src activity and display anti-non-small cell lung cancer activity in vitro and in vivo. BRP800, one of these compounds, was chosen for further studies. BRP800 mainly displayed antiproliferative but not proapoptotic activity. Molecularly, BRP800 did not show significant effects on the expression of antiapoptotic genes, such as Bcl-2 and Mcl1, or on the activation of apoptotic enzymes, such as caspase-3, -8 or 9. However, BRP800 decreased expression of cell cycle promoting genes such as cyclins D1, D3, E, A and CDK4 and 6, and increased the expression of cell cycle negative regulators including p21, p27 and p53. Consistent with these findings, BRP800 arrested cells at the G0/G1 phase in a concentration-dependent manner, and the G0/G1 fraction was increased from 64% in control to 85% in BRP800-treated cells. We also evaluated the effects of BRP800 on NSCLC xenografts using H460 as a model in nude mice. Compared with the known NSCLC drug docetaxel, BRP800 displayed potent and similar antitumor activity but with less toxicity. These findings suggest that the deuterated analog of dasatinib is antiproliferative by inhibiting c-Src and disrupting cell cycle progression, and could be further developed as a novel drug for non-small lung cancer treatment.


Unusual Presentation of Myasthenia Crisis Following Thymectomy and Thyroidectomy.
Respiratory distress after thyroidectomy and thymectomy can be challenging. We encountered a 70-year-old lady with a long-standing goiter with concomitant thymoma. She underwent the surgery and developed respiratory distress upon extubation with loss of laryngeal sensation causing severe aspiration. She was diagnosed myasthenia gravis and symptoms resolved with MG treatments.


Variation in ACS patient hospital resource utilization: Is it time for advanced NSTEMI risk stratification in the ED?
A majority of patients who experience acute coronary syndrome (ACS) initially receive care in the emergency department (ED). Guidelines for care of patients experiencing ACS, specifically ST-segment elevation myocardial infarction (STEMI) are well defined. We examine the utilization of hospital resources between patients with NSTEMI as compared to STEMI and unstable angina (UA). We then make the case that as NSTEMI patients are the majority of ACS cases, there is a great opportunity to risk stratify these patients in the emergency department. We examined hospital resource utilization measure between those with STEMI, NSTEMI, and UA. These included hospital length of stay (LOS), any intensive care unit (ICU) care time, and in-hospital mortality. The sample included 284,945 adult ED patients, of whom 1195 experienced ACS. Among the latter, 978 (70%) were diagnosed with NSTEMI, 225 (16%) with STEMI, and 194 with UA (14%). We observed 79.1% of STEMI patients receiving ICU care. 14.4% among NSTEMI patients, and 9.3% among UA patients. NSTEMI patients' mean hospital LOS was 3.7 days. This was shorter than that of non-ACS patients 4.75 days and UA patients 2.99. In-hospital mortality for NSTEMI was 1.6%, compared to, 4.4% for those with STEMI patients and 0% for UA. There are recommendations for risk stratification among NSTEMI patients to evaluate risk for major adverse cardiac events (MACE) that can be used in the ED to guide admission decisions and use of ICU care, thus optimizing care for a majority of ACS patients.


Rapid and sustained restoration of astrocytic functions by ketamine in depression model mice.
Molecules with fast-acting antidepressant effects have potentials to become new antidepressants. Here we report the fast-acting (1hr) antidepressant effects of ketamine (10 mg/kg, i.p.) in chronic adreno-cortico-tropic-hormone (ACTH)-induced and chronic unpredictable mild stress (CUMS)-induced depression mouse models. These behavioral anti-depressant effects are associated with normalized expression of glutamate transporter-1(GLT-1), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and eukaryotic elongation factor 2 phosphorylation (p-eEF2) in the prelimbic prefrontal cortex (PrL-PFC). Excitatory neurons in PrL also showed reduced ambient glutamate responses to synaptic stimulation, and reduced ambient NMDA receptor responses after ketamine injection. Interestingly, ketamine induced biochemical and electrophysiological changes still occurred with GLT-1 knockdown in PrL, suggesting that elevated GLT-1 level is not required for ketamine to exert its antidepressant effect. At the same time, ketamine did not elevate GLT-1 level in the isolated astrocytes, suggesting distinct contributions from neurons and astrocytes to ketamine-induced changes.


Molecular cloning and cDNA sequence analysis of carboxypeptidases A1, A2 and B from the Japanese flounder Paralichthys olivaceus.
Although pancreatic serine proteases have been cloned in teleosts, no sequence data are currently available on members of the carboxypeptidase (CP) family. Here, we cloned cDNAs coding for two preproCPAs, corresponding to mammalian preproCPA1 and preproCPA2, and one preproCPB from a pancreatic cDNA library of the Japanese flounder, Paralichthys olivaceus. The activation peptides of flounder proCPs completely retained the sequences for inhibition of enzymatic activity of proCPs just like mammalian proCPs. Of 306-309 amino acids in total, 95 amino acids are completely conserved between bovine CPA1 and CPB and flounder CPs. Notably, amino acid residues for Zn(2+) ligands, catalysis and substrate anchoring are completely conserved between flounder and bovine CPs. Three species of flounder preproCPs are all expressed in the pancreas of first feeding larvae.


Muscarinic receptors on cultured cells of rat hippocampus: cholinergic regulation and presence of subtypes.
Muscarinic acetylcholine receptors in intact, cultured explants of rat hippocampus were investigated in binding experiments with tritiated quinuclidinyl benzilate ([3H]QNB) as ligand. Dissociation constants (Kd) were determined to 320-575 pM and maximal binding capacity (Bmax) to 67-87 fmol/explant. The KdS obtained in kinetic experiments were very similar. Hippocampal explants cultured alone contained more muscarinic receptors than hippocampal explants reinnervated by cholinergic fibers from co-cultured septal explants. Pretreatment of hippocampal explants with carbachol resulted in a down-regulation of receptor number which was counteracted by the simultaneous addition of atropine. Atropine added alone had no effect on receptor number in hippocampal explants cultured alone whereas it occasionally caused an up-regulation in co-cultured hippocampus. Displacement experiments with scopolamine and oxotremorine as competitors, showed that hippocampal explants cultured alone contain multiple types of muscarinic receptors. With atropine, pirenzepine and AF-DX 116, only one class of receptors could be detected.


The Theos/ComRes survey into public perception of Darwinism in the UK: a recipe for confusion.
A survey of the general public in the UK, conducted in 2008, suggested that more than half of the British population are unconvinced by Darwinism. That survey, conducted by the polling company ComRes on behalf of the theological think-tank Theos, reported its full findings in March 2009 and found them to be "complex and confused." This paper argues that the confusion identified may have been partly engendered by the way in which the survey questionnaire was constructed and that the survey itself, not simply its respondents, was confused. A source of the confusion, it is argued, could be found, first, in the definitions used for the four positions of young earth creationism, theistic evolution, atheistic evolution and intelligent design. Second, a failure to define the key terms "evolution" and "science," used in some of the survey questions, resulted in responses that were difficult to interpret.


Crystal structure and density functional theory study on structural properties and energies of a isonicotinohydrazide compound.
An X-ray and a theoretical study of the structure of the isoniazid derivative N'-(4-dimethylaminobenzylidene)-isonicotinohydrazide monohydrate (1) are reported. In this work, we will report a combined experimental and theoretical study on the molecular structure, vibrational spectra and energies of N'-(4-dimethylaminobenzylidene)-isonicotinohydrazide monohydrate. The calculated parameters are in good agreement with the corresponding X-ray diffraction values. The FTIR spectrum in the range of 400-4000 cm-1 of N'-(4-dimethylaminobenzylidene)-isonicotinohydrazide monohydrate has been recorded. The molecular geometry and vibrational frequencies and energies in the ground state are calculated by using the DFT (B3LYP, PBE1PBE) methods with 6-311G** basis sets. The calculated HOMO and LUMO energies also confirm that charge transfer occurs within the molecule. The geometries and normal modes of vibrations obtained from B3LYP/PBE1PBE/6-311G** calculations are in good agreement with the experimentally observed data.


Introduction: An Overview.
The use of biologicals for clinical use is rapidly increasing. One of the logical questions is what constitutes a biological? The official definition of biological products by the Food and Drug Administration is "Biological products can be composed of sugars, proteins, or nucleic acids, or a combination of these substances. They may also be living entities, such as cells and tissues. Biologics are made from a variety of natural resources-human, animal, and microorganism-and may be produced by biotechnology methods."


Q fever vaccines: present status and application in man.
Of three Q fever vaccine candidates available at present, i.e., phase I corpuscular untreated, soluble, and phase I corpuscular chloroform-methanol treated vaccines, the first two were tested on hundreds of subjects exposed to Q fever. Based on their sufficient immunogenicity (which depends also on the tests employed) and low reactogenicity (providing that subjects with previous contact with Coxiella (C.) burnetii are excluded from vaccination) these two vaccines can be recommended for vaccination of humans at risk. Further studies are required, however, to answer definitively which vaccine type is the most suitable, and facing the problem of C. burnetii strain heterogeneity, to decide whether a monovalent vaccine will be sufficient or a polyvalent vaccine will be necessary.


Anchoring a dynamic in vitro model of human neuronal differentiation to key processes of early brain development in vivo.
We characterize temporal pathway dynamics of differentiation in an in vitro neurotoxicity model with the aim of informing design and interpretation of toxicological assays. Human neural progenitor cells (hNPCs) were cultured in differentiation conditions up to 21 days. Genes significantly changed through time were identified and grouped according to temporal dynamics. Quantitative pathway analysis identified gene ontology (GO) terms enriched among significantly changed genes and provided a temporal roadmap of pathway trends in vitro. Gene expression in hNPCs was compared with publicly available gene expression data from developing human brain tissue in vivo. Quantitative pathway analysis of significantly changed genes and targeted analysis of specific pathways of interest identified concordance between in vivo and in vitro expression associated with proliferation, migration, differentiation, synapse formation, and neurotransmission. Our analysis anchors gene expression patterns in vitro to sensitive windows of in vivo development, helping to define appropriate applications of the model.