Effects of cadmium on intestinal histology and microbiota in freshwater crayfish (Procambarus clarkii).
In this study, Procambarus clarkii (P. clarkii) were exposed to different concentrations (0, 2, 5 and 10 mg/L) of cadmium (Cd). We studied the effects of Cd exposure on intestinal histology and microbiota in P. clarkii. The results demonstrated that exposure to Cd caused histological alterations in the intestines of P. clarkii. Meanwhile, high-throughput sequencing analysis revealed that Cd exposure could alter the richness, diversity, and composition of intestinal microbiota in P. clarkii. At the phylum level, the relative abundances of the prevalent phyla Firmicutes, Proteobacteria, Bacteroidetes, Fusobacteria, and Actinobacteria changed significantly after exposure to Cd. At the genus level, the most prevalent genera with significant difference in relative abundance were Bacteroides, Clostridium XlVb, Hafnia, Buttiauxella, Shewanella, Anaerorhabdus, Alistipes, Arcobacter, Azoarcus, Chryseobacterium, and so on. Furthermore, functional prediction analysis of intestinal microbial communities showed that Cd exposure could significantly alter the pathways related to metabolism, diseases, cellular processes, and so on. Taken together, exposure to Cd could induce intestinal histological damage and affect intestinal microbiota composition and functions of P. clarkii. Our study can be an important step toward a better understanding of the toxic effects of Cd on aquatic crustaceans.


Design, synthesis, growth and characterization of 4-methoxy-4'-dimethylamino-benzylidene aniline (MDMABA): a novel third order nonlinear optical material.
Synthesis, growth, X-ray crystal structure and characterization of a novel third order nonlinear optical material, 4-methoxy-4'-dimethylamino-benzylidene aniline (MDMABA), are reported for the first time. The asymmetric unit of MDMABA compound contains two crystallographically independent molecules (A and B), and they exist in the E-configuration. The structural perfection of the grown crystal is analyzed by high-resolution X-ray diffraction rocking curve analysis. The functional groups present in MDMABA are investigated by FTIR and FT-Raman spectral analyses. The placement of the protons is determined using HNMR spectrum. The range and percentage of optical transmission were ascertained by recording UV-vis-NIR spectrum. Thermal and mechanical properties are reported. Dielectric study shows that the dielectric constant of the crystal varies with frequency and temperature. The third order nonlinear optical absorption coefficient of the MDMABA crystal is determined by the Z-scan technique.


Imaging of metal-coated biological samples by scanning tunneling microscopy.
A method for imaging biological samples by scanning tunneling microscopy (STM) is presented. There are two main difficulties in imaging biological samples by STM: (1) the low conductivity of biological material and (2) finding a method of reliably depositing the sample on a flat conducting surface. The first of these difficulties was solved by coating the samples with a thin film of platinum-carbon. The deposition problem was solved by a method similar to a procedure used to deposit biological molecules onto field ion microscope (FIM) tips. STM images of bacteriophage T7 and filamentous phage fd are shown. The substrate on which the samples were absorbed was atomically flat gold. The images do not show molecular detail due to the metal coating, but the gross dimensions and morphology are correct for each type of virus. Also, the surface density of virus particles increases and decreases in the way expected when the conditions of deposition are changed. These methods allow reliable and reproducible STM imaging of biological samples.


Cortical dysfunction underlies disability in multiple sclerosis.
Gray matter atrophy has been implicated in the development of secondary progressive multiple sclerosis (SPMS). Cortical function may be assessed by transcranial magnetic stimulation (TMS). Determining whether cortical dysfunction was a feature of SPMS could be of pathophysiological significance. Consequently, novel paired-pulse threshold tracking TMS techniques were used to assess whether cortical dysfunction was a feature of SPMS. Cortical excitability studies were undertaken in 15 SPMS, 25 relapsing-remitting MS patients (RRMS) and 66 controls. Short interval intracortical inhibition (SPMS 3.0 ± 2.1%; RRMS 12.8 ± 1.7%, p < 0.01; controls 10.5 ± 0.7%, p < 0.01) and motor evoked potential (MEP) amplitude (SPMS 11.5 ± 2.2%; RRMS 26.3 ± 3.6%, p <0.05; controls 24.7 ± 1.8%, p < 0.01) were reduced in SPMS, while intracortical facilitation (SPMS -5.2 ± 1.9%; RRMS -2.0 ± 1.4, p < 0.05; controls -0.9 ± 0.7, p < 0.01) and resting motor threshold were increased (SPMS 67.5 ± 4.5%; RRMS 56.0 ± 1.5%, p < 0.01; controls 59.0 ± 1.1%, p < 0.001). Further, central motor conduction time was prolonged in SPMS (9.1 ± 1.2 ms, p < 0.001) and RRMS (7.0 ± 0.9 ms, p < 0.05) patients compared with controls (5.5 ± 0.2 ms). The observed changes in cortical function correlated with the Expanded Disability Status Scale. Together, these findings suggest that cortical dysfunction is associated with disability in MS, and documentation of such cortical dysfunction may serve to quantify disease severity in MS.


Oligosaccharide composition, localization, and developmental changes of a CNS-specific (F3-87-8) glycoprotein.
The F3-87-8 glycoprotein was isolated from rat brain by immunoaffinity chromatography after biosynthetic labeling by intracerebral administration of [3H]glucosamine, and the oligosaccharide composition of pronase-derived glycopeptides was determined by sequential lectin affinity chromatography and alkali treatment. Triantennary complex oligosaccharides (65%) and O-glycosidic oligosaccharides (18%) were the predominant types present, accompanied by 7-10% each of biantennary and high-mannose oligosaccharides. Twenty-two percent of the complex oligosaccharides had a fucose residue linked to the proximal N-acetylglucosamine of the chitobiose units. No poly(N-acetyllactosaminyl) or hybrid oligosaccharides were detected. Immunocytochemical studies on the localization of this glycoprotein in developing rat brain demonstrated that in 1-week postnatal cerebellum, there is light staining of the internal granule cell layer and surrounding the Purkinje cells. By 2 weeks, an intense staining of myelinating fiber tracts appears, accompanied by much lighter staining in the granule cell layer and at the base of the molecular layer. Staining of the white matter remains strong at 3 weeks postnatal, together with significant staining throughout the molecular layer, and then decreases in both areas by 1 month. In adult brain there is relatively uniform staining of approximately equal intensity in the white matter, granule cell layer, and molecular layer, whereas the Purkinje cell bodies appear unstained throughout development. In agreement with a previously reported immunochemical analysis, no staining was seen in other tissues, confirming the CNS-specific localization of this glycoprotein.


First bacteraemic human infection with Escherichia albertii.
The facultative anaerobic Gram-negative species Escherichia albertii has been isolated from human faeces in gastrointestinal infection and from a range of wild bird species. Here we report the first case of a febrile infection associated with E. albertii bacteraemia in a 76-year-old woman with gastric dysplasia.


Targeted genome editing restores T cell differentiation in a humanized X-SCID pluripotent stem cell disease model.
The generation of T cells from pluripotent stem cells (PSCs) is attractive for investigating T cell development and validating genome editing strategies in vitro. X-linked severe combined immunodeficiency (X-SCID) is an immune disorder caused by mutations in the IL2RG gene and characterised by the absence of T and NK cells in patients. IL2RG encodes the common gamma chain, which is part of several interleukin receptors, including IL-2 and IL-7 receptors. To model X-SCID in vitro, we generated a mouse embryonic stem cell (ESC) line in which a disease-causing human IL2RG gene variant replaces the endogenous Il2rg locus. We developed a stage-specific T cell differentiation protocol to validate genetic correction of the common G691A mutation with transcription activator-like effector nucleases. While all ESC clones could be differentiated to hematopoietic precursor cells, stage-specific analysis of T cell maturation confirmed early arrest of T cell differentiation at the T cell progenitor stage in X-SCID cells. In contrast, genetically corrected ESCs differentiated to CD4 + or CD8 + single-positive T cells, confirming correction of the cellular X-SCID phenotype. This study emphasises the value of PSCs for disease modelling and underlines the significance of in vitro models as tools to validate genome editing strategies before clinical application.


Sham feeding. Cephalic-vagal influences on gastric myoelectric activity.
The effects of sham feeding on gastric motility of human subjects have not previously been studied. The amplitude of 3-cpm electrogastrogram (EGG) waves increases after the ingestion of food. We hypothesized that sham feeding would stimulate a similar, but briefer gastric myoelectric response. Healthy human subjects chewed and expectorated a hot dog on a roll and later ate a second hot dog. EGGs were continuously recorded before, during, and after sham feeding and eating. The results of experiment I (N = 27) showed that the hand-scored amplitude of the 3-cpm waves increased significantly (P less than 0.01) during sham feeding. Two minutes after sham feeding, the mean amplitude of 3-cpm EGG waves returned to baseline level. The increase in EGG amplitude during eating was also significant (P less than 0.01), and remained increased for approximately 30 min after ingestion. The procedure used in experiment II (N = 20) was similar to experiment I, but EGGs were computer analyzed and power, ie, spectral intensities, at 3 cpm were obtained. The increase in power at 3 cpm during sham feeding and during eating was significant (P less than 0.05 and P less than 0.02, respectively). Similar to experiment I, the duration of increase in power at 3 cpm was brief during sham feeding compared to the postprandial increase. Four vagotomized subjects failed to show an increase in power at 3 cpm in response to sham feeding. We conclude: (1) The cephalic-vagal stimulation of sham feeding increases briefly the amplitude and power of 3-cpm gastric myoelectric activity in healthy subjects but not vagotomized patients.(ABSTRACT TRUNCATED AT 250 WORDS)


The Forensic Pathology of the Sexual Abuse of a Group of Chickens.
Twelve chickens were discovered dead in a barn with a human male suspect observed on closed-circuit television. Post-mortem examination of two of the chickens revealed traumatic injury to the ventral cloaca with fibrinoheterophilic coelomitis associated with coelomic contamination by gut contents. The presence of human DNA was subsequently confirmed in cloacal swabs. This report highlights animal sexual abuse, which may occur in a range of species including chickens, as a significant challenge to animal welfare. Veterinary surgeons should be vigilant for signs of injury to the anogenital regions of animal patients, including birds, as evidence of potential sexual abuse.


Purification and characterization of a metabolite-regulated pyruvate kinase from Leishmania major promastigotes.
The pyruvate kinase (ATP:pyruvate 2-O-phosphotransferase, EC 126.96.36.199) of Leishmania major promastigotes is a multimer of 59 kDa subunits having an Mr 181000. It is activated by its substrate phosphoenolpyruvate (PEP) in a positively cooperative manner, and heterotropically by fructose 1,6-bisphosphate (FBP). Kinetics with regard to the phosphate acceptor adenosine 5'-diphosphate (ADP), MgCl2, and KCl are hyperbolic and unaffected by FBP. The enzyme is strongly inhibited by the reaction product ATP, as well as GTP and ITP, and to a lesser degree by citrate. Of seven amino acids reported to inhibit the pyruvate kinases of other organisms, none have any effect on the L. major pyruvate kinase in vitro. The enzyme shows its maximum activity at pH 7.0 in the absence of FBP, and at pH 7.6 in its presence. Contrary to previous suggestions, the enzyme appears to be well-suited for a regulatory role in the metabolism of an aerobic organism capable of net glucose synthesis.


Interactions of the plant flavonoid fisetin with macromolecular targets: insights from fluorescence spectroscopic studies.
Fisetin (3,7,3',4'-tetrahydroxyflavone) is a bioactive plant flavonoid of immense importance as a potentially useful therapeutic drug, for various free radical mediated as well as other diseases. In a recent paper, we demonstrated the novel uses of the exquisitely sensitive intrinsic fluorescence of this compound to explore its binding characteristics in liposomal membranes [B. Sengupta, A. Banerjee, P.K. Sengupta, Investigations on the binding and antioxidant properties of the plant flavonoid fisetin in model biomembranes, FEBS Lett. 570 (2004) 77-81]. Here, we have exploited this technique to examine its interactions with relevant macromolecular targets, namely double stranded DNA (from calf thymus), and the physiologically important circulatory protein, Human Serum Albumin (HSA). In the presence of DNA dramatic changes are observed in the intrinsic fluorescence behaviour of fisetin. These, along with other relevant supporting spectroscopic data, suggest that fisetin binds intercalatively between the base pairs of DNA. From the studies on fisetin-HSA interaction, the existence of two distinct binding sites are inferred. Furthermore we present evidence for the occurrence of efficient Förster type fluorescence resonance energy transfer from tryptophan to fisetin, indicating that both binding sites of fisetin in HSA are proximal to the unique tryptophan - 214 residue present in the interdomain (between IIA and IIIA domains) loop region of the protein.


Effects of nickel chloride and oxygen depletion on behaviour and vitality of zebrafish (Danio rerio, Hamilton, 1822) (Pisces, Cypriniformes) embryos and larvae.
We examined acute (2 h exposure of 5-day-old larvae) and subchronic (exposure from fertilization up to an age of 11 days) effects of NiCl(2).6H2O on embryos and larvae of zebrafish (Danio rerio), both alone and in combination with oxygen depletion. The following endpoints were recorded: acute exposure: locomotory activity and survival; subchronic exposure: hatching rate, deformations, locomotory activity (at 5, 8 and 11 days) and mortality. In acute exposures nickel chloride (7.5-15 mg Ni/L) caused decreasing locomotory activity. Oxygen depletion (<or=2.45+/-0.16 mg O2/L) also resulted in significantly reduced locomotory activity. In the subchronic test, exposure to >or=10 mg Ni/L resulted in delayed hatching at an age of 96 h, in decreased locomotory activity at an age of 5 days, and increased mortality at an age of 11 days (LC20=9.5 mg Ni/L). The observed LOEC for locomotory activity (7.5 mg Ni/L) is in the range of environmentally relevant concentrations. Since locomotory activity was already affected by acute exposure, this parameter is recommended to supplement commonly recorded endpoints of toxicity.


Molecular and spatial mechanisms governing STING signalling.
Detection of microbial nucleic acids via innate immune receptors is critical for establishing host defence against pathogens. The DNA-sensing cGAS-STING pathway has gained increasing attention in the last decade as a key pathway for combating viral and bacterial infections. cGAS-STING activation primarily promotes the secretion of antiviral type I IFNs via the key transcription factor, IRF3. In addition, cGAS-STING signalling also elicits proinflammatory cytokines through NF-κB activity. Activation of IRF3 and NF-κB is mediated by the chief signalling receptor protein STING. Interestingly, STING undergoes significant trafficking events across multiple subcellular locations, which regulates both the activation of downstream signalling pathways, as well as appropriate termination of the responses. Studies to date have provided a comprehensive view of the regulation and role of the IRF3-IFN pathway downstream of STING. However, many aspects of STING signalling remain relatively poorly defined. This review will explore the current understanding of the mechanisms through which STING elicits inflammatory and antimicrobial responses, focusing on the precise signalling and intracellular trafficking events that occur. We will also discuss exciting and emerging concepts in the field, including the importance of IFN-independent STING responses for host defence and during STING-related disease.


Covid-19 pandemic and food: Present knowledge, risks, consumers fears and safety.
COVID-19 is a pandemic disease that has paralyzed social life and the economy around the world since the end of 2019, and which has so far killed nearly 600,000 people. The rapidity of its spread and the lack of detailed research on the course and methods of transmission significantly impede both its eradication and prevention. Due to the high transmission rate and fatality resulting from COVID-19 disease, the paper focuses on analyzing the current state of knowledge about SARS-CoV-2 as well as its potential connection with food as a source of pathogen and infection. There is currently no evidence (scientific publications, WHO, EFSA etc.) that COVID-19 disease can spread directly through food and the human digestive system. However, according to the hypothesis regarding the primary transmission of the virus, the source of which was food of animal origin (meat of wild animals), as well as the fact that food is a basic necessity for humans, it is worth emphasizing that food can, if not directly, be a carrier of the virus. Particular attention should be paid to this indirect pathway when considering the potential for the spread of an epidemic and the development of prevention principles.


Cooperative catalysis with metal and secondary amine: synthesis of 2-substituted quinolines via addition/cycloisomerization cascade.
A cooperative catalytic system, consisting of CuI and pyrrolidine, has been developed for an efficient synthesis of 2-substituted quinolines. A combination of both the catalysts is necessary; the use of either catalyst alone does not give the product.


Nickel-doped iridium echinus-like nanosheets for stable acidic water splitting.
Nickel-doped iridium echinus-like nanosheets (NiIr-ENS) have a superior acidic oxygen evolution reaction (OER) activity with a TOF of 1.72 s-1 at an overpotential of 300 mV, 8.6-fold higher than that of IrO2.


Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits.
Heterotrimeric G-proteins bind to cell-surface receptors and are integral in transmission of signals from outside the cell. Upon activation of the Galpha subunit by binding of GTP, the Galpha and Gbetagamma subunits dissociate and interact with effector proteins for signal transduction. Regulatory proteins with the 19-amino-acid GoLoco motif can bind to Galpha subunits and maintain G-protein subunit dissociation in the absence of Galpha activation. Here we describe the structural determinants of GoLoco activity as revealed by the crystal structure of Galpha(i1) GDP bound to the GoLoco region of the 'regulator of G-protein signalling' protein RGS14. Key contacts are described between the GoLoco motif and Galpha protein, including the extension of GoLoco's highly conserved Asp/Glu-Gln-Arg triad into the nucleotide-binding pocket of Galpha to make direct contact with the GDP alpha- and beta-phosphates. The structural organization of the GoLoco Galpha(i1) complex, when combined with supporting data from domain-swapping experiments, suggests that the Galpha all-helical domain and GoLoco-region carboxy-terminal residues control the specificity of GoLoco Galpha interactions.


Congenital diaphragmatic hernia in Northern Queensland.
To investigate the survival of non-syndromic live born infants diagnosed in Northern Queensland with congenital diaphragmatic hernia (CDH). Case note audit was completed of all live born newborns with a diagnosis of CDH admitted between February 1987 and December 2010. Demographic and clinical data were extracted. Overall survival to time of discharge for all infants was 67.3% (n = 35/52). For infants born before 2003 survival was 59.5% and for those born in 2003 and onwards was 86.7% (P = 0.10, OR 4.4, 95% confidence interval (CI) 0.87-22.55). Infants born prior to 2003, compared to those born from 2003 onwards, were less likely to survive with an isolated defect (P = 0.04, OR 8.0, 95% CI 0.93-68.62). Isolated congenital diaphragmatic hernia survival since 2003 was 92.3%. A significant difference was found in the time to surgery with those born in 2003 onwards having surgery significantly later, median 134 h, compared to the earlier cohorts median time to surgery of 83 h (P < 0.005, 95% CI 32.61-167.09). Premature infants had poorer survival (46.7%) compared to term infants (75.7%) (P < 0.0001 OR 3.6, 95% CI 1.99-6.68). Univariate analysis identified low birthweight was associated with poorer survival. Survival to discharge in our cohort equals other reported rates in Australia and around the world, including centres with tertiary paediatric services. The current management strategies used for these infants have seen a significant improvement in outcomes over time.


The effect of ligation combined with section on anterograde axonal transport in rabbit hypoglossal nerve.
The axonal transport of radiolabeled slow phase proteins and fast phase glycoproteins was studied in rabbit hypoglossal nerve one week after axotomy. The nerves were ligated and cut to prevent axonal regeneration into the distal stump. In this situation of obstructed axonal outgrowth, the axonal transport of these components into the proximal part of the nerve was increased. This increase, however, was significantly less pronounced compared with the increase previously found after nerve crush, when the axons were free to regenerate. The results suggest that the axonal transport response concerning structural axonal proteins after nerve lesions depends on the type of trauma, and that the neuronal export of these components during regeneration is modified if axonal outgrowth is impaired. The results are discussed in the light of the present understanding of the role of axonal transport in nerve regeneration.


Evaluation of color Doppler ultrasonography in diagnosing hepatic alveolar echinococcosis.
To assess the accuracy of color Doppler ultrasonography in diagnosing hepatic alveolar echinococcosis, 129 patients were examined at the First Affiliated Hospital of Xinjiang Medical University between July 2004 and June 2010. Those patients suspected of having hepatic alveolar echinococcosis were examined and diagnosed by color Doppler ultrasound. All the cases were compared with the gold standard. The findings of their sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and 95% confidence interval were recorded. Sensitivity: 95% (95% confidence interval: 90.7%-99.3%); specificity: 20.7% (95% confidence interval: 6.0%-35.4%); positive predictive value: 80.5%; negative predictive value: 54.5%; positive likelihood ratio: 1.2: negative likelihood ratio: 0.2. Our study indicates that color Doppler ultrasonography, when used in diagnosing hepatic alveolar echinococcosis, has high sensitivity although specificity is low. Color Doppler ultrasound is, thus, considered to be an efficient means for diagnosing hepatic alveolar echinococcosis.


High field superconducting properties of Ba(Fe1-xCox)2As2 thin films.
In general, the critical current density, Jc, of type II superconductors and its anisotropy with respect to magnetic field orientation is determined by intrinsic and extrinsic properties. The Fe-based superconductors of the '122' family with their moderate electronic anisotropies and high yet accessible critical fields (Hc2 and Hirr) are a good model system to study this interplay. In this paper, we explore the vortex matter of optimally Co-doped BaFe2As2 thin films with extended planar and c-axis correlated defects. The temperature and angular dependence of the upper critical field is well explained by a two-band model in the clean limit. The dirty band scenario, however, cannot be ruled out completely. Above the irreversibility field, the flux motion is thermally activated, where the activation energy U0 is going to zero at the extrapolated zero-kelvin Hirr value. The anisotropy of the critical current density Jc is both influenced by the Hc2 anisotropy (and therefore by multi-band effects) as well as the extended planar and columnar defects present in the sample.


Assessment of phase and amplitude effects due to susceptibility variations in MR imaging of the brain.
Susceptibility effects due to the presence of hemorrhage have been observed in a substantial number of patients and are a potential source of artifact in in vivo spectroscopy. The studies so far have concentrated on observations of phase differences, but amplitude variations also exist. This article reviews the degree to which the two are independent and suggests that at least three different pulse sequences are necessary to characterize effects due to local field inhomogeneities arising in clinical studies.


Lower Resting State Heart Rate Variability Relates to High Pain Catastrophizing in Patients with Chronic Whiplash-Associated Disorders and Healthy Controls.
Vagally mediated heart rate variability (vmHRV) is widely respected as a psychophysiological measure of emotion regulation capacity and serves as a readily available index of executive brain areas that exert an inhibitory influence on subcortical structures. Pain catastrophizing (PC) is conceptualized as the tendency to misinterpret and exaggerate pain-related situations that may be threatening. Chronic pain patients show lower vmHRV and higher PC. Previously, no study has investigated the association of PC and vmHRV. We examined the association of PC and vmHRV in a sample of patients with chronic whiplash-associated disorders (WAD, n = 30) and healthy controls (n = 31). Patients with WAD showed lower vmHRV, indexed by high-frequency HRV (effect size, Cohen's d = 0.442), and greater PC (d = 0.815). Zero-order and partial correlations controlling for age and sex revealed that vmHRV and PC are inversely related. The results provide evidence for a psychophysiological mechanism underlying PC, in particular in chronic pain patients.


PD1hi cells associate with clusters of proliferating B-cells in marginal zone lymphoma.
Abnormally sustained immune reactions drive B-cell proliferation in some cases of marginal zone lymphoma but the CD4+ T-cell subsets, which are likely to contribute to the B-cell responses in the tumour microenvironment, are not well characterised and neither has the spatial distribution of the different subsets in involved lymph nodes been investigated. Employing a workflow of multiplex semi-automated immunohistochemistry combined with image processing we investigated association between infiltrating T-cells and proliferating lymphoma B-cells. Both total numbers of activating follicular helper (Tfh) cells (defined by high expression of PD1) and suppressive regulatory (Treg) T-cells (defined by FOXP3+ expression) and the Tfh:Treg ratio, assessed over relatively large areas of tissue, varied among cases of marginal zone lymphoma. We determined spatial distribution and demonstrated that PD1hi cells showed significantly more clustering than did FOXP3+. To investigate the association of infiltrating T-cells with lymphoma B-cells we employed Pearson correlation and Morisita-Horn index, statistical measures of interaction. We demonstrated that PD1hi cells were associated with proliferating B-cells and confirmed this by nearest neighbour analysis. The unexpected architectural complexity of T-cell infiltration in marginal zone lymphoma, revealed in this study, further supports a key role for Tfh cells in driving proliferation of lymphoma B-cells. We demonstrate the feasibility of digital analysis of spatial architecture of T-cells within marginal zone lymphoma and future studies will be needed to determine the clinical importance of these observations.


Antiarrhythmic Effect of Artemisinin in an Ex-vivo Model of Brugada Syndrome Induced by NS5806.
Brugada syndrome (BrS) is an inherited arrhythmia syndrome that presents as sudden cardiac death (SCD) without structural heart disease. One of the mechanisms of SCD has been suggested to be related to the uneven dispersion of transient outward potassium current (Ito) channels between the epicardium and endocardium, thus inducing ventricular tachyarrhythmia. Artemisinin is widely used as an antimalarial drug. Its antiarrhythmic effect, which includes suppression of Ito channels, has been previously reported. We investigated the effect of artemisinin on the suppression of electrocardiographic manifestations in a canine experimental model of BrS. Transmural pseudo-electrocardiograms and epicardial/endocardial transmembrane action potentials (APs) were recorded from coronary-perfused canine right ventricular wedge preparations (n=8). To mimic the BrS phenotypes, acetylcholine (3 μM), calcium channel blocker verapamil (1 μM), and Ito agonist NS5806 (6-10 μM) were used. Artemisinin (100-150 μM) was then perfused to ameliorate the ventricular tachyarrhythmia in the BrS models. The provocation agents induced prominent J waves in all the models on the pseudo-electrocardiograms. The epicardial AP dome was attenuated. Ventricular tachyarrhythmia was induced in six out of 8 preparations. Artemisinin suppressed ventricular tachyarrhythmia in all 6 of these preparations and recovered the AP dome of the right ventricular epicardium in all preparations (n=8). J wave areas and epicardial notch indexes were also significantly decreased after artemisinin perfusion. Our findings suggest that artemisinin has an antiarrhythmic effect on wedge preparation models of BrS. It might work by inhibition of potassium channels including Ito channels, subsequently suppressing ventricular tachycardia/ventricular fibrillation.


The impact of catecholamines in patients with or without beta-blockers on the ventricular fibrillation cycle length and ventricular fibrillation cycle length variability.
To evaluate the impact of epinephrine, norepinephrine, or placebo on the ventricular fibrillation cycle length (VFCL) and the variability of VFCL (cvVFCL) measurements in implantable cardioverter defibrillator (ICD) patients with or without beta-blockers. Forty-three patients scheduled for their 6-week post-ICD placement noninvasive electrophysiologic study were included in the study at the Arrhythmia Procedure Laboratory at Hartford Hospital, Hartford, CT. This randomized, double-blind, placebo-controlled evaluation was approved by the Hartford Hospital Institutional Review Board. After 2 seconds of continuous VF, 7 consecutive VFCLs were measured from the ICD device recording printout using a 0.5 mm scale ruler under magnification at baseline and after the infusion of catecholamines (epinephrine or norepinephrine at 2 mcg/min) or matching placebo at steady state. The average VFCL and the cvVFCL were determined for each study phase. Subgroup analysis based on chronic beta-blocker use was performed. No between-group differences were noted for epinephrine, norepinephrine, or placebo group for baseline (P=0.538) or postinfusion VFCL (P=0.749) or for baseline (P=0.561) or postinfusion cvVFCL (P=0.623) Regardless of catecholamine group randomization, longer pre- and postinfusion VFCL were noted in those receiving beta-blockers (P=0.157, P=0.019) but no differences in cvVFCL were noted (P=0.216, P=0.474) versus those without beta-blockers, respectively. Moderately dosed epinephrine or norepinephrine does not affect either VFCL or the variability of VFCL after short duration of ventricular fibrillation. Chronic cardioselective beta-blockade prolongs VFCL without any impact on coefficient of variation of VFCL.


On impulsive autoassociative neural networks.
Many systems existing in physics, chemistry, biology, engineering, and information science can be characterized by impulsive dynamics caused by abrupt jumps at certain instants during the process. These complex dynamical behaviors can be modeled by impulsive differential systems or impulsive neural networks. This paper formulates and studies a new model of impulsive autoassociative neural networks. Several fundamental issues, such as global exponential stability and existence and uniqueness of equilibria of such neural networks, are established.


Dissociating cue-related and task-related processes in task inhibition: evidence from using a 2:1 cue-to-task mapping.
Performance of task sequences is assumed to rely on activation and inhibition of tasks. An empirical marker of task inhibition is the so-called n-2 repetition cost, which is assessed by comparing performance in trial n-2 task repetitions (i.e., ABA) with that in n-2 task switches (i.e., CBA). Current theoretical accounts assume that inhibition acts on the level of task representations (i.e., task sets). However, another potential target of task inhibition could be the representation of the task cue. To decide between these two alternatives, the authors used a 2:1 cue-to-task mapping design. They found significant n-2 task repetition costs both with n-2 cue repetitions and n-2 cue switches. These costs were about equal (Experiment 1), and this data pattern was found for both short and long cuing intervals (Experiment 2). Together, the data suggest that task inhibition acts on task sets and not on cue representations.


Tissue establishment as a necessary institution within the country health care system: importance, requirements and structure.
A tissue establishment is a unit or service, inside or outside of a public or private hospital, generally operated by public or non-profit-making bodies or in some countries by private profit-making institutions that procure, process, sterilise, store, and distribute sterilised human tissues to private or public hospitals to be used in certain medical treatments. Each tissue establishment should adopt the best possible structure, hired the necessary well-trained staff, according to the level of its activities, and should establish the necessary internal committees to ensure the highest quality of its operation. In addition, the tissue establishment should adopt a quality management system in order to reduce the risk and maximize the benefits of the transplantation process.


Anisotropic morphology, formation mechanisms, and fluorescence properties of zirconia nanocrystals.
ZrO2 nanocrystals with spheres and elongated platelets were systemically prepared through a simple hydrothermal method by the use of ZrOCl2·8H2O and CH3COOK as raw materials. The anisotropic morphology and formation mechanism of the monoclinic and/or tetragonal ZrO2 were investigated by X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, scanning electron microscope, and high-resolution transmission electron microscope techniques. The uniform elongated platelets and star-like structures were composed of short nanorods with a diameter of approximately 5 nm and a length of approximately 10 nm. The different morphologies were formed due to the different contents of CH3COO- and Cl- and their synergy. The fluorescence band position and the band shape remained about the same for excitation wavelengths below 290 nm and the different morphologies of the nanocrystals.


Selecting data sources for substance abuse services research.
In this article we discuss the strengths and weaknesses of using different types of data sources for alcohol and drug abuse services research. To do this, we describe four types of data sources used in substance abuse services research: surveys of organizations, medical records, claim and encounter data and program-level administrative data. For each, we outline where to obtain data, how each type has been used, and the advantages and challenges. This overview should allow investigators to think more critically about the datasets they now use; providers to understand the types of data sources most appropriate for specific research questions so as to participate more fully in research; and policy makers to interpret correctly results based on different types of data. Moreover, it should foster better communication among these stakeholders in collaborative projects to improve the effectiveness of services for people with addictions.


[Molecular diagnosis of autoimmune dermatoses].
Bullous autoimmune diseases are organ-specific disorders characterized by an autoantibody-mediated blistering of skin and mucous membranes. The detection of tissue-bound and serum autoantibodies is prerequisite for the diagnosis of autoimmune blistering diseases. The individual entities of this group may be difficult to differentiate on clinical grounds alone. An accurate diagnosis is however important for prognosis and therapy. A preliminary diagnostic step includes direct and indirect immunofluorescence microscopy, which provide information about the binding pattern and isotype of autoantibodies and allow the diagnosis of the autoimmune blistering disease. Subsequent characterization of the molecular specificity of autoantibodies is necessary for the exact classification of autoimmune bullous dermatoses. The quantitative measurement of autoantibodies against structural proteins of the skin may be often used to assess disease severity at follow-up.


Nifedipine prevents sympathetic vasoconstriction distal to severe coronary stenoses.
Cardiac sympathetic nerve stimulation ( CSNS ) can induce vasoconstriction distal to severe coronary stenoses by activation of vascular alpha 2-adrenoceptors. Whether nifedipine can antagonize this CSNS -induced vasoconstriction was tested in 11 anesthetized, vagotomized dogs. CSNS decreased the end-diastolic resistance of intact coronary arteries from 0.76 +/- 0.07 to 0.56 +/- 0.05 mm Hg x min x 100 g/ml (p less than 0.05). In contrast, the resistance distal to severe stenoses, which were defined by a reduction of the postocclusive reactive hyperemia to almost zero, was increased during CSNS from 0.52 +/- 0.06 to 0.87 +/- 0.14 mm Hg x min x 100 g/ml (p less than 0.05). This increase in resistance was associated with severe ischemia, as indicated by a net lactate production of the circumflex-perfused myocardium and a decrease in systolic segment shortening from 8.4 +/- 0.7 to 7.0 +/- 0.7% (p less than 0.05). Both intracoronary (10 micrograms) and intravenous (10 micrograms/kg) administration of nifedipine did not change the poststenotic resistance at rest, but did prevent the CSNS -induced increase in resistance, the decrease in regional contraction, and the net lactate production. We conclude that nifedipine can prevent the deleterious role of alpha-adrenoceptor-mediated vasoconstriction in the genesis of myocardial ischemia.


Bilateral medial frontal infarction in a case of azygous anterior cerebral artery stenosis.
We describe the unusual case of a 63-year-old woman with a history of arterial hypertension who presented a sudden weakness of the lower limbs followed by mutism, akinesia and dyspraxia. Magnetic resonance images showed a bilateral medial frontal infarction. Digital subtraction angiography documented a right azygous anterior cerebral artery with severe stenosis in its sub-callosal tract; the left anterior cerebral artery showed mild hypoplasia with only sub-frontal and fronto-polar branches. No embolic source was documented. Afterwards the patient presented a gradual and partial recovery of both motor and cognitive functions.


Regulatory functions of adenosine.
Adenosine has emerged as an important regulator of many physiological processes. This review briefly describes the formation and inactivation of the nucleoside, its effects in different tissues and the mechanism by which these effects are executed.


Evolutionary steps of ecophysiological adaptation and diversification of ruminants: a comparative view of their digestive system.
A review is made of the ruminant digestive system in its morphophysiological variations and adaptations relating to foraging behaviour, digestive physiology, to interactions between plants and ruminants and to geographic and climatic diversity of ruminants' ecological niches. Evidence is provided for evolutionary trends from an extreme selectivity mainly for plant cell contents and dependence upon a fractionated fore- and hindgut fermentation, to an unselective intake of bulk roughage subjected to an efficient plant cell wall fermentation, mainly in the forestomachs. The review is based on detailed comparative morphological studies of all portions of the digestive system of 65 ruminant species from four continents. Their results are related to physiological evidence and to the classification of all extant ruminants into a flexible system of three overlapping morphophysiological feeding types: concentrate selectors (40%), grass and roughage eaters (25%) and intermediate, opportunistic, mixed feeders (35%). Several examples are discussed how ruminants of different feeding types are gaining ecological advantage and it is concluded that ruminants have achieved high levels of digestive efficiency at each evolutionary stage, (including well-documented seasonal adaptations of the digestive system) and that ruminant evolution is still going on. Deductions made from the few domesticated ruminant species may have, in the past, biased scientific evaluation of the free-ranging species' ecology. The main threat to a continuous ruminant evolution and diversity appears to be man's neglect for essential ecological interactions between wild ruminants and their specific habitats, which he alters or destroys.


Revealing antimicrobial resistance profile of the novel probiotic candidate Faecalibacterium prausnitzii DSM 17677.
Faecalibacterium prausnitzii, a resident anaerobic bacterium commonly found in healthy gut microbiota, has been proposed as a next generation probiotic with high potential for application in food matrices and pharmaceutical formulations. Despite its recognized health benefits, detailed information regarding its antimicrobial susceptibility profile is still lacking. However, this information is crucial to determine its safety, since the absence of acquired antimicrobial resistance is required to qualify a probiotic candidate as safe for human and animal consumption. Herein, the antimicrobial susceptibility profile of F. prausnitzii DSM 17677 strain was evaluated by integrating both phenotypic and in silico data. Phenotypic antimicrobial susceptibility was evaluated by determining minimum inhibitory concentrations of 9 antimicrobials using broth microdilution and E-test® methods. Also, the whole genome of F. prausnitzii DSM 17677 was analysed, using several databases and bioinformatics tools, to identify possible antibiotic resistance genes (ARG), genomic islands (GI) and mobile genetic elements (MGE). With exception of erythromycin, the same classification (susceptible or resistant) was obtained in both broth microdilution and E-test® methods. Phenotypic resistance to ampicillin, gentamycin, kanamycin and streptomycin were detected, which was supported by the genomic context. Other ARG were also identified but they seem not to be expressed under the tested conditions. F. prausnitzii DSM 17677 genome contains 24 annotated genes putatively involved in resistance against the following classes of antimicrobials: aminoglycosides (such as gentamycin, kanamycin and streptomycin), macrolides (such as erythromycin), tetracyclines and lincosamides. The presence of putative ARG conferring resistance to β-lactams could only be detected using a broader homology search. The majority of these genes are not encoded within GI or MGE and no plasmids were reported for this strain. Despite the fact that most genes are related with general resistance mechanisms, a streptomycin-specific ARG poses the only potential concern identified. This specific ARG is encoded within a GI and a MGE, meaning that it could have been laterally acquired and might be transferred to other bacteria present in the same environment. Thus, our findings provide relevant insights regarding the phenotypic and genotypic antimicrobial resistance profiles of the probiotic candidate F. prausnitzii DSM 17677.


Molecular mechanisms of l-DOPA-induced dyskinesia.
Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by the development of dystonic and choreic motor complications, or dyskinesia. This chapter describes the molecular mechanisms implicated in the emergence and manifestation of l-DOPA-induced dyskinesia (LID). Particular emphasis is given to the role played in this condition by abnormalities in signal transduction at the level of the medium spiny neurons (MSNs) of the striatum, which are the principal target of l-DOPA. Recent evidence pointing to pre-synaptic dysregulation is also discussed.


Simplified coagulum pyelolithotomy using cryoprecipitate.
Coagulum pyelolithotomy has been beneficial in removing calyceal calculi when the diameter of the infundibulum and pelvis is adequate. By utilizing a simple, precise ratio of cryoprecipitate, thrombin, and calcium chloride (25:4:1), an effective coagulum was obtained in 7 consecutive cases with complete stone removal in 5.


Microsurgical cerebral revascularization for the treatment of stroke.
A study of 1,000 STA-MCA by-pass procedures in stroke patients is described as "extremely encouraging", with greater than 90% patency rate and marked improvement in patients who had not responded to medical management or had been turned away from routine vascular surgery.


The structural relationship of blood group-related oligosaccharides in human carcinoma to biological function: a perspective.
Blood group-related oligosaccharides have been isolated from a limited number of carcinomas. The carcinoma-associated oligosaccharides show chain elongation, for example due to repeating Gal 1,4 GlcNAc 1,3 sequences, or a higher degree of branching, which permit increased sialylation and fucosylation. Abnormal carbohydrate structures have been demonstrated on tumor cell membranes by immunological techniques, which suggests deletion of ABH, accumulation of 'crypt' antigens such as I and T antigens, and abnormal expression of Lewis antigens. Changes in carcinoma-associated oligosaccharides can result from altered biosynthetic processing in the Golgi apparatus or the occurrence of abnormal tumor glycosyltransferase isoenzymes. Structural alterations of oligosaccharides on the tumor cell membrane are related to the regulation of tumor growth, cell-cell interaction, cell differentiation, and metastasis. Glycoproteins secreted by tumor cells into the circulation evoke cellular and humoral immunity and cause immune suppression by binding to cytotoxic T lymphocytes and lymphocyte subsets. The relationship of oligosaccharide structures to biologic function awaits elucidation.


Antiemetic efficacy of single-dose palonosetron and dexamethasone in patients receiving multiple cycles of multiple day-based chemotherapy.
The goal of pharmacological prophylaxis of chemotherapy-induced nausea and vomiting (CINV) should be the elimination of both nausea and vomiting symptoms during all planned chemotherapy cycles. The aim of this study was to assess the efficacy of a single dose of palonosetron and dexamethasone to prevent CINV and to guarantee an adequate food intake (FI) in patients receiving several cycles of multiple day-based chemotherapy (MD-CT). Patients with advanced cancer but without a compromised nutritional status (bone mass index ≥ 18.5) were treated with 0.25 mg palonosetron plus 20 mg dexamethasone before MD-CT. The MD-CT regimen was either epirubicin plus ifosfamide or paclitaxel plus cisplatin and ifosfamide. Nausea, vomiting, and FI were monitored in a 7-day diary. Complete response (CR: no vomiting and no rescue therapy) was the primary endpoint, while complete control (CC: CR and no more than mild nausea) and the evaluation of FI were secondary endpoints. The endpoints were evaluated during the overall timescale (0-168 h) of the chemotherapy regimen. Fifty patients were enrolled, 80% of whom achieved CR and 78% achieved CC. During the six chemotherapy cycles, CR and CC ranged from 76% to 88% and from 62% to 88%, respectively. Moreover, patients with CR had a significantly (p < 0.0001) higher weekly food intake compared with patients not achieving CR. This trial was the first to assess the efficacy of palonosetron and dexamethasone for the prevention of both nausea and vomiting in patients receiving multiple cycles of MD-CT. In this trial, the ability of patients to intake an adequate amount of food each week was correlated with nausea, thus providing clinicians with an objective parameter for the measurement of the effects of nausea. A single dose of palonosetron and dexamethasone was able to prevent CINV in most patients receiving 3 days of chemotherapy during all planned chemotherapy cycles.


The effect of four chemical forms of selenium on mammary tumor incidence in BALB/c female mice treated with 7-12-dimethylbenz[a]anthracene.
The study was conducted to determine the effect of four forms of selenium on inhibition of DMBA-induced mammary tumors. BALB/c virgin female mice were fed the AIN-76 diet containing 0.2 or 2.0 ppm Se as selenite, selenate, selenomethionine, or selenocystine prior to and for 6 months post DMBA-treatment. At necropsy, mammary glands were histologically treated for confirmation of adenocarcinomas and the livers were removed for analysis of glutathione-peroxidase (GSHPx) activity and selenium concentrations. Dietary levels or forms of selenium had no effect on body weights. Inorganic selenium fed at 2.0 ppm Se (selenite and selenate) decreased mammary tumor incidence, but organic selenium (selenomethionine and selenocystine) had no effect on mammary tumor incidence. Hepatic GSHPx activity was highest with the 2.0 ppm selenium as selenocystine diet, but hepatic selenium levels were highest with the 2.0 ppm selenium as selenite. This study showed that the dietary form of selenium affects inhibition of mammary tumorigenesis. Furthermore, the study suggested that the pathways for selenium incorporation into GSHPx and for tumor inhibition are different.


The effect of repeated administration of insulin on pain threshold and gamma-aminobutyric acid level in mouse brain.
In experiments on male Albino-Swiss mice weighing 18-22 g insulin given in doses of 2 i.u./kg caused no change in the time of reaction to pain, while the same dose administered daily for 7 days potentiated the analgesic action of morphine (3 mg/kg s.c.). Glucose caused no change in this effect of insulin. After 14 days of insulin treatment the time of reaction to pain in the animals subjected to the action of morphine returned to its initial value. Twenty-four hours after the last administration of morphine the level of gamma-aminobutyric acid (GABA) was found to be decreased in the animals receiving insulin with glucose. These results suggest that the central action of insulin is dependent not only on hypoglycaemia produced by it, but may be due also to its direct action on the central structures and an indirect action mediated by its effect on other neurotransmitter systems.


On the mechanism of activation of fat cell adenylate cyclase by guanine nucleotides. An explanation for the biphasic inhibitory and stimulatory effects of the nucleotides and the role of hormones.
Adenylate cyclase activity in purified plasma membranes from rat fat cells displays transient kinetic characteristics in the absence and presence of guanyl=5'=yl imidodiphosphate (Gpp(NH)p). Gpp(NH)p causes immediate inhibition of enzyme activity; the inhibitory phase is followed by a slow increase in activity which, depending on incubation temperature, exceeds activity stimulated in the presence of hormones (glucagon, secretin, epinephrine, or adrenocorticotropin). Basal activity displays an initial high rate of activity which decays to a low state of activity within 2 min of incubation. Hormones do not alter the initial rate but prevent the decay in enzyme activity. The inhibitory phase of Gpp(NH)p action and the previously reported (Harwood, J.P., Low, H., and Rodbell, M. (1973) J. Biol. Chem. 248, 6239-6245) inhibitory effects of GTP are abolished by increasing (Mg2+) and pH to 50 mM and 8.5, respectively. Under these conditions, Gpp(NH)p and GTP cause marked stimulation of activity, the stimulatory effect of Gpp(NH)p being greater than that of GTP both in the absence and presence of hormones...


Identification of PARP14 inhibitors using novel methods for detecting auto-ribosylation.
Poly(ADP-ribose) polymerases (PARPs) use nicotinamide adenine dinucleotide (NAD+) as a co-substrate to transfer ADP-ribose when it releases nicotinamide as the metabolized product. Enzymes of the PARP family play key roles in detecting and repairing DNA, modifying chromatin, regulating transcription, controlling energy metabolism, and inducing cell death. PARP14, the original member of the PARP family, has been reported to be associated with the development of inflammatory diseases and various cancer types, making it a potential therapeutic target. In this study, we purified the macrodomain-containing PARP14 enzyme and established an assay for detecting the auto-ribosylation activity of PARP14 using RapidFire high-throughput mass spectrometry and immunoradiometric assay using [3H]NAD+. Subsequently, we performed high-throughput screening using the assays and identified small-molecule hit compounds, which showed NAD+-competitive and PARP14-selective inhibitory activities. Co-crystal structures of PARP14 with certain hit compounds revealed that the inhibitors bind to the NAD+-binding site. Finally, we confirmed that the hit compounds interacted with intracellular PARP14 by a cell-based protein stabilization assay. Thus, we successfully identified primary candidate compounds for further investigation.


Multidrug-resistant high-risk Enterococcus faecium clones: can we really define them?
Enterococcus faecium is a significant opportunistic human pathogen with a broad host range, including humans, farm animals, pets and wildlife. Specialised subpopulations have globally evolved towards a powerful and convergent adaption to the healthcare environment by acquiring a cocktail of key antimicrobial resistance and virulence genes, enabling them to thrive in the disturbed microbiota of hospitalised patients. These populations can also be found in different community reservoirs, but the relevance of their dispersal in non-human hosts is greatly unknown and is here discussed. This review provides a brief historical overview of what we have been considering E. faecium high-risk clones worldwide alongside the advances in strain typing technologies that have revolutionised our understanding of the genetic evolution of this species over the last three decades.


Regulation of telomerase expression in human lymphocytes.
The function of lymphocytes is highly dependent on the ability of cell to divide. Among the various factors that regulate this cellular process, telomerase-dependent maintenance of telomere length has recently drawn considerable attention. Unlike most normal human somatic cells that express telomerase only during development but not after differentiation, lymphocytes express telomerase during development and retain the ability to express telomerase after maturation in response to antigenic challenge. How telomerase is regulated and its precise role in lymphocytes is not fully understood. The recent progress in characterizing regulation of telomerase expression in human lymphocytes is discussed.


Lightweight, multi-contact, slip-ring commutator for recording and stimulation with small animals.
A slip-ring commutator which can be used to electrically stimulate and/or record from the brains of small, unrestrained animals is described. In addition to providing 4 to 10 independent electrical contacts, featues of this model include its small size, low torque characteristics, low rate of contact oxidation, and minimal noise generated at the brush-ring surface. The compactness and light weight of this unit permit it to be suspended from a counterweighted boom assembly, thus providing additional freedom for vertical movement.


18th Annual Meeting of the Safety Pharmacology Society: drug safety assessment on gastrointestinal system functions.
Introduction: The 18th Annual Meeting of the Safety Pharmacology Society included a session dedicated to the assessment of drug safety on the gastrointestinal (GI) system.Areas covered: GI anatomy, physiology, adverse effects (AEs) of chemical and biological therapies, and approaches to mitigate them.Expert opinion: GI AEs, albeit common and generally of minor intensity, may prolong clinical development time and reduce patient compliance.


Intimate partner violence during pregnancy and the risk for adverse infant outcomes: a systematic review and meta-analysis.
Intimate partner violence (IPV) is of particular concern during pregnancy when not one, but two lives are at risk. Previous meta-analyses have suggested an association between IPV and adverse birth outcomes; however, many large studies have since been published, illustrating the need for updated pooled effect estimates. To evaluate the relationship between IPV during pregnancy and the risk of preterm birth (PTB), low-birthweight (LBW), and small-for-gestational-age (SGA) infants. We searched PubMed and SCOPUS (from inception until May 2015), and the reference lists of the relevant studies. Observational studies comparing the rates of at least one adverse birth outcome (SGA, LBW, or PTB) in women who experienced IPV during pregnancy and those who did not. Data extracted from 50 studies were pooled and pooled odds ratios were calculated using random-effects models. Intimate partner violence (IPV) was significantly associated with PTB (OR 1.91, 95% CI 1.60-2.29) and LBW (OR 2.11, 95% CI 1.68-2.65), although a large level of heterogeneity was present for both (I(2) = 84 and 91%, respectively). The association with SGA was less pronounced and marginally significant (OR 1.37, 95% CI 1.02-1.84), although fewer studies were available for meta-analysis (n = 7). Our meta-analysis indicates that women who experienced IPV during pregnancy are at increased risk of having a PTB, and an LBW or an SGA infant. More studies examining the association between IPV and SGA are needed. Meta-analysis of IPV during pregnancy finds increased risk for preterm birth, LBW and SGA infants.


Progressively impaired proteasomal capacity during terminal plasma cell differentiation.
After few days of intense immunoglobulin (Ig) secretion, most plasma cells undergo apoptosis, thus ending the humoral immune response. We asked whether intrinsic factors link plasma cell lifespan to Ig secretion. Here we show that in the late phases of plasmacytic differentiation, when antibody production becomes maximal, proteasomal activity decreases. The excessive load for the reduced proteolytic capacity correlates with accumulation of polyubiquitinated proteins, stabilization of endogenous proteasomal substrates (including Xbp1s, IkappaBalpha, and Bax), onset of apoptosis, and sensitization to proteasome inhibitors (PI). These events can be reproduced by expressing Ig-mu chain in nonlymphoid cells. Our results suggest that a developmental program links plasma cell death to protein production, and help explaining the peculiar sensitivity of normal and malignant plasma cells to PI.


Do weak interactions affect the biological behavior of DNA? A DFT study of CpG island-like chains.
The origin, stability, and contribution to the formation of noncovalent interactions, such as hydrogen bonds and π - π stacking, have been already widely discussed. However, there are few discussions about the relevance of these weak interactions in DNA performance. In this work, we seek to shed light on the effect of hydrogen bonds and π - π stacking interactions on the biological behavior of DNA through the description of these intermolecular forces in CpG island-like (GC-rich) chains. Furthermore, we made some comparisons with TATA box-like (TA-rich) chains in order to describe hydrogen bond and π - π stacking interactions as a function of the DNA sequence. For hydrogen bonds, we found that there is not a significant effect related to the number of base pairs. Whereas for π - π stacking interactions, the energy tended to decrease as the number of base pairs increased. We observed anticooperative effects for both hydrogen bonds and π - π stacking interactions. These results are in contrast with those of TATA box-like chains since cooperative and additive effects were found for both hydrogen bonds and π - π stacking, respectively. Based on the chemical hardness and density of states, we can conclude that proteins may interact easier with GC-rich chains. We conclude that regardless of the chain length, a protein could interact more easily with these genomics regions because the π - π stacking energies did not increase as a function of the number of base pairs, making, for the first time, a first approximation of the influence of noncovalent interaction on DNA behavior. We did all this work by means of DFT framework included in the DMol3 code (M06-L/DNP). Graphical Abstract Cartoon representation of how nocovalent interactions affect the interaction of DNA with a protein, i.e., how hydrogen bond and π - π stacking interactions influence the biological behavior of DNA.


Repression: A Critical Assessment and Update of Freud's 1915 Paper.
The concept of repression has been relegated to the periphery in current psychoanalytic theorizing. This is in part due to a reflexive and ill-informed avoidance of Freudian metapsychology, and in part due to preoccupation with 'primitive' and 'deeper' states of mind, a perspective that presumes that repression operates exclusively in 'higher level' or 'neurotic' forms of psychopathology. A careful scrutiny of psychoanalytic theory and clinical practice does not uphold such compartmentalization. Repression is ubiquitous in mental life. It contributes to normality (e.g., onset of latency), undergirds the 'psychopathology of everyday life' (e.g., parapraxes), exists alongside splitting in severe character disorders (e.g., borderline patients "forgetting" their appointments) and, by permitting a modified return of exiled mental contents, gives birth to neurotic symptoms as well as creative imagination. Taking Freud's seminal discourse on repression (in: Repression. Standard Edition, vol 14. Hogarth, London, pp 141-158 1915a) as its starting point, this paper elucidates the complex, nuanced, and pervasive nature of this defense. It deconstructs Freud's unitary concept of repression into four implicit binaries and updates his proposals in the light of contemporary psychoanalytic theory. The paper offers clear guidelines for clinical applications of these ideas.


The Relationship Between Psychosocial Interventions and Child Wellbeing in Zambia.
Psychosocial factors contribute to persistence of poverty, but are rarely addressed in poverty reduction programs. We use mixed methods to investigate the relationship between a psychosocial behaviour change approach-empowered worldview (EWV), and investment decisions in children wellbeing among smallholder farmers in Zambia. Three years after exposure to EWV, logistic regression model results suggest that exposure to EWV was associated with an increased probability of parents providing basic needs of children including school fees, clothes, and food. This probability increased with more trainings. Using a matched sample, the average treatment effect on the treated of EWV is positive and statistically significant. Qualitative results reveal EWV enhanced participant agency, spouses' propensity to work together and with others in the community, and aspirations for themselves and their children. These results point to the prevalence of psychosocial constraints and the need for interventions to sustainably address them to support human development.


Escherichia coli O157:H7 strains in bovine carcasses and the impact on the animal production chain.
Foodborne diseases are characterized by conditions that can induce symptomatic illnesses in their carriers, and therefore represent a serious problem. They are important conditions from a clinical and epidemiological point of view, and are associated with the occurrence of serious public health problems, with a strong impact on morbidity and mortality. The Escherichia coli (E. coli) is an enterobacterium associated with enteric conditions of variable intensity and which are accompanied by blood. The transmission routes are mainly based on the consumption of contaminated food and water sources. Shiga toxin-producing E. coli (STEC) are considered a serogroup of E. coli, are capable of producing Shiga-type toxins (Stx 1 and Stx 2) and the O157:H7 strain is one of the best-known serotypes. The early detection of this pathogen is very important, especially due to the capacity of contamination of carcasses destined for food consumption and supply of productive markets. Sanitary protocols must be developed and constantly reviewed in order to prevent/control the presence of the pathogen.


[Cost/need relations in medicine. Reuse of re-sterilized intravascular catheters].
The costs of catheters in a university radiology department are listed and the reasons for re-sterilization of catheters discussed. Questionnaires have been sent to 17 German university radiology departments. Thirteen of them routinely re-sterilize catheter material. The advantages and complications of catheter re-use are discussed.


The role of sleep dysfunction in temporomandibular onset and progression: A systematic review and meta-analyses.
Painful temporomandibular (TM) disorders result in 4.3 billion dollars spent annually in the United States. The complex interplay of physiological processes in persistent pain and dysfunctional sleep has been established. Recently, dysfunctional sleep has been identified as a potential pathway to the onset of painful TM disorder. The aims were to (1) identify self-report outcome measures (SROMs) of sleep quality that are clinimetrically sound in patients with painful TM disorders and (2) determine whether sleep dysfunction has any diagnostic or prognostic value for this population. A systematic search following PRISMA guidelines was run in six databases: CINAHL, Dental, PsychALL, PubMed, Scopus and Web of Science. Any study involving minors was excluded. Risks of biases were examined in all studies. Diagnostic pooled findings were reported. Of the identified articles (n = 681), 18 were included in this systematic review (n = 1 clinimetric studies, n = 11 diagnostic studies, n = 6 prognostic studies). Nine different assessment tools were used; only the Pittsburg Sleep Quality Index (PSQI) has been validated in patients with painful TM disorders. Overall, sleep dysfunction was diagnostic for painful TM disorders. The pooled relative risk of sleep dysfunction was 1.71 (95% CI 1.30. 2.26). When PSQI scores were greater than 5/21, the unadjusted hazard ratio for development of painful TM disorders was reported to be 2.1. At present, the only SROM that has diagnostic and prognostic value in evaluating and managing patients with painful TM disorders is the PSQI.


Acquisition of threat responses are associated with elevated plasma concentration of endocannabinoids in male humans.
Endocannabinoids (eCBs) are involved in buffering threat and stress responses. Elevation of circulating eCBs in humans was reported to strengthen inhibition (i.e., extinction) of threat responses and to reduce effects of stressors. However, it remains unclear whether the acquisition of threat responses involves a physiological change in circulating eCBs. Here, we demonstrate in male human volunteers that the plasma concentration of the eCB N-arachidonoylethanolamine (AEA) and its metabolite arachidonic acid (AA) are increased during acquisition of threat responses. Furthermore, elevated responses to a learned threat cue (e.g., rating of fear) were associated with individual increases in plasma concentration of the eCB 2-arachidonoylglycerol (2-AG). In complementing these observations, we found individual increases in AEA associated with elevated neural responses during threat learning in the amygdala. Our results thereby suggest that physiological increases in circulating eCB levels are part of a response mechanism to learned threats.


Thermally Induced Carbohydroxylation of Styrenes with Aryldiazonium Salts.
The radical carbohydroxylation of styrenes with aryldiazonium salts has been achieved under mild thermal conditions. A broad range of aryldiazonium salts was tolerated, and the reaction principle based on a radical-polar crossover mechanism could be extended to carboetherification as well as to a two-step, metal-free variant of the Meerwein arylation leading to stilbenes.


One-electron reduction of the oxyform of 2,4-diacetyldeuterocytochrome P-450cam.
The reaction of the hydrated electron with a ferrous oxygenated form of modified cytochrome P-450cam, containing 2,4-diacetyldeuteroheme, was investigated by the use of pulse radiolysis. The ferrous oxygenated form of this enzyme was reduced by hydrated electrons to form the product, which exhibits absorption maximum at 470 and 370 nm. From the spectrum obtained, the oxidation state of the product is discussed in relation to the higher oxidation states of chloroperoxidase.


Association between the TLR2 Arg753Gln polymorphism and the risk of sepsis: a meta-analysis.
Recently, researchers in a number of studies have explored the association between the Toll-like receptor 2 (TLR2) Arg753Gln polymorphism and sepsis risk. However, the results were conflicting. In this meta-analysis, we aimed to confirm the effect of the TLR2 Arg753Gln polymorphism on sepsis risk. Relevant records up to 1 June 2015 were retrieved from the PubMed, Embase, and Web of Knowledge databases. The odds ratios with their corresponding 95 % confidence intervals were used to assess the association between the TLR2 Arg753Gln polymorphism and sepsis risk. The selection of a fixed or random effects model was made according to a heterogeneity test in total and subgroup analyses. Sensitivity analysis and publication bias test were performed to ensure the reliability of our results. A total of 12 studies with aggregate totals of 898 cases and 1517 controls met our inclusion criteria for meta-analysis. There were significant associations between the TLR2 Arg753Gln polymorphism and sepsis risk in overall analyses under two genetic models (the allele comparison and the dominant model). In addition, subgroup analyses based on age group, ethnicity, sepsis type, and source of control also showed a significant effect of the TLR2 Arg753Gln polymorphism on sepsis risk. Our present meta-analysis supports a direct effect of the TLR2 Arg753Gln polymorphism on sepsis risk, especially in Europeans. The TLR2 Arg753Gln polymorphism might be used as a relevant risk estimate for the development of sepsis. Studies with larger sample sizes and homogeneous groups of patients with sepsis are required for further analysis.


A phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and 90 yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B-cell non-Hodgkin lymphoma.
Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial, we tested systemic administration of both CpG and RIT. Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m(2) days 1,8, and 15; (111) In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of (90) Y-ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hr without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18-NR); and median duration of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation.


Disordered control of the urinary bladder after human spinal cord injury: what are the problems?
Spinal cord injury has a profound impact on the storage and voiding functions of the urinary bladder. Loss of autonomic and somatic control mechanisms leads to hypo- or hyperactivity of the bladder wall and sphincters causing problems that range from incontinence to complete loss of the capacity to empty the bladder. This chapter outlines the types of bladder dysfunction that occur after spinal cord injury, their relative prevalence and current practices used to manage the problems. With all the interventions that are available, management of bladder function often still remains a compromise, as the medications and physical interventions available may stimulate or block components of the voiding reflex, but are often not fully restorative in this effort.


[Ecoepidemiology of leishmaniasis in Syria. 1. Leishmania major Yakimoff and Schokhor (Kinetoplastida-Trypanosomatidae) infestation of Psammomys obesus Cretzschmar (Rodentia-Gerbillidae)].
During an epidemiological survey of zoonotic cutaneous leishmaniasis in South-West Syria, Leishmania major zymodème MON-26 was isolated from a reservoir host, Psammomys obesus terraesanctae (Rodentia-Gerbillidae). The abundance of this rodent, its close contact with infected villages and the high prevalence of the infection (63,1%) indicate that this is the main reservoir host of oriental sore in the semi desert area of this country.


Baseline clinical characteristics predict overall survival in patients undergoing radioligand therapy with [177Lu]Lu-PSMA I&T during long-term follow-up.
Radioligand therapy (RLT) with 177Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [177Lu]Lu-PSMA I&T RLT in a long-term follow-up. Ninety-two mCRPC patients treated with [177Lu]Lu-PSMA I&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (intervalDiagnosis-RLT, per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan-Meier analyses. Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95% CI 1.02-1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95% CI 1.01-1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95% CI 1.06-1.26; P = 0.001), and intervalDiagnosis-RLT (HR, 0.95, 95% CI 0.91-0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and intervalDiagnosis-RLT, 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan-Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged intervalDiagnosis-RLT (P ≤ 0.01, respectively). In mCRPC patients treated with [177Lu]Lu-PSMA I&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [177Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.


Beta-blocker therapy in advanced heart failure: clinical characteristics and long-term outcomes.
To evaluate the clinical characteristics and long-term outcomes of advanced heart failure patients (NYHA Class IIIb-IV) receiving beta-blocker therapy vs. those patients not receiving beta-blockers at randomization in the FIRST trial, a randomized, double-blind, placebo-controlled trial of epoprostenol vs. usual care in advanced heart failure. The patient population consisted of 471 patients enrolled in FIRST with Class IIIb-IV heart failure, left ventricular ejection fraction (LVEF) of <30%, advanced hemodynamic abnormalities, and standard pharmacologic treatment of ACE-inhibitor, diuretics, and/or digoxin. The study cohort consisted of 448 patients not receiving beta-blockers and 23 patients receiving beta-blockers at randomization for the FIRST trial. Patients in the beta-blocker group had decreased rates of any clinical event (P = 0.03), worsening heart failure (P = 0.001), and death or worsening heart failure (P = 0.0008) than patients not receiving beta-blockers. After adjusting for prognostically important variables, the favorable effect of beta-blockers on worsening heart failure (P = 0.02) and death or worsening heart failure (P = 0.02) persisted. Patients with advanced heart failure who receive beta-blocker therapy have a lower rate of hospitalization and are less likely to experience worsening heart failure or death at 6 months than patients who are not treated with beta-blockers. These observational data contribute to the growing body of data demonstrating a favorable effect of beta-blockers on clinical outcomes in heart failure.


Simultaneous diversion of the urinary and fecal streams utilizing a single abdominal stoma: the double-barreled wet colostomy.
A new technique to achieve simultaneous diversion of the urinary and fecal streams using a single abdominal stoma is described. The procedure consists of the construction of a diverting loop colostomy with division of the colon approximately 10 to 15 cm. distal to the stoma. The segment of colon distal to the stoma, the urine limb, acts as a urinary conduit. To date 3 patients have undergone the procedure with followup of 3, 13 and 18 months. Neither upper tract infection nor upper tract deterioration has occurred. The potential role of this procedure to treat a difficult group of patients is discussed.


Near Spurious-Free Thickness Shear Mode Lithium Niobate Resonator for Piezoelectric Power Conversion.
Piezoelectric power converters, where acoustic resonators replace the inductors as energy storage elements, promise much higher power density and higher efficiency compared to conventional circuits. Recently, lithium niobate (LiNbO3) piezoelectric resonators have been integrated within power converter circuits, showing good conversion efficiency, thanks to their high quality factor ( Q ) and electromechanical coupling ( kt 2 ). However, the converter output power range is limited by large spurious modes near resonance. This work reports a near-spurious-free LiNbO3 thickness shear (TS) resonator, demonstrating a high Q of 3500 and kt 2 of 45% at 5.94 MHz, with a fractional suppressed region of 35%. First, we identify the best LiNbO3 crystal orientation for efficient TS resonators. Then, we propose a novel acoustic design without busbars for spurious suppression, which is extensively simulated, fabricated, and characterized. Further analysis is done to identify existing spurious modes in our proposed design, specifically the effect of dicing on our TS resonator design. Upon optimization, LiNbO3 TS resonators could potentially empower a new design space for low-loss and compact power converters.


Pain as a learned response: a review of behavioral factors in chronic pain.
This review of the literature on pain behavior suggests that learning factors may have a critical role in shaping an individual's response to pain. Understanding these pain behaviors becomes especially helpful in diagnosis and treatment of patients with chronic pain.


Relationship of free-recall memory to hypertension in the elderly. The Iowa 65+ Rural Health Study.
The relationship between hypertension and performance on a test of free recall memory was explored in a geographically-defined population of free-living subjects 65 years and older. Those with diastolic but not isolated systolic hypertension had a significantly lower performance on the memory test, after controlling for general health status, antihypertensive medication use and other factors which might confound or modify this association. These findings from a population study confirm the results of prior investigations in smaller numbers of highly selected subjects and suggest that further study may lead to improved prevention of cognitive decline in the elderly.


Pathology of renal xenograft rejection in pig to non-human primate transplantation.
Xenotransplantation has the potential to alleviate the critical shortage of organs for transplantation in humans. Miniature swine are a promising donor species for xenotransplantation. However, when swine organs are transplanted into primates, hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), acute cellular xenograft rejection (ACXR), and chronic xenograft rejection prevent successful engraftment. Developing a suitable regimen for preventing xenograft rejection requires the ability to accurately diagnosis the severity and type of rejection in the graft. For this purpose, histopathology remains the most definitive and reliable tool. We discuss here the characteristic features of xenograft rejection in a preclinical pig-to-non-human primate transplantation model. In miniature swine to baboon xenotransplantation, marked interstitial hemorrhage develops in HAR, and renal microvascular injury develops with multiple platelet-fibrin microthrombi in both HAR and AHXR. T-cell-mediated cellular immunity plays an important role in ACXR. Chronic humoral and cellular rejection may induce chronic xenograft rejection, and will be a major cause of graft loss in discordant xenotransplantation.


Seasonal variations of plant water use in the karst desertification control.
Understanding the water use characteristics of plants is crucial for the sustainability of forest water management and vegetation restoration. The vegetation restoration program in the karst desertification areas of southwest China has been implemented for more than two decades, and remarkable achievements have been made in ecological restoration. However, the water use characteristics of revegetation are still poorly understood. We investigated the water uptake patterns and water use efficiency of four woody plants (Juglans regia, Zanthoxylum bungeanum, Eriobotrya japonica, and Lonicera japonica) using stable isotopes (δ2H, δ18O, and δ13C) in combination with the MixSIAR model. The results showed that plants responded to seasonal changes in soil moisture with flexible water uptake patterns. Differences in water use sources among the four plant species during the growing season indicated the occurrence of hydrological niche separation, which is the key to vegetation symbiosis. Throughout the study period, groundwater made the lowest contribution to plants (9.39 %~16.25 %), and fissure soil water made the highest contribution (39.74 %~64.71 %). Among them, shrubs and vines were more dependent on fissure soil water compared to trees (50.52 %~64.71 %). Furthermore, plant foliar δ13C was higher in the dry season than in the rainy season. Evergreen shrubs (-27.94 ‰) exhibited higher water use efficiency compared to other tree species (-30.48 ‰~-29.04 ‰). The water use efficiency of four plants showed seasonal variation and was influenced by the water availability caused by soil moisture. Our study demonstrates that fissure soil water is an important water source for karst desertification revegetation and that seasonal changes in water use characteristics are influenced by species-level water uptake patterns and water use strategies. This study provides a reference for vegetation restoration and water resource management in karst areas.


Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded α-synuclein within the central nervous system (CNS). Visual problems in PD patients are common, although retinal pathology associated with PD is not well understood. The purpose of this study was to investigate retinal pathology in a transgenic mouse model (TgM83) expressing the human A53T α-synuclein mutation and assess the effect of α-synuclein "seeding" on the development of retinal pathology. Two-month-old TgM83 mice were intracerebrally inoculated with brain homogenate from old (12-18 months) TgM83 mice. Retinas were then analyzed at 5 months of age. We analyzed retinas from 5-month-old and 8-month-old uninoculated healthy TgM83 mice, and old (12-18 months) mice that were euthanized following the development of clinical signs. Retinas of B6C3H mice (genetic background of the TgM83 mouse) served as control. We used immunohistochemistry and western blot analysis to detect accumulation of α-synuclein, pTauThr231, inflammation, changes in macroautophagy, and cell death. Raman spectroscopy was used to test the potential to differentiate between retinal tissues of healthy mice and diseased mice. This work demonstrates retinal changes associated with the A53T mutation. Retinas of non-inoculated TgM83 mice had accumulation of α-synuclein, "pre-tangle" tau, activation of retinal glial cells, and photoreceptor cell loss by 8 months of age. The development of these changes is accelerated by inoculation with brain homogenate from clinically ill TgM83 mice. Compared to non-inoculated 5-month-old TgM83 mice, retinas of inoculated 5-month-old mice had increased accumulation of α-synuclein (pSer129) and pTauThr231 proteins, upregulated microglial activation, and dysregulated macroautophagy. Raman spectroscopic analysis was able to discriminate between healthy and diseased mice. This study describes retinal pathology resulting from the A53T mutation. We show that seeding with brain homogenates from old TgM83 mice accelerates retinal pathology. We demonstrate that Raman spectroscopy can be used to accurately identify a diseased retina based on its biochemical profile, and that α-synuclein accumulation may contribute to accumulation of pTauThr231 proteins, neuroinflammation, metabolic dysregulation, and photoreceptor cell death. Our work provides insight into retinal changes associated with Parkinson's disease, and may contribute to a better understanding of visual symptoms experienced by patients.


Prognostic value of paravertebral muscle density in patients with spinal metastases from gastrointestinal cancer.
Morphometric analyses have shown that trunk muscle mass and density are associated with mortality in cancer patients. Because of the low incidence of spinal metastasis from gastrointestinal cancer and the limited life expectancy of these patients, few studies have been reported in this population. We evaluated the prognostic value of trunk muscle area and density in predicting overall survival. The data from 78 patients with spinal metastases from gastrointestinal cancer, collected from February 2009 to July 2016, were evaluated. Psoas muscle and paravertebral muscle area and density were measured at the L3 level on CT scans taken at the time nearest to the diagnosis of spinal metastasis. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. The mean patient age was 68.3 years (range, 42-88 years). The overall median survival time was 4.8 months: 2.2 months in the extremely rapid growth group (stomach, biliary tract, and pancreas) and 7.6 months in the rapid growth group (esophagus, liver, and colorectum). Multivariate analyses showed that lower paravertebral muscle density (HR 2.23 [95% CI 1.24-3.99], p = 0.007), extremely rapid growth group, presence of abnormal laboratory data, poor performance status, and chemotherapy after spinal metastasis were independent prognostic factors. Median overall survival was poor among patients with spinal metastases from gastrointestinal carcinoma, especially among those with gastric, biliary tract, or pancreatic cancer. Lower paravertebral muscle density was an independent poor prognostic factor in patients with spinal metastases from gastrointestinal cancer.


Application of different spectrophotometric methods for quantitative analysis of direct acting antiviral drugs simeprevir and sofosbuvir.
Simeprevir and sofosbuvir are direct-acting antiviral drugs approved for the treatment of chronic HCV infection. Reports demonstrate the similarities between HCV and SARS-CoV-2 in terms of structure and replication mechanism. Therefore, it is suggested that a combination of simeprevir and sofosbuvir may be considered for COVID-19 patients. To date, no spectrophotometric methods have been published for quantitative analysis of simeprevir and sofosbuvir in combination. In this work, two simple spectrophotometric methods allowed quantitative analysis of the studied drugs in the mixed form. The zero-order direct method allowed quantitative analysis of simeprevir at 333 nm, with sofosbuvir showing zero absorbance values. The dual wavelength method allowed quantitative analysis of sofosbuvir by measuring the difference in absorbance values at 259.40 and 276 nm, where the difference in absorbance values of simeprevir was zero. With the applied methods, the investigated drugs in the mixtures and tablets prepared in the laboratory were successfully analyzed quantitatively with acceptable results.


Real-world data for pediatric medulloblastoma: can we improve outcomes?
Medulloblastoma (MB) is a malignant embryonal tumor that develops especially in childhood, with overall survival (OS) at 5 years of up to 70%. The objective of this study is to analyze treatment delivery variables in a retrospective cohort and evaluate the impact of these treatment quality parameters on survival. From 2000 to 2018, 40 pediatric patients with medulloblastoma, treated according to current international protocols, were retrospectively analyzed. Treatment delivery quality indicators were analyzed including the extent of surgery, radiotherapy (RT) parameters, and chemotherapy variables, related with time and dose-intensity deviations. With a median follow-up of 74 months (range, 6-195), OS at 5 years was 74 ± 7%, 81 ± 8% for standard-risk, and 55 ± 16% for high-risk patients (p = 0.090). Disease-free survival at 5 years was not significantly affected by extent of surgery (p = 0.428) and RT-related variables such as surgery-RT interval (p = 0.776) neither RT duration (p = 0.172) or maintenance chemotherapy compliance (p = 0.634). Multivariate analysis identified risk groups predictive of worse DFS (p = 0.032) and leptomeningeal dissemination associated with inferior OS (p = 0.029).Conclusion: Treatment delivery optimization has improved survival rates of patients with MB. Despite this, in our study, we have not established a clear influence of the considered radiotherapy and chemotherapy treatment quality parameters on outcomes. What is Known: • Improvement in treatment modalities during the last decades has reached a 5-year OS of up to 70% in these patients. • Extent of resection and radiotherapy parameters such as interval between surgery-radiotherapy and radiotherapy duration has been described as probable survival prognostic factors. What is New: • Differences in medulloblastoma survival rates between prospective studies and retrospective series. • The impact on survival of the three main treatment variables, surgery, radiotherapy and chemotherapy, susceptible to improvement.


Evidence for a K+, Na+ permeable channel in sarcoplasmic reticulum.
Potassium and sodium cation permeabilities of skeletal sarcoplasmic reticulum vesicles were characterized by means of 3H-choline, 22Na+ and 86Rb+ isotope efflux and membrane potential measurements. Membrane potentials were generated by diluting K gluconate filled sarcoplasmic reticulum vesicles and liposomes into Tris or Na gluconate media, in the presence or absence of valinomycin, and were measured using the voltage-sensitive membrane probe 3,3'-dipentyl-2,2'-oxacarbocyanine. About 2/3 of the sarcoplasmic reticulum vesicles, designated Type I, were found to be permeable to Rb+, K+ and Na+. The remaining 1/3, Type II vesicles, were essentially impermeable to these ions. The two types of vesicles were impermeable to larger cations such as choline or Tris. Both were present in about the same ratio in fractions derived from different parts of the reticulum structure. Studies with cations of different size and shape suggested that in Type I vesicles permeation was restricted to molecules fitting through a pore with a cross-section of 4--5 A by 6 A or more. When vesicles were sonicated, vesicles permeable to K+ decreased more than those impermeable to K+. These data suggest the existence of K+, Na+ permeable channels which are probably randomly dispersed in the intact reticulum structure at an estimated density of 50 pores/micrometer2. The function of the channel may be to allow rapid K+ movement to counter Ca2+ fluxes during muscle contraction and relaxation.


[Results of surgical and radiotherapeutic treatment of adenoid cystic carcinoma of the salivary glands].
Surgical treatment in patients with rare adenoid cystic carcinoma (ACC) of the salivary glands is considered to be the state of the art. With respect to an additional radiotherapy there are different approaches regarding the type of radiotherapy and timing. In this study the overall survival and recurrence-free survival in 52 individuals with salivary gland ACC who were treated at the University Hospital in Essen and received irradiation with fast neutrons and photons (mixed beam technique) either A) immediately following surgical treatment or B) only after the appearance of local recurrence were compared. Group A (n = 28, first diagnosis, FD September 1991-September 2009) received adjuvant radiotherapy immediately postoperative, group B (n = 24, FD June 1979-November 2001) underwent primarily surgical tumor resection according to the treatment regimen at that time and were irradiated only on the appearance of a local recurrence. In comparison to group B, patients in group A showed a lower recurrence rate and a significantly longer local relapse-free survival. Group B, however, showed a significantly higher overall survival. The frequency of distant metastasis occurred equally in both groups but the onset of distant metastasis was significantly earlier in group A. In general, overall survival was negatively influenced by distant metastasis. The local recurrence rate was very high after primary surgical treatment only. The immediate adjuvant high-linear energy transfer (LET) radiotherapy reduced the local recurrence rates. Irradiation after the appearance of a recurrence had a positive influence on overall survival. Overall, definitive high-LET radiotherapy in the mixed beam technique enabled high local control rates both primarily postoperative and also locoregional recurrences.


Ribozyme activity in the genomic and antigenomic RNA strands of hepatitis delta virus.
In the hepatitis delta virus, ribozymes are encoded in both the genomic strand RNA and its complement, the antigenomic strand. The two ribozymes are similar in sequence and structure, are most active in the presence of divalent cation and catalyze RNA cleavage reactions which generate a 5'-hydroxyl group and a 2',3'-cyclic phosphate group. Recent progress has been made in understanding the catalytic mechanism. One key was a crystal structure of the genomic ribozyme that revealed a specific cytosine positioned to act as a general acid-base catalyst. The folding of the ribozyme in the context of the longer viral RNA is another area of interest. The biology requires that each ribozyme act only once, and mechanisms proposed for regulation of ribozyme activity sometimes invoke alternative RNA structures. Likewise, interference of ribozyme function by polyadenylation of the antigenomic RNA strand could be controlled through alternative structures, and a model for such control is proposed.


[Treat calcified stenoses correctly].
Due to the demographic changes with an increasing aging process of the population and the increasing incidence of comorbidities, such as diabetes mellitus, arterial hypertension, and chronic kidney disease, older patients with high-risk profiles and calcified coronary lesions are being treated more often in interventional cardiology. Despite advances in technical possibilities and materials, the treatment of severely calcified stenoses continues to be associated with an increased periprocedural risk of complications and poor long-term clinical outcomes. The purpose of this article is to discuss the various treatment approaches and summarize them in an algorithm for the treatment of severely calcified stenoses.


Correction to: Concurrent psychiatry for patients enrolled in opioid agonist treatment: a propensity score matched cohort study in Ontario Canada.
Following publication of the original article [1], we have been notified that the following changes should occur in the content of the article. The details are below.