High expression of REV7 is an independent prognostic indicator in patients with diffuse large B-cell lymphoma treated with rituximab.
REV7 is a multifunctional protein involved in DNA damage tolerance, cell-cycle regulation, gene expression, and carcinogenesis. Although its expression is reportedly associated with poor prognosis in human solid tissue cancers, the significance of REV7 expression in hematopoietic malignancies is unclear. This study evaluated the prognostic significance of REV7 expression in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-combined chemotherapy. Using immunohistochemistry, we analyzed 83 specimens of de novo DLBCL [38 germinal center B-cell-like (GCB) and 45 non-GCB DLBCLs] treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone for REV7 expression. Aberrant REV7 expression was detected in DLBCL cell nuclei. High REV7 expression was associated with significantly shorter overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis and log-rank tests (P < 0.01 and P < 0.01, respectively). Multivariate analysis revealed that REV7 expression is an independent prognostic factor for both OS and PFS. Additionally, when patients were divided into four groups using a combination of REV7 expression and international prognostic index (IPI) or Bcl-2 expression, REV7(High)/IPI(Poor) and REV7(High)/Bcl-2(High) patients showed the poorest outcome. These results indicate that REV7 may be a useful biomarker to predict the prognosis of patients with DLBCL treated with rituximab.


Central activation of cardiac vagal nerve by α2-adrenergic stimulation is impaired in streptozotocin-induced type 1 diabetic rats.
To elucidate the abnormality of cardiac vagal control in streptozotocin-induced type 1 diabetic rats, we measured left ventricular myocardial interstitial acetylcholine (ACh) release in response to α2-adrenergic stimulation as an index of in vivo cardiac vagal nerve activity. A cardiac microdialysis technique was applied to the rat left ventricle, and the effect of α2-adrenergic stimulation by intravenous medetomidine (100 μg/kg) on myocardial interstitial ACh levels was examined in anesthetized diabetic rats (4-6 weeks after intraperitoneal streptozotocin) and age-matched control rats (protocol 1). The effect of electrical vagal nerve stimulation on ACh levels was also examined in separate rats (protocol 2). In protocol 1, medetomidine increased the ACh levels in control (from 1.76 ± 0.65 to 3.13 ± 1.41 nM, P < 0.05, n = 7) but not in diabetic rats (from 2.01 ± 0.47 to 1.62 ± 0.34 nM, not significant, n = 7). In protocol 2, electrical vagal nerve stimulation at 20 Hz significantly increased the ACh levels in both control (from 1.49 ± 0.26 to 6.39 ± 1.81 nM, P < 0.001, n = 6) and diabetic rats (from 1.77 ± 0.54 to 6.98 ± 1.38 nM, P < 0.001, n = 6). In conclusion, medetomidine-induced central vagal activation was impaired in diabetic rats, whereas peripheral cardiac vagal control of ACh release was preserved. The impairment of central vagal activation may lead to relative sympathetic predominance and promote cardiovascular complications in diabetes.


Itraconazole therapy for disseminated candidiasis in a very low birthweight neonate.
The management of a preterm neonate with systemic candidiasis using oral itraconazole is described. Oral itraconazole was well tolerated and effected a clinical and mycological cure.


Neuromodulation for Epilepsy.
Several palliative neuromodulation treatment modalities are currently available for adjunctive use in the treatment of medically intractable epilepsy. Over the past decades, a variety of different central and peripheral nervous system sites have been identified, clinically and experimentally, as potential targets for chronic, nonresponsive therapeutic neurostimulation. Currently, the main modalities in clinical use, from most invasive to least invasive, are anterior thalamus deep brain stimulation, vagus nerve stimulation, and trigeminal nerve stimulation. Significant reductions in seizure frequency have been demonstrated in clinical trials using each of these neuromodulation therapies.


Probing many-body dynamics in a two-dimensional dipolar spin ensemble.
The most direct approach for characterizing the quantum dynamics of a strongly interacting system is to measure the time evolution of its full many-body state. Despite the conceptual simplicity of this approach, it quickly becomes intractable as the system size grows. An alternate approach is to think of the many-body dynamics as generating noise, which can be measured by the decoherence of a probe qubit. Here we investigate what the decoherence dynamics of such a probe tells us about the many-body system. In particular, we utilize optically addressable probe spins to experimentally characterize both static and dynamical properties of strongly interacting magnetic dipoles. Our experimental platform consists of two types of spin defects in nitrogen delta-doped diamond: nitrogen-vacancy colour centres, which we use as probe spins, and a many-body ensemble of substitutional nitrogen impurities. We demonstrate that the many-body system's dimensionality, dynamics and disorder are naturally encoded in the probe spins' decoherence profile. Furthermore, we obtain direct control over the spectral properties of the many-body system, with potential applications in quantum sensing and simulation.


Tertiary structure of Bacillus thermoproteolyticus [4Fe-4S] ferredoxin. Evolutionary implications for bacterial ferredoxins.
The structure of a low-potential [4Fe-4S] ferredoxin from Bacillus thermoproteolyticus has been solved using anomalous scattering data from iron atoms in the diffraction data of native crystals and refined partially to a crystallographic R-factor of 0.33, with 2.3 A (1 A = 0.1 nm) resolution data. The least-squares refinement based on the Bijvoet differences has determined that the four iron atoms in the cluster are an equal distance, approximately 2.8 A, apart. The NH ... S hydrogen bonds between polypeptide nitrogen atoms, and both cysteine and inorganic sulfur atoms, are present, as in ferrodoxin from Peptococcus aerogenes. The polypeptide chain of the B. thermoproteolyticus ferredoxin has a fold closely similar to that of 2[4Fe-4S] ferredoxin from P. aerogenes. The structural correspondence indicates strongly that both types of ferredoxin evolved from a common ancestor. The second cluster-binding region in P. aerogenes ferredoxin corresponds to the alpha-helix in B. thermoproteolyticus ferredoxin. The secondary-structure predictions strongly suggest that the alpha-helix is generally present in the monocluster-type ferredoxins. The conformational change to alpha-helix, insertions of a loop and a protrusion, as well as the absence of the second cluster in B. thermoproteolyticus ferredoxin, result in the lack of 2-fold symmetry present in P. aerogenes ferredoxin. So, the track of gene duplication is no longer detectable in the tertiary structure alone. The evolutionary events that may have occurred in the ferredoxins with the [4Fe-4S] cluster are discussed.


Animal studies on the efficacy of an inactivated herpes simplex virus vaccine against recurrent herpes infection.
The efficacy of inactivated herpes simplex virus vaccines for the treatment of recurrent herpes infection was studied in an animal model. Neither the frequency nor the severity of recurrent herpetic lesions could be influenced by long-term treatment of the animals with these vaccines.


Dietary treatment of hyperlipidemia in the elderly.
Elderly people are vulnerable to a variety of nutritional, medical, and socioeconomic stringencies. The additional imposition of a restrictive diet for those with hypercholesterolemia is a matter to be decided on the merits of individual cases; however, such diet therapy generally is both problematic and unproductive.


Redox signaling and the MAP kinase pathways.
The mitogen-activated protein (MAP) kinases are a large family of proline-directed, serine/threonine kinases that require tyrosine and threonine phosphorylation of a TxY motif in the activation loop for activation through a phosphorylation cascade involving a MAPKKK, MAPKK and MAPK, often referred to as the MAP kinase module. Three separate such modules have been identified, based on the TxY motif of the MAP kinase and the dual-specificity kinases that strictly phosphorylate their specific TxY sequence. They are the extracellular signal regulated kinases (ERKs), c-jun N-terminal kinases (JNKs) and p38 MAPKs. The ERKs are mainly associated with proliferation and differentiation while the JNKs and p38MAP kinases regulate responses to cellular stresses. Redox homeostasis is critical for proper cellular function. While reactive oxygen species (ROS) and oxidative stress have been implicated in injury, a rapidly growing literature suggests that a transient increase in ROS levels is an important mediator of proliferation and results in activation of various signaling molecules and pathways, among which the MAP kinases. This review will summarize the role of ROS in MAP kinase activation in various systems, including in macrophages, cells of myeloid origin that play an essential role in inflammation and express a multi-component NADPH oxidase that catalyzes the receptor-regulated production of ROS.


Peroral endoscopic myotomy for cricopharyngeal bar.
Definitive treatment options for refractory dysphagia due to cricopharyngeal bar are limited. We aimed to demonstrate a novel adaptation of peroral endoscopic myotomy to treat this condition (cricopharyngeal peroral endoscopic myotomy [c-POEM]). The approach to c-POEM is similar to that in the distal esophagus for the treatment of achalasia. A submucosal injection and overlying mucosal incision are performed, ideally 1.5 to 2 cm upstream of the upper esophageal sphincter, and then a submucosal tunnel is extended beyond the level of the cricopharyngeus. The target muscle is then transected before closure of the mucosotomy. In 3 cases of refractory cricopharyngeal bar, c-POEM was successfully performed. Although no major adverse events occurred, significant postprocedural edema at the level of the upper esophageal sphincter prolonged hospitalization in 2 of the 3 patients. After recovery, all patients reported complete resolution of dysphagia and tolerated an unrestricted diet. C-POEM allows reliable and complete muscular division in patients with refractory cricopharyngeal bar who have limited treatment options.


Computerized tomography of retroperitoneal lymphadenopathy: benign or malignant.
A distinguishing feature has been noted to help differentiate between malignant retroperitoneal nodes and nodes which contain reactive hyperplasia. This sign is the presence of a cleavage plane between the mass of nodes and the great vessels which are easily visible in benign disease. This distinction is in reference to malignant nodal disease where the contours of the vessels are obscured. The ability to make a diagnosis of benign disease on CAT scan has enabled us to choose the appropriate course of therapy and, in some patients, allowed us to avoid exploratory laparotomy for diagnosis.


New perspectives in cyclic AMP-mediated axon growth and guidance: The emerging epoch of Epac.
In the search for a cure to brain and spinal cord injury much has been learned about the inhibitory environment of the central nervous system (CNS), and yet a clinical therapy remains elusive. In recent years great advances have been made in understanding intracellular molecular mechanisms that transduce cell surface receptor-mediated signals that neurons receive from their environment. Many of these signalling pathways share common mechanisms, which presents the possibility that manipulating activities of key cell signalling molecules such as those regulated by 3'-5'-cyclic adenosine monophosphate (cAMP) might allow axons to simultaneously overcome the inhibitory effects of a number of extracellular ligands. The identification of Epac, a novel direct intracellular target for cAMP, has opened up a new avenue of research that is beginning to explain how cAMP can mediate a range of neuronal functions including distinct axon growth and guidance decisions. With current research tools that allow more specific activation of proteins or knock-down of their expression, as well as quantitation of protein activities in live cells, it is already becoming clear that Epac plays highly important roles in the development and function of the nervous system. Here, we focus on emerging evidence that Epac mediates cAMP-regulated axon growth and chemoattraction, and thus represents a novel target for overcoming axon growth inhibition and promoting CNS regeneration.


Topography of the chloroplast cytochrome b6: orientation of the cytochrome and accessibility of the lumen-side interhelix loops.
The topography of chloroplast cytochromes f and b6 was probed with proteases carboxypeptidase A (CpA), trypsin, and Staph, aureus V8. The cytochrome and its proteolytic products were detected by heme stain and, in most experiments, by immunoreaction. In thylakoids, the only protease that significantly affected the intactness of cytochrome f was CpA that caused a small (delta Mr = -1-2000) decrease in the apparent molecular weight. In SDS-treated thylakoids, both trypsin and V8 degraded cytochrome f. The inferred topography of cytochrome f., with the COOH-terminus on the stromal (n) side, one membrane-spanning alpha-elix near the COOH-terminus, and most of the Cyt f mass on the lumen (p) side, is consistent with that previously inferred by others. Cytochrome b6 was not sensitive to CpA, but was more sensitive to trypsin and V8 protease than cytochrome f, cytochrome b-559, or the 17 kDa OEC extrinsic protein. Trypsin caused a small decrease in size of cytochrome b6, which was observed using whole protein antibody as a single smaller band (delta Mr approximately 2000) or two smaller discrete bands (delta Mr = -1000 and 2500, respectively) which, unlike the untreated protein, did not react with antibody generated to a peptide mimicking Asp-5-Gln-14 near the NH2-terminus. These shortened tryptic fragments were attributed to cleavage after R-10 and K-23 near the NH2-terminus, implying an orientation with the NH2-terminus on the stromal side of the membrane. The sensitivity of cytochrome b6 toward this trypsin cleavage was increased if the membranes were first incubated with CpA, showing that the NH2-terminal region of cytochrome b6 is masked by the COOH-terminal domain of one or more thylakoid proteins.(ABSTRACT TRUNCATED AT 250 WORDS)


Calcaneal Broadband Ultrasound Attenuation and Speed of Sound Measurements in a Population of Nigerian Children: Reference Data and the Influence of Sociodemographic Variables.
The aim of our study was to establish a reference database of calcaneal broadband ultrasound attenuation (BUA) and the speed of sound (SOS) in a healthy Nigerian population of children aged 6 to 14 years and also to investigate the influence of sociodemographic and anthropometric variables on them. The BUA and SOS of 1016 healthy children were measured by quantitative ultrasound densitometry. Height and weight were measured with a stadiometer and weighing balance, respectively, whereas the sociodemographic parameters of the participants were collected on a semistructured questionnaire. A multiple regression model using stepwise selection and Pearson correlation coefficients were used to examine the relationship between the ultrasound parameters and sociodemographic and anthropometric parameters. Comparisons between various age groups were made by analysis of variance. The mean BUA and SOS ± SD of the participants were 60.57 ± 16.21 dB/MHz and 1563.48 ± 21.74 m/s, respectively, for boys and 58.18 ± 15.16 dB/MHz and 1560.03 ± 22.32 m/s for girls. The BUA in both sexes was positively influenced by age and weight (P < .05), whereas only the father's educational status was its predictor (P < .05) in the boys. For the girls, the family size and mother's educational status were predictors of the BUA (P < .05). The SOS was marginally influenced by age and family size in the boys (P < .05), whereas the father's educational status was the predictor in the girls. The established BUA and SOS values in this study are baseline values, and further study, which would also involve data from a large number of Nigerian children, would be needed to support their effectiveness as reference values.


KDM5A regulates the growth and gefitinib drug resistance against human lung adenocarcinoma cells.
KDM5A, a histone demethylase, has been shown to be involved in several cancer-related process. The present study was undertaken to explore the role and therapeutic potential of KDM5A in human lung adenocarcinoma. The results of the qRT-PCR, immunohistochemistry, and western blotting showed significant upregulation of KDM5A expression in lung adenocarcinoma tissues and cell lines. The RNA interference-mediated silencing of KDM5A in lung adenocarcinoma cell line SK-LU-1 led to significant inhibition of in vitro cell proliferation via induction of apoptosis. The induction of apoptosis in SK-LU-1 lung adenocarcinoma cells was concomitant with upregulation of Bax and downregulation of Bcl-2 expression. In contrary, overexpression of KDM5A prompted the proliferation of SK-LU-1 lung adenocarcinoma cells. Interestingly, the SK-LU-1 cancer cells showed remarkably higher sensitivity to gefitinib under KDM5A transcriptional knockdown. Taken together, KDM5A is significantly upregulated in human lung adenocarcinoma and regulates the proliferation of the lung adenocarcinoma cells. These findings suggest potential of KDM5A to act as a therapeutic target for the management of human lung adenocarcinoma.


Continuous 12-lead ST-segment monitoring improves identification of low-risk patients with chest pain and a worse in-hospital outcome.
Various strategies have been proposed to improve diagnosis and triage of patients with chest pain at low risk, but uncertainty still exists on the optimal combination of diagnostic tools that should be used in this subset of patients. The aim of this study was to evaluate the incremental benefit of continuous 12-lead ST-segment monitoring over that provided by conventional diagnostic tools in patients with chest pain. Of 232 consecutive patients referred because of chest pain, 52 were classified as low-risk according to the Agency for Health Care Policy and Research unstable angina guidelines and observed for 12 h with serial cardiac enzymes and electrocardiograms (ECG) (every 3 h). All patients also underwent both echocardiography at entry and continuous 12-lead ST-segment monitoring during the observation period. During a mean hospital stay of 3.7 days (range 1-14 days), a benign outcome was observed in 37 patients (71%), whereas 15 patients (29%) had major cardiac events or recurrence of chest pain of ischemic origin. Addition of ST-segment monitoring findings to baseline clinical data as well as to serial enzymes and ECG features added significant incremental prognostic value (p < 0.001). Multivariate analysis showed reproduction of pain by chest pressure (p < 0.05) and presence of ST-segment changes (> or = 0.1 mV) during 12-lead ST-segment monitoring (p < 0.001) as independent predictors of a benign or unfavorable outcome. In low-risk patients with chest pain, continuous 12-lead ST-segment monitoring provides significant incremental diagnostic and prognostic information to currently used clinical, enzymatic, and ECG data, and is helpful in identifying the subset of patients with a worse in-hospital outcome.


Timescales of Human Hair Cortisol Dynamics.
Cortisol is a major human stress hormone, secreted within minutes of acute stress. Cortisol also has slower patterns of variation: a strong circadian rhythm and a seasonal rhythm. However, longitudinal cortisol dynamics in healthy individuals over timescales of months has rarely been studied. Here, we measured longitudinal cortisol in 55 healthy participants using 12 cm of hair, which provides a retrospective measurement over one year. Individuals showed (non-seasonal) fluctuations averaging about 22% around their baseline. Fourier analysis reveals dominant slow frequencies with periods of months to a year. These frequencies can be explained by a mathematical model of the hormonal cascade that controls cortisol, the HPA axis, when including the slow timescales of tissue turnover of the glands. Measuring these dynamics is important for understanding disorders in which cortisol secretion is impaired over months, such as mood disorders, and to test models of cortisol feedback control.


Establishing a rat model for the study of vitamin K deficiency.
The main vitamin K-deficient model, minidose warfarin, is different from the pathological mechanism of vitamin K deficiency, which is a shortage of vitamin K. The objective of this study was to establish a new method of vitamin K-deficient model combining a vitamin K-deficient diet with the intragastrical administration of gentamicin in rats. The clotting was assayed by an automated coagulation analyser. The plasma PIVKA-II was assayed by ELISA. The vitamin K status was detected by an HPLC-fluorescence system. In the diet- and gentamicin-induced vitamin K-deficient 14-day group, the rats had undetected vitamin K1 and vitamin K2 in the liver and a prolonged APTT. In the 21-day group, there was also a prolonged PT and a decrease of the FIX activities. In the 28-day group, the undetected vitamin K1 and vitamin K2, the prolonged PT and APTT, and the decrease of the FII, FVII, FIX, and FX activities prompted the suggestion that there were serious deficiencies of vitamin K and vitamin K-dependent coagulation in rats. It is suggested that the diet- and gentamicin-induced vitamin K-deficient 14-day or 21-day model can be used for studies related to the status of vitamin K. The vitamin K-deficient 28-day model can be applied to research involving both the status of vitamin K and of vitamin K-dependent coagulation. In conclusion, the combination of a vitamin K-deficient diet with the administration of gentamicin results in a useful model of vitamin K-deficieny.


Swim exercise training and adaptations in the antioxidant defense system of myocardium of old rats: relationship to swim intensity and duration.
We examined a suitable swim program of different intensities and durations that could evoke changes in the myocardial antioxidant capacity in 22-month-old rats. Male rats (Rattus norvegicus) were assigned to either a sedentary control (SE-C) group or one of six trainee groups. Animals were swim-exercised for 4 weeks with either 20 min or 40 min/day, and three intensities, low, moderate and high. Low-intensity at 20 min/day elicited maximum swim velocity (Sv) and endurance capacity (P<0.05). While serum total cholesterol, triglyceride and low-density lipoprotein (LDL-C) levels were significantly reduced, high-density lipoprotein (HDL-C) showed an increase (P<0.05) in low-intensity trained rats (20 min/day) over SE-C. Notable reduction in blood lactate was also evident. Exercise training significantly increased superoxide dismutase (Mn-SOD), decreased lipid peroxidation products, malondialdehyde and lipofuscin in the left and right ventricles. Increased Mn-SOD with concomitant decrease in lipofuscin in left ventricle was significantly greater than in right ventricle. Moderate- to high-intensity exercise was not effective in either reducing lipid peroxidation products or elevating Mn-SOD activity. These data suggest that swim training at low-intensity of 20 min/day is beneficial as a major protective adaptation against oxidative stress in old myocardium.


Molecular dynamics of genome editing with CRISPR-Cas9 and rAAV6 virus in human HSPCs to treat sickle cell disease.
Ex vivo gene correction with CRISPR-Cas9 and a recombinant adeno-associated virus serotype 6 (rAAV6) in autologous hematopoietic stem/progenitor cells (HSPCs) to treat sickle cell disease (SCD) has now entered early-phase clinical investigation. To facilitate the progress of CRISPR-Cas9/rAAV6 genome editing technology, we analyzed the molecular changes in key reagents and cellular responses during and after the genome editing procedure in human HSPCs. We demonstrated the high stability of rAAV6 to serve as the donor DNA template. We assessed the benefit of longer HSPC pre-stimulation in terms of increased numbers of edited cells. We observed that the p53 pathway was transiently activated, peaking at 6 h, and resolved over time. Notably, we revealed a strong correlation between p21 mRNA level and rAAV6 genome number in cells and beneficial effects of transient inhibition of p53 with siRNA on genome editing, cell proliferation, and cell survival. In terms of potential immunogenicity, we found that rAAV6 capsid protein was not detectable, while a trace amount of residual Cas9 protein was still detected at 48 h post-genome editing. We believe this information will provide important insights for future improvements of gene correction protocols in HSPCs.


Tyrokeradines G and H, new bromotyrosine alkaloids from an Okinawan Verongid sponge.
Two new bromotyrosine alkaloids, tyrokeradines G (1) and H (2), have been isolated from an Okinawan marine sponge of the order Verongida. The structures of 1 and 2 were elucidated on the basis of spectroscopic data. Tyrokeradine G (1) is the first bromotyrosine alkaloid possessing a β-alanine unit, while tyrokeradine H (2) is a rare bromotyrosine alkaloid possessing a N-substituted pyridinium ring. Tyrokeradines G (1) and H (2) showed antifungal activity.


Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization.
Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only). Three new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell-target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo. APRIL-CAR T cells in a trimeric ligand binding conformation conferred fast but not sustained antitumor responses in vivo in mouse xenograft models. In vitro trimer-BBζ CAR T cells were more polyfunctional and formed stronger immune synapses than monomer-BBζ CAR T cells. After CAR T cell-myeloma cell contact, BCMA was rapidly downmodulated on target cells with all evaluated binding moieties. CAR T cells acquired BCMA by trogocytosis, and BCMA on MM cells was rapidly internalized. Since BCMA can be re-expressed during progression and persisting CAR T cells may not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell-MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo. Antitumor responses with APRIL-CAR T cells were fast but not sustained. Rapid BCMA downmodulation occurred independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM when targeting BCMA and can inform the development of improved treatment strategies.


Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response.
The Middle East respiratory syndrome coronavirus (MERS-CoV) closely resembled severe acute respiratory syndrome coronavirus (SARS-CoV) in disease manifestation as rapidly progressive acute pneumonia with multi-organ dysfunction. Using monocyte-derived-dendritic cells (Mo-DCs), we discovered fundamental discrepancies in the outcome of MERS-CoV- and SARS-CoV-infection. First, MERS-CoV productively infected Mo-DCs while SARS-CoV-infection was abortive. Second, MERS-CoV induced significantly higher levels of IFN-γ, IP-10, IL-12, and RANTES expression than SARS-CoV. Third, MERS-CoV-infection induced higher surface expression of MHC class II (HLA-DR) and the co-stimulatory molecule CD86 than SARS-CoV-infection. Overall, our data suggests that the dendritic cell can serve as an important target of viral replication and a vehicle for dissemination. MERS-CoV-infection in DCs results in the production of a rich combination of cytokines and chemokines, and modulates innate immune response differently from that of SARS-CoV-infection. Our findings may help to explain the apparent discrepancy in the pathogenicity between MERS-CoV and SARS-CoV.


Interference filter calibration for vision research.
The radiant flux (F) transmitted by bandpass interference filters of similar type is approximately proportional to the product of peak transmittance (tp) and half-height bandwidth (Wh). A study of 297 filters of varied design (1-, 2-, 3-cavity), the collections of six vision laboratories, showed that this relation was not accurate across all filters. However, a simple function, incorporating Wh and another bandwidth Wi at a lower transmittance t, predicts F with a precision that is ample (+/- 5%) for most psychophysical research. This function provides a rapid means of calibration. Bandwidth errors caused by 2- and 3-cavity filters are discussed as well as their luminous 'blocking' efficacy.


Using artificial intelligence to predict the risk for posterior capsule opacification after phacoemulsification.
To apply artificial intelligence models to predict the occurrence of posterior capsule opacification (PCO) after phacoemulsification. Farabi Eye Hospital, Tehran, Iran. Clinical-based cross-sectional study. The posterior capsule status of eyes operated on for age-related cataract and the need for laser capsulotomy were determined. After a literature review, data polishing, and expert consultation, 10 input variables were selected. The QUEST algorithm was used to develop a decision tree. Three back-propagation artificial neural networks were constructed with 4, 20, and 40 neurons in 2 hidden layers and trained with the same transfer functions (log-sigmoid and linear transfer) and training protocol with randomly selected eyes. They were then tested on the remaining eyes and the networks compared for their performance. Performance indices were used to compare resultant models with the results of logistic regression analysis. The models were trained using 282 randomly selected eyes and then tested using 70 eyes. Laser capsulotomy for clinically significant PCO was indicated or had been performed 2 years postoperatively in 40 eyes. A sample decision tree was produced with accuracy of 50% (likelihood ratio 0.8). The best artificial neural network, which showed 87% accuracy and a positive likelihood ratio of 8, was achieved with 40 neurons. The area under the receiver-operating-characteristic curve was 0.71. In comparison, logistic regression reached accuracy of 80%; however, the likelihood ratio was not measurable because the sensitivity was zero. A prototype artificial neural network was developed that predicted posterior capsule status (requiring capsulotomy) with reasonable accuracy. No author has a financial or proprietary interest in any material or method mentioned.


Gravity matters: Motion perceptions modified by direction and body position.
Motion coherence thresholds are consistently higher at lower velocities. In this study we analysed the influence of the position and direction of moving objects on their perception and thereby the influence of gravity. This paradigm allows a differentiation to be made between coherent and randomly moving objects in an upright and a reclining position with a horizontal or vertical axis of motion. 18 young healthy participants were examined in this coherent threshold paradigm. Motion coherence thresholds were significantly lower when position and motion were congruent with gravity independent of motion velocity (p=0.024). In the other conditions higher motion coherence thresholds (MCT) were found at lower velocities and vice versa (p<0.001). This result confirms previous studies with higher MCT at lower velocity but is in contrast to studies concerning perception of virtual turns and optokinetic nystagmus, in which differences of perception were due to different directions irrespective of body position, i.e. perception took place in an egocentric reference frame. Since the observed differences occurred in an upright position only, perception of coherent motion in this study is defined by an earth-centered reference frame rather than by an ego-centric frame.


External validation of the Japanese difficulty score for laparoscopic hepatectomy in patients undergoing robotic-assisted hepatectomy.
The Japanese difficulty score (JDS) categorizes laparoscopic hepatectomy into low, intermediate, and high complexity procedures, and correlates with operative and postoperative outcomes. We sought to perform a validation study to determine if the JDS correlates with operative and postoperative indicators of surgical complexity for patients undergoing robotic-assisted hepatectomy. Retrospective review of 657 minimally invasive hepatectomy procedures was performed between January 2008 through March 2019. Outcomes included operative time, estimated blood loss (EBL), blood transfusion, complications, post-hepatectomy liver failure (PHLF), length of stay, 30-day readmission, and 30-day and 90-day mortality. Patients were grouped based on JDS defined as: low (< 4), intermediate (4-6), and high (7 +) complexity procedures. Statistical comparisons were analyzed by ANOVA or χ2 test. 241 of 657 patients underwent robotic-assisted resection. Of these patients, 137 were included in the analysis based on JDS: 25 low, 58 intermediate, and 54 high. High JDS was associated with more major resections (≥ 4 contiguous segments) versus minor resections (median JDS 8 vs. 5, P < 0.0001). High JDS was associated with significantly longer operative times, higher EBL, and more blood transfusions. High JDS was associated with higher rates of PHLF at 16.7%, compared with 5.2% intermediate and 0.0% low, (P = 0.018). Complication rates, 30-day readmissions, and mortality rates were similar between groups. Median LOS was longer in patients with high JDS compared with intermediate and low (4 days vs. 3 days vs. 2 days; P = 0.0005). Higher JDS was associated with multiple indicators of operative complexity, including greater extent of resection, increased operative time, EBL, blood transfusion, PHLF, and LOS. This validation study supports the ability of the JDS to categorize patients undergoing robotic-assisted hepatectomy by complexity.


Analysis of amadori peptides enriched by boronic acid affinity chromatography.
Glycation of peptides and proteins by D-glucose is a universal, nonenzymatic reaction with important implications for the pathogenesis and diagnosis of many diseases, including diabetes mellitus. Whereas some modification sites have been identified in serum albumin and hemoglobin, a general approach to map glycation sites for nonabundant proteins present in complex mixtures, such as serum, is still missing. Here, we describe a universal enrichment procedure for glycated peptides using boronic acid affinity chromatography in the first dimension followed by reversed-phase chromatography, coupled either online to electrospray ionization mass spectrometry (ESI-MS) or offline to matrix-assisted laser desorption/ionization (MALDI) MS. This two-dimensional approach was optimized for high recoveries and low cross reactivities. For bovine serum albumin, a total of 31 Amadori peptides were identified in a tryptic digest corresponding to 26 different glycation sites.


One step closer to fixing association studies: evidence for age- and gender-specific allele frequency variations and deviations from Hardy-Weinberg expectations in controls.
Association studies are the most powerful method available for identifying modest gene effects in complex disorders, but they often produce inconsistent results. With the rapidly growing SNP databases, haplotype maps and high throughput genotyping, the use of association studies is expected to increase; therefore, it is critical and timely that the problems with study design are identified and fixed. We questioned if unrecognized allele and genotype frequency variations in controls could be responsible for some of the inconsistent association findings. We performed a population genetic study of apolipoprotein E (APOE) and cytochrome P450 2D6 (CYP2D6) in 1,748 individuals ranging in age from newborns to centenarians. Although APOE and CYP2D6 are two of the most commonly used candidate genes, this is the first study to examine age- and gender-specific frequency distributions over the entire age spectrum, using a large, ethnically and geographically uniform population. We found significant, previously unrecognized variations in APOE allele frequencies, and deviations from Hardy-Weinberg expectations in CYP2D6 genotype frequencies starting at birth. The allele frequency variations within controls were larger than some reported case-control differences. We demonstrate that unrecognized frequency fluctuations in controls are a serious and potentially common confounder whose impact on association studies has not been appreciated, and one that can be addressed with proper study design. We recommend that population genetic studies be performed on commonly used candidate markers and that rigorous standards be applied for case-control matching.


Quantification of crystal growth of calcium oxalate in gel and its modification by urinary constituents in a new flow model of crystallization.
To use a new flow model of crystallization to quantify the growth of calcium oxalate monohydrate (COM) in a gel matrix under simulated physiological conditions. Artificial urine supersaturated in COM was conducted through channels containing a gel with COM seed crystals (flow rate: 0.5 ml. per minute; reaction time: 4 hours; 37 +/- 1C). A relative crystal growth parameter, Vcr, was quantified by discontinuous measurement of scattered light intensity by microphotometry. The effects on Vcr of varying a series of urinary parameters were investigated within the system. The following order of effectiveness in changing COM growth could be derived: dilution > oxalate > calcium > magnesium approximately citrate. Drinking therapy and lowering of urinary oxalate excretion can be concluded to be the most promising means of preventing CaOx urolithiasis. The new crystallization model demonstrated here should be suitable to new applications in the investigation of urinary stone formation.


Delayed 2-h post-stroke administration of R18 and NA-1 (TAT-NR2B9c) peptides after permanent and/or transient middle cerebral artery occlusion in the rat.
Following positive results with the poly-arginine peptide R18 when administered intravenously 30 or 60min after permanent and/or transient middle cerebral artery occlusion (MCAO; 90min) in the rat, we examined the effectiveness of the peptide when administered 2h after MCAO. R18 was administered intravenously (1000nmol/kg via jugular vein) after permanent MCAO or a transient 3-h MCAO or when administered intra-arterially (100nmol/kg via internal carotid artery) immediately after reperfusion following a transient 2-h MCAO. In the transient MCAO studies, the neuroprotective NA-1 peptide was used as a positive control. Infarct volume, cerebral edema and functional outcomes were measured 24h after MCAO. Following permanent or transient MCAO, neither R18 nor NA-1 significantly reduced infarct volume. However, following permanent MCAO, R18 appeared to reduce cerebral edema (p=0.006), whereas following a transient 3-h MCAO, R18 improved the time to remove adhesive tape (p=0.04) without significantly affecting cerebral edema. There was also a trend (p=0.07) towards improved rota-rod performance with R18 in both permanent and transient 3-h MCAO. Following a transient 2-h MCAO, R18 had no significant effects on cerebral edema or neurological score but did lessen the extent of weight loss. Overall, while R18 had no effect on infarct volume, the peptide reduced cerebral edema after permanent MCAO, and improved some functional outcomes after transient MCAO.


Treatment of PC-3 and DU145 prostate cancer cells by prenylflavonoids from hop (Humulus lupulus L.) induces a caspase-independent form of cell death.
Xanthohumol (X), isoxanthohumol (IX), 8-prenylnaringenin (8PN) and 6-prenylnaringenin (6PN), prenylflavonoids from hop (Humulus lupulus L.), were investigated for their cytotoxicity and the mechanism by which they exert cell death when incubated with prostate cancer cell lines PC-3 and DU145. All compounds induced cell death in the absence of caspase-3 activation and typical apoptotic morphological features. The general pan-caspase inhibitor zVAD-fmk could not protect this form of cell death. In addition, the formation of vacuoles was observed in PC-3 cells treated with IX and 6PN, and in DU145 treated with IX, 8PN and 6PN, which could suggest the induction of autophagy and consequent cell death. The results indicate that hop-derived prenylflavanones (IX, 8PN, 6PN), but not prenylchalcones (X) induce a caspase-independent form of cell death, suggested to be autophagy. Therefore, IX, 8PN and 6PN appear to be promising candidates for further investigation in prostate anticancer therapy.


Spectrum of injuries with "less-lethal" beanbag weapons: pictorial essay.
Beanbag weapons are gaining popularity with increasing daily use as a non-lethal or less-lethal alternative to traditional firearms. While these are considered "less-lethal," these are associated with a spectrum of serious injuries. We present a pictorial essay of these injuries ranging from mild skin contusions to more severe solid organ injuries.


Reference ranges and impact of selected confounders on classic serum and urinary renal markers in neonatal period.
Renal injury in term and pre-term neonates may be an antecedent to chronic kidney disease in the child's further life. The aim of the paper was to compile a reference range for selected serum and urinary renal markers in the neonatal period for full-term (FT) and pre-term (PT) newborns. The prospective study included 23 FT infants (birth weight - BW≥2500g and gestational age - GA≥37Hbd) and 32 PT children (BW<2500g and GA<37Hbd) in good general condition, without acute kidney injury (AKI) or sepsis. Between the 4th and 28th DOL, urinary concentrations of the studied renal markers (uCr, uNa, uOsm) were determined on a daily basis, while serum creatinine (SCr) was assessed minimum every 48-72h. The mean GA and BW of the FT and PT infants were respectively as follows: 38.5±1.7Hbd; 3433±495.2g and 32.7±2.6Hbd; 1836.7±419.8g. For serum glomerular (SCr, eGFR) and tubular markers (FENa, RFI), the median values with normal ranges were compiled. For urinary renal markers (uCr, uNa, uOsm) and those values standardized for kg of body weight, percentile tables for 4-28DOL were elaborated. The study has resulted in determining the normal ranges of serum glomerular and tubular renal markers, as well as percentile tables of selected urinary renal parameters during the neonatal period. The percentile tables may prove to be helpful for further standardization of other urinary parameters per urinary creatinine in neonatal population.


Targeting hippocampal neurogenesis to protect astronauts' cognition and mood from decline due to space radiation effects.
Neurogenesis is an essential, lifelong process during which neural stem cells generate new neurons within the hippocampus, a center for learning, memory, and mood control. Neural stem cells are vulnerable to environmental insults spanning from chronic stress to radiation. These insults reduce their numbers and diminish neurogenesis, leading to memory decline, anxiety, and depression. Preserving neural stem cells could thus help prevent these neurogenesis-associated pathologies, an outcome particularly important for long-term space missions where environmental exposure to radiation is significantly higher than on Earth. Multiple developments, from mechanistic discoveries of radiation injury on hippocampal neurogenesis to new platforms for the development of selective, specific, effective, and safe small molecules as neurogenesis-protective agents hold great promise to minimize radiation damage on neurogenesis. In this review, we summarize the effects of space-like radiation on hippocampal neurogenesis. We then focus on current advances in drug discovery and development and discuss the nuclear receptor TLX/NR2E1 (oleic acid receptor) as an example of a neurogenic target that might rescue neurogenesis following radiation.


Functional characterization of Dictyostelium discoideum mutant myosins equivalent to human familial hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy (FHC) is caused by missence mutations in beta-myosin heavy chain or other various sarcomeric proteins. To elucidate the functional impact of FHC mutations in myosin heavy chain, we generated Dictyostelium discoideum myosin II mutants equivalent to human FHC mutations by site-directed mutagenesis, and characterized their molecular-basis motor function. The current mutants, i.e. R397Q, F506C, G575R, A699R, K703Q and K703W are equivalent to R403Q, F513C, G584R, G716R, R719Q and R719W FHC mutants respectively. We measured the molecular-basis force and the sliding velocity generated by these myosin mutants. The measurement revealed that the A699R, K703Q and K703W myosins exhibited the lowest level of force with their preserved actin-activated MgATPase activity. F506C mutant showed the least impairment of the motile and enzymatic activities. The motor function of R397Q and G575R myosins were classified as intermediate. These results suggest that ELC binding domain might be important for force production.


Depression and pulmonary function in outpatients with asthma.
The purpose of this study was to examine the relation between depression, anxiety and pulmonary function in asthmatics. Thirty-eight adult asthmatic patients underwent psychometric evaluation with the DSSI/sAD questionnaire, filled in an asthma questionnaire and underwent spirometry. The majority of patients suffered from mild-persistent asthma. Twenty-six reported symptoms of anxiety and 25 reported symptoms of depression. A statistically significant reduction in FEV1 and FEV1/FVC values was observed in asthmatic patients with symptoms of depression. The mean value of FEV1 was 81.84(+/-20.83) in patients without symptoms and 63.73(+/-17.99) in patients with symptoms of depression. The mean values of FEV1/FVC were 0.85(+/-0.11) and 0.75(+/-0.10), respectively. These findings indicate a high frequency of depression and anxiety in adult asthmatic patients. A biological linkage between depression and impaired pulmonary function is proposed.


Surviving long submergence in the egg stage-a successful strategy of terrestrial arthropods living on flood plains (Collembola, Acari, Diptera).
Sampling experiments show that some terrestrial arthropod species which predominate on the flood plains of Eder Reservoir (Germany) survive long-term inundations in the egg stage under water, hatching immediately after the floods: the Collembola Isotoma viridis, Anurida tullbergi, Sminthurides malmgreni, Sminthurinus aureus, and Sminthurus nigromaculatus; the land mites Cheylostigmaeus pannonicus and Zerconopsis müstairi; and the ephydrid fly Scatella stagnalis. Some other dominant species seem to have the same survival strategy, because they show the same characteristic pattern of appearance in the study area (bdellid and oribatid mites, ephydrid and sphaerocerid flies).


Correcting for Brain Swelling's Effects on Infarct Volume Calculation After Middle Cerebral Artery Occlusion in Rats.
Evaluating infarct volume is the primary outcome for experimental ischemic stroke studies and is a major factor in determining translation of a drug into clinical trials. Numerous algorithms are available for evaluating this critical value, but a major limitation of current algorithms is that brain swelling is not appropriately considered. The model by Lin et al. is widely used, but overestimates swelling within the infarction, yielding infarct volumes which do not reflect the true infarct size. Herein, a new infarct volume algorithm is developed to minimize the effects of both peri-infarct and infarct core swelling on infarct volume measurement. 2,3,5-Triphenyl-2H-tetrazolium chloride-stained brain tissue of adult rats subjected to middle cerebral artery occlusion was used for infarct volume analysis. When both peri-infarct swelling and infarction core swelling are removed from infarct volume calculations, such as accomplished by our algorithm, larger infarct volumes are estimated than those of Lin et al.'s algorithm. Furthermore, the infarct volume difference between the two algorithms is the greatest for small infarcts (<10% of brain volume) when peri-infarct swelling is the greatest. Finally, using data from four published studies, our algorithm is compared to Lin et al.'s algorithm. Our algorithm offers a more reliable estimation of the infarct volume after ischemic brain injury, and thus may provide the foundation for comparing infarct volumes between experimental studies and standardizing infarct volume quantification to aid in the selection of the best candidates for clinical trials.


Long-term biological investigations in space.
Missions in space within the next two decades will be of longer duration than those carried out up to the present time, and the effects of such long-term flights on biological organisms are unknown. Results of biological experiments that have been performed to date cannot be extrapolated to results in future flights because of the unknown influence of adaptation over a long period of time. Prior experiments with Axolotl, fishes, and vertebrates by our research team (in part with sounding rockets) showed that these specimens did not appear to be suitable for long-term missions on which minimization of expense, technique, and energy is required. Subsequent investigations have shown the suitability of the leech (Hirudo medicinalis), which consumes blood of mammals up to ten times its own weight (1 g) and can live more than 2 years without further food supply. Emphasis in the experiments with Hirudo medicinalis is placed on metabolic rhythm and motility. Resorption and diffusion in tissue, development, and growth under long-term effects of cosmic proton radiation and zero-gravity are other focal points. The constancy of cellular life in the mature animals is a point in favor of these specimens. We have also taken into account the synergistic effects of the space environment on the problems just mentioned. The life-support system constructed for the leech has been tested successfully in four sounding rocket flights and, on that basis, has been prepared for a long-term mission. Long-term investigations out of the terrestrial biosphere will provide us with information concerning the degree of adaptation of certain physiological and biochemical functions and as to what extent biological readjustment or repair processes can occur under the specific stress conditions of space flight.


Probiotics reduce enterohemorrhagic Escherichia coli O157:H7- and enteropathogenic E. coli O127:H6-induced changes in polarized T84 epithelial cell monolayers by reducing bacterial adhesion and cytoskeletal rearrangements.
The aim of this study was to determine if probiotics reduce epithelial injury following exposure to Escherichia coli O157:H7 and E. coli O127:H6. The pretreatment of intestinal (T84) cells with lactic acid-producing bacteria reduced the pathogen-induced drop in transepithelial electrical resistance. These findings demonstrate that probiotics prevent epithelial injury induced by attaching-effacing bacteria.


Efficacy of oral fluoroquinolones versus conventional intravenous antipseudomonal chemotherapy in treatment of cystic fibrosis.
The clinical efficacy of the conventional aminoglycoside plus beta-lactam treatment was compared to that of monotherapy with oral quinolones in 26 adult cystic fibrosis patients in an open prospective clinical trial in which six two-week courses of antipseudomonas treatment were administered with an interval of approximately three months between treatments. In each patient two courses of conventional treatment were followed by two courses of quinolone treatment and then by another two courses of conventional treatment. The observed improvements in pulmonary function were somewhat higher when the patients received conventional treatments, and in the most seriously affected patients conventional treatment was significantly better than quinolone treatment. On the basis of these findings it is suggested that quinolone monotherapy cannot replace conventional antipseudomonal chemotherapy in patients with severe pulmonary involvement.


The pattern of accumulation of cauliflower mosaic virus-specific products in infected turnips.
The concentrations of cauliflower mosaic virus (CaMV) DNA and protein products in the developing leaves of a host, turnip, have been measured and the results have been correlated with symptom production. Virus-specific products were limited to the symptomatic leaves. CaMV DNA was detected in the youngest foliar tissues showing full systemic symptoms and continued to accumulate as the leaf expanded, indicating that virus multiplication was not restricted to meristematic tissues of the host plant and that virus concentration was not a primary determinant for symptom production. Using specific antisera for Western blot analysis, the distribution of CaMV-specific proteins (P1-P6) in a range of subcellular fractions of infected tissue was determined. The protein products (P2-P6) of genes II-VI were all detected in fractions enriched for virus inclusion bodies, although P5 was present only at low levels. A high-speed pellet fraction enriched for virus replication complexes revealed P5 in higher concentrations, and also contained P4 and small amounts of P6 in proportions which indicated that replication complexes had been released from inclusion bodies. In the different leaves of the host, P2, 3, 4, 5, and 6 all increased in concentration in parallel with viral DNA, although there appeared to be a bias toward protein rather than DNA synthesis in the very young leaves. P1 showed a different pattern of accumulation; it was most concentrated in the very young and the oldest infected tissues, and showed a different spectrum of products between leaves. The experiments described provide a more complete picture of the relationship between CaMV multiplication and expression, and leaf development, and an increased understanding of how the disease syndrome is established.


Effects of lipids and aging on the neurotoxicity and neuronal loss caused by intracerebral injections of the amyloid-beta peptide in the rat.
The influence of diet and age on the area of lesion and on the neuronal density in the cerebral cortex was studied in rats following local injections of the amyloid-beta peptide (Abeta1-40) in PBS vehicle into the left frontal and cingulate cortices and compared with effects of injections of PBS alone into the corresponding regions of the right hemisphere The experiments were carried out in two groups of animals: one group of young adult rats and a second group of aged rats. Each group of animals, depending on the diet received, was divided into high-cholesterol, high-fat, and a control group. In order to evaluate the interaction of Abeta/PBS-cholesterol and of Abeta/PBS-fat, animals without dietary manipulation receiving Abeta and PBS injection were used as controls. The results showed that the greatest area of lesion was at Abeta injection sites in the high-cholesterol fed group of aged animals. The results also revealed a significant variance in the neuronal density by group and by injection type. Thus, high-cholesterol fed animals showed a greater reduction in neuronal density at Abeta and PBS-injected sites than that seen in the high-fat or control groups. The results also indicate that the loss of neurons at the Abeta injection site exceeds that seen in the PBS-injected area. The greatest reduction in the neuronal density was found at Abeta-injected site in the high-cholesterol fed group of aged animals. In conclusion, our findings indicate an interaction between lipids, age, and Abeta neurotoxicity, and might provide insights into the basic mechanisms involved in a short-term (acute-to-subchronic) response to Abeta peptide.


Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis.
Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33's profibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.


Association between thyroid cancer and cardiovascular disease risk: a nationwide observation study.
Treatment with levothyroxine and radioiodine contribute alternative cardiovascular function in adults with thyroid cancer. The risks of long-term cardiovascular conditions among thyroid cancer patients is unknown. This study aimed to compare the incidence of coronary heart disease (CHD), ischemic stroke (IS), and atrial fibrillation (AF) among adults with thyroid cancer with that of the general population, especially when stratified by age (< 65 and ≥ 65 years old). This observational cohort study enrolled patients between January 1, 2011 and December 31, 2016 with a follow-up until December 31, 2018. This study analyzed the data of Taiwanese thyroid cancer patients registered on the National Taiwan Cancer Registry Database, with CHD and IS. SIR models were used to evaluate the association between thyroid cancer and CHD, IS, AF, and cardiovascular disease outcome, stratified by age and sex. SIR analyses were also conducted for both sexes, age groups (< 65, ≥ 65 years), and different follow-up years. After excluding 128 individuals (< 20 years or ≥ 85 years old) and with missing index data, 4274 eligible thyroid cancer patients without CHD history, 4343 patients without IS history, and 4247 patients without AF history were included for analysis. During the median follow-up of 3.5 (1.2) years among thyroid cancer patients, the observed number of new CHD events was 70; IS, 30; and AF, 20, respectively. The SIR was significantly higher for CHD (SIR, 1.57; 95% confidence interval [CI] 1.2-1.93) among thyroid cancer patients compared with the age- and sex-specific standardized population. However, the association between thyroid cancer and the risks of IS (SIR, 0.74; 95% CI 0.47-1), cardiovascular disease (SIR, 0.88; 95% CI 0.7-1.05), and atrial fibrillation (SIR, 0.74; 95% CI 0.42-1.06) were insignificant. Moreover, stratification by age < 65 or age ≥ 65 years old and by sex for CHD suggested that the diagnosis of thyroid cancer in the young may attenuate the CHD risk (SIR, 2.08; 95% CI 1.5-2.66), and the CVD risk was constant among both men (SIR, 1.63; 95% CI 1.03-2.24) and women (SIR, 1.53; 95% CI 1.06-1.99). The patients had persistent higher CHD risk for 5 years after cancer diagnosis. Thyroid cancer survivors have a substantial CHD risk, even at long-term follow-up, especially in those patients < 65 years old. Further research on the association between thyroid cancer and CHD risk is warranted.


Posttransplant donor-specific anti-HLA antibodies negatively impact pancreas transplantation outcome.
During a 9-year follow-up, 167 consecutive pancreas transplant recipients (152 simultaneous pancreas-kidney [SPK]) were followed for the detection of posttransplant anti-HLA antibodies. Forty patients (24%) developed anti-HLA antibodies, 26 (65%) had donor-specific antibodies (DSA; 61% anticlass 2) and 14 (35%) non-DSA (78.6% anticlass 1). More rejection episodes were observed in patients with positive anti-HLA antibodies than in patients without antibodies (42.5% vs. 11%; p = 0.001), with the highest incidence observed in DSA patients (53.8%). More severe rejections (according to rescue therapy) were observed in DSA patients compared to non-DSA (p < 0.05) or to negative patients (p < 0.001). Contrasting with the kidney, pancreas graft survival did not differ between patients with or without anti-HLA antibodies. On the contrary, pancreas and kidney survivals were significantly lower in DSA positive patients (75% for both organs) as compared to non-DSA positive patients (100% for pancreas and 92% for kidney) or to HLA-negative patients (91% for pancreas and 89% for kidney). Nontechnical pancreas and kidney graft failures were significantly higher in positive than in negative anti-HLA patients (32.5% vs. 11%; p < 0.01). Occurrence of posttransplant DSA was an independent risk factor for both pancreas and kidney survival (HR 3.2; p = 0.039) in diabetic transplant recipients.


The antidepressant-like effect of inosine in the FST is associated with both adenosine A1 and A 2A receptors.
Inosine is an endogenous purine nucleoside, which is formed during the breakdown of adenosine. The adenosinergic system was already described as capable of modulating mood in preclinical models; we now explored the effects of inosine in two predictive models of depression: the forced swim test (FST) and tail suspension test (TST). Mice treated with inosine displayed higher anti-immobility in the FST (5 and 50 mg/kg, intraperitoneal route (i.p.)) and in the TST (1 and 10 mg/kg, i.p.) when compared to vehicle-treated groups. These antidepressant-like effects started 30 min and lasted for 2 h after intraperitoneal administration of inosine and were not accompanied by any changes in the ambulatory activity in the open-field test. Both adenosine A1 and A2A receptor antagonists prevented the antidepressant-like effect of inosine in the FST. In addition, the administration of an adenosine deaminase inhibitor (1 and 10 mg/kg, i.p.) also caused an antidepressant-like effect in the FST. These results indicate that inosine possesses an antidepressant-like effect in the FST and TST probably through the activation of adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.


Efficient saccharification of ammonia soaked rice straw by combination of Clostridium thermocellum cellulosome and Thermoanaerobacter brockii β-glucosidase.
Clostridium thermocellum is known to produce the cellulosomes with efficient plant cell wall degradation ability. To bring out the maximum cellulolytic ability of the cellulosomes, it is necessary to eliminate the end product inhibition by cellobiose. Combinations of β-glucosidases from thermophilic anaerobic bacteria and Aspergillusniger and C.thermocellum S14 cellulosomes were evaluated for optimization of cellulose degradation. β-Glucosidase (CglT) from Thermoanaerobacterbrockii, in combination with cellulosomes, exhibited remarkable saccharification ability for microcrystalline cellulose. When rice straw, soaked in 28% aqueous ammonia for 7 days at 60°C, was hydrolyzed by an enzyme loading combination of 2mg cellulosome and 10 units CglT per g glucan, 91% of glucan was hydrolyzed to glucose, indicating roughly1/10 the enzyme load of a Trichodermareesei cellulase (Celluclast 1.5L) and Novozyme-188 combination is enough for the combination of C.thermocellum S14 cellulosomes and CglT to achieve the same level of saccharification of rice straw.


The costs of depression.
The data reported herein show clearly that major depression is a commonly occurring and burdensome disorder. The high prevalence, early age of onset, and high persistence of MDD in the many different countries where epidemiologic surveys have been administered confirm the high worldwide importance of depression. Although evidence is not definitive that MDD plays a causal role in its associations with the many adverse outcomes reviewed here, there is clear evidence that depression has causal effects on a number of important mediators, making it difficult to assume anything other than that depression has strong causal effects on many dimensions of burden. These results have been used to argue for the likely cost -effectiveness of expanded depression treatment from a societal perspective. Two separate, large-scale, randomized, workplace depression treatment effectiveness trials have been carried out in the United States to evaluate the cost effectiveness of expanded treatment from an employer perspective. Both trials had positive returns on investment to employers. A substantial expansion of worksite depression care management programs has occurred in the United States subsequent to the publication of these trials. However, the proportion of people with depression who receive treatment remains low in the United States and even lower in other parts of the world. A recent US study found that only about half of workers with MDD received treatment in the year of interview and that fewer than half of treated workers received treatment consistent with published treatment guidelines. Although the treatment rate was higher for more severe cases, even some with severe MDD often failed to receive treatment. The WMH surveys show that treatment rates are even lower in many other developed countries and consistently much lower in developing countries. Less information is available on rates of depression treatment among patients with chronic physical disorders, but available evidence suggests that expanded treatment could be of considerable value. Randomized, controlled trials are needed to expand our understanding of the effects of detection and treatment of depression among people in treatment for chronic physical disorders. In addition, controlled effectiveness trials with long-term follow-ups are needed to increase our understanding of the effects of early MDD treatment interventions on changes in life course role trajectories, role performance, and onset of secondary physical disorders.


Clinical and genetic study of a family with spinocerebellar ataxia type 1 (SCA1) and beta-thalassemia.
We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis. Genetic analysis demonstrated a CAG expansion in the SCA1 locus in five members, while all subjects with microcytosis revealed a C-T substitution at codon 39 of the beta-globin gene. A pure cerebellar syndrome with prominent gait ataxia characterized the first stages of the neurological disease. The fully developed disease included additional clinical findings such as dysarthria and dysphagia, and instrumental signs of axonal involvement of the peripheral nerves. Ophthalmoplegia was not observed. The coexistence of hereditary spinocerebellar degeneration and erythropathies or hemoglobinopathies has been previously described. We discuss the possible linkages between these two pathologies.


The role of a surgical learning curve in urethral obstruction following autologous fascial sling: a case-series study.
Iatrogenic female urethral obstruction resulting from sling operations may be related to surgical inexperience and must be better understood. Although there are no widely recognized parameters for this type of study, a single-surgeon consecutive series offers an opportunity to study the role of expertise in sling operations over time. This study consecutively examined 176 women who underwent an autologous fascial sling procedure. Postoperative urethral obstruction was identified by the occurrence of voiding dysfunctions. Clinically obstructed patients were invited to undergo a postoperative urodynamic evaluation after 3 months. To enable comparison, patients were placed into 6-month groups according to the time of surgery. A total of 159 cases were evaluated with a mean follow-up time of 32.4 ± 13.4 months. Stress continence was cured in 97.5% of cases. Although 29 patients were identified as obstructed, only 20 underwent a postoperative urodynamic evaluation. Only five of the clinically obstructed cases showed a high P(det)Q(max). All of the other cases met one or more of the non-classic parameters linked to obstruction. Overactive bladder was present in 14 (63.6%) of the obstructed cases. Iatrogenic urethral obstruction was more common among the early cases (30.4%) than among the later ones (5%) (P < 0.001). Postoperative urodynamic evaluation showed a trend toward obstruction on pressure flow studies. Autologous fascial sling operations require expertise and involve a clear surgical learning curve. Iatrogenic obstruction in females does not fit a single model and may be difficult to recognize. Obstruction in females must be identified through clinical indicators and postoperative urinary complaints rather than the high detrusor pressure observed in men. Furthermore, iatrogenic female obstruction can probably be minimized but not eliminated.


Revealing the mechanism of Zanthoxylum armatum DC. extract-induced liver injury in mice based on lipidomics.
Zanthoxylum armatum DC. (Z. armatum) is an herbal medicine with various active ingredients and pharmacological effects. However, modern studies found that Z. armatum is hepatotoxic. The liver is the target organ for toxic effects and an important site for lipid metabolism. The effects of Z. armatum on lipid level and metabolism in the liver are still unclear. This study aimed to analyze hepatic lipid levels, lipid metabolites and metabolic pathways of action of Z. armatum based on lipidomics, to investigate the potential hepatotoxic mechanism of Z. armatum. Different doses (62, 96, and 150 mg/kg) of the methanolic extract of Z. armatum (MZADC) were administered to ICR mice by gavage. The hepatotoxicity of MZADC was assessed by the liver index, serum biochemical measurements, and histopathological examination. Lipid levels measured by the serum lipid index were evaluated in the mice. Lipidomics was used to screen for differential lipid metabolism markers and lipid metabolism pathways in the liver. Western blot analysis was performed to investigate the effects of MZADC on the liver. Liver index values and serum alanine transaminase and aspartate transaminase levels were increased in the MZADC group. Histopathology examination revealed hepatocyte necrosis, watery degeneration of the hepatocytes, and hepatic cord rupture in the livers of mice. Serum levels of low-density lipoprotein cholesterol, cholesterol, and triglycerides were elevated, and high-density lipoprotein cholesterol levels were decreased. Lipidomics screening for markers of differential lipid metabolism in the liver, and altered profiles of differential metabolites indicated that glycerophospholipid metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, glycosylphosphatidylinositol-anchored biosynthesis, sphingolipid metabolism and arachidonic acid metabolic pathways were significantly associated with MZADC-induced liver injury. Western blots confirmed that the protein expression of LC3, Beclin-1, ATG5, ATG12 and ATG16L1 was decreased, and p62 was increased in the MZADC group. The proportion of p-PI3K/PI3K and p-AKT/AKT was increased. The liver injury induced by MZADC involved many different lipid metabolites and lipid metabolic pathways, which may be related to autophagy. This study provides a new perspective on the hepatotoxicity study of Z. armatum and provides a reference for the safe application of Z. armatum in the medicine and food fields.


[Forensic odontology within the Disaster Victim Identification team of the Dutch Police Force].
The author participated as a forensic odontologist in the Dutch Disaster Victim Identification (DVI-)team during the period 1977-1995. In this article he describes the organization and procedure of this police unit, which is especially trained for the recovery and identification of victims. He also gives an impression of the organization and the special manner of identification of the forensic odontologists within the group of external specialists of the DVI-team. He describes the technical aspects of the identification activities of the forensic odontologists, as well as the identification problems at different sorts of mass disasters. The quality of the records obtained from the victims' dentists greatly influences the final results of dental identification.


A Review of the Biology and Control of Whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae), with Special Reference to Biological Control Using Entomopathogenic Fungi.
Whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae), consists of genetically diverse species known to cause significant destruction in several crops around the world. Nymphs and adults of B. tabaci cause damage to plants during feeding, and they can act as a virus vector, thus causing significant yield loss to crops in the tropical and subtropical regions. Chemical pesticides are widely used to control B. tabaci due to their immediate action, but this approach has several drawbacks including food safety issues, insecticide resistance, environmental pollution, and the effect on non-target organisms. A biological control agent using entomopathogenic fungi (EPF) has therefore been developed as an alternative against the conventional use of chemical pesticides in an integrated pest management (IPM) system to effectively control B. tabaci. It is apparent from this review that species of hyphomycetes fungi are the most common EPF used to effectively control B. tabaci, with the second instar being the most susceptible stage of infection. Therefore, this review article focuses specifically on the control of B. tabaci with special emphasis on the use of EPF as biological control agents and their integration in IPM.


Ankle motion after external fixation of tibial fractures.
Loss of ankle movement is a complication of severe tibial fractures. This can be exacerbated if the foot is allowed to drop into equinus, particularly when an external fixator is employed. The range of ankle motion following external fixation of tibial fractures as compared to the opposite normal ankle was studied in 40 of 55 patients treated over a ten-year period. Nine were excluded due to other causes of ankle stiffness, leaving 31 cases for analysis. The mean follow up was 2 years 7 months (range 1 year to 8 years 3 months), and union had occurred by a mean of 35 weeks (range 9-100 weeks). The mean loss of ankle movement was 8 degrees of plantar-flexion and 12 degrees of dorsiflexion (overall loss 20 degrees), the difference between the two being highly significant (P greater than 0.001, t test). Loss of ankle motion closely paralleled the degree of soft tissue trauma, being 6 degrees for closed fractures and 22 degrees for open fractures (0.05 greater than P greater than 0.02). Ankle function is therefore at risk when a severe tibial fracture is treated by external fixation, and appropriate measures should be taken to preserve movement and prevent an equinus contracture.


Response to glucose and lipid infusions in sepsis: a kinetic analysis.
The kinetics and oxidation of glucose and free fatty acid (FFA) metabolism were assessed in control and Escherichia coli septicemic dogs by using primed, constant infusions of U-14C-glucose and 1,2, 13C-palmitic acid. In the controls, the infusion of glucose suppressed endogenous glucose production completely, whereas, in the septic dogs, only a 30% suppression of glucose production occurred. The ability of the septic dogs to oxidize endogenous or exogenous glucose was decreased significantly. The basal rate of appearance of FFA was significantly higher in the septic dogs, but their ability to oxidize FFA was comparable to that of the control dogs; therefore, the basal rate of FFA oxidation was higher in the septic dogs. These studies indicate that septic dogs have a decreased capacity to oxidize glucose, but that they retain their ability to oxidize long-chain fatty acids. Because the rate of lipolysis was increased in sepsis, lipid was the predominate energy substrate in this septic model.


Development of a process for efficient use of CO2 from flue gases in the production of photosynthetic microorganisms.
A new methodology to use efficiently flue gases as CO(2) source in the production of photosynthetic microorganisms is proposed. The CO(2) is absorbed in an aqueous phase that is then regenerated by microalgae. Carbonated solutions could absorb up to 80% of the CO(2) from diluted gas reaching total inorganic carbon (TIC) concentrations up to 2.0 g/L. The pH of the solution was maintained at 8.0-10.0 by the bicarbonate/carbonate buffer, so it is compatible with biological regeneration. The absorption process was modeled and the kinetic parameters were determined. Anabaena sp. demonstrated to tolerate pH (8.0-10.0) and TIC (up to 2.0 g/L) conditions imposed by the absorption step. Experiments of regeneration of the liquid phase demonstrated the feasibility of the overall process, converting CO(2) into organic matter. The developed process avoids heating to regenerate the liquid whereas maximizing the efficiency of CO(2) use, which is relevant to achieve the commercial production of biofuels from microalgae.


Adhesion to laminin-1 and collagen IV induces the formation of Ca2+ microdomains that sensitize mouse T cells for activation.
During an immune response, T cells migrate from blood vessel walls into inflamed tissues by migrating across the endothelium and through extracellular matrix (ECM). Integrins facilitate T cell binding to endothelial cells and ECM proteins. Here, we report that Ca2+ microdomains observed in the absence of T cell receptor (TCR)/CD3 stimulation are initial signaling events triggered by adhesion to ECM proteins that increase the sensitivity of primary murine T cells to activation. Adhesion to the ECM proteins collagen IV and laminin-1 increased the number of Ca2+ microdomains in a manner dependent on the kinase FAK, phospholipase C (PLC), and all three inositol 1,4,5-trisphosphate receptor (IP3R) subtypes and promoted the nuclear translocation of the transcription factor NFAT-1. Mathematical modeling predicted that the formation of adhesion-dependent Ca2+ microdomains required the concerted activity of two to six IP3Rs and ORAI1 channels to achieve the increase in the Ca2+ concentration in the ER-plasma membrane junction that was observed experimentally and that required SOCE. Further, adhesion-dependent Ca2+ microdomains were important for the magnitude of the TCR-induced activation of T cells on collagen IV as assessed by the global Ca2+ response and NFAT-1 nuclear translocation. Thus, adhesion to collagen IV and laminin-1 sensitizes T cells through a mechanism involving the formation of Ca2+ microdomains, and blocking this low-level sensitization decreases T cell activation upon TCR engagement.


Interaction between the impact of the Coronavirus disease 2019 pandemic and demographic characteristics on sexual/erectile dysfunction in Latin America: cross-sectional study.
Our objective was to investigate whether there is an interaction between the COVID-19 pandemic, demographic characteristics and erectile/sexual (E/S) function in individuals from Latin America. Cross-sectional study which included Latin American individuals over 18 years old, recruited through social media and interviewed between July and August 2020 by online surveys (Google Forms) in Portuguese and Spanish languages. The E/S function was evaluated through the following questionnaires: Simplified International Index of Erectile Function (IIEF-5) and Female Sexual Function Index (FSFI); while post-traumatic stress disorder (PTSD) triggered by the COVID-19 pandemic was assessed through the Impact of Event Scale Revised (IES-R). The data was analyzed by T Student, bivariate and multivariate logistic regression, with significance determined by the Wald test (p<0.05), using the R software v4.0. Out of the 2016 individuals that responded to the survey, 1986 were included and 743 of them presented E/S dysfunction. PTSD occurrence was greater among people with E/S dysfunction when compared to those without E/S dysfunction, in the total score (males: IES-R=26.54[±19.17] and females: IES-R=35.92[±19.25]) and also in the three domains. It was found that those who do not live with a partner were 74% more likely to have E/S dysfunction, but living with a partner during the pandemic had a greater impact on E/S function. A negative interaction between the impact of the COVID-19 pandemic and erectile/sexual function of the Latin American population was observed, with greater implications among the individuals who live with their partners.


Immunological comparison between OXA-2 beta-lactamase and those mediated by other R plasmids.
Antibodies to the OXA-2 beta-lactamase inhibited both OXA-2 and OXA-3 enzymes, but there was no effect on any other beta-lactamase. The cross-neutralization indicates considerable homology between the OXA-2 and OXA-3 enzymes and supports the suggestion that the OXA-3 beta-lactamase may have been derived from the OXA-2 gene via a deletion.


The retained twin/triplet following a preterm delivery--an analysis of the literature.
We summarized the overall experience of the management and outcome of the retained twin/triplet and statistically analyzed the effects of the different variables such as cervical cerclage, tocolysis, use of antibiotics etc. on the retained fetal survival; 45 case reports in English were analyzed. The survival rate of the first born was very poor in contrast to the second and third-born infants. Spontaneous rupture of the membranes was the most common cause of the loss of the first born, whereas for the second born, premature labour was the commonest cause. Despite substantial obstetric events leading to delivery of the first-born infant, interval problems were uncommon. The mean period of retention of the surviving retained twin/triplet was 48.9 +/- 37.9 days compared to 25.7 +/- 31.6 days for the dead retained twins/triplets (p=0.08). The female retained twins/triplets were retained much longer than the males (p=0.008). The pregnancies lasted 45.9 days in the tocolytic group and 37 days in the nontocolytic group (p=0.51). The delivery interval of the second born in the cerclage group was 52 +/- 42 days compared to 34 +/- 30 days in the noncerclage group (p=0.1). The longer the twins/triplets were retained the better was their survival. Tocolysis, cervical cerclage and prophylactic use of antibiotics failed to make a statistically significant difference in the fetal outcome. The birth-weights, gestations and sex of the retained twins/triplets affected their survival significantly.


Severe Aortic Stenosis: More Than an Imaging Diagnosis.
The definition of severe aortic stenosis has undergone significant change casting a wider net to avoid missing patients who could benefit from valve replacement. The presence or absence of symptoms remains the key decision-making element; however, individuals presently undergoing evaluation are older, more likely asymptomatic, and have lower gradients. Due to numerous potential measurement errors, attention to detail when performing diagnostic testing and understanding their limitations are necessary to render appropriate treatment. Exercise testing adds useful information for individuals with severe aortic stenosis felt to be asymptomatic. Dobutamine echocardiography, in low flow-low gradient aortic stenosis, distinguishes between a myopathic and valvular cause of left ventricular dysfunction. Evaluation of patients when normotensive minimizes measurement errors. The amount of aortic valve calcification adds useful information when the degree of aortic stenosis is uncertain. A good history and physical integrated with high-quality imaging data allows for appropriate clinical treatment decisions for patients with aortic stenosis. The goal is simultaneously to provide aortic valve replacement for patients in need while avoiding overdiagnosis and performance of unnecessary procedures.


Family capital and the invisible transfer of privilege: intergenerational support and social class in early adulthood.
Sociologists have long recognized the relationships between family background and social class attainment. However, by neglecting the multiple ways in which families and parents provide advantages and the extent to which these advantages extend into adulthood, they may still be underestimating the role of families in the reproduction of class inequalities. This chapter explores these impacts under the conceptual rubric of family capital. A new battery of interviews with a diverse collection of young adults is used to illustrate these points and offer suggestions for future research and analysis.


Early neurological deterioration in acute ischemic stroke.
Early neurological deterioration (END) in acute ischemic stroke (AIS), patients is defined as clinical worsening or recurrence during first 72 h after onset of AIS. We have conducted this study to determine the association between END and functional outcome at 3 months of onset of AIS along with associated risk factors of END in AIS cases. This study was conducted after approval of Institute Ethics Committee. Two hundred three consecutive patients were admitted from September 2020 to January 2022 at a tertiary care hospital. One hundred ninety patients were included in the study; patients were divided into two groups: (1) early neurological deterioration (END) and (2) non-early neurological deterioration (non-END). Patients were followed-up either telephonically or in person at approximately 3 months using modified Rankin Scale 0-6. All the clinically significant prognostic markers and p < 0.10 variables were considered significant in univariate analysis; P < 0.05 were considered statistically significant for the multivariate analysis. Out of 190 cases included in the cohort 34/190 (17.8%) cases showed END with mean age (56.56 (± 16.6)) and males (20/34 (58.8%)). END was independently associated with high blood glucose at admission (OR = 1.015; P = 0.002; 95%CI = 1.005-1.024) and low serum albumin (OR = 0.208; P = 0.002; 95%CI = 0.077-0.562). Patients with END showed poor functional outcome (mRS > 2) at end of 3 months (32 (94.1%); P < 0.001) and death was also statistically significant (22 (64.7%); P < 0.001) as compared to AIS cases having non-END. Our study showed END may be associated with poor functional outcome in AIS patients. Higher blood glucose at admission and low serum albumin may be statistically significant causing END. Future prospective cohort with larger sample size may confirm the findings.


CD and NMR investigation of collagen peptides mimicking a pathological Gly-Ser mutation and a natural interruption in a similar highly charged sequence context.
Even a single Gly substitution in the triple helix domain of collagen leads to pathological conditions while natural interruptions are suggested to play important functional roles. Two peptides-one mimicking a pathological Gly-Ser substitution (ERSEQ) and the other one modeling a similar natural interruption sequence (DRSER)-are designed to facilitate the comparison for elucidating the molecular basis of their different biological roles. CD and NMR investigation of peptide ERSEQ indicates a reduction of the thermal stability and disruption of hydrogen bonding at the Ser mutation site, providing a structural basis of the OI disease resulting from the Gly-Ser mutation in the highly charged RGE environment. Both CD and NMR real-time folding results indicate that peptide ERSEQ displays a comparatively slower folding rate than peptide DRSER, suggesting that the Gly-Ser mutation may lead to a larger interference in folding than the natural interruption in a similar RSE context. Our studies suggest that unlike the rigid GPO environment, the abundant R(K)GE(D) motif may provide a more flexible sequence environment that better accommodates mutations as well as interruptions, while the electrostatic interactions contribute to its stability. These results shed insight into the molecular features of the highly charged motif and may aid the design of collagen biomimetic peptides containing important biological sites.


Veterinary drugs in the environment and their toxicity to plants.
Veterinary drugs used for treatment and prevention of diseases in animals represent important source of environmental pollution due to intensive agri- and aquaculture production. The drugs can reach environment through the treatment processes, inappropriate disposal of used containers, unused medicine or livestock feed, and manufacturing processes. Wide scale of veterinary pharmaceuticals e.g. antibiotics, antiparasitic and antifungal drugs, hormones, anti-inflammatory drugs, anaesthetics, sedatives etc. enter the environment and may affect non-target organisms including plants. This review characterizes the commonly used drugs in veterinary practice, outlines their behaviour in the environment and summarizes available information about their toxic effect on plants. Significant influence of many antibiotics and hormones on plant developmental and physiological processes have been proved. However, potential phytotoxicity of other veterinary drugs has been studied rarely, although knowledge of phytotoxicity of veterinary drugs may help predict their influence on biodiversity and improve phytoremediation strategies. Moreover, additional topics such as long term effect of low doses of drugs and their metabolites, behaviour of mixture of veterinary drugs and other chemicals in ecosystems should be more thoroughly investigated to obtain complex information on the impact of veterinary drugs in the environment.


Vaccination against polio should not be stopped.
The striking 50-year-long decline in the incidence of poliomyelitis has stalled in the past 7 years, which has led to calls for an urgent re-assessment of eradication and post-eradication campaign strategies. The current plan of eliminating the circulation of wild poliovirus so that further immunization will be unnecessary does not take into account recent scientific data and political realities that limit the likelihood that this strategy can sustain prevention of the disease. It is crucially important that high levels of population immunity are maintained against polio in the foreseeable future.


Three-dimensional mapping and intracardiac echocardiography in the treatment of sinoatrial nodal tachycardias.
Three-dimensional mapping and intracardiac echocardiography are important tools for the study of the site of origin of an arrhythmia and its substrate. This review examines the application of these techniques in the diagnosis and treatment of sinoatrial tachycardias with a special focus on the syndrome of inappropriate sinus tachycardia. The use of these techniques in electrophysiologic mapping and interventions such as catheter ablation is discussed. Three-dimensional mapping provides unique insights into the generation of normal and abnormal sinus impulses in man and their propagation in the atrium. It permits precise placement of ablation lesions and assessment of real-time electrophysiologic impact of these interventions. Intracardiac echocardiography provides delineation of important anatomic structures in the vicinity of the sinoatrial node complex and monitors the safety of interventions such as catheter ablation.


Mast cells and vascular diseases.
Mast cells are increasingly being recognized as effector cells in many cardiovascular conditions. Many mast-cell-derived products such as tryptase and chymase can, through their enzymic action, have detrimental effects on blood vessel structure while mast cell-derived mediators such as cytokines and chemokines can perpetuate vascular inflammation. Mice lacking mast cells have been developed and these are providing an insight into how mast cells are involved in cardiovascular diseases and, as knowledge increase, mast cells may become a viable therapeutic target to slow progression of cardiovascular disease.


Evaluation of the anaerobic degradation of food waste collection bags made of paper or bioplastic.
The amount of compostable bioplastics collected with the food waste is constantly growing, particularly due to the bags used for collection. According to the Italian legislation, compostable bioplastics must be accepted by all biological treatment plants, including aerobic and anaerobic facilities. Anyway, the compostability standard requires only the assessment of the aerobic degradability, while it is generally not required to test the behaviour under anaerobic conditions. This aspect is evaluated in the paper, where the anaerobic degradability of bioplastic bags used for the food waste collection is assessed. First, Biochemical Methane Potential (BMP) tests were performed on four commercial types of bioplastic bags, including those designed only for the collection of food waste and the shoppers, that can be reused for the same purpose. Subsequently, an innovative approach for this kind of substrate was applied, subjecting two bags to semi-continuous co-digestion tests together with the food waste. Both tests were performed by comparing the behaviour of bioplastic bags with that of an alternative collection paper bag. Finally, tests to evaluate the influence of physical phenomena on the degradation of bioplastics were performed to better understand the results of biological tests. BMP tests indicated a good degradability (>71%) of bioplastic bags, while semi-continuous tests showed a much lower degradability (<27%), confirmed by the observation of the undigested bag pieces. On the contrary, the paper bag presents interesting characteristics, because its degradability in the semi-continuous tests (82%) resulted even higher than that observed in the BMP tests (74%). These results highlight an important difference between the bags mono-digestion by means of BMP tests and the semi-continuous co-digestion tests with food waste, which better simulate the full-scale operational conditions.