Heterogeneity in maize starch granule internal architecture deduced from diffusion of fluorescent dextran probes.
Heterogeneity in maize starch granules was investigated by studying the diffusion of fluorescent dextran probes (20, 70 and 150kDa) inside granules using fluorescence recovery after photobleaching combined with confocal microscopy. Access of probes to the interior of granules was greatly enhanced by limited (2.4%) amylolysis. The diffusion of probes within granules was found to be either 'fast' with diffusion coefficients in the order of 10(-6)cm(2)s(-1) or 'slow' with diffusion coefficients in the order of 10(-7)cm(2)s(-1), independent of the size of dextran probes or prior treatment of the granules by α-amylase. Results were compared with observations of pores and channels in granules by electron microscopy and by confocal microscopy after labelling with 8-amino-1,3,6-pyrenetrisulfonic acid. It is proposed that there is an inherent heterogeneity of internal architecture in maize starch granules due to the presence or absence in individual granules of (a) pores leading to a central cavity, resulting in 'fast' diffusion of dextran probes and (b) accessibility of the starch polymer matrix to dextran probes, leading to 'slow' diffusion behaviour. The observed heterogeneity of maize starch granule porosity has implications for chemical modification reactions and the kinetics of digestion with amylases.


Penfluridol: An antipsychotic agent suppresses lung cancer cell growth and metastasis by inducing G0/G1 arrest and apoptosis.
Lung cancer remains the leading cause of cancer mortality because of highly malignant and metastatic potential. The current status of lung cancer treatment is limited, and more treatment options are needed. Interesting, antipsychotic drugs have been reported to show anti-cancer effects. In this present study, we investigated the anticancer potential of penfluridol (PF), an anti-schizophrenic drug, in lung cancer and its underlying mechanism in vitro and in vivo. In vitro, it could inhibit the viability of various lung cancer cells with G0/G1 phase arrest via increasing the expression level of p21/p27 and decreasing the expression levels of cyclin-CDK complex. Meanwhile, cell-cycle arrest causes DNA repair in the nucleus, which was associated with the upregulation of H2A.X and p-H2A.X. Moreover, PF could also decrease mitochondrial membrane potential and increase reactive oxygen species levels in the lung cancer cells. These results implied that PF might induce the mitochondria-mediated intrinsic apoptosis. In addition, PF inhibits the migration and invasion of lung cancer cells via downregulation of FAK-MMP signaling. In vivo, oral administration of PF at concentration of 10 mg/kg inhibited tumor growth in A549 xenograft model. Notably, PF is an approved drug and the price is exceedingly cheap, so this study demonstrates the potential of PF to treat lung cancer.


Respiratory and non-respiratory symptoms associated with pesticide management practices among farmers in Ghana's most important vegetable hub.
The data presented here are from the Offinso North District Farm Health Study (ONFAHS), a population-based cross-sectional study among vegetable farmers in Ghana. The paper addresses knowledge, pesticide handling practices, and protective measures related to pesticide use by self-reported symptoms for 310 adult farmers who completed a comprehensive questionnaire on pesticide management practices and health. In addition, an inventory was prepared using information supplied by pesticide sellers/dealers in this district. We report that cough and wheezing (but not breathlessness) are positively associated with stirring pesticide preparations with bare hands/drinking water while mixing/applying pesticides, and stirring pesticide preparations with bare hands/drinking water/smoking cigarettes while mixing/applying pesticides. There is a significant exposure-response association between the number of precautionary measures practiced while handling pesticides and cough and wheezing but not with breathlessness. We also found unsafe practices to be associated with sexual dysfunction, nervousness, and lack of concentration. The results also suggest a negative association between practice of any precautionary measure when mixing/applying pesticides and sexual dysfunction, nervousness, and lack of concentration. We found that in spite of the fact that farmers have adequate knowledge about the environment and health effects of pesticides, several unhygienic practices are in widespread use, indicating that knowledge is not necessarily always translated in action. Further action is necessary to promote the safe use of pesticides and to replace existing poor management practices among these and other farmers in Ghana.


Obsessive intrusive thoughts in nonclinical subjects. Part I. Content and relation with depressive, anxious and obsessional symptoms.
The present study reports on the development and preliminary validation of a 52 item self-report instrument designed to assess intrusive thoughts, images and impulses that are similar to the aggressive, sexual and disease-related thinking characteristic of clinical obsessions. Two hundred and ninety-three students completed the Obsessive Intrusions Inventory (OII) as well as standard self-report measures of negative cognitions and obsessive, anxious and depressive symptoms. Regression analysis revealed that intrusive thinking was a significant and unique predictor of obsessional but not anxious or depressive symptoms. Furthermore, intrusive thinking showed a moderate correlation with anxious but not depressive cognitions. The results indicate that the intrusive thoughts assessed by the OII are distinct from other forms of negative thinking and may, in fact, constitute an analogue form of clinical obsessions in nonclinical populations.


Beneficial effects of curcumin on hyperlipidemia and insulin resistance in high-fat-fed hamsters.
This study investigated the effect of curcumin (0.05-g/100-g diet) supplementation on a high-fat diet (10% coconut oil, 0.2% cholesterol, wt/wt) fed to hamsters, one of the rodent species that are most closely related to humans in lipid metabolism. Curcumin significantly lowered the levels of free fatty acid, total cholesterol, triglyceride, and leptin and the homeostasis model assessment of insulin resistance index, whereas it elevated the levels of high-density lipoprotein cholesterol and apolipoprotein (apo) A-I and paraoxonase activity in plasma, compared with the control group. The levels of hepatic cholesterol and triglyceride were also lower in the curcumin group than in the control group. In the liver, fatty acid beta-oxidation activity was significantly higher in the curcumin group than in the control group, whereas fatty acid synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and acyl coenzyme A:cholesterol acyltransferase activities were significantly lower. Curcumin significantly lowered the lipid peroxide levels in the erythrocyte and liver compared with the control group. These results indicate that curcumin exhibits an obvious hypolipidemic effect by increasing plasma paraoxonase activity, ratios of high-density lipoprotein cholesterol to total cholesterol and of apo A-I to apo B, and hepatic fatty acid oxidation activity with simultaneous inhibition of hepatic fatty acid and cholesterol biosynthesis in high-fat-fed hamsters.


2-Methylresorcinarene: a very high packing coefficient in a mono-anion based dimeric capsule and the X-ray crystal structure of the tetra-anion.
Mono- and tetra-deprotonated 2-methylresorcinarene anions ( and ) as their trans-1,4-diammoniumcyclohexane inclusion complexes are reported. The mono-anion forms a fully closed dimeric capsule [·H2O·MeOH]2(2-) with a cavity volume of 165 Å(3) and as the guest with an extremely high packing coefficient, PC = 84.2%, while the tetra-anion forms a close-packed structure with two structurally isomeric tetra-anions and with a 50 : 50 ratio in the crystal lattice.


Simultaneous quantification of vitamin E, γ-oryzanols and xanthophylls from rice bran essences extracted by supercritical CO2.
Since the nutrition value of rice is diminished during rice processing, technology that can preserve and sustain functional compounds is necessary. In this study, supercritical carbon dioxide (SC-CO2) extraction was optimized for operational conditions (time, temperature, pressure and modifier) to extract vitamin E, γ-oryzanols and xanthophylls from rice bran. The simultaneous quantification of the compounds was developed using high-performance liquid chromatography with diode array and fluorescence detectors. Central composite design and respond surface methodology were applied to achieve optimum extraction conditions. The optimized conditions were 60min, 43°C, 5420psi with 10% ethanol as a modifier. Pigmented rice bran extracts contained greater amounts of functional phytochemicals than non-pigmented rice bran extracts (0.68, 1410, and non-detectable μg/g compared with 16.65, 2480, and 0.10μg/g of vitamin E, γ-oryzanols and xanthophylls in pigmented and non-pigmented ones, respectively). SC-CO2 extraction with modifier would be promising for preparation of phytochemical essences for therapeutic purpose.


Affinity chromatographic purification of nucleosomes containing transcriptionally active DNA sequences.
The unfolding of nucleosome cores in transcriptionally active chromatin uncovers the sulfhydryl groups of histone H3, making them accessible to SH-reagents. This has suggested that nucleosomes from active genes could be retained selectively on organomercurial/agarose columns. When nucleosomes released from rat liver nuclei by limited digestion with micrococcal nuclease were passed through an Hg affinity column, a run-off fraction of compact, beaded nucleosomes was separated from a retained nucleosome fraction. Although both contained monomer-length DNA and a full complement of core histones, histones in the retained fraction were hyperacetylated. Dot blot hybridizations showed the Hg-bound nucleosome fraction to be enriched in DNA sequences transcribed by hepatocytes (serum albumin and transferrin genes), while a brain-specific gene (preproenkephalin) was not retained, but appeared in the nucleosomes of the run-off fraction. The results are discussed in light of other evidence linking hyperacetylation of histones H3 and H4 to conformational changes at the middle of the nucleosome core.


Using multiple heart-cutting valves and stop-flow operation to enable variable second dimension gradient times in online comprehensive two-dimensional liquid chromatography.
Online comprehensive two-dimensional liquid chromatography (LC×LC) is the preferred method currently for the separation of highly complex mixtures of non-volatile compounds. With fully automated commercial instrumentation and software making the method appealing to both researchers and industry, the demand for systems with improved separation capabilities for highly complex mixtures such as those found in natural products or proteomics has increased. In this study we report an approach that enables variable second dimension analysis times based on the use of multiple heart-cutting valves and stop-flow operation to circumvent the requirement for very fast second dimension (2D) analyses in online LC×LC. As application, the HILIC×RP-LC analysis of condensed tannins (proanthocyanidins) in cocoa, grape seed and quebracho extracts is used to demonstrate the performance on the proposed methodology. The method offers increased flexibility compared to conventional online LC×LC separations in that longer 2D gradients can be used to accommodate more complex portions of the chromatogram, while shorter 2D gradients can be used in sections containing fewer peaks, while largely maintaining the benefits of comprehensive separation. We present an evaluation of the performance of the variable gradient time stop-flow HILIC×RP-LC method compared to a comparable, conventional online HILIC×RP-LC system in terms of practical peak capacities using established 2D-LC theory. The improved separation of especially low-level intermediate molecular weight proanthocyanidin oligomers by the former method demonstrates the benefits of the developed approach.


Liver blood flow measured by indocyanine green in conscious unrestrained miniature pigs.
For studies in physiology and biochemistry of the liver the measurement of hepatic blood flow is a fundamental precondition. Therefore, the least invasive method, the measurement of liver blood flow by indocyanine green (ICG) dye elimination, was re-evaluated for the miniature pig, an animal model of increasing interest. The accuracy of spectrophotometric determination of ICG was enhanced by addition of 5% of desoxycholic acid. It was shown that ICG was eliminated exclusively by the liver. An extraction rate of 30%-50% was found in mini-pigs, but an insufficient rate of 5%-10% in pigs of German landrace. A liver blood flow ranging from 70 to 160 ml/100 g X min-1 was measured. These values are in good accordance with datas from simultaneous estimation of blood flow by 133Xenon washout. As shown for a starvation/refeeding cycle, liver blood flow measurement by ICG combined with permanently implanted catheters is a practicable tool for studies of the metabolic and pharmacologic fate of substances resorbed from the gut.


Unusual osteopathy in a newborn.
A newborn baby presented with hyaline membrane disease, interstitial pneumonia, jaundice, hepatosplenomegaly, and unusual bone manifestations with lytic and sclerotic bone lesions and virtually absent periosteal reaction. He subsequently developed intracranial calcifications and mental retardation. The pneumonia and hepatosplenomegaly resolved. At the time of the delivery, a sibling was suffering from a severe undetermined viral infection. The clinical evolution of the disease and the radiologic findings led us to believe that this patient had a prenatal viral infection. The laboratory tests and the histologic picture of the bone biopsy supported the diagnosis.


Feasibility and Safety of Transradial Aneurysm Embolization: A Systematic Review and Meta-Analysis.
Use of the transradial access (TRA) approach for neuroendovascular procedures has been increasing in recent years. Our aim is to assess the feasibility, success rate, and complications associated with TRA for intracranial aneurysm embolization. PubMed, Scopus, and Embase were systematically searched for studies using TRA for intracranial aneurysm embolization. Random-effects models were used to obtain pooled rates of procedural success and complications. Twenty-four studies comprising 1283 (85.9%) TRA and 122 (8.2%) distal TRA aneurysm embolization procedures were included. The pooled success rate of the 18 studies in the meta-analysis was 93.5% (95% confidence interval [CI], 91.1%-95.8%). The pooled thromboembolic complication rate was 0.5% (95% CI, 0.1%-0.9%), the hemorrhagic complication rate was 0.5% (95% CI, 0.1%-0.9%), and the access site complication rate was 0.8% (95% CI, 0.3%-1.3%). One study (4.3%) used exclusively a 7-French guide catheter, and most used a 6-French guide catheter (22 of 23 studies, 95.7%), which was further incorporated as part of a triaxial configuration through a sheathless 8-French system in 4 studies (17.4%), 7-French guide catheter in 2 studies (8.7%), and 8-French sheath in 1 study (4.3%). The embolization techniques used were flow diverter placement in 451 cases (39.1%), coiling in 376 (32.6%), stent-assisted coiling in 127 (11.0%), balloon-assisted coiling in 104 (9.0%), Woven EndoBridge system in 50 (4.3%), and flow diverter placement plus coiling in 42 (3.6%). Treating intracranial aneurysms using various embolization techniques through TRA is feasible and associated with low access site and intraoperative complications.


Analysis of possible genetic risk factors contributing to development of childhood acute lymphoblastic leukaemia in the Latvian population.
Childhood acute lymphoblastic leukaemia (ALL) is a complex disease caused by a combination of genetic susceptibility and environmental exposure. Previous genome-wide association studies have reported several single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. Several variations in genes encoding enzymes involved in carcinogenesis are suggested as being associated with an increased risk of ALL development. We enrolled 77 paediatric ALL patients and 122 healthy controls, and in addition parental DNA was also available for 45 probands. SNPs rs10821936 (ARID5B), rs4132601 (IKZF1), rs2239633 (CEBPE), rs3731217 (CDKN2A) and rs1800566 (NQO1) and the presence of GSTT1 and GSTM1 null variants were detected. For statistical analysis the hybrid method of two designs 'Haplin' was used as well as linkage disequilibrium for family-based association studies. We identified the SNP rs10821936 in the ARID5B gene as being statistically significantly associated with childhood ALL, especially if the C allele is in a homozygous state, relative risk (RR) 4.65, 95% CI: 2.03-10.6, p = 0.0006. Statistically significant differences were not found in other SNPs. We found risk combinations including all five variations, the strongest association being found in a combination where all five genetic variants are in a homozygous state, CCTTTTTTCC, p = 0.032. The identified SNP rs10821936 could serve as a potential risk marker for childhood ALL development. Further studies in an independent population are needed for verification.


Association between monocyte to high-density lipoprotein cholesterol ratio and multi-vessel coronary artery disease: a cross-sectional study.
Patients with multi-vessel coronary artery disease (MV-CAD) have poorer clinical outcomes than those with single-vessel coronary artery disease (SV-CAD). Solid evidence underlines that high-density lipoprotein cholesterol (HDL-C) plays a protective role and monocyte plays a negative role in coronary artery disease (CAD). However, the monocyte to high-density lipoprotein ratio (MHR) has not been studied in relation to MV-CAD. In this study, 640 patients underwent coronary angiography, of whom 225 had severe coronary artery disease. Then divide the above two groups of patients into three groups based on the MHR tertiles, respectively. Logistic regression and subgroup analysis were carried out to estimate the association between MHR and MV-CAD. The receiver operating characteristic (ROC) curve analysis was constructed by combining classic CAD risk factors with MHR in response to MV-CAD. In addition, the mediating effect of MHR between smoking and MV-CAD in suspected CAD Patients was analyzed. Among the three MHR groups, a statistically discrepant was observed in the number of patients with CAD, Severe-CAD and MV-CAD (PCAD < 0.001; PSevere-CAD < 0.001; PMV-CAD = 0.001) in suspected CAD patients. Furthermore, the number of patients with MV-CAD (P < 0.001) was different in Severe-CAD patients among three MHR groups. Non-CAD and CAD patients showed statistically discrepant in MHR levels (P < 0.001), and this difference also was observed between SV-CAD and MV-CAD patients (P < 0.001). In the analysis of suspected CAD patients, a significantly positive relationship was found between MHR and CAD, Severe-CAD, and MV-CAD (P for trend < 0.001). The effect of MHR on MV-CAD was consistent across all subgroups, with no significant randomized factor-by-subgroup interaction (P-interaction = 0.17-0.89). ROC analysis showed that the model constructed with MHR and classic influencing factors of CAD was superior to the model constructed solely based on classic influencing factors of CAD (0.742 vs.0.682, P = 0.002). In the analysis of Severe-CAD patients, patients with higher MHR levels had a higher risk of MV-CAD [OR (95%CI): 2.90 (1.49, 5.62), P for trend = 0.002] compared to patients with lower MHR. The trends persisted after adjusting for demographic (P for trend = 0.004) and classic influencing factors of CAD (P for trend = 0.009). All subgroup factors for patients with MV-CAD had no interaction with MHR (P-interaction = 0.15-0.86). ROC analysis showed that the model combining MHR and classic influencing factors of CAD was superior to the one including only the classic influencing factors of CAD (0.716 vs.0.650, P = 0.046). Assuming that MHR played a mediating effect between smoking and MV-CAD in suspected CAD patients. The results indicated that MHR played a partial mediating effect of 0.48 (P < 0.001). A higher MHR was mainly associated with multi-vessel coronary artery disease and MHR partially mediated the association between smoking and MV-CAD.


The emergence of political priority for addressing child sexual abuse in the United Kingdom.
Child sexual abuse (CSA) is widespread. Few countries, however, prioritize the issue. The United Kingdom is an exception, ranked first in its response to the issue in a 2019 country comparison. In 2015, Prime Minister David Cameron designated the issue one of three national threats. Funding commitments and policies to address CSA followed. To investigate how CSA emerged as a national political priority in the United Kingdom, and to identify insights for proponents seeking to advance priority for addressing the issue. Documents were analyzed and semi-structured interviews conducted with actors in the United Kingdom central to CSA advocacy, research, and/or programming, as well as with policymakers. Drawing on the multiple streams public policy model, a thematic analysis was conducted on collected documents (n = 160) and 21 interview transcripts. Our analysis delineates three critical developments that led to national prioritization for addressing CSA. First, high-profile scandals and the re-framing of CSA survivors as deserving of support raised public awareness of the problem. Second, champions concerned with CSA developed evidence-based and politically-feasible solutions. Third, the Prime Minister's concern and other political developments opened a policy window. The case provides insights for proponents on generating political priority for addressing CSA. Proponents need to (1) ensure survivors are not seen as culpable but rather as deserving of support, (2) be ready with solutions and (3) cultivate high-level political support, so that when policy windows open they can jump to push the issue onto the national agenda.


The association between vaccination status identification and societal polarization.
Public discord between those vaccinated and those unvaccinated for COVID-19 has intensified globally. Theories of intergroup relations propose that identifying with one's social group plays a key role in the perceptions and behaviours that fuel intergroup conflict. We test whether identification with one's vaccination status is associated with current societal polarization. The study draws on panel data from samples of vaccinated (n = 3,267) and unvaccinated (n = 2,038) respondents in Germany and Austria that were collected in December 2021 and February, March and July 2022. The findings confirm that vaccination status identification (VSI) explains substantial variance in a range of polarizing attitudes and behaviours. VSI was also related to higher psychological reactance toward mandatory vaccination policies among the unvaccinated. Higher levels of VSI reduced the gap between intended and actual counterbehaviours over time by the unvaccinated. VSI appears to be an important measure for predicting behavioural responses to vaccination policies.


Relative effectiveness of the adjuvanted vs non-adjuvanted seasonal influenza vaccines against severe laboratory-confirmed influenza among hospitalized Italian older adults.
In this study, we aimed to investigate the relative vaccine effectiveness (rVE) of the MF59-adjuvanted trivalent (aTIV) and non-adjuvanted quadrivalent (QIVe) egg-based standard-dose vaccines against severe laboratory-confirmed influenza. This test-negative case-control study was conducted in a hospital setting during four recent Italian influenza seasons (from 2018/19 to 2021/22). The clinical outcome was severe acute respiratory infection (SARI) with laboratory confirmation diagnosed among subjects aged ≥65 years. rVE of aTIV versus QIVe was estimated through propensity score matching followed by logistic regression. The influenza virus circulated to a significant extent only during the 2018/19 and 2019/20 seasons. The final population included 512 vaccinated older adults, of which 83 were cases and 429 were test-negative controls. aTIV and QIVe users differed substantially from the point of view of several baseline characteristics. The propensity score adjusted rVE of aTIV vs QIVe was 59.2% (95% CI: 14.6%, 80.5%), 54.7% (95% CI: -28.7%, 84.0%) and 56.9% (95% CI: -7.8%, 82.8%) against any influenza, A(H1N1)pdm09 and A(H3N2), respectively. aTIV was more effective than QIVe in preventing laboratory-confirmed SARI. The benefits of aTIV may be obscured by confounding indication.


Small-angle x-ray scattering investigation of the integration of free fatty acids in polysorbate 20 micelles.
A critical quality attribute for liquid formulations is the absence of visible particles. Such particles may form upon polysorbate hydrolysis resulting in release of free fatty acids into solution followed by precipitation. Strategies to avoid this effect are of major interest for the pharmaceutical industry. In this context, we investigated the structural organization of polysorbate micelles alone and upon addition of the fatty acid myristic acid (MA) by small-angle x-ray scattering. Two complementary approaches using a model of polydisperse core-shell ellipsoidal micelles and an ensemble of quasiatomistic micelle structures gave consistent results well describing the experimental data. The small-angle x-ray scattering data reveal polydisperse mixtures of ellipsoidal micelles containing about 22-35 molecules per micelle. The addition of MA at concentrations up to 100 μg/mL reveals only marginal effects on the scattering data. At the same time, addition of high amounts of MA (>500 μg/mL) increases the average sizes of the micelles indicating that MA penetrates into the surfactant micelles. These results together with molecular modeling shed light on the polysorbate contribution to fatty acid solubilization preventing or delaying fatty acid particle formation.


Can serum periostin predict bronchopulmonary dysplasia in premature infants?
Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects long-term respiratory outcomes. The objectives of this study were to establish whether serum periostin at birth, day of life (DOL) 28, and corrected 36 weeks' gestational age could be potential biomarkers for BPD. A total of 98 preterm Japanese infants born at <32 weeks and comparing 41 healthy controls born at term, were divided into BPD (n = 44) and non-BPD (n = 54) cohorts. Serum periostin levels were measured using an enzyme-linked immunosorbent assay. Among 98 preterm infants, the median serum periostin levels at birth were higher with BPD (338.0 ng/mL) than without (275.0 ng/mL, P < 0.001). Multivariate analysis revealed that serum periostin levels at birth were significantly associated with BPD (P = 0.013). Serum periostin levels at birth with moderate/severe BPD (345.0 ng/mL) were significantly higher than those with non-BPD/mild BPD (283.0 ng/mL, P = 0.006). Serum periostin levels were significantly correlated with birth weight and gestational age, and serum periostin levels at birth in BPD infants were significantly higher than that in non-BPD infants. This study found higher serum periostin levels at birth in preterm infants subsequently diagnosed with bronchopulmonary dysplasia. It also emerged that serum periostin levels at birth significantly correlated with gestational age and birth weight. The mechanism by which serum periostin is upregulated in BPD infants needs further investigation.


Interdisciplinarity and Integration: An Introduction to the Special Issue on Psychopathology in Medical Settings.
As the world views, incredulously, the calamitous consequences of the COVID-19 pandemic, the inseparable connections between body and mind become more and more apparent, even for the heretics (i.e., biological determinists). Such realizations also bolster the understanding of the close link between medical conditions and psychopathology. Launched prior to the COVID-19 epidemic, this special issue sets out to illuminate the prevalence, course, etiology, and responses to a myriad of psychopathological conditions in medical conditions. The 13 articles in this special issue address a variety of medical conditions (chronic illness and chronic pain, Pica, cancer, acute delirium, factitious disorders, functional neurological symptoms, sleep disorders, fetal conditions), mental disorders (depression, anxiety, suicidality, eating disorders, personality disorders, PTSD), medical settings (primary care vs. specialty clinics), and developmental levels (children, adolescents, and adults). The overarching theme emanating from reading these articles is that clinical-health psychology, or clinical psychology in medical settings, is an ever-needed field of inquiry, epitomizing interdisciplinarity and science/practice integration.


The effect of presenting symptoms and patient characteristics on prehospital delay in MI patients presenting to emergency department by ambulance: a cohort study.
There is little recent information about prehospital delay time for Australian patients with myocardial infarction (MI). This study: (1) describes prehospital delay time for patients with MI; (2) identifies variables and presenting symptoms which contribute to the delay. This retrospective cohort study identified patients with an Emergency Department (ED) discharge diagnosis of MI, transported by ambulance to one of the seven Perth metropolitan EDs, between January 2008 and October 2009. Prehospital delay times were analysed using linear regression models. Non-numeric (word descriptions) of delay time were categorised. Of 1,633 patients, symptom onset-time was available for 1,003. For 829 patients with a numeric onset-time, median delay was 2.2hours; decreased delay was associated with age <70 years, presenting with chest pain, and diaphoresis. Increased delay was associated with being with a primary health care provider, and if the patient was at home and if the person who called the ambulance was anyone other than the spouse. For 174 patients with non-numeric onset-times, 37% patients delayed one to three days and 110 (64.0%) patients described their symptoms as intermittent and/or of gradual onset. Given that prehospital delay times remain longer than is optimal, public awareness of MI symptoms should be enhanced in order to decrease prehospital delay.


TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL-2R signalling pathway.
IL-2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti-cancer effect. Here, we demonstrated the anti-cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL-2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL-2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL-2R and down-regulated the mRNA and protein levels of IL-2R. Furthermore, TPD7 suppressed the downstream cascades of IL-2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl-2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti-cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL-2R signalling pathway.


High Efficient Solar Cell Based on Heterostructure Constructed by Graphene and GaAs Quantum Wells.
Despite the fascinating optoelectronic properties of graphene, the power conversion efficiency (PCE) of graphene based solar cells remains to be lifted up. Herein, it is experimentally shown that the graphene/quantum wells/GaAs heterostructure solar cell can reach a PCE of 20.2% and an open-circuit voltage (Voc ) as high as 1.16 V at 90 K. The high efficiency is a result of carrier multiplication (CM) effect of graphene in the graphene/GaAs heterostructure. Especially, the external quantum efficiency (EQE) in the ultraviolet wavelength can be improved up to 72.2% based on the heterostructure constructed by graphene/In0.15 Ga0.85 As/GaAs0.75 P0.25 quantum wells/GaAs. The EQE increases as the light wavelength decreases, which indicates more carriers can be effectively excited by the higher energy photons through CM effect. Owing to these physical characters, the graphene/GaAs heterostructure solar cell will provide a possible way to exceed Shockley-Queisser (S-Q) limit.


Performance of a pre-procedural Mehran score to predict acute kidney injury after percutaneous coronary intervention.
Acute kidney injury (AKI) is a known complication of patients undergoing cardiac catheterization or percutaneous coronary interventions (PCI).The Mehran score was developed to identify patients at risk for AKI after cardiac catheterization or PCI, but its use of contrast volume as part of the score calculation limits its application prior to the procedure. In this study, we evaluated the utility of a modified Mehran score that utilizes only pre-procedural data by excluding contrast volume. This was done in a retrospective fashion using data from patients who received PCI at our institution between July 2015 and December 2017 by evaluating the discriminative ability of the scoring systems for predicting outcomes through a receiver-operator characteristic curve analysis. One thousand five hundred and seven patients were included in the study. A total of 70 (4.6%) patients developed AKI. The removal of contrast volume from the Mehran score resulted in a small loss of discrimination with AUROC 0.73 vs 0.74, P = .01 for the pre-procedural Mehran and the original Mehran, respectively. When compared to the original score, the pre-procedural Mehran score had a four-category net discrimination index (NRI) of -0.10 and an integrated discrimination index (IDI) for of -0.12. Despite a small loss in discrimination, there was no difference in the four-category net discrimination index between the two scores. The pre-procedural modified Mehran score is a useful clinical predictor of the risk of AKI in patients undergoing PCI.


Recombinant L7/L12 protein entrapping PLGA (poly lactide-co-glycolide) micro particles protect BALB/c mice against the virulent B. abortus 544 infection.
Brucella abortus is the etiologic agent of Brucellosis, a zoonotic infection affecting a wide range of animals. It is a highly infectious disease of pandemic potential reporting over 500,000 new human cases annually. Till date, there is no reported vaccine for humans and the available animal vaccines are unsafe, therefore a safe and effective subunit vaccine is highly sought for. In this study, we have evaluated rL7/L12 protein encapsulated in microparticles of PLGA (85:15), a biocompatible and biodegradable polymer approved by FDA for human use. In this work, BALB/c mice have been immunized with rL7/L12 entrapped in microparticles in a prime-boost regimen. Further, evaluation of the immunogenicity of the formulation showed that the IgG antibody titre reached a maxima of 2.2×10(5) (p value 0.0001 v/s control) after the injection of the booster dose. A mixed IgG isotype profile (IgG1/IgG2a) indicated the stimulation of both the cellular as well as humoral immunity which has increased parallely and gradually since the first immunization. High levels of IFN-γ, 815±55pg/ml were recorded depicting an optimal elicitation of the cellular wing of immunity leading to clearance of splenic bacteria upto 1.69 log units.


Effects of sediment amended with Deepwater Horizon incident slick oil on the infaunal amphipod Leptocheirus plumulosus.
Crude oil released from the Deepwater Horizon disaster into the Gulf of Mexico posed potential impacts to infaunal invertebrates inhabiting near shore habitats. The effects of sediment-associated weathered slick oil on the amphipod Leptocheirus plumulosus was assessed using 28-d exposures to total PAH sediment concentrations ranging from 0.3 to 24mg/kg (sum of 50 PAHs or tPAH50). Survival and growth rate were significantly decreased in the 2.6, 11.4 and 24.2mg/kg treatments, but only growth in 5.5mg/kg. Offspring production was dramatically decreased but was variable and significantly different only for 24.2mg/kg. The concentrations associated with 20% decreases relative to reference were 1.05 (95% CI=0-2.89) mg/kg tPAH50 for growth rate and 0.632 (95% CI=0.11-2.15) mg/kg tPAH50 for offspring production. The concentrations of PAHs affecting amphipods are within the range of concentrations measured in marsh areas reportedly impacted by DWH oil after its release.


Removal of water binding proteins from dentin increases the adhesion strength of low-hydrophilicity dental resins.
To investigate the role of proteoglycans (PGs) on the physical properties of the dentin matrix and the bond strength of methacrylate resins with varying hydrophilicities. Dentin were obtained from crowns of human molars. Enzymatic removal of PGs followed a standard protocol using 1 mg/mL trypsin (Try) for 24 h. Controls were incubated in ammonium bicarbonate buffer. Removal of PGs was assessed by visualization of glycosaminoglycan chains (GAGs) in dentin under transmission electron microscopy (TEM). The dentin matrix swelling ratio was estimated using fully demineralized dentin. Dentin wettability was assessed on wet, dry and re-wetted dentin surfaces through water contact angle measurements. Microtensile bond strength test (TBS) was performed with experimental adhesives containing 6% HEMA (H6) and 18% HEMA (H18) and a commercial dental adhesive. Data were statistically analyzed using ANOVA and post-hoc tests (α = 0.05). The enzymatic removal of PGs was confirmed by the absence and fragmentation of GAGs. There was statistically significant difference between the swelling ratio of Try-treated and control dentin (p < 0.001). Significantly lower contact angle was found for Try-treated on wet and dry dentin (p < 0.002). The contact angle on re-wet dentin was not recovered in Try-treated group (p = 0.9). Removal of PGs significantly improved the TBS of H6 (109% higher, p < 0.001) and H18 (29% higher, p = 0.002) when compared to control. The TBS of commercial adhesive was not affected by trypsin treatment (p = 0.9). Changing the surface energy of dentin by PGs removal improved resin adhesion, likely due to more efficient water displacement, aiding to improved resin infiltration and polymerization.


COX-2/PGE2 axis regulates hippocampal BDNF/TrkB signaling via EP2 receptor after prolonged seizures.
The objective of this study was to identify the signaling pathway that is immediately triggered by status epilepticus (SE) and in turn contributes to the excessive brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor B (TrkB) signaling within the hippocampus. We used quantitative PCR, enzyme-linked immunosorbent assay, and Western blot analysis to examine gene expression at both mRNA and protein levels in the hippocampus following prolonged SE in mice and rats. Three classical animal models of SE were utilized in the present study to avoid any model- or species-specific findings. We showed that both cyclooxygenase-2 (COX-2) and BDNF in the hippocampus were rapidly upregulated after SE onset; however, the induction of COX-2 temporally preceded that of BDNF. Blocking COX-2 activity by selective inhibitor SC-58125 prevented BDNF elevation in the hippocampus following SE; prostaglandin E2 (PGE2), a major product of COX-2 in the brain, was sufficient to stimulate hippocampal cells to secrete BDNF, suggesting that a PGE2 signaling pathway might be directly involved in hippocampal BDNF production. Inhibiting the Gαs-coupled PGE2 receptor EP2 by our recently developed selective antagonist TG6-10-1 decreased the SE-triggered phosphorylation of the cAMP response element-binding protein (CREB) and activation of the BDNF/TrkB signaling in the hippocampus. The molecular mechanisms whereby BDNF/TrkB signaling is upregulated in the hippocampus by SE largely remain unknown. Our findings suggest that COX-2 via the PGE2/EP2 pathway regulates hippocampal BDNF/TrkB activity following prolonged seizures. EP2 inhibition by our bioavailable and brain-permeable antagonists such as TG6-10-1 might therefore provide a novel strategy to suppress the abnormal TrkB activity, an event that can sufficiently trigger pathogenic processes within the brain including acquired epileptogenesis.


Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.
Data regarding the risk of gastrointestinal and extraintestinal cancers in Crohn's disease (CD) and ulcerative colitis (UC) are needed to understand the clinical course of inflammatory bowel diseases (IBDs) and their treatments. We performed a nationwide historical cohort study using Danish health care databases. We identified patients with a diagnosis of CD or UC, recorded from 1978 through 2010, and followed them up until the first occurrence of cancer, death, or emigration. We used standardized incidence ratios (SIRs) to compare cancer incidence in CD and UC patients with that expected in the general population. Excluding cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among 13,756 patients with CD (SIR, 1.3; 95% confidence interval [CI], 1.2-1.4) and 2331 occurred among 35,152 patients with UC (SIR, 1.1; 95% CI, 1.0-1.1). CD was associated weakly with gastrointestinal cancers (SIR, 1.2; 95% CI, 1.0-1.4) and extraintestinal cancers (SIR, 1.3; 95% CI, 1.2-1.4), with the strongest associations for hematologic malignancies (SIR, 1.9; 95% CI, 1.5-2.3), smoking-related cancers (SIR, 1.5; 95% CI, 1.3-1.8), and melanoma (SIR, 1.4; 95% CI, 1.0-1.9). Associations between UC and gastrointestinal and extraintestinal cancers were weaker (SIR, 1.1; 95% CI, 1.0-1.2; and SIR, 1.1; 95% CI, 1.0-1.1, respectively). The relative risk of extraintestinal cancers among patients with IBD was relatively stable over time, although the risk of gastrointestinal cancers decreased. Patients with IBD, particularly CD, are at increased risk for gastrointestinal and extraintestinal malignancies. The relative risk of gastrointestinal malignancy has decreased since 1978, without a concomitant increase in the risk of nongastrointestinal malignancy.


Development of shuttle vectors for rapid prototyping of engineered Synechococcus sp. PCC7002.
Cyanobacteria are of particular interest for chemical production as they can assimilate CO2 and use solar energy to power chemical synthesis. However, unlike the model microorganism of Escherichia coli, the availability of genetic toolboxes for rapid proof-of-concept studies in cyanobacteria is generally lacking. In this study, we first characterized a set of promoters to efficiently drive gene expressions in the marine cyanobacterium Synechococcus sp. PCC7002. We identified that the endogenous cpcBA promoter represented one of the strongest promoters in PCC7002. Next, a set of shuttle vectors was constructed based on the endogenous pAQ1 plasmid to facilitate the rapid pathway assembly. Moreover, we used the shuttle vectors to modularly optimize the amorpha-4,11-diene synthesis in PCC7002. By modularly optimizing the metabolic pathway, we managed to redistribute the central metabolism toward the amorpha-4,11-diene production in PCC7002 with enhanced product titer. Taken together, the plasmid toolbox developed in this study will greatly accelerate the generation of genetically engineered PCC7002. KEY POINTS: • Promoter characterization revealed that the endogenous cpcBA promoter represented one of the strongest promoters in PCC7002 • A set of shuttle vectors with different antibiotic selection markers was constructed based on endogenous pAQ1 plasmid • By modularly optimizing the metabolic pathway, amorpha-4,11-diene production in PCC7002 was improved.


Interactive effects of an insecticide and a fungicide on different organism groups and ecosystem functioning in a stream detrital food web.
Freshwater ecosystems are often affected by cocktails of multiple pesticides targeting different organism groups. Prediction and evaluation of the ecosystem-level effects of these mixtures is complicated by the potential not only for interactions among the pesticides themselves, but also for the pesticides to alter biotic interactions across trophic levels. In a stream microcosm experiment, we investigated the effects of two pesticides targeting two organism groups (the insecticide lindane and fungicide azoxystrobin) on the functioning of a model stream detrital food web consisting of a detritivore (Ispoda: Asellus aquaticus) and microbes (an assemblage of fungal hyphomycetes) consuming leaf litter. We assessed how these pesticides interacted with the presence and absence of the detritivore to affect three indicators of ecosystem functioning - leaf decomposition, fungal biomass, fungal sporulation - as well as detritivore mortality. Leaf decomposition rates were more strongly impacted by the fungicide than the insecticide, reflecting especially negative effects on leaf processing by detritivores. This result most like reflects reduced fungal biomass and increased detritivore mortality under the fungicide treatment. Fungal sporulation was elevated by exposure to both the insecticide and fungicide, possibly representing a stress-induced increase in investment in propagule dispersal. Stressor interactions were apparent in the impacts of the combined pesticide treatment on fungal sporulation and detritivore mortality, which were reduced and elevated relative to the single stressor treatments, respectively. These results demonstrate the potential of trophic and multiple stressor interactions to modulate the ecosystem-level impacts of chemicals, highlighting important challenges in predicting, understanding and evaluating the impacts of multiple chemical stressors on more complex food webs in situ.


A phage T4 in vitro packaging system for cloning long DNA molecules.
Recombinant plasmid DNAs containing long DNA inserts that can be propagated in Escherichia coli would be useful in the analysis of complex genomes. We tested a bacteriophage T4 in vitro DNA packaging system that has the capacity to package about 170 kb of DNA into its capsid for cloning long DNA fragments. We first asked whether the T4 in vitro system can package foreign DNA such as concatemerized lambda imm434 DNA and phage P1-pBR322 hybrid DNA. The data suggest that the T4 system can package foreign DNA as efficiently as the mature phage T4 DNA. We then tested the system for its ability to clone foreign DNA fragments using the P1-pBR322 hybrid vectors constructed by Sternberg [Proc. Natl. Acad. Sci. USA 87 (1990) 103-107]. E. coli genomic DNA fragments were ligated with the P1 vectors containing two directly oriented loxP sites, and the ligated DNA was packaged by the T4 in vitro system. The packaged DNA was then transduced into E. coli expressing the phage P1 cyclization recombination protein recombinase to circularize the DNA by recombination between the loxP sites situated at the ends of the transduced DNA molecule. Clones with long DNA inserts were obtained by using this approach, and these were maintained as single-copy plasmids under the control of the P1 plasmid replicon. Clones with up to about 122-kb size inserts were recovered using this approach.


Disulfiram implantation in alcoholism treatment. A review.
The literature pertaining to the use of implanted disulfiram as a therapeutic modality in the treatment of alcoholism is reviewed.


The role of monoamine oxidase A in the neurobiology of aggressive, antisocial, and violent behavior: A tale of mice and men.
Over the past two decades, research has revealed that genetic factors shape the propensity for aggressive, antisocial, and violent behavior. The best-documented gene implicated in aggression is MAOA (Monoamine oxidase A), which encodes the key enzyme for the degradation of serotonin and catecholamines. Congenital MAOA deficiency, as well as low-activity MAOA variants, has been associated with a higher risk for antisocial behavior (ASB) and violence, particularly in males with a history of child maltreatment. Indeed, the interplay between low MAOA genetic variants and early-life adversity is the best-documented gene × environment (G × E) interaction in the pathophysiology of aggression and ASB. Additional evidence indicates that low MAOA activity in the brain is strongly associated with a higher propensity for aggression; furthermore, MAOA inhibition may be one of the primary mechanisms whereby prenatal smoke exposure increases the risk of ASB. Complementary to these lines of evidence, mouse models of Maoa deficiency and G × E interactions exhibit striking similarities with clinical phenotypes, proving to be valuable tools to investigate the neurobiological mechanisms underlying antisocial and aggressive behavior. Here, we provide a comprehensive overview of the current state of the knowledge on the involvement of MAOA in aggression, as defined by preclinical and clinical evidence. In particular, we show how the convergence of human and animal research is proving helpful to our understanding of how MAOA influences antisocial and violent behavior and how it may assist in the development of preventative and therapeutic strategies for aggressive manifestations.


Antagonism of the effects on thermoregulation of delta9-tetrahydrocannabinol by clomipramine in the rat.
1 The effect of pretreatment with clomipramine hydrochloride (15 mg/kg, i.p.) on the (--)-trans-delta9-tetrahydrocannabinol (delta9-THC)-induced changes in body temperature and brain amines of the rat was investigated. 2 A dose of 0.05 mg/kg of delta9-THC produced hyperthermia and a decrease in whole brain concentration of 5-hydroxyindoleacetic acid (5-HIAA). Doses of 2 and 5 mg/kg produced hypothermia and increases in brain 5-HIAA whereas 0.5 mg/kg did not affect either parameter. delta9-THC, at any of the doses, did not affect the whole brain concentrations of dopamine, noradrenaline or 5-hydroxytryptamine. 3 Clomipramine modified these responses of delta9-THC in that the dose-response curves appeared to be shifted to the right. 4 It is concluded that clomipramine acts as an antagonist to these actions of delta9-THC by interfering with entry of delta9-THC into tryptaminergic neurones.


The unheralded value of arthroscopy using local anesthesia for diagnostic specificity and intraoperative corroboration of therapeutic achievement.
The senior author has performed more than 600 "therapeutic" arthroscopies under local anesthesia since 1978. The authors believe that the cases presented illustrate the increased diagnostic accuracy offered by performing arthroscopy of the knee under local anesthetic in certain types of cases. We are by no means advocating that all arthroscopies of the knee be performed under local anesthesia. Certainly, the majority of knee arthroscopies need not be performed under local anesthesia, because the diagnosis is usually evident. Perhaps when the diagnosis is not clear, a combination of local with regional or with general would be best, with performance of the diagnostic portion of the arthroscopy under local anesthesia. When an instantaneous improvement is possible, such as change in joint motion, or when some change in joint dynamics may be visualized, local should then be continued through the therapeutic conclusion of the procedure. Arthroscopy under local anesthesia has also been performed by the authors on the shoulder, elbow, and ankle, where the diagnostic benefits have been realized. Certain reconstructive operations, such as patellar realignments, are worthy of performance under local anesthesia in selected cases. In conclusion, the authors believe that arthroscopy of the knee and other joints under local anesthesia may add measurably to the diagnostic capability of the arthroscopist, and not infrequently to a therapeutic advantage.


Assessing soil microbes that drive fairy ring patterns in temperate semiarid grasslands.
Fairy rings occur in diverse global biomes; however, there is a critical knowledge gap regarding drivers of fairy rings in grassland ecosystems. Grassland fairy rings are characterized belowground by an expanding mycelial front and aboveground by vigorous vegetation rings that develop concentrically with each growing season. We evaluated fairy ring dynamics in a field study conducted in semiarid grasslands to elucidate above- and belowground interactions driving distinct vegetation patterns. We followed this initial field investigation with a complementary greenhouse experiment, using soils collected from specific fairy ring zones (inside, ring-edge, outside) to examine plant-soil-microbial interactions under controlled conditions. We selected Leymus chinensis (a dominant grass) as our model plant species to assess the role of diverse fairy ring microbial communities on plant growth and nutrition. In our field study, plants on the ring-edge produced greater shoot biomass with higher concentrations of N and P, compared to plants inside the ring or adjacent (outside) controls. Soil microbial community biomarkers indicate shifts in relative microbial biomass as fairy rings expand. Inside the ring, plant roots showed greater damage from pathogenic fungi, compared to outside or ring-edge. Our greenhouse experiment confirmed that inoculation with live ring-edge soil generally promoted plant growth but decreased shoot P concentration. Inoculation with soil collected from inside the ring increased root pathogen infection and reduced shoot biomass. We propose that soil microbial activity within ring-edges promotes plant growth via mobilization of plant-available P or directed stimulation. However, as the ring expands, L. chinensis at the leading edge may increase pathogen accumulation, resulting in reduced growth at the center of the ring in subsequent growing seasons. Our results provide new insights into the plant-soil-microbial dynamics of fairy rings in grasslands, helping to elucidate these mysterious vegetation patterns.


Lnc-PXMP4-2-4 alleviates myocardial cell damage by activating the JAK2/STAT3 signaling pathway.
The aim of this study was to investigate the protective effect of long non-coding lnc-PXMP4-2-4 on myocardial cell damage caused by acute myocardial infarction (AMI). Peripheral blood mononuclear cells (PBMC) were collected from 24 patients with AMI on the day of admission, the first day after percutaneous coronary intervention (PCI) and the third day after surgery, and 24 patients with clinical control group. Real-time quantitative PCR(QRT-PCR) was used to detect the expression of related genes. Then in human cardiomyocytes (AC16), Cell Counting Kit-8 (CCK-8) was used to determine cell viability, lactate dehydrogenase release assay (LDH) was used to determine the release of lactate dehydrogenase, PCR was used to detect the expression of genes, cell death was detected by flow cytometry, and the expression of related proteins was measured by Western blot. The effect of lnc-PXMP4-2-4 was further studied by silencing and overexpressing lnc-PXMP4-2-4. Compared with clinical control group, the expression of lnc-PXMP4-2-4 in PBMC of AMI patients was significantly higher than it. Compared with pre-operation, the expression of lnc-PXMP4-2-4 was significantly up-regulated on day 1 after PCI, and recovered to pre-operation level on day 3 after surgery. In AC16 cells, lnc-PXMP4-2-4 inhibited the proliferation of AC16, promoted the release of LDH and increased cell death, aggravated the cardiomyocyte injury caused by H2O2, and inhibited the expression of JAK2 and STAT3 mRNA and protein. The up-regulation of lnc-PXMP-4-2-4 had the opposite effect. In addition, the inhibition of the signal pathway by JAK2/STAT3 pathway inhibitor AG490 partially weakened the enhanced viability of AC16 cells, decreased LDH release and apoptosis induced by lnc-PXMP4-2-4 overexpression, increased Bcl-2 expression and down-regulated Bax expression. Therefore, we conclude that lnc-PXMP4-2-4 protects cardiomyocytes from injury by activating the JAK2/STAT3 signaling pathway.


Audiometry as a possible indicator of quinine plasma concentration during treatment of malaria.
The spread of chloroquine-resistant malaria has led to a resurgence of quinine in clinical use. One of the well-known side effects of quinine, reversible hearing loss, is closely related to the plasma concentration. We suggest that this hearing effect could be used as an aid in therapy control when quinine drug assay is not available.


The changing scenario of 1st line therapy in non-oncogene addicted NSCLCs in the era of immunotherapy.
During the last two decades front-line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) has profoundly changed moving from the old "one size fits all" concept to a "histology-based" approach and then, for a small subgroup of patients to a "molecularly-selected" one. The development of immune checkpoint inhibitors and the unprecedented results reported in 2nd/3rd line prompted the evaluation of these novel therapeutic agents in chemotherapy-naïve patients either alone or in combination with platinum-based chemotherapy. Several randomized trials are evaluating the impact of immune-checkpoint inhibitors in 1st line and some of them have yet produced preliminary evidence of efficacy. However, still a long way to go and several questions are still unanswered, including proper patients selection, optimal sequential/combinatorial use of these agents, appropriate treatment duration, and finally the identification of predictive biomarkers. The aim of this paper is to provide a comprehensive overview on the growing role of immune checkpoint inhibitors in the upfront treatment of advanced non-oncogene addicted NSCLC either as single agent or in combination with other agents.


Hormonal control of neuron number in sexually dimorphic spinal nuclei of the rat: I. Testosterone-regulated death in the dorsolateral nucleus.
Adult male rats have substantially more motoneurons than do females in two motor nuclei in the lumbar spinal cord: the spinal nucleus of the bulbocavernosus (SNB) and the dorsolateral nucleus (DLN). Previous studies of the development of the SNB revealed that the sex difference in SNB motoneuron number is established through a differential motoneuron death which is under the control of androgens. In this study the development of the sexually dimorphic DLN was examined to test the hypothesis that early androgen action also determines the sex difference in DLN motoneuron number by regulating normally occurring motoneuron death. Because SNB motoneurons may migrate from the DLN, quantitative examination of DLN development was necessary in order to understand more completely the cellular mechanisms contributing to the establishment of dimorphic motoneuron number. At 5 days before birth, the number of motoneurons in the DLN is significantly higher than in adulthood in both sexes, and no sex difference is present. There is a decrease in motoneuron numbers prenatally in both sexes, which is consistent with the emigration of presumptive SNB motoneurons. Motoneuron number declines differentially through the first week of postnatal life and by postnatal day 10 motoneuron numbers are in the adult range and the sex difference is fully expressed. Females lose significantly more DLN motoneurons than males through a differential death as revealed by the higher incidence of degenerating cell profiles. Females treated with testosterone propionate have a male-typical motoneuron loss and incidence of degenerating cells. These results indicate that steroid hormones establish the sex difference in DLN motoneuron number by regulating normally occurring cell death.


Influence of a bacterial extract on antigen presentation and protection against experimental infections.
Although substances known as immunodulators are usually used to stimulate nonspecific immunity, their mode of action is not well understood. In an effort to clarify this mechanism, we investigated the effect of a lyophilized bacterial extract (Broncho-Vaxom) on experimental infections, on normal or irradiated mice, and on antigen processing.


The utility of a digital simulation language for ecological modeling.
Dynamic modeling of ecological phenomena has been greatly facilitated by the recent development of continuous system simulator programs. This paper illustrates the application of one of these programs, S/360 Continuous System Modeling Program (S/360 CSMP), to four systems of graduated complexity. The first is a two species system, with one feeding on the other, using differential equations with constant coefficients. The second and third systems involve two competing plant species in which the coefficients of the differential equations are varying with time. The final example considers the management of a postulated buffalo herd in which the dynamics of the herd population and composition by sex and age is combined with various strategies to control its size and to optimize buffalo production.


Solution structure of human plasma fibronectin using small-angle X-ray and neutron scattering at physiological pH and ionic strength.
Human plasma fibronectin has been investigated at physiological pH and ionic strength, by using small-angle X-ray and neutron scattering techniques. The results indicate that the molecule is disc shaped with an axial ratio of about 1:10. In fact, an ellipsoid of revolution with semiaxes a = 1.44 nm and b = c = 13.8 nm is in agreement with the experimental scattering data, and can also fully explain the rather extreme hydrodynamic parameters reported for fibronectin. The X-ray data gave a radius of gyration of 8.9 nm and a molecular weight of 510,000, whereas the neutron data gave slightly larger values, 9.5 nm and 530,000, respectively. From the volume of the best fitting ellipsoid we obtain a degree of hydration of 0.61 g H2O/g protein (dry weight). Neutron data, recorded at different D2O concentrations in the solvent, gave a match point of 43% D2O, which indicates that approximately 80% of the hydrogens bound to oxygen and nitrogen are exchangeable.


Janus (Mo/β-Mo2C)@C heterostructure as an efficient electrocatalyst for the hydrogen evolution reaction in acidic and alkaline media.
To explore low-cost, high-efficiency, and noble-metal-free catalysts for electrocatalytic water splitting in both acidic and alkaline media, the metal-metal carbide Janus hierarchical structure comprising Mo andβ-Mo2C embedded on a carbon layer (Mo/β-Mo2C)@C is synthesized by a hydrothermal reaction and subsequent low-temperature magnesium thermic process. Systematic characterization by XRD, XPS, Raman scattering, and SEM/TEM reveals the successful formation of metallic Mo andβ-Mo2C nanoparticles. The synthesized (Mo/β-Mo2C)@C has a large specific surface area and boasts highly efficient hydrogen evolution reaction activity including low overpotentials of 152 and 171 mV at a current density of 10 mA cm-2and small Tafel slopes of 51.7 and 63.5 mV dec-1in acidic and alkaline media, respectively. In addition, the catalyst shows outstanding stability for 48 h in both acidic and alkaline media. The excellent catalytic activity originates from more active sites and greater electron conductivity bestowed by the carbon layer, which also improves the long-term stability in both acidic and alkaline solutions.


Effects of inhaled cholinesterase inhibitors on bronchial tonus and on plasma and erythrocyte acetylcholine esterase activity in rats.
Young adult male and female Wistar rats were inhalationally exposed head-only for 1 or 4 h to different anticholinesterase aerosols. The compounds tested were dichlorvos, fenamiphos, methamidophos, parathion, a pyrimidine thiophosphate and the carbamate propoxur. These compounds are direct or indirect inhibitors of cholinesterase activity. Immediately after termination of exposure to the compounds, the rats were anesthetized with barbiturate and subjected to pulmonary function tests. An acetylcholine provocation test was performed to correlate the effect of the cholinesterase inhibition and lung resistance. The results basically revealed that by inhalation exposure bronchoconstriction in the absence of acetylcholine provocation did not occur at toxicologically significant doses of the pesticides. An increase in lung resistance was observed only after provocation. However, measurements of plasma cholinesterase activity proved to be more sensitive than the provocation test. With regard to their diagnostic value, the results of the reported study may be summarized as follows (beginning with the most sensitive parameter): plasma cholinesterase activity depression greater than or equal to acetylcholine-induced bronchoconstriction greater than or equal to cholinergic symptoms greater than erythrocyte cholinesterase activity depression greater than pulmonary resistance without acetylcholine provocation.


Transperineal mapping biopsy improves selection of brachytherapy boost for men with localized prostate cancer.
To determine if transperineal mapping biopsy (TPMB) can improve the selection of brachytherapy alone (BT) or brachytherapy boost (BTB) in men with localized prostate cancer. Two hundred and eighteen men underwent TPMB with a mean of 48.6 cores retrieved. Comparisons were made between prebiopsy risk features and biopsy results to treatment choice with associations tested with ANOVA (bootstrap), χ2 test (Pearson), and linear regression. Survival estimates were tested by the Kaplan-Meier method with comparisons by log rank. Mean age, prostate specific antigen (PSA), prostate specific antigen density (PSAD), and prostate volume were 67.2 years, 8.1 ng/mL, 0.19, and 50.3 cc, respectively. 105 (48.2%) biopsies were positive for Gleason Group (GG) 1: 34 (32.4%), 2: 21 (20%), 3: 31 (29.5%), 4: 7 (6.7%), and 5: 12 (11.4%). The mean number of positive cores (PCs) was 7.3 (median 6, range 1-37). Men with six or more PCs had higher PSA (11.3 vs. 6.0 ng/mL, p = 0.025) and PSAD (0.34 vs. 0.13, p = 0.013). Overall brachytherapy was used in 74 (70.5%) as either monotherapy or boost therapy. Men with BTB had higher PSA (9.7 vs. 6.7 ng/mL, p = 0.029), PSAD (0.27 vs. 0.16, p = 0.007), GG (3.3 vs. 1.8, p < 0.001), more bilateral disease (75.9% vs. 55.6%, odds ratio 3.9, p = 0.008), and PCs (10.9 vs. 4.4, p < 0.001). On linear regression, only GG (p = 0.008) and PCs (p = 0.044) were associated with BTB. Biochemical-free failure at 5 years was 92.7%. TPMB improves the selection of patients for BTB. Men with more PCs are more likely to have BTB. Restricting the need for BTB to those with greater volume prostate cancer may reduce radiation side effects.


Noninvasive diagnosis of congenital left coronary artery to right ventricle fistula by nuclear magnetic resonance imaging.
In two children with left coronary artery to right ventricle fistula, nuclear magnetic resonance imaging provided high-quality images of the course of the dilated coronary artery and its termination in the right ventricular apex. The advantages of this noninvasive multiplanar imaging technique for visualization of coronary fistulae and dilated coronary arteries are described. This report represents the first description of coronary artery fistula by nuclear magnetic resonance imaging.


[Reticulated telangiectasic erythema following morphine pump implantation].
Reticulated telangiectasic erythema is a cutaneous complication reported after in the implementation of pacemakers and cardiac defibrillators. Here we report a case occurring after the implantation of a morphine pump. Reticulated and pigmented telangiectasic erythema was observed at the morphine pump implantation site in a 56-year-old man presenting chronic lower back pain. To date, cutaneous telangiectasic erythema has been reported following implantation of cardiac defibrillators and pacemakers although the physiopathogenesis of the condition is poorly understood. An identical case was recently described following implantation of morphine pump, as in our case. We discuss hypotheses concerning the possible physiopathogenesis of such lesions.


Predictors for hemorrhagic transformation and cerebral edema in stroke patients with first-pass complete recanalization.
Predictors of radiological complications attributable to reperfusion injury remain unknown when baseline setting is optimal for endovascular treatment and procedural setting is the best in stroke patients with large vessel occlusion (LVO). To identify clinical and radiological/procedural predictors for hemorrhagic transformation (HT) and cerebral edema (CED) at 24 hr in patients obtaining complete recanalization in one pass of thrombectomy for ischemic stroke ⩽ 6 h from symptom onset with intra-cranial anterior circulation LVO and ASPECTS ⩾ 6. We conducted a cohort study on prospectively collected data from 1400 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. HT was reported in 248 (18%) patients and early CED was reported in 260 (19.2%) patients. In the logistic regression model including predictors from a first model with clinical variables and from a second model with radiological/procedural variables, diabetes mellitus (odds ratio (OR) = 1.832, 95% confidence interval (CI) = 1.201-2.795), higher National Institutes of Health Stroke Scale (NIHSS) (OR = 1.076, 95% CI = 1.044-1.110), lower Alberta Stroke Program Early CT (ASPECTS) (OR = 0.815, 95% CI = 0.694-0.957), and longer onset-to-groin time (OR = 1.005, 95% CI = 1.002-1.007) were predictors of HT, whereas general anesthesia was inversely associated with HT (OR = 0.540, 95% CI = 0.355-0.820). Higher NIHSS (OR = 1.049, 95% CI = 1.021-1.077), lower ASPECTS (OR = 0.700, 95% CI = 0.613-0.801), intravenous thrombolysis (OR = 1.464, 95% CI = 1.061-2.020), longer onset-to-groin time (OR = 1.002, 95% CI = 1.001-1.005), and longer procedure time (OR = 1.009, 95% CI = 1.004-1.015) were predictors of early CED. After repeating a fourth logistic regression model including also good collaterals, the same variables remained predictors for HT and/or early CED, except diabetes mellitus and thrombolysis, while good collaterals were inversely associated with early CED (OR = 0.385, 95% CI = 0.248-0.599). Higher NIHSS, lower ASPECTS, and longer onset-to-groin time were predictors for both HT and early CED. General anesthesia and good collaterals were inversely associated with HT and early CED, respectively. Longer procedure time was predictor of early CED.


Novel Epigenetic Markers on Chromosome 21 for Noninvasive Prenatal Testing of Fetal Trisomy 21.
Until now, fetal placenta-specific epigenetic markers for noninvasive prenatal testing of fetal trisomy 21 (T21) have been identified based only on differences in tissue-specific epigenetic characteristics between placenta and maternal blood, but these characteristics have not been validated in T21 placenta. We aimed to discover novel epigenetic markers on chromosome 21 that show a hypermethylated pattern in fetal placenta compared with blood, regardless of the presence of T21. We performed a high-resolution tiling array analysis of chromosome 21 using the methylated-CpG binding domain protein-based method. We identified 93 epigenetic regions that showed fetal placenta-specific differential methylation patterns; among these, three regions showed fetal placenta-specific methylation patterns in T21 placenta samples. The methylation patterns of these three regions in the array were confirmed by bisulfite direct sequencing. The three regions were detectable in first-trimester maternal plasma. Moreover, a combination of their methylation ratio achieved high diagnostic accuracy for noninvasive prenatal testing of fetal T21 by further statistical analysis. These three novel regions with fetal placenta-specific differential methylation patterns on chromosome 21 were identified irrespective of the presence of T21. Our findings suggest that epigenetic characteristics of markers according to the presence or absence of T21 should be considered in the development of noninvasive prenatal testing of fetal T21 using fetal placenta-specific epigenetic markers.


Basic fibroblast growth factor inhibited Ca2+ ionophore-induced apoptotic cell death of cultured cortical neurons from embryonic rats.
The effect of basic fibroblast growth factor (bFGF) on apoptotic cell death of cultured cortical neurons from embryonic rats induced by ionomycin, a potent Ca2+ ionophore, was investigated. bFGF inhibited Ca2+ ionophore-induced neurotoxicity in a dose-dependent manner. bFGF also reduced the degree of fragmentation of DNA of Ca2+ ionophore-treated neurons. These findings strongly suggest that bFGF inhibited ionomycin-induced neurotoxicity by preventing apoptosis.


Staple line covering procedure after thoracoscopic bullectomy for the management of primary spontaneous pneumothorax.
Thoracoscopic bullectomy together with a pleural adhesive procedure is generally accepted as the standard for the definitive treatment of primary spontaneous pneumothorax (PSP). The purpose of this study was to evaluate whether the results of a thoracoscopic bullectomy followed by coverage of the staple line with cellulose mesh and fibrin glue could be comparable with those of adhesive procedures described in the literature. Between May 2000 and February 2003, we performed 227 thoracoscopic surgeries on 219 patients with PSP using a single technique. After the bullectomy, the staple line was covered with cellulose mesh and fibrin glue. The postoperative status was evaluated with a mean follow-up of 46 months. The mean patient age was 24.3 years and 90.9 % of the 219 patients were male. Recurrent pneumothorax (37.4 %) was the most common operative indication, followed by persistent air leakage of more than 5 days (28.2 %). The mean duration of postoperative chest tube drainage was 1.6 days and the mean postoperative hospital stay was 3.8 days. Six patients experienced surgical complications (2.2 %); there was air leakage of more than 3 days in two cases, a small apical dead space in one case, a fever-associated wound problem in one case, and a reoperation due to air leakage of more than 7 days in two cases. Eleven patients (4.8 %) suffered a recurrence of pneumothorax during the follow-up period. Of these, nine cases required readmission and three (1.3 %) of these cases required a reoperation. Given the nature of a meticulous thoracoscopic bullectomy followed by coverage with cellulose mesh and fibrin glue, good surgical results can be expected without the need for a pleural adhesive procedure.


Docosahexaenoic acid differentially affects TNFα and IL-6 expression in LPS-stimulated RAW 264.7 murine macrophages.
Docosahexaenoic acid (DHA) is generally reported to have anti-inflammatory properties, however, prior work has documented differential effects on individual pro-inflammatory cytokines: reduced IL-6, but not TNFα, mRNA expression in macrophages. To elucidate the mechanism, the roles of prostaglandin E2 (PGE2), cyclic AMP response element-binding protein (CREB), and NFκB were examined in RAW 264.7 macrophages. DHA did not influence CREB activity, but significantly reduced PGE2 production by 41% and NFκB activity by 32%. Exogenous PGE2 inhibited TNFα mRNA expression dose dependently. Unexpectedly, inhibiting PGE2 production with NS-398 also decreased TNFα mRNA expression, suggesting a concentration-dependent dual role of PGE2 in regulating TNFα expression. IL-6 expression was unaffected by endogenous or exogenous PGE2. Partial block of NFκB activation (SN50; 46%, or, BAY-11-7082; 41%) lowered IL-6 to a greater extent than TNFα mRNA expression. The differential effect of DHA on TNFα and IL-6 mRNA expression may be mediated via reduction in NFκB activity.


Prolidase-Associated Trace Elements (Mn, Zn, Co, and Ni) in the Patients with Parkinson's Disease.
Micronutrients and trace elements have been identified to play an important role in the development of Parkinson's disease (PD). In our previous study, we observed that prolidase activity is associated with oxidative stress and progression of PD. In present study, we aimed to study the association of prolidase-associated trace elements, such as Co, Mn, Ni, and Zn in the plasma of patients with PD by inductively coupled plasma spectrometry. Plasma levels of Co, Mn, and Ni were significantly increased, whereas plasma levels of Zn was significantly decreased (all P < 0.05) in the patients with PD than healthy controls. Plasma prolidase activity was not correlated to its associated trace elements in PD. A positive, linear, and significant correlation was observed between age and Co, and Mn, and Ni while negative and non-significant between age and status of Zn in the patients. Co, Mn, and Ni were continually elevated with increase in age as well as duration of disease in the patients with PD, whereas status of Zn was continually decreased. Thus, the study concluded that trace elements Co, Ni, and Mn status were increased and Zn status was decreased in the plasma of patients with PD. It is also concluded that elevated Co, Mn, and Ni has been associated with progression of Parkinson's disease.


Nutritional and biochemical effects of nutrition programs in the elderly.
The nutritional status of this population of elderly was generally quite good. However, these individuals were interested in the program and able to participate in the program. As age in years increases and the aging process continues, all the factors mentioned earlier may combine to contribute to less frequent or nonattendance and perhaps to deterioration of nutritional status. For example, an 80-year-old may be able to drive to a site, but a 90-year-old may not. Also, the older elderly may be more likely to live alone, with all the disincentives to eat well that living alone may be associated with at any age. Therefore, one cannot assume that all of the old elderly are as adequately nourished as this group. The less well nourished may be those not participating in programs for the elderly. Finally, the data presented here illustrate the need to learn more about the differences between middle-aged elderly and the old elderly, and to better differentiate pathologic from normal aging processes.


Seasonal covariation in progesterone and odorant emissions among breeding crested auklets (Aethia cristatella).
Crested auklets emit a citrus-like odorant that is seasonally modulated, suggesting that it is a secondary sexual trait. We hypothesized that expression of the chemical odorant is facilitated by steroid hormones, similar other secondary sexual traits in birds. Therefore we examined variation in concentrations of hormones in blood plasma and odor production during incubation and early chick rearing. A novel method was used to obtain and measure chemical emissions of crested auklets. Blood plasma samples were analyzed by radioimmunoassay. Progesterone was detected in all birds, and it varied during the breeding season. Octanal emissions covaried with progesterone levels in males but not in females. No seasonal patterns were detected in testosterone, estrogen or DHT, and these hormones were not detected in all breeding adults. Covariance of progesterone and octanal emissions in males suggests there could be at least an indirect relationship between odor emissions and steroid hormones in this species. Thus expression of the citrus-like odorant of crested auklets, like other secondary sexual traits in birds, could be regulated by steroid hormones.


The regio- and stereoselective one-pot catalytic preparation of beta-selenyl acrylamides.
Pd(PPh(3))(4) is found to catalytically assemble sulfenamides, terminal aliphatic alkynes, carbon monoxide, and diphenyl diselenides regio- and stereoselectively in a single-pot reaction to produce good yields of beta-selenyl acrylamides. [reaction: see text]


High temperature mechanical field-cycling setup.
A new design of a mechanical field-cycling setup, operating in the wide temperature range up to 1200 K has been implemented. The sample is moved by a stepping motor in the stray field of a superconducting magnet inside a furnace of homogeneous temperature profile. For a field range from 0.75 to 7 T (transfer length 24 cm), the transfer time is less than 100 ms. The temperature profile is homogenized to better than 1% of the absolute set temperature. The main objective of this design is to extend the T1 relaxation dispersion range covered by electronic field-cycling to higher frequencies.


Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C.
The clinical significance of serum interleukin-6 (IL-6) and its correlation with cystatin C (Cyst C), an endogenous inhibitor of cysteine proteinase cathepsin K, was investigated by immunoassays in patients with bone metastasis from breast cancer (BCa) or prostate cancer (PCa). Additional studies were also performed in these patients to assess the effects of zoledronic acid (ZA) administration on the circulating levels of these molecules. Mean IL-6 and Cyst C serum concentrations were significantly increased in BCa patients and in patients with primary osteoporosis (PO) compared to healthy subjects (HS). However, Cyst C, but not IL-6, resulted significantly more elevated in BCa patients than in PO patients. Furthermore, in BCa patients no correlation was highlighted between IL-6 and Cyst C or between these molecules and some clinicobiological parameters of malignant progression. Mean IL-6 levels were also higher in PCa patients and in patients with benign prostatic hyperplasia (BPH) than in HS while Cyst C resulted significantly higher in PCa but not in BPH patients as compared to HS. In PCa patients, a positive correlation was highlighted between IL-6 and number of bone metastases or serum prostate-specific antigen but not with the Gleason score. Conversely, Cyst C levels did not correlate with any of the parameters considered above or with IL-6. Receiver operating characteristic (ROC) curve analysis showed a poor diagnostic accuracy of IL-6 and Cyst C to detect BCa patients with skeletal metastases while, in PCa patients, only IL-6 showed a fair diagnostic performance in this respect. Finally, the administration of ZA to patients with bone metastases induced a statistically significant increase of serum IL-6 and Cyst C only PCa patients with bone metastasis. These data indicate that IL-6 and Cyst C may be regarded as novel targets for cancer treatment and as markers of increased osteoblastic activity associated to bisphosphonate treatments in PCa patients with bone metastases.


Time-restricted eating (16/8) and energy-restricted diet: effects on diet quality, body composition and biochemical parameters in healthy overweight females.
Time-restricted eating (TRE) is a current popular dietary strategy for noncommunicable diseases. However, studies demonstrated contradictory results for it and in all dietary strategies, diet quality is an the important part of the well-being. Our study aimed to investigate the effect of TRE and energy-restricted diet (ERD) on the nutritional status and diet quality of individuals. This pilot study was completed 23 healthy overweight female. Anthropometric and body composition measurements of individuals were taken. The energy expenditure was measured using indirect calorimetry. Blood pressure and heart rate measurements were made. Biochemical parameters were evaluated and food consumption were taken. The quality of dietary intake was assessed using the Healthy Eating Index (HEI) -2015. The physical activity levels of the individuals were estimated using the physical activity record. The Statistical Package for the Social Sciences (version 22.0) software was used for all analyses. A p-value of less than 0.05 was considered to be statistically significant. After 8 weeks of intervention, while no change was observed in the diet quality of the individuals in the TRE group (p > 0.05), a significant increase was found in the diet quality score of the individuals in the ERD group (p < 0.05). There was a 3.2% and 5.5% decrease in body weight of individuals in the TRE and ERD groups, respectively (p < 0.05). While no significant change was observed in the body fat percentage of individuals in the TRE group (p > 0.05), a 7.1% decrease was observed in the ERD group (p < 0.05). A statistically significant decrease was found in the total cholesterol (3.7%) in the ERD group, and in the total cholesterol (6.7%) and low density lipoprotein cholesterol (LDL-C) (6.5%) in the TRE group. In addition, a statistically significant increase was found in adiponectin (77.3%) and total antioxidant status (TAS) (13.2%) in the ERD group. Energy-restricted diet yielded better results in weight loss and improvement of body composition and diet quality compared to TRE. Also, a decrease in total cholesterol level was found in the ERD group. However, more studies should be done with longer follow-ups and high sample sizes are very important in terms of creating public health-based recommendations.


No change in calreticulin with fetal growth restriction in human and rat pregnancies.
Calreticulin is a ubiquitously expressed protein that was detected in the circulation and is significantly increased in maternal blood during human pregnancy compared to the non-pregnant state. Calreticulin is further increased in the plasma of women with the pregnancy-related disorder pre-eclampsia compared to normotensive pregnancy. The aims of this study were to compare calreticulin in human pregnancy with calreticulin in rat pregnancy, and to compare calreticulin during fetal growth restriction with normal control pregnancies. Women were recruited who either had normal pregnancies or had pregnancies complicated with fetal growth restriction; maternal blood samples and placentas were collected. Blood was also taken from women who were not-pregnant. Growth restriction was induced in pregnant rats by uterine vessel ligation; blood and placental samples were collected. Blood was also taken from non-pregnant rats. Western blot was used to quantify the placental expression of calreticulin and the concentrations of calreticulin in plasma. Although calreticulin was significantly increased in maternal plasma during human pregnancy compared to the non-pregnant state; it did not increase in plasma during rat pregnancy. These results suggest that there may be differences in the role of extracellular calreticulin in human compared to rat pregnancy. Calreticulin was not significantly altered in either placental extracts or maternal plasma in both the human and rat pregnancies complicated by fetal growth restriction compared to gestational matched control pregnancies. This study found that there was no change in calreticulin during human pregnancy complicated with fetal growth restriction or when growth restriction is induced in rats.


Lethal doses of oxbile, peptones and thiosulfate-citrate-bile-sucrose agar (TCBS) for Acanthaster planci; exploring alternative population control options.
Effective control of outbreaks of Acanthaster planci represents the most immediate and practical intervention to reverse sustained declines in coral cover on reefs in the Indo-Pacific. This study explored the minimum doses of oxbile, oxgall, and thiosulfate-citrate-bile-sucrose agar (TCBS) that result in reliable and comprehensive mortality when injected into adult A. planci. The minimum doses required to induce 100% mortality among starfish (n=10) were 4 g l(-1) of oxbile, 8 g l(-1) of oxgall and 22 g l(-1) of TCBS. Moreover, there was no evidence of unintended side effects for other coral reef organisms (e.g., scleractinian corals, echinoderms and fishes) when using oxbile, oxgall, or TCBS at minimum doses. The effectiveness of peptones in killing crown-of-thorns starfish was also tested, but inconsistency in the results revealed that these proteins are unreliable.


"Conversion surgery" for locally advanced pancreatic cancer: A position paper by the study group at the joint meeting of the International Association of Pancreatology (IAP) & Japan Pancreas Society (JPS) 2022.
Locally advanced pancreatic cancer (LAPC), which progresses locally and surrounds major vessels, has historically been deemed unresectable. Surgery alone failed to provide curative resection and improve overall survival. With the advancements in treatment, reports have shown favorable results in LAPC after undergoing successful chemotherapy therapy or chemoradiation therapy followed by surgical resection, so-called "conversion surgery", at experienced high-volume centers. However, recognizing significant regional and institutional disparities in the management of LAPC, an international consensus meeting on conversion surgery for LAPC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of Japan Pancreas Society (JPS) in Kyoto in July 2022. During the meeting, presenters reported the current best multidisciplinary practices for LAPC, including preoperative modalities, best systemic treatment regimens and durations, procedures of conversion surgery with or without vascular resections, biomarkers, and genetic studies. It was unanimously agreed among the experts in this meeting that "cancer biology is surpassing locoregional anatomical resectability" in the era of effective multiagent treatment. The biology of pancreatic cancer has yet to be further elucidated, and we believe it is essential to improve the treatment outcomes of LAPC patients through continued efforts from each institution and more international collaboration. This article summarizes the agreement during the discussion amongst the experts in the meeting. We hope that this will serve as a foundation for future international collaboration and recommendations for future guidelines.


Acute burn induced coagulopathy.
Acute traumatic coagulopathy is well described in the trauma population. Major burns are characterised by a similar endothelial injury and cellular hypoperfusion. These features could be a driver for an acute burn induced coagulopathy (ABIC). Patients admitted to a regional burn centre over a 71 months period with a total body surface area burn of 30% or more were identified. The metavision electronic patient database was scrutinised for a predetermined list of demographics, interventions and admission investigations to identify any clinically significant ABIC. On admission 39.3% of the 117 patients analysed met our criteria for a coagulopathy. Of the patients with a coagulopathy, 71.7% had an elevated Prothrombin Time (PT), 2.2% had an elevated Activated Partial Thromboplastin time (APPT) and 26.1% had an elevation of both. Patients with a coagulopathy received a similar volume of fluid (p=0.08). There was a statistically significant correlation between the PT and the abbreviated burn severity index (p=0.0013, r=0.292) and serum lactate (p=0.0013, r=0.292). ABIC was an independent predictor of 28 day mortality, OR 3.42(1.11-10.56). In patients with major thermal injuries a clinically significant ABIC exists. Early diagnosis and treatment of ABIC should be considered particularly in those undergoing total burn wound excision.


Cytogenetic markers in hematoproliferative disorders.
In the last decade the improvement of methods of chromosome analysis has allowed new insights into the correlation of specific chromosome changes and certain types of malignant hematologic disorders. Even if a clear-cut correlation between a certain chromosomal marker and a certain malignancy is the exception, it is well established that specific chromosome aberrations occur nonrandomly in specific tumors. Moreover, it has been shown that so-called cellular oncogenes are located on those chromosome regions which are involved in translocations and other structural chromosome abnormalities in particular malignant tumors. The significance of chromosome alterations in leukemias and lymphomas is illustrated by examples concerning well-established data, on the one hand, and findings which have still to be confirmed, on the other. This may demonstrate that human tumor cytogenetics are a dynamically and vigorously developing branch of cancer research.


Pilomyxoid astrocytoma of the cerebellum with Williams syndrome: a case report.
A 3-year-old boy with Williams syndrome associated with supravalvular aortic stenosis was admitted to our hospital with disturbance of consciousness and a 2-month history of truncal ataxia. T1-weighted magnetic resonance imaging with contrast medium showed a heterogeneously enhanced tumor in the right cerebellum with severe hydrocephalus. The patient underwent tumor resection via suboccipital craniotomy. At the end of resection of the tumor, sudden cardiac arrest occurred after ST segment elevation. Despite immediate cardiopulmonary resuscitation, the patient died. Histological examination of the cerebellar tumor revealed that the tumor consisted of monomorphous bipolar spindle cells on a background of myxoid matrix, and angiocentric arrangement without Rosenthal fibers or eosinophilic granular body. The final diagnosis was pilomyxoid astrocytoma. This case of Williams syndrome with cerebellar pilomyxoid astrocytoma suggests the importance of investigation of the development of brain tumors and occurrence of intraoperative cardiac arrest associated with Williams syndrome.


Acute and chronic pericholangiolitis in association with multifocal hepatic lymphangiomatosis.
Multifocal, lymphangiomatous lesions were found in the right lobe of the liver of a 9-year-old girl who died seven days after head trauma. We believe the lesions represent a cystic and pseudoneoplastic dilatation of liver lymphatics secondary to a posttraumatic complication, acute and chronic inflammation primarily of small bile ducts, and canaliculi (pericholangiolitis). The findings provide new evidence that inflammation and fluid overload, in the absence of a congenital malformation, are cardinal factors in the pathogenesis of some forms of lymphangiomatosis.


Celecoxib is a substrate of CYP2D6: Impact on celecoxib metabolism in individuals with CYP2C9*3 variants.
Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent Km, Ki, and Vmax of 67.2 μM, 12.6 μM, and 1.33 μM/min, respectively. In human liver microsomes (HLMs), a concentration-dependent inhibition of celecoxib hydroxylation by quinidine was observed after CYP2C9 and CYP3A4 were inhibited. In individual HLMs with variable CYP2D6 activities, a significant correlation was observed between celecoxib hydroxylation and CYP2D6-selective dextromethorphan O-demethylation when CYP2C9 and CYP3A4 activities were suppressed (r = 0.97, P < 0.0001). Molecular modeling showed two predominant docking modes of celecoxib with CYP2D6, resulting in either a substrate or an inhibitor. A second allosteric binding antechamber, which stabilized the inhibition mode, was revealed. Modeling results were consistent with the observed substrate inhibition kinetics. Using HLMs from individual donors, the relative contribution of CYP2D6 to celecoxib metabolism was found to be highly variable and dependent on CYP2C9 genotypes, ranging from no contribution in extensive metabolizers with CYP2C9*1*1 genotype to approximately 30% in slow metabolizers with allelic variants CYP2C9*1*3 and CYP2C9*3*3. These results demonstrate that celecoxib may become a potential victim of CYP2D6-associated drug-drug interactions, particularly in individuals with reduced CYP2C9 activity.


Silicon Nitride-Based Composites with the Addition of CNTs-A Review of Recent Progress, Challenges, and Future Prospects.
In this overview, the results published to date concerning the development, processing, microstructure characteristics, and properties of silicon nitride/carbon nanotube (Si3N4 + CNTs) composites are summarized. The influence of the different processing routes on the microstructure development of the Si3N4 + CNTs is discussed. The effects of the CNTs addition on the mechanical properties-hardness, bending strength and fracture toughness-and tribological characteristics-wear rate and coefficient of friction-are summarized. The characteristic defects, fracture origins, toughening and damage mechanisms occurring during the testing are described. The influence of the CNTs' addition on the thermal and functional properties of the composites is discussed as well. New trends in the development of these composites with significant potential for future applications are outlined.


The ethos of physical activity delivery in mental health: a narrative study of service user experiences.
Our research into the physical activity experiences of people with severe mental illness has led us to take seriously the social and cultural environment in which physical activity is delivered. In this study, through narrative methodology, we examine service user accounts of physical activity to illuminate the characteristics of physical activity groups that are experienced as positive, helpful, or beneficial. We present several qualities and show how effective leadership and coaching is central to these qualities being present. We conclude that it is not so much what activity is delivered, but how it is delivered that is critical for sustained participation and positive outcomes.