Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro.
Our objective was to study the characteristics of transfer and biotransformation of nicotine in the human term placenta. Nicotine transfer was studied by dually perfusing an isolated cotyledon of the human placenta in vitro. Nicotine metabolism to cotinine was investigated in intact tissue during perfusion and in placental microsomal fractions. Following the addition of nicotine (40 ng/ml) to the maternal side of the placenta, distribution into placental tissue (0.43 +/- 0.13 ng/ml/min) was three times higher than transfer to the fetal side of the placenta (0.15 +/- 0.01 ng/ml/min). The steady-state maternal-to-fetal transfer of nicotine was approximately 90% that of antipyrine (a marker of flow-dependent transfer). There was no evidence of nicotine metabolism to cotinine by intact placental tissue or in microsomal fractions. The observation that nicotine readily crosses the human placenta with no evidence of metabolism suggests that nicotine has the potential to cause adverse affects on the developing fetus.


Heparin inhibits fibrin, but not leukocytes, in a model of deep-vein thrombosis.
Previous studies with models of deep-vein thrombosis (DVT) have demonstrated that leukocyte (PMN)-mediated vein injury may be an initiating event in DVT (14, 17). Since heparin (H) can prevent DVT, we studied its effect on vascular injury and thrombosis in our model. Three groups of rabbits were treated with H either sc (73 and 147 U/kg) or iv (662 U/kg). Scanning electron microscopy revealed that the 73 U/kg sc dose was ineffective. All veins had PMN accumulation, fibrin deposition and complex thrombus formation. There was no increase in anti-Xa activity; activated partial thromboplastin times (APTT) and whole blood clotting times were normal. The 147 U/kg sc and the intravenous dose did not inhibit PMN-mediated vein injury. The endothelium was sloughed by migrating PMNs, basement membrane was exposed, and platelets adhered to it. Thrombosis was completely absent in the iv dose group. This correlated with increased anti-Xa activity and prolonged APTT and whole blood clotting times. Our results indicate that heparin does not inhibit the PMN adhesion and migration which produces vascular injury. However, the anticoagulant activity of heparin effectively reduces fibrin deposition and complex thrombus formation.


Comparison of early period sexual function parameters between surgical repair and conservative treatment after penile fracture.
Comparison of early period sexual function parameters in patients who had surgical repair and conservative follow-up after penile fracture and the evaluation of surgical intervention time on these parameters were planned in this study. Total of 26 patients who were treated for penile fracture were evaluated. 19 patients had surgical repair and 7 patients had conservative treatment. Sexual function and erectile dysfunction (ED) degree of the patients before penile fracture and in the 12th week after fracture were evaluated with 5-question International Index of Erectile Function (IIEF-5) questionnaire, Erection Hardness Score (EHS), Sexual Encounter Profile(SEP) 2 and SEP 3. Parameters showing sexual function before and after the fracture were compared. In both groups, a significant change was detected in IIEF-5 score, EHS, SEP-2 and SEP-3 parameters of the patients measured after penile fracture compared to the values before the fracture (all parameters, p<0.05). No difference was detected in the parameters measured before and after the fracture among surgical repair and conservative treatment groups (all parameters p>0.05). Mean time passing until the surgery after fracture was measured as 9.6±6.85h in 19 patients who had surgery. A difference wasn't detected in sexual parameters in conservative treatment and surgical repair groups in this study. As a significant decrease was observed in sexual function parameters even in conservative treatment cases without sudden detumescence and tunica albuginea rupturing, we think that quick surgical exploration would be useful in cases considered to have penile fracture.


The acute effects of antimicrobials and lipopolysaccharide on the cellular mechanisms associated with neurodegeneration in pubertal male and female CD1 mice.
Exposure to stressors during puberty can cause enduring effects on brain functioning and behaviours related to neurodegeneration. However, the mechanisms underlying these effects remain unclear. The gut microbiome is a complex and dynamic system that could serve as a possible mechanism through which early life stress may increase the predisposition to neurodegeneration. Therefore, the current study was designed to examine the acute effects of pubertal antimicrobial and lipopolysaccharide (LPS) treatments on the cellular mechanisms associated with neurodegenerative disorders in male and female mice. At five weeks of age, male and female CD-1 mice received 200 μL of broad-spectrum antimicrobials or water, through oral gavage, twice daily for seven days. Mice received an intraperitoneal (i.p.) injection of either saline or LPS at 6 weeks of age (i.e., pubertal period). Sickness behaviours were recorded and mice were euthanized 8 h post-injection. Following euthanasia, brains and blood samples were collected. The results indicated that puberal antimicrobial and LPS treatment induced sex-dependent changes in biomarkers related to sickness behaviour, peripheral inflammation, intestinal permeability, and neurodegeneration. The findings suggest that pubertal LPS and antimicrobial treatment may increase susceptibility to neurodegenerative diseases later in life, particularly in males.


Effect of ultrasound on enzymatic acylation of konjac glucomannan.
A comparative study was made of enzymatic acylation of konjac glucomannan with vinyl esters under ultrasonic irradiation and shaking in organic solvent tert-butanol. Among the 13 enzymes selected, Novozym 435 exhibited the highest acylation activity towards KGM whether under ultrasonic irradiation or shaking. The application of ultrasonic irradiation instead of shaking during the acylation led to improvement in the initial reaction rate, yield and degree of substitution of the modified KGM. Appropriate ultrasound power (100 W) and water activity (0.75) were found to accelerate enzymatic reaction. The acceleration effect of ultrasound on Novozym 435-catalyzed acylation decreased with an increase in the chain length of the acyl donors from C2 to C18. Moreover, the acylation of KGM in tert-butanol was proved to be a regioselective one, with C6-OH being acylated. Compared with shaking, ultrasound did not change regioselectivity of Novozym 435 in the acylation.


Recent behavioral findings of pathophysiological involvement of lactate in the central nervous system.
Lactate was initially thought of as a fatigue substance. In recent years, however, lactate not only functions as an energy carrier and contributes to ATP production, but also its role as a signal transmitter has been attracting attention due to the identification of lactate receptors. Lactate is synthesized from glucose and glycogen through the glycolytic system. The central nervous system is a major organ of glucose metabolism and is rich in glycogen. Therefore, this review summarizes the recent findings on the contribution of lactate to the pathophysiology of the central nervous system.


C-reactive protein predicts death in patients with previous premature myocardial infarction--a 10 year follow-up study.
Atherosclerosis is an inflammatory disease. C-reactive protein (CRP), a marker of inflammation, is associated with coronary heart disease (CHD). We measured CRP in a cohort of 247 patients (193 males and 54 females) who had had their first myocardial infarction (MI) at age < or = 55 (males) or < or = 60 (females). The cut-off values of the 25th, 50th and 75th centiles of CRP were 1.20, 2.37 and 4.20 mg/l. After 10 years, a total of 44 patients (17.8%) had died, 36 (81.8%) of cardiac causes. Unadjusted and adjusted (i.e. for age, ejection fraction (EF), serum total cholesterol (TC), fibrinogen, smoking and hypertension) relative risks (RRs) for total and cardiac mortality were generated. CRP was a strong predictor of death of all causes due to its strength as predictor of cardiac death. The RR of cardiac death was doubled with increasing CRP quartiles, and patients in the top quartile had six times as high risk of cardiac death as patients in the lowest quartile. The RRs were moderately attenuated after adjustment, but still significant. We conclude that CRP is a strong predictor of mortality in patients with premature MI. Thus, inflammation appears to be a critical prognostic factor in patients with previous premature MI.


Malignant abdominal mesothelioma: defining the role of surgery.
Determine the role of surgery for patients with malignant abdominal mesotheliomas (MAMs). The Surveillance, Epidemiology, and End Results (SEER) database (1973-2005) was queried. Overall, 10,589 cases of malignant mesotheliomas were identified. Of these, 9,211 cases were thoracic (TM) and 1,112 cases were MAM (10.5%). Patients with TM presented with more localized disease than those patients with MAM (P < 0.001). MAM more often affected younger patients (63 years vs. 71 years) (P < 0.001). The annual incidence of MAM was approximately 1.00 case per 100,000 in 2005. Overall median survival for MAM patients was 8 months, with a significant difference between women and men (13 months vs. 6 months, respectively) (P < 0.001). Patients who successfully underwent surgical resection had a considerably longer median survival (20 months vs. 4 months, P < 0.001) as well as a significantly higher 5-year survival (28% vs. 12%, P < 0.001). Multivariate analysis identified that a poorly differentiated tumor grade, failure to undertake surgical resection, advanced age, and male gender were all independent predictors of poorer outcome. Surgical extirpation of MAM may be associated with significantly improved survival. All patients with MAM should be evaluated for potential surgical resection.


TGEV corona virus ORF4 encodes a membrane protein that is incorporated into virions.
The coding potential of the open reading frame ORF4 (82 amino acids) of transmissible gastroenteritis virus (TGEV) has been confirmed by expression using a baculovirus vector. Five monoclonal antibodies (MAbs) raised against the 10K recombinant product immunoprecipitated a polypeptide of a similar size in TGEV-infected cells. Immunofluorescence assays performed both on insect and mammalian cells revealed that ORF4 was a membrane-associated protein, a finding consistent with the prediction of a membrane-spanning segment in ORF4 sequence. Two epitopes were localized within the last 21 C-terminal residues of the sequence through peptide scanning and analysis of the reactivity of a truncated ORF4 recombinant protein. Since the relevant MAbs were found to induce a cell surface fluorescence, these data suggest that ORF4 may be an integral membrane protein having a Cexo-Nendo orientation. Anti-ORF4 MAbs were also used to show that ORF4 polypeptide may be detected in TGEV virion preparations, with an estimated number of 20 molecules incorporated per particle. Comparison of amino acid sequence data provided strong evidence that other coronaviruses encode a polypeptide homologous to TGEV ORF4. Our results led us to propose that ORF4 represents a novel minor structural polypeptide, tentatively designated SM (small membrane protein).


The effect of carnitine supplemented total parenteral nutrition on lipid, energy and nitrogen metabolism in severely ill patients.
To analyse the effects of L-carnitine supplemented TPN on lipid, energy and nitrogen metabolism, 16 severely injured patients were studied during the first 8 days after trauma. An L-carnitine solution (3g = 18.6mmol) was added to the fat emulsion and infused over 16h in a blind randomised fashion to half of the patients. Plasma triglyceride, free fatty acid and 3-OH-butyrate concentrations increased during the fat infusion, and fell to pre-infusion concentrations within 24h. There were no differences in plasma levels before, during or after infusion between the groups. ATP and phosphocreatine in muscle tissue were not influenced by carnitine supplementation. Glycogen, however, remained unchanged in the carnitine group and fell in the non-carnitine group. A cumulative N-balance measured from day 2 to day 8 was equally negative in both groups. Plasma carnitine levels were significantly higher in the supplemented group from day 3. The mean daily urinary carnitine excretion was increased 15-fold in the supplemented group. Muscle carnitine, however, remained unchanged in both groups and did not differ between them. The present results do not demonstrate any beneficial effects of parenterally administered L-carnitine on lipid, energy or nitrogen metabolism except for maintaining normal muscle glycogen levels in critically ill patients receiving TPN during the early phase after trauma.


Identification of novel small molecule TGF-β antagonists using structure-based drug design.
Aberrant transforming growth factor-β (TGF-β) signalling has been associated with a number of disease pathologies, such as the development of fibrosis in the heart, lung and liver, cardiovascular disease and cancer, hence the TGF-β pathway represents a promising target for a variety of diseases. However, highly specific ways to inhibit TGF-β signalling need to be developed to prevent cross-talk with related receptors and minimise unwanted side effects. We have used used virtual screening and molecular docking to identify small molecule inhibitors of TGF-β binding to TßRII. The crystal structure of TGF-β3 in complex with the extracellular domain of the type II TGF-β receptor was taken as a starting point for molecular docking and we developed a structure-based pharmacophore model to identify compounds that competitively inhibit the binding of TGF-β to TβRII and antogonize TGF-β signalling. We have experimentally tested 67 molecules suggested by in silico screening and similarity searching for their ability to inhibit TGF-β signalling in TGF-β-dependent luciferase assays in vitro and the molecule with the strongest inhibition had an IC50 of 18 μM. These compounds were selected to bind to the SS1 subsite (composed of F30, C31, D32, I50, T51 S52, I53, C54 and E55) of TßRII and all share the general property of being aromatic and fairly flat. Molecular dynamics simulations confirmed that this was the most likely binding mode. The computational methods used and the hits identified in this study provide an excellent guide to medicinal chemistry efforts to design tighter binding molecules to disrupt the TGF-β/TßRII interaction.


Galectin-3 modulation of T-cell activation: mechanisms of membrane remodelling.
Galectin-3 (Gal3) is a multifaceted protein which belongs to a family of lectins and binds β-galactosides. Gal3 expression is altered in many types of cancer, with increased expression generally associated with poor prognosis. Although the mechanisms remain unknown, Gal3 has been implicated in several biological processes involved in cancer progression, including suppression of T cell-mediated immune responses. Extracellular Gal3 binding to the plasma membrane of T cells alters membrane organization and the formation of an immunological synapse. Its multivalent capacity allows Gal3 to interact specifically with different membrane proteins and lipids, influencing endocytosis, trafficking and T cell receptor signalling. The ability of Gal3 to inhibit T cell responses may provide a mechanism by which Gal3 aids in cancer progression. In this review, we seek to give an overview of the mechanisms by which Gal3 alters the spatial organization of cell membranes and how these processes impact on T cell activation.


Pseudoaneurysm of the pulmonary artery after the banding procedure: two-dimensional echocardiographic description.
This report describes an infant with double-outlet right ventricle who underwent pulmonary artery banding as palliation for excessive left to right shunting through a ventricular septal defect. Three weeks after this procedure, there was abrupt clinical deterioration, and two-dimensional echocardiography clearly defined a large pseudoaneurysm arising from a breach in the posterior pulmonary artery wall, just proximal to the band. The diagnosis was confirmed at surgery, during which total correction was performed with successful outcome. The two-dimensional echocardiographic features of a pseudoaneurysm of the pulmonary artery are shown and the role of this noninvasive technique in the evaluation of pulmonary artery bands is discussed.


Real-world effectiveness of COVID-19 vaccines: A retrospective cohort study of vaccinated individuals in Jazan, Saudi Arabia.
COVID-19 (Coronavirus Disease 2019) vaccinations are a critical control measure for the coronavirus pandemic that began in 2019. Several COVID-19 vaccines have been developed, and their effectiveness will almost certainly vary. This study aimed to assess how effective two doses of the Pfizer and Oxford-AstraZeneca vaccines were in preventing SARS-CoV-2 infection six months after administration. This is a retrospective cohort study of adult individuals from the Jazan Region of Saudi Arabia who received their second dose of the COVID-19 vaccine [Pfizer and Oxford-AstraZeneca (ASZ)] between April and June 2021. The monitoring and follow-up period continued until the end of January 2022. Data were retrieved from the Health Electronic Surveillance Network and National Vaccination Records. Logistic regression was performed to assess the risk of COVID-19 infection among the vaccinated subjects. This study included randomly enrolled 4458 participants in Jazan who received two doses of the COVID-19 vaccine during the research period. The majority of them received the Pfizer vaccine (3136/4458; 70.3%), while the remaining received the ASZ vaccine (1322/4458; 29.7%). The study participants' mean age was 59.7 years, with a male-to-female ratio of 1.9:1.0 (2920:1538). The results showed that the Pfizer and ASZ vaccines' protection against infection decreased from 93.2% and 90.2%, respectively, during the first three months, to 68.5% and 68.1% after a six-month interval. In the current study population, being Saudi Arabian, younger as well as having longer intervals between vaccines or crossing a 6-month period after the second vaccine dose were factors linked to higher rates of breakthrough infections. Our findings revealed variations in the efficacy of different COVID-19 vaccine types against COVID-19 breakthrough infections. The Pfizer (mRNA-based) vaccine was found to be relatively more effective than the ASZ (DNA-based) vaccine.


Distribution of sensory neurons of the pudendal nerve in the dorsal root ganglia and their projection to the spinal cord. Horseradish-peroxidase studies in the rat.
The morphology and distribution of the sensory neurons of the pudendal nerve within the spinal ganglia of rats were investigated by use of horseradish peroxidase (HRP). The labelling was visualized in diaminobenzidine (DAB) or tetramethyl-benzidine (TMB)-stained sections. Injection of HRP directly into the pudendal nerve labelled perikarya predominantly in the sixth lumbar DRG (L6). Following injection of HRP into the scrotal skin, however, additional cells were labelled in L5 and S1. Labelling was invariably unilateral. Approximately equal numbers of small (less than 30 micrometers) and large neurones (greater than 40 micrometers) were labelled following subcutaneous injections although injections into the nerve marked twice as many small cells as large cells. This suggests that, in the rat, most of the small-diameter fibers within the pudendal nerve ascend through L6. Although a cluster of neurones was observed in one experiment, the remaining 25 experiments did not reveal any somatotopic arrangement since the labelled perikarya were distributed evenly throughout the ganglion. Similar numbers of retrogradely labelled neurones (somatopetal transport of the tracer) were observed in both DAB- and TMB-stained sections, although TMB allowed the demonstration of anterograde (somatofungal) HRP transport by terminal labelling in the superficial laminae of the lumbar spinal cord, extending into laminae II--IV.


Purification of a laccase from fruiting bodies of the mushroom Pleurotus eryngii.
A purification scheme involving ion exchange chromatography on diethylaminoethyl (DEAE) cellulose, carboxymethyl (CM) cellulose, and Q-Sepharose, followed by fast protein liquid chromatography-gel filtration on Superdex 75, was utilized to isolate a laccase from the fruiting bodies of the mushroom Pleurotus eryngii. The laccase was adsorbed on DEAE-cellulose and Q-Sepharose and unadsorbed on CM-cellulose. The molecular mass of the laccase in sodium dodecyl sulfate-polyacrylamide gel electrophoresis was 34 kDa. The laccase activity was maximal at 70 degrees C and remained high at 80 degrees C. High activity of the laccase was maintained at ph 3 to 5. The activity underwent an abrupt decline at pH 6 and 7 and was indiscernible at ph 8 and 9. The laccase exhibited an inhibitory activity toward HIV-1 reverse transcriptase with an IC50 of 2.2 microM. Its N-terminal sequence was dissimilar to those of laccase isoenzymes previously isolated from cultured mycelia of the same species.


Energy balance in Speliphron violaceum (Hymenoptera) and use of meconium weight as an index of bioenergetics components.
Speliphron violaceum deposits its larva and a few paralysed spiders inside the holes of electrical sockets. The larva feeds on the spiders, completes development in 6 days and emerges after 18 days of pupation. When provided with spiders to the maximum capacity of the hole, a larva consumed 1.746 KJ and converted 1.360 KJ. Restriction of the quantity of spiders provided, resulted in decreased consumption and extension of larval duration to 7 or 8 days. Consumption of 0.710·718 KJ was the minimum requirement for the completion of larval development. Despite variations in food consumption, assimilation efficiency of the larva remained constant around 97%. Gross production efficiency of the larvae averaged 77%. Larvae ingesting different amounts of host energy emerged with a wide range of body weight (16-62 mg). The efficiency with which pupal energy is transferred to adult was around 30%. Dry weight of meconium egested by the test individuals varied from 1.3 to 4.6 mg. Using simple regression equations, it is possible to predict the bioenergetics components of S. violaceum from the dry weight of meconium.


The use of vasodilators in the treatment of acute decompensated heart failure: novel versus conventional therapy.
The majority of patients who present with acute decompensated heart failure require the addition of vasodilators to adequately reduce filling pressures and improve symptoms. Conventional therapies such as nitroglycerin and nitroprusside, although relatively effective, are difficult to use. Nesiritide, a natriuretic peptide and neurohormonal antagonist with potent vasodilator properties, may be a reasonable alternative. It offers several benefits in safety and convenience over conventional vasodilators, making it particularly suitable for both emergency department and inpatient use.


Crystal structure of Saccharomyces cerevisiae cytoplasmic thioredoxin reductase Trr1 reveals the structural basis for species-specific recognition of thioredoxin.
Thioredoxin reductase (TrxR) is a member of the pyridine nucleotide-disulfide oxidoreductase family of the flavoenzymes. It can use a dithiol-disulfide active-site to transfer reducing equivalents from NADPH to thioredoxin (Trx), via the cofactor FAD. In Saccharomyces cerevisiae, the cytoplasmic thioredoxin reductase Trr1 plays an important role in multiple cellular events under the control of transcription factor Yap1 and/or Rho5. Here we present the crystal structure of Trr1 at the resolution of 2.8 A, the first fungal TrxR structure. Structural analysis shows it shares a very similar overall structure to Escherichia coli TrxR. However, fine comparisons indicate some distinct differences at the Trx recognition sites. These differences might be responsible to the species-specific recognition of Trx, which has been demonstrated by previous biochemical assays.


Inhibition of Niemann-Pick C1-like protein 1 by ezetimibe reduces uptake of deuterium-labeled vitamin D in mice.
For a long time, orally ingested vitamin D was assumed to enter the body exclusively via simple passive diffusion. Recent data from in vitro experiments have described Niemann-Pick C1-like protein 1 (Npc1l1) as an important sterol transporter for vitamin D absorption. However, short-term applications of ezetimibe, which inhibits Npc1l1, were not associated with reduced vitamin D uptake in animals and humans. The current study aimed to elucidate the effect of long-term inhibition of Npc1l1 by ezetimibe on the uptake and storage of orally administered triple deuterated vitamin D3 (vitamin D3-d3). Therefore, 30 male wild-type mice were randomly assigned into three groups and received diets with 25 μg/kg of vitamin D3-d3 that contained 0 (control group), 50 or 100 mg/kg ezetimibe for six weeks. Mice fed diets with 50 or 100 mg/kg ezetimibe had lower circulating levels of cholesterol than control mice (-12 %, -15 %, P < 0.01). In contrast, the concentrations of 7-dehydrocholesterol in serum (P < 0.001) and liver (P < 0.05) were higher in mice treated with ezetimibe than in control mice, indicating an increased sterol synthesis to compensate for cholesterol reduction. Long-term application of ezetimibe significantly reduced the concentrations of vitamin D3-d3 in the serum and tissues of mice. The magnitude of vitamin D3 reduction was comparable between the two ezetimibe groups. In comparison to the control group, mice treated with ezetimibe had lower concentrations of deuterated vitamin D3 compared with the control group in serum (62 %, P < 0.001), liver (79 %, P < 0.001), kidney (54 %, P < 0.001), adipose tissues (55 %, P < 0.001) and muscle (41 %, P < 0.001). Surprisingly, the serum concentration of deuterated 25-hydroxyvitamin D3 was higher in the group fed 100 mg/kg ezetimibe than in the control group (P < 0.05). The protein expression of the vitamin D hydroxylases Cyp2r1, Cyp27a1, Cyp3a11, Cyp24a1 and Cyp2j3 in liver and Cyp27b1 and Cyp24a1 in kidney remained largely unaffected by ezetimibe. To conclude, Npc1l1 appears to be crucial for the uptake of orally ingested vitamin D because long-term inhibition of Npc1l1 by ezetimibe strongly reduced the levels of deuterium-labeled vitamin D in the body; the observed rise in deuterated 25-hydroxyvitamin D3 in serum of these mice can not be explained by the expression levels of the key enzymes involved in vitamin D hydroxylation.


Ocular toxicity of intravitreal melphalan for retinoblastoma in Chinese patients.
To evaluate the efficacy, complications, and clinical characteristics, including the ocular toxicity, of intravitreal melphalan(IVM) treatment for vitreous seeding in Chinese retinoblastoma patients. This was a retrospective, non-comparative analysis including 30 consecutive eyes of 23 patients with viable persistent or recurrent vitreous seeding following retinoblastoma treatment. All of the eyes received IVM injections (20-33 μg). Vitreous seeding control, determination of the ocular toxicity, and the clinical characteristics of intravitreal melphalan treatments were observed. The mean patient age at the time of the injection was 28 months (median = 22 months, range = 12-50 months). In total, 80 injections were administered in 30 eyes, the overall enucleation-free survival rate was 83.3% (25/30). The complications included retinal pigment epithelium (RPE) and choroidal atrophy (19/30, 63.3%), pupillary synechiae (13/30, 43.3%), iris atrophy (12/30, 40%), retinal vascular occlusion (12/30, 40.0%), optic atrophy (6/30, 20%), vitreous hemorrhage (3/30, 10%), persistent hypotonia and phthisis bulbi (4/30 13.3%), and cataracts (8/30, 26.6%). Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean dosage given showed significant difference between the groups. There were no significant differences in the retinal toxicity grades regarding the seed classification or seed regression patterns. Intravitreal melphalan is an effective treatment for refractory vitreous seeding from retinoblastoma, but exhibits both anterior and posterior segment toxicity in Chinese patients.


Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kβ to BCR signalosome while reducing PDK1 in post-therapy CLL cells.
Idelalisib targets PI3Kδ in the BCR pathway generating only a partial response in CLL patients, indicating that the leukemic cells may have evolved escape signals. Indeed, we detected increased activation of AKT accompanied by upregulation of MYC/BCL2 in post-therapy CLL cells from patients treated with idelalisib/ofatumumab. To unravel the mechanism of increased AKT-activation, we studied the impact of idelalisib on a CLL-derived cell line, MEC1, as a model. After an initial inhibition, AKT-activation level was restored in idelalisib-treated MEC1 cells in a time-dependent manner. As BCAP (B-cell adaptor for PI3K) and CD19 recruit PI3Kδ to activate AKT upon BCR-stimulation, we examined if idelalisib-treatment altered PI3Kδ-recruitment. Immunoprecipitation of BCAP/CD19 from idelalisib-treated MEC1 cells showed increased recruitment of PI3Kδ in association with PI3Kβ, but not PI3Kα or PI3Kγ and that, targeting both PI3Kδ with PI3Kβ inhibited AKT-reactivation. We detected similar, patient-specific recruitment pattern of PI3K-isoforms by BCAP/CD19 in post-idelalisib CLL cells with increased AKT-activation. Interestingly, a stronger inhibitory effect of idelalisib on P-AKT (T308) than S473 was discernible in idelalisib-treated cells despite increased recruitment of PI3Kδ/PI3Kβ and accumulation of phosphatidylinositol-3,4,5-triphosphate; which could be attributed to reduced PDK1 activity. Thus, administration of isoform-specific inhibitors may prove more effective strategy for treating CLL patients.


Association of asymmetric unit membrane plaque formation in the urinary bladder of adult humans with therapeutic radiation.
Asymmetric unit membrane (AUM) is a component of the luminal membrane of urinary bladder in many species. In normal human adults it is inconspicuous, but it becomes prominent following incidental exposure to therapeutic irradiation.


Mitochondrial ROS-induced ROS release: an update and review.
Unstable mitochondrial membrane potential and redox transitions can occur following insults including ischemia/reperfusion injury and toxin exposure, with negative consequences for mitochondrial integrity and cellular survival. These transitions can involve mechanisms such as the recently described process, "Reactive Oxygen Species (ROS)-induced ROS-release" (RIRR), and be generated by circuits where the mitochondrial permeability transition (MPT) pore and the inner membrane anion channel (IMAC) are involved. The exposure to excessive oxidative stress results in an increase in ROS reaching a threshold level that triggers the opening of one of the requisite mitochondrial channels. In turn, this leads to the simultaneous collapse of the mitochondrial membrane potential and a transient increased ROS generation by the electron transfer chain. Generated ROS can be released into cytosol and trigger RIRR in neighboring mitochondria. This mitochondrion-to-mitochondrion ROS-signaling constitutes a positive feedback mechanism for enhanced ROS production leading to potentially significant mitochondrial and cellular injury. This review and update considers a variety of RIRR mechanisms (involving MPT, IMAC and episodes of mitochondrial transient hyperpolarization). RIRR could be a general cell biology phenomenon relevant to the processes of programmed mitochondrial destruction and cell death, and may contribute to other mechanisms of post-ischemic pathologies, including arrhythmias.


An assessment of the response of human MSCs to hydrostatic pressure in environments supportive of differential chondrogenesis.
Mechanical stimulation can modulate the chondrogenic differentiation of stem/progenitor cells and potentially benefit tissue engineering (TE) of functional articular cartilage (AC). Mechanical cues like hydrostatic pressure (HP) are often applied to cell-laden scaffolds, with little optimization of other key parameters (e.g. cell density, biomaterial properties) known to effect lineage commitment. In this study, we first sought to establish cell seeding densities and fibrin concentrations supportive of robust chondrogenesis of human mesenchymal stem cells (hMSCs). High cell densities (15*106 cells/ml) were more supportive of sGAG deposition on a per cell basis, while collagen deposition was higher at lower seeding densities (5*106 cells/ml). Employment of lower fibrin (2.5 %) concentration hydrogels supported more robust chondrogenesis of hMSCs, with higher collagen type II and lower collagen type X deposition compared to 5 % hydrogels. The application of HP to hMSCs maintained in identified chondro-inductive culture conditions had little effect on overall levels of cartilage-specific matrix production. However, if hMSCs were first temporally primed with TGF-β3 before its withdrawal, they responded to HP by increased sGAG production. The response to HP in higher cell density cultures was also associated with a metabolic shift towards glycolysis, which has been linked with a mature chondrocyte-like phenotype. These results suggest that mechanical stimulation may not be necessary to engineer functional AC grafts using hMSCs if other culture conditions have been optimised. However, such bioreactor systems can potentially be employed to better understand how engineered tissues respond to mechanical loading in vivo once removed from in vitro culture environments.


Safety and efficacy of hysteroscopic sterilization compared with laparoscopic sterilization: an observational cohort study.
To compare the safety and efficacy of hysteroscopic sterilization with the "Essure" device with laparoscopic sterilization in a large, all-inclusive, state cohort. Population based cohort study. Outpatient interventional setting in New York State. Women undergoing interval sterilization procedure, including hysteroscopic sterilization with Essure device and laparoscopic surgery, between 2005 and 2013. Safety events within 30 days of procedures; unintended pregnancies and reoperations within one year of procedures. Mixed model accounting for hospital clustering was used to compare 30 day and 1 year outcomes, adjusting for patient characteristics and other confounders. Time to reoperation was evaluated using frailty model for time to event analysis. We identified 8048 patients undergoing hysteroscopic sterilization and 44,278 undergoing laparoscopic sterilization between 2005 and 2013 in New York State. There was a significant increase in the use of hysteroscopic procedures during this period, while use of laparoscopic sterilization decreased. Patients undergoing hysteroscopic sterilization were older than those undergoing laparoscopic sterilization and were more likely to have a history of pelvic inflammatory disease (10.3% v 7.2%, P<0.01), major abdominal surgery (9.4% v 7.9%, P<0.01), and cesarean section (23.2% v 15.4%, P<0.01). At one year after surgery, hysteroscopic sterilization was not associated with a higher risk of unintended pregnancy (odds ratio 0.84 (95% CI 0.63 to 1.12)) but was associated with a substantially increased risk of reoperation (odds ratio 10.16 (7.47 to 13.81)) compared with laparoscopic sterilization. Patients undergoing hysteroscopic sterilization have a similar risk of unintended pregnancy but a more than 10-fold higher risk of undergoing reoperation compared with patients undergoing laparoscopic sterilization. Benefits and risks of both procedures should be discussed with patients for informed decisions making.


Surgery in patients with hemoglobin-S disease.
Sixty-eight patients with sickle cell disease who underwent surgery are reviewed. Fifty-two were homozygous for hemoglobin-S, whereas 16 had heterozygous variants. Associated diseases were common. Both the types of operative procedures and the complications of surgery, in large measure, were determined by these associated diseases. Splenectomy (12 patients) and cholecystectomy (11 patients) were the common major operations; infections (21 patients) were the most common complications. Precise management ensured acceptably low morbidity and mortality (1 death) in this series.


Fluoride contamination in drinking water in rural habitations of northern Rajasthan, India.
This study was carried out to assess the fluoride concentration in groundwater in some villages of northern Rajasthan, India, where groundwater is the main source of drinking water. Water samples collected form deep aquifer based hand-pumps were analysed for fluoride content. Fluoride in presently studied sites was recorded in the ranges of 4.78 and 1.01 mg/l. The average fluoride concentration for this region was recorded 2.82 mg/l. As per the desirable and maximum permissible limit for fluoride in drinking water, determined by WHO or by Bureau of Indian Standards, the groundwater of about 95 of the studied sites is unfit for drinking purposes. Due to the higher fluoride level in drinking water several cases of dental and skeletal fluorosis have appeared at alarming rate in this region. The middle and eastern parts of the Hanumangarh, a northern most district of the state, can be classified as higher risk area for fluorosis; due to relatively high concentrations of fluoride (3-4 mg/l) in groundwater of this region. After evaluating the data of this study it is concluded that there is an instant need to take ameliorative steps in this region to prevent the population from fluorosis.


Recent advances in the preparation and application of monolithic capillary columns in separation science.
Novel column technologies involving various materials and efficient reactions have been investigated for the fabrication of monolithic capillary columns in the field of analytical chemistry. In addition to the development of these miniaturized systems, a variety of microscale separation applications have achieved noteworthy results, providing a stepping stone for new types of chromatographic columns with improved efficiency and selectivity. Three novel strategies for the preparation of capillary monoliths, including ionic liquid-based approaches, nanoparticle-based approaches and "click chemistry", are highlighted in this review. Furthermore, we present the employment of state-of-the-art capillary monolithic stationary phases for enantioseparation, solid-phase microextraction, mixed-mode separation and immobilized enzyme reactors. The review concludes with recommendations for future studies and improvements in this field of research.


Posterior circumflex humeral artery pathological lesions with digital ischemia in an elite volleyball player: A case report and literature review.
The posterior circumflex humeral artery, a branch of the axillary artery, is compressed by the humeral head during repeated abduction and external rotation of the shoulder joint owing to its anatomical structure. This damages the vascular endothelium, resulting in thrombi, arterial dissection, and aneurysms, a condition known as posterior, circumflex humeral artery pathological lesions. A thrombus may form at the site and becomes a peripheral embolus, resulting in peripheral arterial occlusion.A 21-year-old right-handed elite man college volleyball player noticed coldness and pain in his right hand during a game. Cyanosis was present except in the middle finger, and the beating radial artery was palpable; however, the ulnar artery was not. Doppler ultrasound examination revealed thrombus occlusion of the ulnar artery and common palmar artery of the index finger. Peripheral arterial occlusion was diagnosed due to embolization of a thrombus from this site. The patient stopped practicing volleyball immediately after the onset of symptoms and was started on cilostazol 200 mg and rivaroxaban 15 mg. Subjective coldness of the fingers improved one week after the start of treatment. The patient resumed practice four weeks after the start of treatment and participated in a game by the seventh week.Posterior circumflex humeral artery pathological lesions are caused by overhead motions such as pitching. They are most commonly reported in athletes playing volleyball, although rare, and many cases of aneurysm formation have been reported.Observing a cold sensation in the periphery after practice is necessary for screening.


Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1.
Chronic changes caused by a high-fat diet (HFD) may be associated with weakened lung function in obese patients. However, few studies have focused on the role of senescent cells in HFD-induced pulmonary fibrosis. This study aimed to determine whether (i) obesity causes the accumulation of aging cells in the lungs, (ii) p16 accumulation in aging epithelial cells or fibroblasts exacerbates long-term HFD-induced senescence-associated pulmonary fibrosis (SAPF) and (iii) p16 deletion or clearance of aging cells ameliorates HFD-induced SAPF through inactivation of the inflammasome and metabolic remodelling. Twelve-month old male mice of p16INK4a (hereafter p16) knockout (p16-- ) and wild-type (WT), ApoE knockout (ApoE-- ) and ApoE-- p16-- were fed a HFD to induce obesity, and the effects of treatment with the senolytic drug ABT263 or the SGK1 specific inhibitor EMD638683 on fibrosis, inflammaging, gene expression, integrin-inflammasome signalling and metabolism were examined. A549 and IMR-90 cells were transduced with p16-overexpressing adenovirus, and treated with palmitic and oleic acids (P&O) to induce steatosis in vitro. We found that long-term HFD promoted the expression of p16 and the increase of senescent cells in the lung. P16 knockout or ABT263 treatment alleviated pulmonary fibrosis, the increase of senescent cells and senescence-associated secretory phenotype (SASP) in HFD-fed mice, as well as in P&O-treated A549 and IMR-90 cells. RNA sequencing and bioinformatics analyses revealed that p16 knockout inhibited activation of the integrin-inflammasome pathway and cellular glycolysis. Mass spectrometry, co-immunoprecipitation and GST pull-down assays demonstrated that p16 bound to the N-terminal of SGK1, thereby interfering with the interaction between the E3 ubiquitin ligase NEDD4L and SGK1, and subsequently inhibiting K48-polyubiquitin-dependent degradation of SGK1 mediated by the NEDD4L-Ubch5 complex. EMD638683 was found to alleviate HFD-induced pulmonary fibrosis and activation of the integrin-inflammasome pathway. P16 accumulation promoted activation of integrin- inflammasome pathway and cell glycolysis by binding to the N- terminal of SGK1, intefering with the interaction between the E3 ubiquitin ligase NEDD4L and SGK1, thereby inhibiting K48- polyubiquitin- dependent degradation of SGK1 mediated by the NEDD4L-Ubch5 complex. ABT263 or EMD638683 could be used as potential drugs to treat pulmonary fibrosis in obese patients.


Fingolimod Rebound: A Review of the Clinical Experience and Management Considerations.
Because the treatment of multiple sclerosis (MS) may span decades, the need often arises to make changes to the treatment plan in order to accommodate changing circumstances. Switching drugs, or the discontinuation of immunomodulatory agents altogether, may leave patients vulnerable to relapse or disease progression. In some cases, severe MS disease activity is noted clinically and on MRI after treatment withdrawal. When this disease activity is disproportionate to the pattern observed prior to treatment initiation, patients are said to have experienced rebound. Of the US Food and Drug Administration (FDA)-approved agents to treat MS, the drugs most commonly implicated in rebound are natalizumab and fingolimod. In this review based on the reported cases and data from clinical trials, we characterize disease rebound after fingolimod cessation. We also outline fingolimod rebound management considerations, summarizing what evidence is available to help clinicians mitigate the risk of rebound, switch therapies, and treat rebound events when they occur. The commonly encountered situation of fingolimod discontinuation prior to pregnancy is also discussed.


Retinol-regulated gene expression in human tracheobronchial epithelial cells. Enhanced expression of elongation factor EF-1 alpha.
Conducting airway epithelial cells requires vitamin A or its synthetic chemicals (retinoids) for their survival and for the expression of normal mucociliary functions. By using molecular cloning, we have shown that one of the effects of retinol on cultured human tracheobronchial epithelial (HTBE) cells is the enhancement (from 2- to 4-fold) of the mRNA encoding the elongation factor EF-1 alpha. Sequence analysis has shown that clone HT7, which was identified by differential hybridization procedures, contained a cDNA insert which encoded a protein closely resembling (81%) elongation factor EF-1 alpha from brine shrimp and completely identical to the published sequence of human elongation factor EF-1 alpha (Brands, H.H.G.M., Maassen, J.A., Van Hemert, F.J., Amons, R., and Moller, W. (1986) Eur. J. Biochem. 155, 167-171). Regions of homology of HT7 to EF-Tu from yeast mitochondria, plant chloroplasts, and Escherichia coli are also evident. A single RNA band at 1700 bases was observed for both untreated and retinol-treated HTBE cells, and for mouse liver and parotid glands when Northern transfer from denaturing agarose gel was probed with a 32P-labeled HT7 insert. An enhanced amino acid incorporation and increased protein content per cell for HTBE cells grown in the presence of retinol were observed. Results presented by these studies indicate that retinol may regulate the transcription of a factor required for translation.


Use of the modified Robbins device to study the in vitro biofilm removal efficacy of NitrAdine, a novel disinfecting formula for the maintenance of oral medical devices.
To evaluate the use of the modified Robbins device (MRD) to test disinfection strategies against biofilms that form on oral medical devices and to test the biofilm removal efficacy of NitrAdine, a disinfectant for the maintenance of oral medical devices. Biofilms were grown on discs using the MRD and biofilms formed in this system were used to evaluate the efficacy of NitrAdine and to determine the optimal disinfection conditions. Our data indicate that the use of the MRD allows for the rapid and reproducible formation of high-density biofilms. Determination of the efficacy of NitrAdine revealed high activity against biofilms tested (e.g. >3 log reduction for Candida albicans and Staphylococcus aureus) and allowed the determination of the optimal conditions for its use. The high reproducibility and flexibility of the MRD make it an excellent candidate for standardized testing of disinfectants aimed at reducing biofilms on oral medical devices. Using this system, we were able to demonstrate that NitrAdine exhibits high activity against biofilms formed by the micro-organisms tested. Our data suggest that our procedure is appropriate for standardized testing of disinfectants aimed at reducing biofilms on oral medical devices.


Identification of the insulin receptor tyrosine residues undergoing insulin-stimulated phosphorylation in intact rat hepatoma cells.
Tyr(P)-containing proteins were purified from extracts of insulin-treated rat hepatoma cells (H4-II-E-C3) by antiphosphotyrosine immunoaffinity chromatography. Two major insulin-stimulated, Tyr(P) proteins were recovered: an Mr 95,000 protein (identified as the insulin receptor beta subunit by its immunoprecipitation by a patient-derived anti-insulin receptor serum and several anti-insulin receptor (peptide) antisera) and an Mr 180,000 protein (which was unreactive with all anti-insulin receptor antibodies). After purification and tryptic digestion of the Mr 95,000 protein, tryptic peptides containing Tyr(P) were purified by sequential antiphosphotyrosine immunoaffinity, reversed-phase, anion-exchange chromatography. The partial amino acid sequence obtained by gas- and solid-phase Edman degradation was compared to the amino acid sequence of the intracellular extension of the rat insulin receptor deduced from the genomic sequence. Approximately 80% of all beta subunit [32P]Tyr(P) resides on two tryptic peptides: 50-60% of [32P]Tyr(P) is found on the tryptic peptide Asp-Ile-Tyr-Glu-Thr-Asp-Tyr-Tyr-Arg from the tyrosine kinase domain, which is recovered mainly as the double phosphorylated species (predominantly in the form with Tyr(P) at residues 3 and 7 from the amino terminus; the remainder with Tyr(P) at residues 3 and 8), with 10-15% as the triple phosphorylated species. A second tryptic peptide is located near the carboxyl terminus, contains 2 tyrosines, and has the sequence, Thr-Tyr-Asp-Glu-His-Ile-Pro-Tyr-Thr-; this contains 20-30% of beta subunit [32P]Tyr(P) and is identified primarily in a double phosphorylated form. Approximately 10% of beta subunit [32P]Tyr(P) resides on an unidentified tryptic peptide of Mr 4,000-5,000. The insulin-stimulated tyrosine phosphorylation of the insulin receptor in intact rat hepatoma cells thus involves at least 6 of the 13 tyrosine residues located on the beta subunit intracellular extension. These tyrosines are clustered in several domains in a distribution virtually identical to that previously found for partially purified human insulin receptor autophosphorylated in vitro in the presence of insulin. This multisite regulatory tyrosine phosphorylation is the initial intracellular event in insulin action.


Pulmonary complications after major abdominal surgery: National Surgical Quality Improvement Program analysis.
Postoperative pulmonary complications (PPCs) after major abdominal surgery are common and associated with significant morbidity and high cost of care. The objective of this study was to identify the risk factors for PPCs after major abdominal surgery. The American College of Surgeons' National Surgical Quality Improvement Program database from 2005-2012 was queried for patients who underwent major abdominal surgery (esophagectomy, gastrectomy, pacnreatectomy, enterectomy, hepatectomy, colectomy, and proctectomy). Predictors of PPCs were identified using multivariate logistic regression. Of 165,196 patients who underwent major abdominal surgery 9595 (5.8%) suffered PPCs (pneumonia 3.2%, prolonged ventilator support ≥48 h 3.0%, and unplanned intubation 2.8%). On multivariate analysis, significant predictors of overall and individual PPCs include esophagectomy, advanced American Society of Anesthesiology Classification System, dependent functional status, prolonged operative time, age ≥80 y, severe chronic obstructive pulmonary disease, preoperative shock, ascites, and smoking. Obesity was not a risk factor. Female gender was overall protective for PPCs. PPCs after abdominal procedures are associated with a number of clinical variables. Esophageal operations and American Society of Anesthesiology Classification System were the strongest predictors. These results provide a framework for identifying patients at risk for developing pulmonary complications after major abdominal surgery.


Planning study comparison of real-time target tracking and four-dimensional inverse planning for managing patient respiratory motion.
Real-time target tracking (RT-TT) and four-dimensional inverse planning (4D-IP) are two potential methods to manage respiratory target motion. In this study, we evaluated each method using the cumulative dose-volume criteria in lung cancer radiotherapy. Respiration-correlated computed tomography scans were acquired for 4 patients. Deformable image registration was applied to generate a displacement mapping for each phase image of the respiration-correlated computed tomography images. First, the dose distribution for the organs of interest obtained from an idealized RT-TT technique was evaluated, assuming perfect knowledge of organ motion and beam tracking. Inverse planning was performed on each phase image separately. The treatment dose to the organs of interest was then accumulated from the optimized plans. Second, 4D-IP was performed using the probability density function of respiratory motion. The beam arrangement, prescription dose, and objectives were consistent in both planning methods. The dose-volume and equivalent uniform dose in the target volume, lung, heart, and spinal cord were used for the evaluation. The cumulative dose in the target was similar for both techniques. The equivalent uniform dose of the lung, heart, and spinal cord was 4.6 +/- 2.2, 11 +/- 4.4, and 11 +/- 6.6 Gy for RT-TT with a 0-mm target margin, 5.2 +/- 3.1, 12 +/- 5.9, and 12 +/- 7.8 Gy for RT-TT with a 2-mm target margin, and 5.3 +/- 2.3, 11.9 +/- 5.0, and 12 +/- 5.6 Gy for 4D-IP, respectively. The results of our study have shown that 4D-IP can achieve plans similar to those achieved by RT-TT. Considering clinical implementation, 4D-IP could be a more reliable and practical method to manage patient respiration-induced motion.


Role of protein synthesis and proteases in production and inactivation of maturation-promoting activity during meiotic maturation of starfish oocytes.
In starfish oocytes, activity of the maturation-promoting factor (MPF) and that of a major cAMP-independent protein kinase dropped at the time of meiotic cleavage, and rose again after the first but not the second meiotic cleavage. Protein synthesis was required before the first meiotic cleavage for both MPF and protein kinase activity to rise again after the first meiotic cleavage. Microinjection of either leupeptin or soybean trypsin inhibitor early enough prior to first polar body emission suppressed both the meiotic cleavage and the associated drop of MPF activity. Microinjection of leupeptin or soybean trypsin inhibitor during the 10-min period before the first meiotic cleavage also suppressed cytokinesis but did not prevent a decrease in MPF activity at the normal time of cytokinesis. The lysosomotropic inhibitor ammonia neither suppressed cytokinesis nor the drop of MPF activity at the time of first meiotic cleavage. Activity of neutral proteases sensitive to leupeptin and soybean trypsin inhibitor was demonstrated in oocyte homogenates prepared at the time of first meiotic cleavage. It is proposed that such proteases might be involved in degradation of protein kinase(s) and in the drop of MPF activity at the time of first meiotic cleavage.


New species of Tintiyakus Cadena-Castaeda (Orthoptera: Anostostomatidae: Lutosinae) from the Brazilian Mountain Amazon Rainforest.
Tintiyakus is a genus of Chevron Crickets and currently comprises three species with distributions in Colombia and Venezuela, restricted to Amazon rainforest environments between 200400 m altitude. In this work a new species Tintiyakus lari sp. nov. for Serra da Mocidade is the first record of the genus for Brazil. A pictorial key for males of Tintiyakus species is provided.


Validation of a questionnaire about the perception of occupational biohazard in Spanish companies.
The aim of this work was to develop, validate and test a new questionnaire to assess the biological risk in workers with intentional or unintentional exposure to biological agents. A questionnaire including 34 questions was developed to study the perception of workers against occupational biohazard. Content Validity Index (CVI) and Content Validity Ratio (CVR) were calculated for the analysis of content validity. A pilot study was carried out with 60 workers from 17 companies performing analysis of Cronbach's α to assess the internal consistency or reliability. A total of 518 workers from 51 Spanish companies in which there is exposure to biological agents participated in the study yielding a response rate of 90%. The final questionnaire obtained a Cronbach's α > 0.759 with a stable test-retest result. The questionnaire validation demonstrates that it could be used to evaluate the biological risks and help the prevention of occupational accidents and diseases. This study has validated the need to evaluate worker's perception against occupational risks, as well as the application of prevention methods and protective equipment. It is a first step towards developing an occupational biohazards assessment method including all the requirements set by the European Health and Safety Strategy 2013-2020.


[Effectiveness of the glutathione s-transferase assay in diagnosing lung cancer].
The paper deals with a description of a procedure of immunoradiometric assay of glutathione S-transferase pi in blood serum. A significantly increased level of said enzyme of more than 9.85 ng/ml in 75% of patients with different cancers of the lung has been established, as compared with non-tumor pathologies. These findings point to the feasibility of application of this enzyme in lung cancer diagnose.


Metallothionein-enriched hepatocytes are resistant to ferric nitriloacetate toxicity during conditions of glutathione depletion.
Metallothionein (MT) is involved not only in heavy metal homeostasis/detoxification but also in radical scavenging, yet the relevance to other antioxidant systems and physiological significance under oxidative stress has not been clarified. We studied that ability of MT, induced by zinc and cadmium, to protect against oxidative damage induced by ferric nitrilotriacetate (Fe-NTA) in glutathione depleted primary cell cultures. Treatment with Fe-NTA resulted in significant decreases in cell survival and increases in medium LDH activity in control cells following depletion of glutathione. The toxic effects of Fe-NTA were modulated in Zn-MT-enriched cells. In glutathione-depleted cells, but not in non-treated cells, Cd-binding properties of cellular Zn-MT decreased with increasing concentration of Fe-NTA. Both Zn-MT and Cd-MT-enriched cells were resistant to higher doses of Fe-NTA. These results indicate that MT may act a cellular radical scavenger in the absence of GSH. Thus, MT may function as a secondary antioxidant in a cellular protection system.


The Impact of Long-Term Orientation Traits on Pandemic Fatigue Behavior: Evidence from the Columbian Exchange.
Leveraging exogenous variation in time preferences, we measure the causal effects of culturally embodied long-term orientation traits on voluntary social distancing behavior, COVID-19 cases, hospitalizations, and mortality outcomes in 2020 in the United States. We establish that long-term orientation traits with bio-geographical origins causally reduce measures of COVID-19 cases, deaths and hospitalization, inpatient bed utilization, and age-specific excess deaths. Mobility indicators measuring voluntary decisions to socially distance, comprising measures of visitors/visits to recreational locations, and mobility proxy measuring duration of hours away from home show that a lower prevalence of long-term orientation traits explains persistent resistance to social distancing. The online version contains supplementary material available at 10.1007/s10887-022-09218-0.


Development, Validation, and Clinical Utility Assessment of a Prognostic Score for 1-Year Unplanned Rehospitalization or Death of Adult Sepsis Survivors.
The longer-term risk of rehospitalizations and death of adult sepsis survivors is associated with index sepsis illness characteristics. To derive and validate a parsimonious prognostic score for unplanned rehospitalizations or death in the first year after hospital discharge of adult sepsis survivors. This cohort study used data from the Intensive Care National Audit & Research Centre Case Mix Programme database on adult sepsis survivors identified from consecutive critical care admissions to 192 adult general critical care units in England, United Kingdom, between April 1, 2009, and March 31, 2014 (94 748 patients in the derivation cohort), and between April 1, 2014, and March 31, 2015 (24 669 patients in the validation cohort). Statistical analysis was performed from July 5 to October 31, 2019. Generic characteristics (age, sex, race/ethnicity, 2015 Index of Multiple Deprivation [IMD2015] in England quintiles, preadmission dependence, previous hospitalizations in the year preceding index sepsis admission, comorbidity, admission type, Acute Physiology and Chronic Health Evaluation II physiology score, hospital length of stay, worst blood lactate and blood hemoglobin concentrations, and type of hospital) and sepsis-specific characteristics (site of infection, numbers of organ dysfunctions, and organ support) at the index sepsis admission were used as predictors. Prognostic score derived and validated using multivariable logistic regression for the outcome of unplanned rehospitalization or death in the first year after hospital discharge of adult sepsis survivors, as well as clinical usefulness assessed using decision curve analysis. Prognostic score validation was performed for internal validation with bootstrapping and temporal cohort external validation. This cohort study included 94 748 patients (51 164 men [54.0%]; mean [SD] age, 61.3 [17.0] years) in the derivation cohort and 24 669 patients (13 255 men [53.7%]; mean [SD] age, 62.1 [16.8%]) in the validation cohort. Unplanned rehospitalization or death in the first year after hospital discharge occurred for 48 594 patients (51.3%) in the derivation cohort and 13 129 patients (53.2%) in the validation cohort. Eight independent predictors were identified and weighted to generate a prognostic score for every patient: previous hospitalizations, age in 10-year increments, IMD2015 in England quintiles, preadmission dependence, comorbidities, admission type, blood hemoglobin level, and site of infection. The total prognostic score ranged from 0 to 22 points, with lower scores indicating a lower risk of the outcome. The derivation and validation cohorts had similar rates of prognostic scores of 0 to 4 points (5088 of 16 684 patients [30.5%] and 471 of 1725 patients [27.3%]) and prognostic scores of 11 points or more (15 732 of 21 641 patients [72.7%] and 5753 of 7952 patients [72.3%]). The area under the receiver operating characteristic curve for the prognostic score was 0.675 (95% CI, 0.672-0.679). The decision curve analysis highlighted an optimal score cutoff of 7 points or more. The prognostic score reported in this study uses 8 internationally feasible predictors measured during the index sepsis admission and provides clinically useful information on sepsis survivors' risk of unplanned rehospitalization or death in the first year after hospital discharge.


Chemotherapy compliance in high-risk Merkel cell carcinoma treated with chemoradiotherapy.
To evaluate chemotherapy (CT) compliance in patients treated with chemoradiotherapy (CRT) for high-risk Merkel cell cancer (MCC). Data from three prospective clinical trials in high-risk MCC performed by the Trans-Tasman Radiation Oncology Group were included in this analysis. Patients were treated with one of two carboplatin-based CT schedules and standardised radiotherapy (RT) to the primary site and nodes to a dose of 50-60 Gy in 25-30 fractions. Patients' baseline characteristics were analysed using χ2 tests to determine compliance factors for completing CT. A Cox univariate analysis was performed to assess the impact of CT compliance on time to locoregional failure, time-to-distant failure, time-to-recurrence and time-to-death. A total of 88 patients were identified, with a median follow up of 38.5 months. Of these, 75 (85%) completed CT (median age 64.2 years, range 62.0-66.4), while 13 did not (median age 72 years, range 68.1-75.9), P = 0.006. Women comprised 18/75 patients who completed CT and 7/13 patients who did not complete it (P = 0.03). Performance status, site, stage, surgical margins, RT dose and toxicity did not impact on their CT compliance. At 5 years, 26% of patients had locoregional relapse, 26% had distant failure and 34% had died. In this small cohort of patients treated with CRT for high-risk MCC, older age and female sex were associated with failure to complete CT. Severe acute skin and haematological toxicity did not correlate with failure to complete CT.


Recurrent spontaneous breast hematoma: report of a case and review of the literature.
Breast hematomas are common after traumas, surgeries, or contusions. They are rarely spontaneous, but they can occur spontaneously in patients with hematologic disease or with coagulation disorders. The authors report a clinical case of a 48-year-old female with a 27-year history of paroxysmal nocturnal hemoglobinuria who underwent mammography screening because of a painless palpable moveable node in the upper inner quadrant of the right breast. Mammography showed a partially defined heterogeneous node of 35 mm without microcalcifications in the upper inner quadrant of the right breast which, associated with the clinical features, seemed to be an hematoma. Further mammography and ultrasound after 45 days showed retrocession of the lesion, and another mammography obtained after 60 days was normal. Seventy-five days after the first episode, the patient complained of another node with a skin bruise in the upper outer quadrant of the same breast, which seemed to be a recurrent hematoma. Two months later the mammography obtained was normal. Breast hematoma must be thought of as a differential diagnosis for a breast node, regardless of previous trauma or hematologic disorders.


Analysis of Low-Biomass Microbial Communities in the Deep Biosphere.
Over the past few decades, the subseafloor biosphere has been explored by scientific ocean drilling to depths of about 2.5km below the seafloor. Although organic-rich anaerobic sedimentary habitats in the ocean margins harbor large numbers of microbial cells, microbial populations in ultraoligotrophic aerobic sedimentary habitats in the open ocean gyres are several orders of magnitude less abundant. Despite advances in cultivation-independent molecular ecological techniques, exploring the low-biomass environment remains technologically challenging, especially in the deep subseafloor biosphere. Reviewing the historical background of deep-biosphere analytical methods, the importance of obtaining clean samples and tracing contamination, as well as methods for detecting microbial life, technological aspects of molecular microbiology, and detecting subseafloor metabolic activity will be discussed.


Innate and Adaptive Immunity of Murine Neural Stem Cell-Derived piRNA Exosomes/Microvesicles against Pseudotyped SARS-CoV-2 and HIV-Based Lentivirus.
By testing pseudotyped SARS-CoV-2 and HIV-based lentivirus, this study reports that exosomes/microvesicles (Ex/Mv) isolated from murine hypothalamic neural stem/progenitor cells (htNSC) or subtype htNSCPGHM as well as hippocampal NSC have innate immunity-like actions against these RNA viruses. These extracellular vesicles also have a cell-free innate antiviral action by attacking and degrading viruses. We further generated the induced versions of Ex/Mv through prior viral exposure to NSCs and found that these induced Ex/Mv were stronger than basal Ex/Mv in reducing the infection of these viruses, suggesting the involvement of an adaptive immunity-like antiviral function. These NSC Ex/Mv were found to be characterized by producing large libraries of P element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) against genomes of various viruses, and some of these piRNAs were enriched during the adaptive immunity-like reaction, possibly contributing to the antiviral effects of these Ex/Mv. In conclusion, NSC Ex/Mv have antiviral immunity and could potentially be developed to combat against various viruses.


Hydrogen sulphide management in anaerobic digestion: A critical review on input control, process regulation, and post-treatment.
Hydrogen sulphide (H2S) in biogas is a problematic impurity that can inhibit methanogenesis and cause equipment corrosion. This review discusses technologies to remove H2S during anaerobic digestion (AD) via: input control, process regulation, and post-treatment. Post-treatment technologies (e.g. biotrickling filters and scrubbers) are mature with >95% removal efficiency but they do not mitigate H2S toxicity to methanogens within the AD. Input control (i.e. substrate pretreatment via chemical addition) reduces sulphur input into AD via sulphur precipitation. However, available results showed <75% of H2S removal efficiency. Microaeration to regulate AD condition is a promising alternative for controlling H2S formation. Microaeration, or the use of oxygen to regulate the redox potential at around -250 mV, has been demonstrated at pilot and full scale with >95% H2S reduction, stable methane production, and low operational cost. Further adaptation of microaeration relies on a comprehensive design framework and exchange operational experience for eliminating the risk of over-aeration.


Roseovarius algicolus sp. nov., isolated from culture fluid of Cochlidinium polykrikoides.
A Gram-negative, aerobic, non-motile, catalase and oxidase positive rod-shaped bacterium, designated strain 4CoA2(T), was isolated from Cochlidinium polykrikoides culture fluid in the laboratory. The strain formed circular, glistening, grayish yellow colonies and grew at pH 7-8 and 28 °C optimally. On the basis of 16S rRNA gene sequence similarity, the strain was shown to be phylogenetically related to Roseovarius indicus B108(T) (97.6 %), Roseovarius halotolerans HJ50(T) (97.3 %), Roseovarius pacificus 2-81(T) (96.6 %), Roseovarius litoreus GSW-M15(T) (96.3 %) and Roseovarius tolerans EL-172(T) (94.27 %). Chemotaxonomic data revealed that the strain 4CoA2(T) possesses ubiquinone Q-10, and the predominant fatty acid is C18:1 ω6c or C18:1 ω7c. The polar lipids profile of the strain 4CoA2(T) included major amounts of phosphatidylglycerol, phosphatidylcholine, and diphosphatidyl glycerol. The DNA G + C content of the strain 4CoA2(T) is 62.0 %. Strain 4CoA2(T) exhibited relatively low level of DNA hybridization values (<35 %) with other Roseovarius species. On the basis of its phenotypic, genotypic properties and its phylogenetic data, strain 4CoA2(T) can be concluded to represent a novel species in the genus Roseovarius, for which the name Roseovarius algicolus sp. nov. is proposed. The type strain is 4CoA2(T) (=JCM 30823(T), =KEMB 3501-06(T)).


A case of Mollaret's meningitis associated with a lymphoma.
A patient with recurrent benign meningitis (Mollaret's meningitis) responding to treatment with colchicine by a reduction in frequency of attacks who has subsequently developed a non-Hodgkin's lymphoma is described.


Comparison between pernasal flocked swabs and nasopharyngeal aspirates for detection of common respiratory viruses in samples from children.
In this prospective study we compared the use of pernasal flocked swab samples with the use of nasopharyngeal aspirate (NPA) samples for the detection of respiratory viruses from 455 children less than 5 years of age. Overall, the sensitivity and the specificity of the pernasal flocked swab samples were 98.5% and 100%, respectively. The excellent sensitivity of the flocked swab samples in combination with the rapid means by which they may be collected makes them an alternative to NPA samples, whose collection is more invasive.


Gelation of fluorinated liquids by non-fluorinated low-molecular-mass molecules.
A family of tetrahydroxy diesters has been synthesised and observed to gel a range of fluorinated solvents and their mixtures; the phase behaviour and gel microstructure are reported for a homologous family of these diesters in blends of 1H,1H-heptafluorobutanol (HFB) and 2H,3H-perfluoropentane (HPFP).


Single-particle mass analysis of intact ribosomes by mass photometry and Orbitrap-based charge detection mass spectrometry.
Standard methods for mass analysis measure ensembles of thousand to millions of molecules. This approach enables analysis of monodisperse recombinant proteins, whereas some heterogeneous protein assemblies pose a significant challenge, whereby co-occurring stoichiometries, sub-complexes, and modifications hamper analysis using native mass spectrometry. To tackle the challenges posed by mass heterogeneity, single-particle methods may come to the rescue. Recently, two such approaches have been introduced, namely, mass photometry (MP) and Orbitrap-based charge detection mass spectrometry (CDMS). Both methods assess masses of individual molecules, albeit adhering to distinct physical principles. To evaluate these methods side by side, we analyzed a set of ribosomal particles, representing polydisperse ribonucleoprotein assemblies in the MDa range. MP and CDMS provide accurate masses for intact ribosomes and enable quantitative analysis of concomitant distinct particles within each ribosome sample. Here, we discuss pros and cons of these single-molecule techniques, also in the context of other techniques used for mass analysis.


Inactivation of mediator complex protein 22 in podocytes results in intracellular vacuole formation, podocyte loss and premature death.
Podocytes are critical for the maintenance of kidney ultrafiltration barrier and play a key role in the progression of glomerular diseases. Although mediator complex proteins have been shown to be important for many physiological and pathological processes, their role in kidney tissue has not been studied. In this study, we identified a mediator complex protein 22 (Med22) as a renal podocyte cell-enriched molecule. Podocyte-specific Med22 knockout mouse showed that Med22 was not needed for normal podocyte maturation. However, it was critical for the maintenance of podocyte health as the mice developed progressive glomerular disease and died due to renal failure. Detailed morphological analyses showed that Med22-deficiency in podocytes resulted in intracellular vacuole formation followed by podocyte loss. Moreover, Med22-deficiency in younger mice promoted the progression of glomerular disease, suggesting Med22-mediated processes may have a role in the development of glomerulopathies. This study shows for the first time that mediator complex has a critical role in kidney physiology.


Metabolism of mutagenic polycyclic aromatic hydrocarbons by photosynthetic algal species.
Polycyclic aromatic hydrocarbons (PAH) known to produce carcinogenic and mutagenic effects have been shown to contaminate waters, sediments and soils. While it is accepted that metabolites of these compounds are responsible for most of their biological effects in mammals, their metabolism, and to a large extent their bioactivity, in aquatic plants have not been explored. Cultures of photosynthetic algal species were assayed for their ability to metabolize benzo[a]pyrene (BaP), a carcinogenic PAH under conditions which either permitted (white light) or disallowed (gold light) photooxidation of the compound. Growth of Selenastrum capricornutum, a fresh-water green alga, was completely inhibited when incubated in white light with 160 micrograms BaP/l medium. By contrast concentrations at the upper limit of BaP solubility in aqueous medium had no effect on algal growth when gold light was used. BaP quinones and phenol derivatives were found to inhibit growth of Selenastrum under white light incubation. BaP phototoxicity and metabolism were observed to be species-specific. All 3 tested species of the order Chlorococcales were growth-inhibited by BaP in white light whereas neither the green alga Chlamydomonas reinhardtii nor a blue-green, a yellow-green or an euglenoid alga responded in this fashion. Assays of radiolabeled BaP metabolism in Selenastrum showed that the majority of radioactivity associated with BaP was found in media as opposed to algal cell pellets, that the extent of metabolism was BaP concentration dependent, and that the proportion of various metabolites detected was a function of the light source. After gold light incubation, BaP diols predominated while after white light treatment at equal BaP concentrations, the 3,6-quinone was found in the highest concentration. Extracted material from algal cell pellets and from media was tested for mutagenicity in a forward mutation suspension assay in Salmonella typhimurium using resistance to 8-azaguanine for selection. Direct-acting mutagens were detected in extracted media from incubation of Selenastrum with 400 micrograms BaP/l for 1 day in gold light. Extracts of media from algae incubated in gold light from 1 to 4 days with 1200 micrograms BaP/l were found to have direct-acting mutagens as well as those requiring further metabolism. Media extracts from white light incubations of BaP were mutagenic upon addition of rat liver homogenates. Activity of these materials from white light treatment are largely attributable to unmetabolized BaP.


Electrophysiological and fundoscopic detection of intracranial hypertension in craniosynostosis.
To assess the diagnostic accuracy of fundoscopy and visual evoked potentials (VEPs) in detecting intracranial hypertension (IH) in patients with craniosynostosis undergoing spring-assisted posterior vault expansion (sPVE). Children with craniosynostosis undergoing sPVE and 48-hour intracranial pressure (ICP) monitoring were included in this single-centre, retrospective, diagnostic accuracy study. Data for ICP, fundoscopy and VEPs were analysed. Primary outcome measures were papilloedema on fundoscopy, VEP assessments and IH, defined as mean ICP > 20 mmHg. Diagnostic indices were calculated for fundoscopy and VEPs against IH. Secondary outcome measures included final visual outcomes. Fundoscopic examinations were available for 35 children and isolated VEPs for 30 children, 22 of whom had at least three serial VEPs. Sensitivity was 32.1% for fundoscopy (95% confidence intervals [CI]: 15.9-52.4) and 58.3% for isolated VEPs (95% CI 36.6-77.9). Specificity for IH was 100% for fundoscopy (95% CI: 59.0-100) and 83.3% for isolated VEPs (95% CI: 35.9-99.6). Where longitudinal deterioration was suspected from some prVEPs but not corroborated by all, sensitivity increased to 70.6% (95% CI: 44.0-89.7), while specificity decreased to 60% (95% CI: 14.7-94.7). Where longitudinal deterioration was clinically significant, sensitivity decreased to 47.1% (23.0-72.2) and specificity increased to 100% (47.8-100). Median final BCVA was 0.24 logMAR (n = 36). UK driving standard BCVA was achieved by 26 patients (72.2%), defined as ≥0.30 logMAR in the better eye. Papilloedema present on fundoscopy reliably indicated IH, but its absence did not exclude IH. VEP testing boosted sensitivity at the expense of specificity, depending on method of analysis.


Analysing the citizenship agenda in Mathematical Literacy school exit assessments.
Assessments, in particular high stakes assessments, impact the nature of teaching and learning. Given this, the goal of citizenship if seen as important needs to feature within high stakes school exit assessments rather than only as part of curriculum and assessment policy rhetoric. South Africa's Mathematical Literacy (ML) curriculum foregrounds critical democratic citizenship. We analyse the ML Grade 12 exit assessments from their start in 2008 to 2020 to understand the emphasis placed on critical citizenship and how this emphasis has shifted over time. The literature base links critical citizenship orientations with reasoning and reflecting questions, so we focused on examination questions in this category. Our findings show shifts away from critical citizenship related agendas towards foregrounding a life preparation orientation for the self-managing person. Linked with this shift, we note a move away from general societal contexts towards more personal/individual contexts and moves from almost entirely national contexts to inclusion of global contexts. We noted movement from more open-phrased questions towards closed 'check figure calculated is valid'-type questions. Assessment memoranda suggest assessors view these questions as reasoning items, eroding the critical citizenship agenda. While increasing numbers of students are taking ML rather than Mathematics, average performance stands at around 40%. This points to limited and diminishing access to mathematical reasoning and reflecting for critical democratic citizenship. The paper highlights ways in which analysis of examinations over time can provide a window into the presence or absence of the citizenship agenda in mathematics education.


Breast epithelial antigen levels and breast tumor antigen content.
The relationship between the primary tumor expression of a breast epithelial antigen, called non-penetrating glycoprotein (NPGP) or breast epithelial mucin, and the same patient's serum level of this antigen at the time of relapse was studied in 23 cases. The expression of NPGP on breast tumors was measured by immunoperoxidase staining using monoclonal antibody Mc5, and quantitated by a histopathological index created for this purpose. Serum levels were measured by a competitive RIA using the same monoclonal antibody. An inverse correlation between these parameters was found, such that tumors having high NPGP levels in serum had a low index, while low NPGP serum levels had a high index. These results show that cellular events in breast tumors could participate in determining NPGP serum levels in breast cancer.


Dose-dense primary systemic chemotherapy with gemcitabine plus epirubicin sequentially followed by docetaxel for early breast cancer: final results of a phase I/II trial.
We recruited 50 patients with T2-4 N0-2 M0 primary breast cancer into a phase I/II study to define the maximum tolerated dose (MTD), efficacy and tolerability of preoperative gemcitabine (1250 mg/m fixed dose) plus epirubicin (doses escalated from 90 mg/m) for 5 cycles followed by 4 cycles of docetaxel (scheduled fixed dose 100 mg/m) given on day 1 every 2 weeks (q2w) with pegfilgrastim support. The MTD for epirubicin was 100 mg/m, but the docetaxel dose had to be reduced to 80 mg/m. Dose-limiting toxicities included fatigue, stomatitis, diarrhea and dyspnea (all grade 3) during gemcitabine plus epirubicin, and fatigue (grade 3) and allergic reaction (grade 4) during docetaxel treatment, respectively. A pathologic complete response could be achieved in 13 patients (pT0+pTis, 26%), and in the breast and axilla in 12 patients [(pT0 or pTis)+pN0, 24%). Breast-conserving surgery (BCS) was possible in 35 patients (70%). Main grade 3/4 adverse events at MTD were fatigue (57/0%), leukopenia (27/8%), and liver (14/0%) and lung toxicity (14/0%). In conclusion, gemcitabine plus epirubicin 1250/100 mg/m q2w followed sequentially by docetaxel 80 mg/m q2w is highly effective as pre-operative chemotherapy with manageable toxicity. However, response and BCS rates could not be increased by administering gemcitabine plus epirubicin and docetaxel in a dose-dense fashion.


A note on the synthesis of 5'-AMP ester of tris (hydroxymethyl)aminomethane by rat liver plasma membrane.
The alcohol-AMP synthesizine enzyme of rat liver plasma membrane also synthesizes the 5'-AMP ester of tris(hydroxymethyl)aminomethane as judged by the use of [alpha-32P] ATP and [U-14C] ATP. This synthetic process may decrease significantly the concentration of ATP during incubation.


Effect of Bacillus firmus on antibody formation after mucosal and parenteral immunization in mice.
Immunostimulatory properties of B. firmus, a nontoxic, nonpathogenic G + bacterium of external environment, were described previously. Antiinfectious and antitumor activity, macrophage activation and strong polyclonal stimulation of B lymphocytes were proved in human, mice and rats. The adjuvant effect of B. firmus on specific antibody response to ovalbumin in BALB/c mice is the topic of the present study. Against our expectation, B. firmus exerts more suppressive than stimulatory effect on specific antibody response. Formolized B. firmus decreased anti-ovalbumin response after subcutaneous immunization and only slightly increased serum antibodies after intraperitoneal immunization. After mucosal immunization, both oral and rectal, ovalbumin itself did not cause a significant systemic response but induced IgA anti-ovalbumin response in the intestine. B. firmus applied together with ovalbumin increased systemic serum response but absolutely eliminated intestinal response. The rectal route of antigen administration has been found less convenient because of less precise dosing of antigen in this mode of immunization.


[Videoassisted thoracoscopic treatment of retained fluid collection in the pleural cavity after thoracotomy].
One of the common complications of the thoracotomies is the formation of incapsulated fluid collections in the pleural cavity. There are different invasive methods for their treatment. The authors shared their experience with the videoassisted thoracoscopic treatment of 19 patients with pleural collections, treated in the clinic for a period of four years (2000-2003 year). VATS at 17 of the patients leads to healing. We performed rethoracotomy at two of the patients because there were no effect of VATS. VATS is an alternative of rethoracotomy in the operative treatment of postoperative fluid collections in the pleural cavity.


Impact of laparoscopic gastrectomy on relapse-free survival for locally advanced gastric cancer patients with sarcopenia: a propensity score matching analysis.
Recent gastric cancer reports have shown that preoperative sarcopenia worsens long-term prognosis after gastrectomy. We investigated the impact of laparoscopic surgery on the long-term prognosis of locally advanced gastric cancer patients with sarcopenia. This retrospective study included consecutive patients who underwent radical gastrectomy for primary c-stage II or III advanced gastric cancer, between April 2008 and April 2017, with computed tomography records of skeletal muscle mass. The skeletal muscle mass index was calculated, and sarcopenia was defined when values were below the cut-off. The patients were divided into a laparoscopy group and open group, in which the background was adjusted using propensity score matching; the relapse-free survival and overall survival were compared between them. The prognostic factors for relapse-free survival and overall survival were investigated by multivariate analyses. This study included 141 patients with sarcopenia (laparoscopy group, n = 69 [48.9%]; open group, n = 72 [51.1%]). After matching, there were 50 patients in both groups, with no significant differences in patient background. The median follow-up period was 38 months. Relapse-free survival was worse in the open group (hazard ratio: 1.662, 95% confidence interval: 0.910-3.034; P = 0.098), but there was no difference in the overall survival (P = 0.181). Multivariate analysis concluded that open surgery is an independent prognostic factor of relapse-free survival (hazard ratio: 3.219, 95% confidence interval: 1.381-7.502; P = 0.007) but not of OS. Compared with the open surgery group, the laparoscopy group had a better RFS, although the difference was not statistically significant.


Functional connectivity between memory and reward centers across task and rest track memory sensitivity to reward.
External motivation, such as a promise of future monetary reward for remembering an event, can affect which events are remembered. Reward-based memory modulation is thought to result from encoding and post-encoding interactions between dopaminergic midbrain, signaling reward, and hippocampus and parahippocampal cortex, supporting episodic memory. We asked whether hippocampal and parahippocampal interactions with other reward-related regions are related to reward modulation of memory and whether such relationships are stable over time. Individuals' memory sensitivity to reward was measured using a monetary incentive encoding task in which a cue indicated potential monetary reward (penny, dime, or dollar) for remembering an upcoming object pair. Functional connectivity between memory and reward regions was measured before, during, and following the task. Reward-related regions of interest were generated using a meta-analysis of existing studies on reward and included ventral striatum, medial and orbital prefrontal cortices and anterior cingulate cortex, in addition to midbrain. The results showed that connectivity between memory and reward regions tracked individual differences in reward modulation of memory, irrespective of when connectivity was measured. Connectivity patterns of anterior cingulate, orbitofrontal cortex, and ventral striatum covaried together and tracked behavior most strongly. These findings implicate a broader set of reward regions in reward modulation of memory than considered previously and provide new evidence that stable connectivity patterns between memory and reward centers relate to individual differences in how reward impacts memory.


Stress-Strain Model for Lightweight Aggregate Concrete Reinforced with Carbon-Polypropylene Hybrid Fibers.
This research aimed to investigate the hybrid effects of carbon and polypropylene fibers on the stress-strain behavior of lightweight aggregate concrete (LWAC). The considered test variables were two fiber volume fractions of 0.2% and 0.4% and two water/binder ratios of 0.27 and 0.30. Eighteen groups of prisms fabricated with fiber-reinforced LWAC were tested under axial compressive load. Experimental studies were carried out to analyze the influence of different fiber combinations on the complete stress-strain behavior. It was found that the carbon-polypropylene hybrid fibers led to toughness enhancement that was numerically more significant than the sum of individual fibers, indicating a positive synergistic effect between them. Finally, a mathematical expression of the stress-strain curve accounting for the fiber combinations was developed. Compared with existing stress-strain models, the proposed model shows better accuracy in predicting the effect of carbon and polypropylene fibers in both single and hybrid forms on the stress-strain curve of LWAC.


Pyrrolidinium lead iodide from crystallography: a new perovskite with low bandgap and good water resistance.
The crystal structure of a new perovskite material, (C4H8NH2)PbI3 was determined and illustrated by single crystal X-ray diffraction. UV spectra, photoluminescence and XRD results show it is a promising alternative to hybrid organic-inorganic perovskites due to it's good water resistance and suitable bandgap.


Calcium antagonists in acute myocardial infarction.
Calcium antagonists have proved effective in stable angina, unstable angina and vasospastic angina. However, despite a strong theoretical rationale for their use and promising experimental data, these agents have not reduced infarct size in acute myocardial infarction (AMI) in the large clinical trials performed to date. Their role as adjunctive therapy in combination with reperfusion needs to be examined. Diltiazem has been demonstrated to reduce angina and reinfarction in the 2-week period after AMI in patients receiving multidrug therapy. Results of the single large trial of a calcium antagonist (verapamil) for secondary prevention after AMI were negative; however, several well-designed studies are currently ongoing.


Iatrogenic retroposition of the lips sequel after bicuspid extraction-a retrospective study.
This study aims to explore the prevalence of Iatrogenic retroposition of the lips sequel (IRLS) after bicuspid extraction, associated dentofacial characteristics and the effectiveness of surgical treatment. and methods: Patients with bicuspid extraction as part of an orthodontic treatment plan were retrospectively included. IRLS was identified by clinical evaluation and cephalometric Legan and Burstone analysis. Association of demographic and cephalometric variables were assessed. The effectiveness of combined orthodontic-orthognathic correction of the retroposition of the lips was evaluated. Out of 144 patients with extracted bicuspids, eight Class I patients, nine Class II patients and five Class III patients were seeking treatment because their lips had retruded as a consequence of compensating orthodontic treatment. Lower jaw bicuspid extraction and a decreased vertical facial height in Class II patients correlated significantly more with IRLS development. Postoperative cephalometric analysis of orthodontic-orthognathic treated patients reported improvement in lip projection and naso-labial angle. Only two Class I patients reported postoperative normalization of the lip position according to Legan and Burstone. The consequence of bicuspid extractions on soft tissue profile differs according to skeletal jaw relation. The impact of orthognathic surgery on IRLS is beneficial, although insufficient to completely correct the facial profile when judged on cephalometric standards.


Effect of probiotic fermented milk and chlorophyllin on gene expressions and genotoxicity during AFB₁-induced hepatocellular carcinoma.
The aim of this study was to investigate the chemopreventive effect of probiotic fermented milk and chlorophyllin on aflatoxin B₁ (AFB₁) induced hepatocellular carcinoma. In vivo trials were conducted on 200 Wistar rats allocated to eight groups. Rats in the positive control group were given intraperitoneal injection of aflatoxin B₁ at 450 μg/kg body weight twice a week for 6 weeks. The rats were sacrificed and dissected at 25th week of the experiment, and comet assay was carried out in hepatic cells to assess the genotoxicity or DNA damage. The tumour incidence was decreased by approximately one-third than AFB₁ control group. The expression of c-myc bax, bcl-2, cyclin D1, p53 and rasp-21 genes was also studied. A significant (P<0.05) reduction in DNA damage was observed in probiotic fermented milk with chlorophyllin group as compared to aflatoxin B₁ control group. The c-myc, bcl-2, cyclin D1 and rasp-21 level was found to be highest in AFB₁ control group as compared to the treatment group. The results advocate the enhanced protective potential of probiotic fermented milk and chlorophyllin against AFB₁-induced molecular alterations in hepatic cells during carcinogenesis.


Influence of Hospital Formularies on Outpatient Prescribing Practices: Analysis of the Introduction of a Local Formulary: A Single-Center, 2-Year Follow-Up, Retrospective Cohort Study of a Local Formulary in Japan.
The impact of a hospital formulary was evaluated to provide a guide for the establishment of local formularies to optimize patient care and healthcare costs. A formulary was introduced by formulary pharmacists of the Toda Medical Group for suggesting recommended medicines to physicians based on the medication history. Patients who were hospitalized in the rehabilitation ward of the Niiza Hospital and prescribed medicines according to the formulary introduced between April 2017 and March 2018 were included and followed-up for six months. Of the 183 patients screened, 154 patients were enrolled as the formulary's introduction patients (76 males/78 females, median age 78 years); 92% of these patients received formulary-proposed prescriptions at the specified timepoints; and 19 patients re-consulted at the Niiza Hospital after discharge and continued the same formulary medicines. The proposed acceptance rate by physicians was 100%. Most changes suggested introduced generic formulations. The doses were equivalent for all pharmacological classes with the exception of medicines that interfere with the renin-angiotensin system, which fell from 10.7 to 7.2 mg (P< .0001). Overall daily medication costs fell at discharge compared to admission (38.5 vs. 94.6 yen per patient, respectively, P< .0001). This was valid for all pharmacological classes except for calcium channel blockers. Hospital formulary-prescribed medications continued after discharge and promoted significant decreases in costs associated with outpatient prescriptions. Introducing a hospital formulary provides a basis for the introduction of local formularies and contributes to the reduction of local healthcare costs.


Predicting residual lymph node basin disease in melanoma patients with sentinel lymph node metastases.
The incidence of residual occult disease in nonsentinel lymph nodes (NSLN) after a positive sentinel lymph node (SLN) biopsy in patients with melanoma is relatively low. The purpose of this study is to identify factors that may be predictive of occult NSLN metastases after positive SLN biopsy. Fifty-six consecutive melanoma patients with positive sentinel nodes who subsequently underwent complete lymph node dissection (CLND) were evaluated. Only the number of positive SLN predicted the status on NSLN by univariate (P = 0.008) and multivariate (P = 0.028) analyses. None of the other variables (characteristics of SLN metastases, number of draining nodal basins, age, sex, thickness, Clark level, ulceration, number of mitoses/mm(2), histological subtype, and location of the primary) significantly predicted CLND results. Identifying patients with residual lymph node basin disease remains difficult. Thus, lymph node dissection should be performed in all patients after positive sentinel node biopsy.