SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections.
SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. At the same time, SMAD4 pathogenic variants have not been reported in thoracic aortic disease families without JPS-HHT. A SMAD4 heterozygous variant, c.290G>T, p.(Arg97Leu), not present in population databases and predicted to be damaging to protein function, was identified in a family with thoracic aortic disease and no evidence of HHT or JPS. Cellular studies revealed that the SMAD4 p.(Arg97Leu) alteration increased SMAD4 ubiquitination and 26S proteasome-mediated protein degradation. Smooth muscle cells (SMCs) infected with lentivirus expressing the SMAD4 p.(Arg97Leu) variant demonstrated reduced contractile protein gene expression when compared to that of wild-type SMAD4. In addition, two rare variants were identified in individuals with early age of onset of thoracic aortic dissection. These results suggest that SMAD4 rare missense variants can lead to thoracic aortic disease in individuals who do not have JPS or HHT.


Plasma lipidome reveals critical illness and recovery from human Ebola virus disease.
Ebola virus disease (EVD) often leads to severe and fatal outcomes in humans with early supportive care increasing the chances of survival. Profiling the human plasma lipidome provides insight into critical illness as well as diseased states, as lipids have essential roles as membrane structural components, signaling molecules, and energy sources. Here we show that the plasma lipidomes of EVD survivors and fatalities from Sierra Leone, infected during the 2014-2016 Ebola virus outbreak, were profoundly altered. Focusing on how lipids are associated in human plasma, while factoring in the state of critical illness, we found that lipidome changes were related to EVD outcome and could identify states of disease and recovery. Specific changes in the lipidome suggested contributions from extracellular vesicles, viremia, liver dysfunction, apoptosis, autophagy, and general critical illness, and we identified possible targets for therapies enhancing EVD survival.


Biological interaction between anti-epidermal growth factor receptor agent cetuximab and magnesium.
Magnesium plays a role in a large number of cellular metabolic reactions. Cetuximab, by the inhibition of epidermal growth factor (EGR), is able to induce hypomagnesaemia by interfering with magnesium transport in the kidney. To investigate the interactions between magnesium homeostasis and EGF receptor (EGFR) inhibition. We performed an updated literature search using the MEDLINE database for articles published from 1 January 1966 to 15 February 2008. We comprehensively reviewed all the data published in abstract form during the most significant international meetings (American Society of Clinical Oncology, American Association for Cancer Research, European Society for Medical Oncology and European Cancer Organisation). We propose that EGFR inhibition may reduce cancer proliferation and also decrease magnesium levels. These reduced magnesium levels in turn contribute to the inhibition of angiogenesis by directly acting on endothelial cells and indirectly affecting EGFR signalling and the production of angiogenic molecules.


The polarization compass dominates over idiothetic cues in path integration of desert ants.
Desert ants, Cataglyphis, use the sky's pattern of polarized light as a compass reference for navigation. However, they do not fully exploit the complexity of this pattern, rather - as proposed previously - they assess their walking direction by means of an approximate solution based on a simplified internal template. Approximate rules are error-prone. We therefore asked whether the ants use additional cues to improve the accuracy of directional decisions, and focused on 'idiothetic' cues, i.e. cues based on information from proprioceptors. We trained ants in a channel system that was covered with a polarization filter, providing only a single e-vector direction as a directional 'celestial' cue. Then we observed their homebound runs on a test field, allowing full view of the sky. In crucial experiments, the ants were exposed to a cue conflict, in which sky compass and idiothetic information disagreed, by training them in a straight channel that provided a change in e-vector direction. The results indicated that the polarization information completely dominates over idiothetic cues. Two path segments with different e-vector orientations are combined linearly to a summed home vector. Our data provide additional evidence that Cataglyphis uses a simplified internal template to derive directional information from the sky's polarization pattern.


How do humans want causes to combine their effects? The role of analytically-defined causal invariance for generalizable causal knowledge.
The present paper reports two experiments (N = 232, 254) addressing the question: How do reasoners reconcile the desire to have useable (i.e., invariant) causal knowledge - knowledge that holds true when applied in new circumstances/contexts - with the reality that causes often interact with other causes present in the context? The experiments test two views of how reasoners learn and generalize potentially complex causal knowledge. Previous work has focused on reasoners' ability to learn rules (functions) describing how pre-defined candidate causes combine, potentially interactively, to produce an outcome in a domain. This empirical-function-learning view predicts that participants would generalize an acquired combination rule based on similarity to stimuli they experienced in the domain. An alternative causal-invariance view goes beyond empirical learning: it allows for the possibility that one's current representation may not yield useable causal knowledge. This view posits that the human causal-induction process incorporates invariant knowledge as an aspiration, entailing that observed deviation from causal invariance when the knowledge is applied serves as a signal for a need to revise causal knowledge: Only invariance across contexts with potentially new causal factors justifies generalization across them. The invariance view therefore predicts that reasoners would revise their representation so that they have whole causes - potentially consisting of interacting components - that do not interact with each other, even when in their relevant experience all (pre-defined) causes interact. Across both experiments, our results favor the causal-invariance view: Participants generalize their empirically learned function (which may involve interactions) to new stimuli, but switch to the analytic causal-invariance function for both old and new stimuli at the level of the whole cause, indicating that how humans want causes to combine their effects shapes the knowledge they induce.


Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity.
Receptor interacting protein 2 (RIP2) is an intracellular kinase and key signaling partner for the pattern recognition receptors NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2). As such, RIP2 represents an attractive target to probe the role of these pathways in disease. In an effort to design potent and selective inhibitors of RIP2 we established a crystallographic system and determined the structure of the RIP2 kinase domain in an apo form and also in complex with multiple inhibitors including AMP-PCP (β,γ-Methyleneadenosine 5'-triphosphate, a non-hydrolysable adenosine triphosphate mimic) and structurally diverse ATP competitive chemotypes identified via a high-throughput screening campaign. These structures represent the first set of diverse RIP2-inhibitor co-crystal structures and demonstrate that the protein possesses the ability to adopt multiple DFG-in as well as DFG-out and C-helix out conformations. These structures reveal key protein-inhibitor structural insights and serve as the foundation for establishing a robust structure-based drug design effort to identify both potent and highly selective inhibitors of RIP2 kinase.


Comparison of normal saline, hypertonic saline and hypertonic saline colloid resuscitation fluids in an infant animal model of hypovolemic shock.
Incorrect resuscitation after hypovolemic shock is a major contributor to preventable pediatric death. Several studies have demonstrated that small volumes of hypertonic or hypertonic-hyperoncotic saline can be an effective initial resuscitation solution. However, there are no pediatric studies to recommend their use. The aim of this study is to determine if in an infant animal model of hemorrhagic shock, the use of hypertonic fluids, as opposed to isotonic crystalloids, would improve global hemodynamic and perfusion parameters. Experimental, randomized animal study including thirty-four 2-to-3-month-old piglets. 30 min after controlled 30 mL kg(-1) bleed, pigs were randomized to receive either normal saline (NS) 30 mL kg(-1) (n=11), 3% hypertonic saline (HS) 15 mL kg(-1) (n=12), or 5% albumin plus 3% hypertonic saline (AHS) 15 mL kg(-1) (n=11). High baseline heart rate (HR) and low mean arterial pressure (MAP), cardiac index (CI), brain tissue oxygenation index (bTOI), and lactate were recorded 30 min after volume withdrawal, with no significant differences between groups. Thirty minutes after volume replacement there were no significant differences between groups for HR (NS, 188±14; HS, 184±14; AHS, 151±14 bpm); MAP (NS, 80±7; HS, 86±7; AHS, 87±7 mmHg); CI (NS, 4.1±0.4; HS, 3.9±0.4; AHS, 5.1±0.4 mL min(-1)m(-2)); lactate (NS, 2.8±0.7; HS, 2.3±0.6; AHS, 2.4±0.6 mmol L(-1)); bTOI (NS, 43.9±2.2; HS, 40.1±2.5; AHS, 46.1±2.3%). In this model of hypovolemic shock, hypertonic fluids achieved similar end-points as twice the volume of NS. Animals treated with albumin plus hypertonic saline presented prolonged increase in blood volume parameters and recovery of the oxygen debt.


Recurrent wheezing in children with respiratory syncytial virus (RSV) bronchiolitis in Qatar.
Records of 70 infants admitted to Hamad General Hospital with RSV bronchiolitis and a similar number of controls were retrospectively reviewed. Two years after admission, 44% of the infants with RSV bronchiolitis developed recurrent wheezing compared with only 12.9% of controls (P = 0.001). A family history of atopy appeared not to be a significant predisposing factor for the occurrence of recurrent wheezing in post RSV bronchiolitis patients. These results are similar to those from similar studies in industrialized countries.


A single-center experience with infections due to daptomycin-nonsusceptible Enterococcus faecium in liver transplant recipients.
Infections caused by vancomycin-resistant Enterococcus faecium (VRE) are a major cause of morbidity and mortality in the liver transplant population. Daptomycin (DAP) is often used to treat infections caused by VRE, but DAP nonsusceptibility in Enterococcus is increasing. Patients with DAP-nonsusceptible Enterococcus (DNSE) infections who had undergone liver transplantation between January 1, 2010 and July 31, 2014 were retrospectively reviewed. A convenience sample of DNSE isolates was analyzed by pulsed-field gel electrophoresis (PFGE). We identified 14 liver transplant recipients (LTRs) who developed DNSE infections post transplantation. Postoperative complications were common, and most patients required repeat abdominal surgery within 90 days of transplantation. The initial DNSE culture was taken a median of 74.5 days post transplant and was secondary to an intra-abdominal infection in all but 1 patient. Half of patients were VRE colonized before or at the time of organ transplantation, and all those who were not VRE colonized at the time of transplantation later became colonized, a median of 27 days post transplant. Overall mortality in this cohort was 71%. PFGE did not demonstrate genetic relatedness among DNSE isolates. This study, the largest published series to our knowledge of DNSE infections in LTRs, demonstrates that these infections occur in patients with serious surgical complications and are associated with high morbidity and mortality. Established risk factors for VRE infection were common, as was DAP exposure. Although many risk factors for DNSE infection cannot be changed, this case series identifies several potentially modifiable variables. Further work is needed to identify interventions to decrease the risk of developing DNSE infections in this complex patient population.


Development of novel wheat-rye 6RS small fragment translocation lines with powdery mildew resistance and physical mapping of the resistance gene PmW6RS.
Novel wheat-rye 6RS small fragment translocation lines with powdery mildew resistance were developed, and the resistance gene PmW6RS was physically mapped onto 6RS-0.58-0.66-bin corresponding to 18.38 Mb in Weining rye. Rye (Secale cereale L., RR) contains valuable genes for wheat improvement. However, most of the rye resistance genes have not been successfully used in wheat cultivars. Identification of new rye resistance genes and transfer of these genes to wheat by developing small fragment translocation lines will make these genes more usable for wheat breeding. In this study, a broad-spectrum powdery mildew resistance gene PmW6RS was localized on rye chromosome arm 6RS using a new set of wheat-rye disomic and telosomic addition lines. To further study and use PmW6RS, 164 wheat-rye 6RS translocation lines were developed by 60Coγ-ray irradiation. Seedling and adult stage powdery mildew resistance analysis showed that 106 of the translocation lines were resistant. A physical map of 6RS was constructed using the 6RS translocation and deletion lines, and PmW6RS was localized in the 6RS-0.58-0.66-bin, flanked by markers X6RS-3 and X6RS-10 corresponding to the physical interval of 50.23-68.61 Mb in Weining rye genome. A total of 23 resistance-related genes were annotated. Nine markers co-segregate with the 6RS-0.58-0.66-bin, which can be used to rapidly trace the 6RS fragment carrying PmW6RS. Small fragment translocation lines with powdery mildew resistance were backcrossed with wheat cultivars, and 39 agronomically acceptable homozygous 6RS small fragment translocation lines were obtained. In conclusion, this study not only provides novel gene source and germplasms for wheat resistance breeding, but also laid a solid foundation for cloning of PmW6RS.


Metformin inhibited homocysteine-induced upregulation of endothelin receptors through the Sirt1/NF-κB signaling pathway in vascular smooth muscle cells.
Metformin (Met) can improve atherosclerosis (As). Abnormal endothelin receptors [including endothelin type A (ETA) or type B (ETB) receptor] in vascular smooth muscle cells (VSMCs) are involved in As. Hyperhomocysteinemia (HHcy) is an independent risk factor for As. The present study was designed to test our hypothesis that Met inhibits the upregulation of endothelin receptors induced by homocysteine (Hcy) in VSMCs. Rat superior mesenteric artery (SMA) without endothelium, as an in vitro model, was cultured in serum-free medium for 24 h in the presence of Hcy with or without Met or nicotinamide (Nic). In vivo, rats received subcutaneous injections of Hcy in the presence or absence of Met or Nic for 3 weeks. Levels of protein expression were determined by Western blotting. The contractile responses to sarafotoxin 6c (an ETB receptor agonist) or ET-1 (an ETA/ ETB receptor agonist) were studied using a sensitive myograph. The blood pressure of rats was measured using a noninvasive tail-cuff plethysmography method. The results showed that Met could significantly inhibit the Hcy-induced upregulation of endothelin receptors (including ETA and ETB receptor) protein expression and endothelin receptor-mediated vasoconstriction, and it recovered the Hcy-induced decrease in silent information regulator 1 (Sirt1) in a dosage-dependent manner in SMA. However, Nic (a Sirt1 inhibitor) recovered the levels of Met-inhibited endothelin receptors and acetylated p65. Furthermore, the in vivo results showed that Met not only significantly the inhibited HHcy-induced upregulation of endothelin receptors and acetylated p65 but also recovered the HHcy-induced decrease in Sirt1 in a dosage-dependent manner in SMA. In addition, Met significantly inhibited the HHcy-induced blood pressure elevation. However, these effects were reverted by Nic. In conclusion, these data demonstrated that Met inhibited the Hcy-induced increase in endothelin receptor expression by activating Sirt1 and then inhibiting NF-κB in VSMCs. These findings may provide insights into the mechanism underlying of Met-treated cardiovascular diseases induced by Hcy.


Different faces, same attitudes: behavioral mimicry and description of a new termitophilous species of the remarkable rove beetle genus Thyreoxenus (Staphylinidae, Aleocharinae, Corotocini) from Brazil with notes on post-imaginal growth.
Among the termite-associated fauna, rove beetles of the subfamily Aleocharinae are distinguished by exhibiting the majority of convergent evolutions to this lifestyle. This phenomenon known as termitophily brings many advantages, including the care of nestmates and the exploitation of resources. While some mechanisms that ensure the integration of the termitophiles into the colony are well known, such as chemical mimicry, others remain unclear. In this article, we discuss the importance of termitophile behavior for the stability of interactions within termite colonies. We address behavioral mimicry as an important integration mechanism between termitophiles and termites. We compare both termitophile's and termite's behavioral repertoires and found no significant differences between them, suggesting that social parasites can mislead their host through their behavior in order to exploit the colony and to keep positive interactions with their hosts. In addition, we describe a new species of termitophile rove beetle from a highland humid forest in northeastern Brazil: Thyreoxenus alakazam sp. nov., with detailed illustrations and comments on post-imaginal growth in the context of our hypothesis of the post-imago phenotype, known as stenogastry, as a recapitulation of ancestral conditions in physogastric rove beetles.


Corin is down-regulated and exerts cardioprotective action via activating pro-atrial natriuretic peptide pathway in diabetic cardiomyopathy.
Diabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, however its pathogenesis remains unclear. Corin, a cardiac serine protease, is responsible for converting pro-atrial natriuretic peptide (pro-ANP) to biologically active atrial natriuretic peptide (ANP). It has been well established that corin deficiency is associated with the progression of hypertension, cardiac hypertrophy and heart failure. However, because the involvement of corin-mediated pro-ANP processing in DCM has not been clarified, this study aims to investigate the role of corin in the pathogenesis of DCM. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ 65 mg/kg) to Sprague-Dawley rats (180-220 g). DCM was confirmed by monitoring continuously transthoracic echocardiography every 4 weeks and hemodynamic measurements at 20 weeks. Myocardial disorder and fibrosis were detected by HE staining and Masson's trichrome staining. The mRNA and protein levels of corin and ANP in rat hearts and cardiomyocytes were determined by quantitative real-time PCR, western blotting and immunohistochemical staining, respectively. H9c2 cardiomyoblasts proliferation was detected by MTT colorimetric assay and viable cell counting with trypan blue. The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay. The corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts. Corin and ANP levels of neonatal rat cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose were significantly lower than that of normal glucose treated. Precisely, corin and ANP levels decreased in DCM rats at 12, 16, 20 and 33 weeks; neonatal cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose at 36, 48 and 60 h demonstrated significant reduction in corin and ANP levels. Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation. Culture supernatants of Corin-siRNA H9c2 cardiomyoblasts prevented endothelial cell line EA.hy926 migration in the wound healing scratch assay. Furthermore, iso-lectin expression in arteriole and capillary endothelium was down-regulated in DCM rats. Our results indicate that corin plays an important role in cardioprotection by activating pro-atrial natriuretic peptide pathway in DCM. Corin deficiency leads to endothelial dysfunction and vascular remodeling.


Alzheimer's disease related biomarkers in bipolar disorder - A longitudinal one-year case-control study.
Bipolar disorder (BD) is a heterogeneous mental disorder characterized by recurrent relapses of affective episodes: Subgroups of patients with BD have cognitive deficits, and an increased risk of dementia. This prospective, longitudinal, one-year follow-up, case-control study investigated biomarkers for AD and neurodegenerative diseases, namely: cerebrospinal fluid (CSF) amyloid beta (Aβ) isoforms and ratios (Aβ42, Aβ40, Aβ38), CSF soluble amyloid precursor protein (sAPP) α and β, CSF total (t-tau) and phosphorylated tau (p-tau), CSF neurofilament-light (NF-L), CSF neurogranin (NG), plasma-isoforms Aβ42 and Aβ40, plasma-tau, plasma-NF-L, and serum S100B, in patients with BD (N = 62, aged 18-60) and gender-and-age-matched healthy control individuals (N = 40). CSF and plasma/serum samples were collected at baseline, during and after an affective episode, if it occurred, and after a year. Data were analyzed in mixed models. Levels of CSF Aβ42 decreased in patients with BD who had an episode during follow-up (BD-E) (N = 22) compared to patients without an episode (BD-NE) (N = 25) during follow-up (P = 0.002). Stable levels were seen for all other markers in BD-E compared to BD-NE during the one-year follow-up. We found no statistically significant differences between patients with BD and HC at T0 and T3 for Aβ42, Aβ40, Aβ38, Aβ42/38, Aβ42/40, sAPPα, sAPPβ, t-tau, p-tau, p-tau /t-tau, NF-L, NG in CSF and further Aβ40, Aβ42, Aβ42/40, t-tau, NF-L in plasma, S100B in serum, and APOE-status. Furthermore, all 18 biomarkers were stable in HC during the one-year follow-up from T0 to T3. A panel of biomarkers of Alzheimer's and neurodegeneration show no differences between patients with BD and HC. There were abnormalities of amyloid production/clearance during an acute BD episode. The abnormalities mimic the pattern seen in AD namely decreasing CSF Aβ42 and may suggest an association with brain amyloidosis.


Assessment of damage in juvenile-onset systemic lupus erythematosus: a multicenter cohort study.
To investigate the prevalence of cumulative organ damage in patients with juvenile-onset systemic lupus erythematosus (SLE) and its association with demographic and clinical variables, medication use, and quality of life. The occurrence of organ system damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), was determined for 387 patients consecutively enrolled in pediatric rheumatology centers from Europe, the US, Mexico, and Japan. Risk factors for damage included demographic variables; clinical manifestations at diagnosis; previous corticosteroid, immunosuppressive, and antimalarial therapies; disease activity; and quality of life. Overall, 195 (50.5%) patients had damage within a mean of 5.7 years after disease onset. Renal (21.8%) and neuropsychiatric (15.8%) system involvement were observed most frequently, followed by musculoskeletal (11.7%), ocular (10.9%) and skin (9.6%) system involvement, with a mean SDI score of 1.1. In multivariate models, the occurrence of neuropsychiatric manifestations at diagnosis, a longer disease duration, and a greater number of intravenous cyclophosphamide pulses showed the strongest association with the presence of damage. We found evidence of cumulative organ damage, as measured by the SDI, in half of the patients with juvenile-onset SLE. Damage was significantly more likely in patients who had experienced neuropsychiatric manifestations at diagnosis, had a longer disease duration, and had received more intravenous pulses of cyclophosphamide.


Hyalomma anatolicum anatolicum: the role of humoral factors in the acquisition of host resistance.
A significant degree of resistance to Hyalomma anatolicum anatolicum can be adoptively transferred to naive recipients with immune serum from rabbits repeatedly infected with adult H. a. anatolicum. Ticks fed on recipients of immune serum took longer to become engorged and showed a significant decrease (P less than 0.01) in engorgement weight and oviposition compared with ticks that fed on recipients of normal serum. A direct correlation between resistance and anti-saliva IgG antibodies was indicated by a progressive increase in the degree of resistance and IgG antibody titres following successive tick infestations. Challenge feeding sites on actively sensitised hosts and recipients of immune serum revealed significantly greater infiltration of basophils and eosinophils compared with feeding sites on recipients of normal serum. However, both the degree of resistance and the accompanying cutaneous basophil and eosinophil responses in recipients of immune serum were considerably weaker than those induced by active tick feeding, thus suggesting that nonhumoral (cell-mediated) mechanisms might also be involved in acquired host resistance to H. a. anatolicum.


Down-regulation of CRMP-1 in patients with epilepsy and a rat model.
The Collapsin Response Mediator Protein-1 (CRMP-1) is a brain specific protein identified as a signaling molecule of Semaphorin-3A and act as axon repellent guidance factor in nervous system. Recent studies indicated that axon guidance molecules may play a role in synaptic reorganization in the adult brain and thereby promote epileptogenesis. This study aimed to investigate expression pattern of CRMP-1 in epileptogenesis. Using double immunofluorescence labeling, immunohistochemistry and western blot analysis, we looked into the CRMP-1 expression in temporal neocortex from patients with temporal lobe epilepsy (TLE) and histological normal temporal neocortex from the controls. We also studied the expression pattern of CRMP-1 in hippocampus and adjacent cortex of a TLE rat model on 6, 24, 72 h, 1, 2 weeks, 1 month, and 2 months post-seizure, and from control rats. CRMP-1 was mainly expressed in the neuronal cytoplasm in the temporal lobe of intractable TLE patients, which was co-expressed with -2. CRMP-1 expression was downregulated in temporal neocortical of TLE patients. In addition, in pilocarpine-induced animal model of epilepsy, CRMP-1 dynamically decreased in a range of 2 months. Thus, our results indicate that CRMP-1 may be involved in the development of TLE.


Molecular origin of the pH dependence of tyrosine D oxidation kinetics and radical stability in photosystem II.
A role for redox-active tyrosines has been demonstrated in many important biological processes, including water oxidation carried out by photosystem II (PSII) of oxygenic photosynthesis. The rates of tyrosine oxidation and reduction and the Tyr/Tyr reduction potential are undoubtedly controlled by the immediate environment of the tyrosine, with the coupling of electron and proton transfer, a critical component of the kinetic and redox behavior. It has been demonstrated by Faller et al. that the rate of oxidation of tyrosine D (Tyr(D)) at room temperature and the extent of Tyr(D) oxidation at cryogenic temperatures, following flash excitation, dramatically increase as a function of pH with a pK(a) of approximately 7.6 [Faller et al. 2001 Proc. Natl. Acad. Sci. USA 98, 14368-14373; Faller et al. 2001 Biochemistry 41, 12914-12920]. In this work, we investigated, using FTIR difference spectroscopy, the mechanistic reasons behind this large pH dependence. These studies were carried out on Mn-depleted PSII core complexes isolated from Synechocystis sp. PCC 6803, WT unlabeled and labeled with (13)C(6)-, or (13)C(1)(4)-labeled tyrosine, as well as on the D2-Gln164Glu mutant. The main conclusions of this work are that the pH-induced changes involve the reduced Tyr(D) state and not the oxidized Tyr(D)() state and that Tyr(D) does not exist in the tyrosinate form between pH 6 and 10. We can also exclude a change in the protonation state of D2-His189 as being responsible for the large pH dependence of Tyr(D) oxidation. Indeed, our data are consistent with D2-His189 being neutral both in the Tyr(D) and Tyr(D)() states in the whole pH6-10 range. We show that the interactions between reduced Tyr(D) and D2-His189 are modulated by the pH. At pH greater than 7.5, the nu(CO) mode frequency of Tyr(D) indicates that Tyr(D) is involved in a strong hydrogen bond, as a hydrogen bond donor only, in a fraction of the PSII centers. At pH below 7.5, the hydrogen-bonding interaction formed by Tyr(D) is weaker and Tyr(D) could be also involved as a hydrogen bond acceptor, according to calculations performed by Takahashi and Noguchi [J. Phys. Chem. B 2007 111, 13833-13844]. The involvement of Tyr(D) in this strong hydrogen-bonding interaction correlates with the ability to oxidize Tyr(D) at cryogenic temperatures and rapidly at room temperature. A strong hydrogen-bonding interaction is also observed at pH 6 in the D2-Gln164Glu mutant, showing that the residue at position D2-164 regulates the properties of Tyr(D.) The IR data point to the role of a protonatable group(s) (with a pK(a) of approximately 7) other than D2-His189 and Tyr(D), in modifying the characteristics of the Tyr(D) hydrogen-bonding interactions, and hence its oxidation properties. It remains to be determined whether the strong hydrogen-bonding interaction involves D2-His189 and if Tyr(D) oxidation involves the same proton transfer route at low and at high pH.


Quantitative immunocytochemistry of tyrosine hydroxylase in rat brain. I. Development of a computer assisted method using the peroxidase-antiperoxidase technique.
We sought to develop a quantitative immunocytochemical procedure using the peroxidase-antiperoxidase (PAP) technique to analyze amounts of neurotransmitter biosynthetic enzyme tyrosine hydroxylase (TH) within the nucleus locus coeruleus (LC) of rat brain. Rats were perfused with 4% paraformaldehyde. The brains were embedded in paraffin, sectioned at 5 micrometers in the sagittal plane and immunocytochemically stained with antibodies to bovine adrenal TH. Staining intensity, measured by a TV image analysis system was reproducible within +/- 5%. Reaction conditions required so that the intensity of the PAP reaction product was directly and linearly related to the amount of TH enzyme protein in tissue were obtained by reacting tissues with saturating concentrations (2.5 mM) of diaminobenzidine (DAB) substrate, a constant dilution of antibody, and incubation time adjusted so that the darkest elements in tissue were below saturation. Variations in staining intensity of serial sections through the LC were found to be insignificant when compared to variations in staining between animals. In order to increase the amount of immunoreactive TH in the LC, groups of rats were treated with reserpine. Immunocytochemical and biochemical analyses were performed in parallel groups of control and reserpine animals allowed to survive 1-3 days following a single injection (10 mg/kg s.c.) of reserpine. A close correlation was found to exist between the amount of TH enzyme protein determined biochemically and the density of staining for TH. The maximal increase in TH measured immunocytochemically was 2.2-fold which was about 80% of the maximal induction determined biochemically. We conclude that the PAP method can be used for quantitative immunocytochemistry of brain TH providing that optimal reaction conditions are established.


Digastric muscle mass and intensity in older patients with sarcopenic dysphagia by ultrasonography.
The aim of this study was to investigate digastric muscle mass and intensity between no sarcopenic dysphagia and sarcopenic dysphagia. Patients aged ≥65 years were enrolled. According to the diagnostic algorithm for sarcopenic dysphagia, the patients were divided into two groups, no sarcopenic dysphagia and sarcopenic dysphagia. Handgrip strength, gait speed, skeletal muscle mass, tongue pressure, Mini Nutritional Assessment-Short Form and Food Intake LEVEL Scale were investigated. Digastric muscle mass and intensity were examined by ultrasonography. Univariate and multivariate analyses were performed to analyze two groups. Multivariate logistic regression analysis was performed to determine independent factors for the presence of sarcopenic dysphagia. To estimate the accuracy of diagnosing sarcopenic dysphagia, a receiver operating characteristic curve analysis was performed for digastric muscle mass and intensity. Forty-five patients (mean ± SD, 84.3 ± 7.8 years, 22 men, 23 women) including 19 no sarcopenic dysphagia and 26 sarcopenic dysphagia were examined. In sarcopenic dysphagia, lower BMI, Food Intake LEVEL Scale, Mini Nutritional Assessment-Short Form and smaller muscle mass and greater muscle intensity were found compared with no sarcopenic dysphagia. In multivariate logistic regression analysis, digastric muscle mass and intensity were identified as independent factors for sarcopenic dysphagia. The cut-off value of muscle mass was 75.1 mm2 (area under curve: 0.731, sensitivity: 0.692, specificity: 0.737) and muscle intensity was 27.8 (area under curve: 0.823, sensitivity: 0.923, specificity: 0.632). Digastric muscle mass was smaller and muscle intensity was greater in sarcopenic dysphagia than no sarcopenic dysphagia. Ultrasonography of digastric muscle, as well as the tongue and geniohyoid muscle, is useful. Geriatr Gerontol Int 2021; 21: 14-19.


Lack of carcinogenicity of butylated hydroxytoluene on long-term administration to B6C3F1 mice.
Groups of approximately 50 male and 50 female B6C3F1 mice were given butylated hydroxytoluene (BHT) at concentrations of 200, 1000 or 5000 ppm in their diet for 96 wk followed by a basal diet for 8 wk and were then killed. Similar groups of male and female controls were given basal diet throughout the 104 wk. Females given 1000 or 5000 ppm BHT and males given 5000 ppm showed reduced weight gain. Neither survival rates nor food consumption differed between experimental and control groups. No significant changes attributable to BHT treatment were found in the haematological examinations or serum and urine analyses. Tumours were found in many organs, especially the lungs, liver, lymph nodes and spleen, in both the experimental and control groups, but none were related to BHT treatment. Thus this experiment provided no evidence of BHT carcinogenicity in mice.


Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment.
There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. This study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection. Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague-Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways. Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. These results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy.


Localization and stability of hydrogenases from aerobic hydrogen bacteria.
Alcaligenes eutrophus strains H 16, B 19, G 27 and N9A contained two different hydrogenases. One enzyme catalyzed the reduction of NAD by hydrogen and was strictly localized in the soluble cell fraction. While the second enzyme was found to be particulate and unable to react with NAD. All other tested strains, Alcaligenes paradoxus SA 29, Pseudomonas facilis, P. palleronii RH 2, Pseudomonas sp. strain GA 3, Paracoccus denitrificans, Aquaspirillum autotrophicum SA 32, and Corynebacterium autotrophicum 14g and 7C contained only a single enzyme exclusively bound to membranes. This was established using fractional centrifugation, indicator enzyme systems, gently methods of cell disintegration and discontinuous sucrose density gradient centrifugation. In cell-free extracts obtained by rough disruption (sonication) of cells, hydrogenase was associated to particles of different size and sedimentation velocity. A partial solubilization of hydrogenase caused by sonication was observed with P. facilis. Without exception, the particulate hydrogenases were found (1) to be unable to reduce pyridine nucleotides, and (2) to reduce methylene blue at an extremely high activity. The eminent reaction rate of 34 micronmoles H2 oxidized per min and mg protein has been determined in particle suspensions of Pseudomonas sp. strain GA 3. All hydrogenases were stable during storage under hydrogen atmosphere, except the soluble enzyme for A. eutrophus H 16 which was shown to be more stable under aerobic conditions.


Characteristics of divergence excess type intermittent exotropia in Asian children.
Exotropia is twice as common as esotropia in Asian children, with divergence excess intermittent exotropia contributing more than one half of exotropia cases. In this study, distance-near relationships and ratios of accommodative convergence to accommodation (AC/A) are compared using different measurement methods in Asian children with divergence excess intermittent exotropia. Children with intermittent exotropia and a distance deviation exceeding the near by at least 10(Δ) were consecutively recruited. After prism cover test measurements at 6 m and 33 cm, AC/A ratios were calculated using the heterophoria method and the gradient method with -2.0 D and +3.0 D lenses at 6 m and 33 cm, respectively. AC/A ratios were recalculated after 1 hour of monocular patching. A total of 42 children (mean age, 6.9 years; range, 3-16 years) were included. The mean difference between distance and near deviation was 22(Δ) before occlusion and 14(Δ) after (P < 0.001). Approximately one third had a distance-near difference <10(Δ) after occlusion. With the heterophoria method, 100% of patients had high AC/A ratios before occlusion, with 71% continuing to have high AC/A ratios after. With the gradient method, 52% of patients had high AC/A ratios before occlusion, with 68% of this subgroup continuing to have high AC/A ratios after. Pseudo-divergence excess was found in one third of the subjects. More children were diagnosed with high AC/A ratios using the heterophoria method than with the gradient method. Without monocular occlusion, approximately one third of the children with normal AC/A ratios may be mistaken to have high AC/A ratios when measured with either method. Identification of high AC/A ratio exotropic patients is critical due to the risk of developing consecutive esotropia at near after strabismus surgery.


Response preparation involves a release of intracortical inhibition in task-irrelevant muscles.
Action preparation involves widespread modulation of motor system excitability, but the precise mechanisms are unknown. In this study, we investigated whether intracortical inhibition changes in task-irrelevant muscle representations during action preparation. We used transcranial magnetic stimulation (TMS) combined with electromyography in healthy human adults to measure motor-evoked potentials (MEPs) and cortical silent periods (CSPs) in task-irrelevant muscles during the preparatory period of simple delayed response tasks. In experiment 1, participants responded with the left index finger in one task condition and the right index finger in another task condition, whereas MEPs and CSPs were measured from the contralateral nonresponding and tonically contracted index finger. During experiment 2, participants responded with the right pinky finger whereas MEPs and CSPs were measured from the tonically contracted left index finger. In both experiments, MEPs and CSPs were compared between the task preparatory period and a resting intertrial baseline. The CSP duration during response preparation decreased from baseline in every case. A laterality difference was also observed in experiment 1, with a greater CSP reduction during the preparation of left finger responses compared to right finger responses. Despite reductions in CSP duration, consistent with a release of intracortical inhibition, MEP amplitudes were smaller during action preparation when accounting for background levels of muscle activity, consistent with earlier studies that reported decreased corticospinal excitability. These findings indicate that intracortical inhibition associated with task-irrelevant muscles is transiently released during action preparation and implicate a novel mechanism for the controlled and coordinated release of motor cortex inhibition.NEW & NOTEWORTHY In this study, we observed the first evidence of a release of intracortical inhibition in task-irrelevant muscle representations during response preparation. We applied transcranial magnetic stimulation to elicit cortical silent periods in task-irrelevant muscles during response preparation, and observed a consistent decrease in the silent period duration relative to a resting baseline. These findings address the question of whether cortical mechanisms underlie widespread modulation in motor excitability during response preparation.


Approaches to sample pretreatment in the determination of perchlorate in real world samples.
Perchlorate can be determined by the tandem technique of ion chromatography (IC) coupled to electrospray ionization mass spectrometry (ESI-MS). However, detection by ESI-MS can be compromised by the coelution of matrix components that can suppress the analyte signal. In addition, the presence of surface-active and other types of matrix components can cause fouling of the electrospray inlet, reducing overall signal and requiring frequent maintenance. The influences of matrix components can be minimized by using analytical columns with different selectivities, in-line diversion of separated matrix components, and off-line selective removal of matrix components via ion exchange or adsorption. This paper will discuss these sample preparation approaches for samples containing anionic species including surfactants and inorganic ions that elute in the vicinity of perchlorate.


Evidence vs experience in neonatal practices in necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) has been recognized for over 40 years as a cause of inflammation and necrosis of the small and large intestine of infants born at less than 36 weeks of gestation. NEC remains a significant health problem for infants born prematurely and may become the leading cause of morbidity and mortality among these infants worldwide. The sequence of events leading to NEC is complex and multifactorial, although damage to the intestinal epithelium and invasion by bacteria are known to play central roles in disease pathogenesis. Bacteria initiate a cascade of inflammation that may progress to intestinal necrosis and perforation with sepsis and death. Treatment of infants at risk for NEC with probiotic bacteria may be an area of great potential, as probiotic bacteria may promote maturation of the epithelial barrier and function to exclude bacterial pathogens from critical niches in the intestine, thereby disrupting a primary pathway in disease pathogenesis. Understanding how probiotic bacteria, or other novel therapies, prevent or limit disease propagation in NEC will be paramount in limiting the impact of disease in a growing population of premature newborns.


Neuropeptide Y (NPY)-containing nerves in mammalian ureter.
The distribution of neuropeptide Y in the ureter of the rat, rabbit, and man has been determined by radioimmunoassay and chromatographic analysis of the tissue extract. The localization of neuropeptide Y-immunoreactivity has been identified by immunocytochemistry. A regional distribution of neuropeptide Y was found; highest concentrations being present in the ureterovesical junction. Throughout the ureter, neuropeptide Y-immunoreactive nerve fibers were identified to surround the blood vessels and a few plexuses of neuropeptide Y-containing nerves were present within the muscle layers. Neuropeptide Y was not present within ganglion cells. Treatment of rats with 6-hydroxydopamine resulted in a significant reduction of neuropeptide Y concentrations in the upper, middle, and lower thirds of the ureter. This depletion in extractable neuropeptide Y was associated with morphologic changes typical of axonal degeneration of the neuropeptide Y-containing nerve fibers.


Long-term outcome of selective mutism: factors influencing the feeling of being cured.
Some long-term outcomes for participants with selective mutism (SM) are elevated rates of phobic disorders, particularly social phobia, persistent communicative problems, and reduced self-esteem. However, data on the long-term outcomes of SM are scarce. In this study, by analyzing interpersonal anxiety, communication skills, and self-esteem among those who experienced SM and felt cured (SM-C-group: 30 females, 6 males, mean age 28.0, SD = 7.42, range 19-47 years), those who experienced SM and did not feel cured (SM-NC-group: 37 females, 4 males, mean age 27.4, SD = 7.24, age range 19-50 years), and those who had not experienced SM (Non-SM-group: 30 females, 30 males, mean age 26.4, SD = 7.62, age range: 20-48 years), we examined the long-term outcomes of SM and the factors that influence the feeling of being cured of SM. Results showed that the SM-C-group and SM-NC-groups had significantly higher interpersonal anxiety and significantly lower communication skills than the Non-SM-group. Moreover, the SM-C-group showed significantly lower interpersonal anxiety and significantly higher communication skills than the SM-NC-group. However, while there was no significant difference in self-esteem between the SM-C and SM-NCgroups, there was a significant difference between the SM-NC and Non-SM groups. The SM-C and SM-NC groups did not differ on the retrospective symptom load (SMQ-J), but did on the Current level of difficulty with speaking. The results of the logistic regression analysis predicted that communication skills and self-esteem did not influence the feeling of being cured of SM, but interpersonal anxiety and Current level of difficulty to speak did. Therefore, it is speculated that the intensity of this interpersonal anxiety and whether people with SM still felt difficulty in talking to others may have affected the feeling of being cured from SM.


Casein Reactivates Dopaminergic Nerve Injury and Intestinal Inflammation with Disturbing Intestinal Microflora and Fecal Metabolites in a Convalescent Parkinson's Disease Mouse Model.
Parkinson's disease (PD) is the fastest-growing neurodegenerative disease, with pathogenic causes elusive and short of effective treatment options. Investigations have found that dairy products positively correlate with the onset of PD, but the mechanisms remain unexplored. As casein is an antigenic component in dairy products, this study assessed if casein could exacerbate PD-related symptoms by stimulating intestinal inflammation and unbalanced intestinal flora and be a risk factor for PD. Using a convalescent PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the results showed casein reduced motor coordination, caused gastrointestinal dysfunction, reduced dopamine content, and induced intestinal inflammation. Meanwhile, casein disturbed gut microbiota homeostasis by increasing the Firmicutes/Bacteroidetes ratio, decreasing α-diversity, and caused abnormal alterations in fecal metabolites. However, these adverse effects of casein attenuated much when it had hydrolyzed by acid or when antibiotics inhibited the intestinal microbiota of the mice. Therefore, our results suggested that casein could reactivate dopaminergic nerve injury and intestinal inflammation and exacerbate intestinal flora disorder and its metabolites in convalescent PD mice. These damaging effects might be related to disordered protein digestion and gut microbiota in these mice. These findings will provide new insights into the impact of milk/dairy products on PD progression and supply information on dietary options for PD patients.


Efficacy of multiple ring and coil electrode radiofrequency ablation catheters for the creation of long linear lesions in the atria.
Atrial fibrillation is an arrhythmia that may potentially be treated by creating long linear lesions in the atria to create lines of electrical conduction block. While this has been performed with success with open-heart surgery, it has been proposed that a less invasive catheter-based approach could achieve similar success. Radiofrequency energy catheter ablation was performed in vivo with two novel electrode catheters. Each was an expanding loop design: one with 3 mm ring electrodes; and one with 12.5 mm coil electrodes. Power delivery was controlled automatically with temperature (70 degrees C target) feedback from thermistors embedded in each electrode. A total of 39 lines of ablation were created in the atria of 11 normal dogs. The coil electrodes were more effective in creating lesions than the ring electrodes with a similar prevalence of transmurality (89% vs. 85%) but a higher prevalence of continuous transmurality (35% vs. 5%). Sequential electrode energy delivery was better than simultaneous multipolar delivery due to varying efficiencies of tissue heating. Inadequate heating was observed in 47% of simultaneous versus 1% of sequential multipolar deliveries, and excessive heating in 6% versus 1% of cases, respectively. It is feasible to create linear atrial lesions with an expanding loop electrode catheter. Catheters with coil electrodes are more effective than those with ring electrodes. In order to avoid coagulum formation and inefficient heating, sequential electrode energy delivery is preferable to multipolar delivery.


A multi-center survey of age of sexual debut and sexual behavior in Chinese women: suggestions for optimal age of human papillomavirus vaccination in China.
Cervical cancer is the second most common cancer among women worldwide, and over 85% of cervical cancers occur in developing countries such as China. Lack of resources for nationwide cervical cancer screening in China makes vaccination against oncogenic strains of HPV particularly important. Knowledge of age at sexual debut and sexual behavior is essential prior to implementation of a national vaccination program. A cross-sectional epidemiologic survey was conducted across 21 urban and rural sites in China to assess age at sexual debut and sexual behavior. 98.6% of the 11,852 recruited women aged 15-59 years were included in the analysis. Data were collected using a short, nurse-administered questionnaire and analyzed using standard descriptive statistics and survival analysis. In urban areas, more than ten percent of the 15-19 year old age group were already sexually active at the time of interview; this number increased to nearly 44% in the 20-24 year old age group. Chinese young women with an occupation were more likely to be sexually active compared to female students of the same age, irrespective of area of residence. The crude median sexual debut age for the youngest age group was 17 years, earlier than the sexual debut age reported by older cohorts. Younger age cohorts had an earlier menarche age than older cohorts and were more likely to have more sexual partners than older women, and more likely to have partners with more than one female partner. There is a trend towards earlier sexual debut and riskier sexual behaviors in younger age groups of Chinese women. These findings suggest that HPV vaccination of women between the ages of 13 and 15 years, before the completion of national compulsory education, is likely to contribute to the prevention of HPV infection and cervical cancer in China.


The importance of seizure-inducing factors in youth.
Of over forty known epileptogenic mechanisms, some eight involve transient conditions, the regulation of which necessarily involves the understanding cooperation of the patient/parents. Tension states, alterations of the wake-sleep cycle, fatigue and sleep deprivation, CNS stimulation by sensory or drug means, and shifts of the water and acid-base balances constitute the bulk of such seizure-inducing factors. The relative lack of CNS homeostatic control, due to immature development of the blood-brain barrier and cerebral maturation, serve to exaggerate these problems in childhood. In a referred group of 150 refractory epileptic children, the seizure-inducing mechanisms were found to be important (50% reduction of seizure incidence) in 20% and to be of "crucial" importance (complete control) in an additional 14%. These results indicate the importance of such mechanisms in selected children with epilepsy, who were only marginally or inadequately controlled by drug therapy. Reviews of the literature have suggested that this more comprehensive approach to the therapeutic management of epilepsy has not been adequately exploited.


Predictive Performance of Vancomycin Trough Concentrations in Patients With Diabetes With Microalbuminuria.
The performance of a population pharmacokinetic model in predicting trough concentrations after the initial vancomycin dose was evaluated in patients with albuminuria compared with patients who did not have albuminuria. Data were collected from 52 patients infected with methicillin-resistant Staphylococcus aureus (excluding patients undergoing dialysis and acute kidney injury) and treated with vancomycin. The data included urinary albumin concentration. The calculated mean prediction error and mean absolute error for the serum trough concentrations of vancomycin (with 95% confidence intervals) were 4.65 (4.13-5.17) and 6.1 (5.65-6.51), respectively, in microalbuminuria and 0.33 (-0.2 to 0.86) and 4.02 (3.59-4.45), respectively, in those without. There was no significant difference observed in serum creatinine concentration, age, weight, estimation of vancomycin trough concentration in serum, and actual trough concentration of vancomycin in serum between individuals with microalbuminuria and those without albuminuria. Microalbuminuria in patients with diabetes is a marker of the difference between predicted vancomycin trough concentrations and actual vancomycin trough concentrations.


Sarcopenia as a Predictor of Survival in Patients with Pancreatic Adenocarcinoma After Pancreatectomy.
To determine whether sarcopenia can potentially predict worse survival after resection of pancreatic ductal adenocarcinoma. Sarcopenia is correlated with poor outcomes in hepatopancreatobiliary malignancies, but the relationship of both its qualitative and quantitative features with patient survival after pancreatectomy has not been investigated in a western population. Preoperative cross-sectional computed tomography scans of consecutive patients who underwent pancreatectomy in 2005-2017 were evaluated for skeletal muscle index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR). Sex-specific categorical cut-offs were determined. Findings were correlated with outcome. The study included 111 patients, 47% of whom were female, with a median age of 67 years (range: 35-87 years), and median body mass index of 23 kg/m2 (range: 16-40 kg/m2); 77% had a Whipple procedure and 66% received adjuvant chemotherapy. Low SMI correlated with poor overall survival (OS) (P = 0.007), disease-specific survival (DSS) (P = 0.006), and recurrence-free survival (RFS) (P = 0.01). High IMAC correlated with poor OS (P = 0.04). Patients with high IMAC tended to have a shorter DSS (P = 0.09), with no correlation with RFS (P = 0.6). VSR was not associated with survival. Multivariable analysis yielded an independent association of low SMI with OS (HR = 1.7, 95%CI: 1.1-2.8, P = 0.02), DSS (HR = 1.8, 95%CI: 1.03-3.2, P = 0.04), and RFS (HR = 1.8, 95%CI: 1.1-2.8, P = 0.01), and of high IMAC with OS (HR = 1.9, 95%CI: 1.1-3.1, P = 0.01). Both qualitative and quantitative measures of skeletal muscle were independently associated with impaired survival in patients with resectable PDAC. Sarcopenia might serve as an early radiographic surrogate of aggressive tumor behavior, with potential implications for clinical decision-making and future study.


Tumor suppressors: recessive mutations that lead to cancer.
Several lines of evidence point to the involvement of recessive mutations in the predisposition to, and hence initiation of, cancer in vivo. Analyses of the genetic behavior of transformed cells suggest that at least one way to explain these events is to invoke loci which suppress the tumorous phenotype and which are inactivated by mutation. These suppressors are the subject of much speculation, but whether or not they are ultimately determined to be the regulators of differentiation antigens, growth factors, or proto-oncogenes, it is certain that the investigation of such loci will allow yet another glimpse at the inner mysteries of organismal development.


Epidemiology of nocturnal enuresis in a part of Khartoum, Sudan. II. The intensive study.
An intensive study of enuresis nocturna was made on 245 children selected through stratified sampling from a population of 8,462 children. Subjects were 3-15 years and living in a suburban part of Khartoum, Sudan. The prevalence of enuresis nocturna had been found to be high up to the age of ten in the previous extensive study. Few somatic, developmental or behavioural factors, and no family socio-economic or emotional states or child rearing methods including bladder-training, co-varied with enuresis. Climatic conditions and their interaction with possible developmental lags are discussed.


Patients who have dilated cardiomyopathy must have a trial of bridge to recovery (pro).
This article documents the experience that mechanical unloading of a diseased heart by application of a left ventricular assist device showing the consequence of functional improvement and weaning thereafter is a realistic option. The patient who has been weaned first is still doing fine with sufficient and stable cardiac function more than 10 years after device removal. Furthermore, it is discussed how to identify potential patients for weaning, what problems may arise, how the follow-up should be designed, the medication before and after weaning, the surgical procedure, and the general management. Moreover, the authors outline the difficulties that result from the gene and protein expression analysis of the diseased myocardium when compared to the cardiac function.


Physical activity is associated with improved aerobic exercise capacity over time in adults with congenital heart disease.
Impaired exercise capacity is common in adults with congenital heart disease (ACHD). This impairment is progressive and is associated with increased morbidity and mortality. We studied the influence of the frequency of at least moderately strenuous physical activity (PhysAct) on changes in exercise capacity of ACHD patients over time. We studied ACHD patients ≥21 years old who had repeated maximal (RER≥1.09) cardiopulmonary exercise tests within 6 to 24 months. On the basis of data extracted from each patient's clinical records, PhysAct frequency was classified as (1) Low: minimal PhysAct, (2) Occasional: moderate PhysAct <2 times/week, or (3) Frequent: moderate PhysAct ≥2 times/week. PhysAct frequency could be classified for 146 patients. Those who participated in frequent exercise tended to have improved pVO2 (∆pVO2=+1.63±2.67 ml/kg/min) compared to those who had low or occasional activity frequency (∆pVO2=+0.06±2.13 ml/kg/min, p=0.003) over a median follow-up of 13.2 months. This difference was independent of baseline clinical characteristics, time between tests, medication changes, or weight change. Those who engaged in frequent PhysAct were more likely to have an increase of pVO2 of ≥1SD between tests as compared with sedentary patients (multivariable OR=7.4, 95%CI 1.5-35.7). Aerobic exercise capacity also increased for patients who increased activity frequency from baseline to follow-up; 27.3% of those who increased their frequency of moderately strenuous physical activity had a clinically significant (at least +1SD) increase in pVO2 compared to only 11% of those who maintained or decreased activity frequency. ACHD patients who engage in frequent physical activity tend to have improved exercise capacity over time.


Functional Amyloids: Where Supramolecular Amyloid Assembly Controls Biological Activity or Generates New Functionality.
Functional amyloids are a rapidly expanding class of fibrillar protein structures, with a core cross-β scaffold, where novel and advantageous biological function is generated by the assembly of the amyloid. The growing number of amyloid structures determined at high resolution reveal how this supramolecular template both accommodates a wide variety of amino acid sequences and also imposes selectivity on the assembly process. The amyloid fibril can no longer be considered a generic aggregate, even when associated with disease and loss of function. In functional amyloids the polymeric β-sheet rich structure provides multiple different examples of unique control mechanisms and structures that are finely tuned to deliver assembly or disassembly in response to physiological or environmental cues. Here we review the range of mechanisms at play in natural, functional amyloids, where tight control of amyloidogenicity is achieved by environmental triggers of conformational change, proteolytic generation of amyloidogenic fragments, or heteromeric seeding and amyloid fibril stability. In the amyloid fibril form, activity can be regulated by pH, ligand binding and higher order protofilament or fibril architectures that impact the arrangement of associated domains and amyloid stability. The growing understanding of the molecular basis for the control of structure and functionality delivered by natural amyloids in nearly all life forms should inform the development of therapies for amyloid-associated diseases and guide the design of innovative biomaterials.


Structural and mechanical architecture of the intestinal villi and crypts in the rat intestine: integrative reevaluation from ultrastructural analysis.
The ultrastructure of the rat intestinal interstitium was analyzed from the viewpoint of mechanical dynamics to stabilize the intestinal villi, crypts and mucosal folds. In the rat, the small intestine lacks circular folds, but the large intestine possesses spiral folds. The intestinal villi, the largest in the duodenum, decreased in size in the jejunum and ileum successively, and were absent in the large intestine. The intestinal interstitium consisted of lamina propria mucosae (LPM) and tela submucosa (TSM) separated by muscularis mucosae (MM), the LPM was subdivided into an upper part within the villi and a lower part among the crypts in the small intestine. The light microscopic density of interstitium in the intestinal wall was lowest in the upper LPM, moderately dense in the lower LPM and highest in the TSM, and that among the intestinal region was highest in the duodenum and decreased successively in the jejunum and ileum. In the large intestine, the TSM bulged to form spiral folds with very low density. The intestinal epithelium in the villi possessed wide intercellular spaces and that in the crypts had closed intercellular spaces. At electron microscopic level, the upper and lower LPM contained subepithelial supportive meshwork that consisted of collagen fibrils and myofibroblast processes. The lower LPM and TSM contained conspicuous bundles of collagen fibrils and, in addition, TSM contained minor populations of scattered collagen fibrils near the smooth muscle layer (SML). The diameter of collagen fibrils was the largest in the bundles of TSM, and decreased from the duodenum through the jejunum and ileum to the large intestine. On the basis of these observations, we hypothesize that the intestinal villi are mechanically stabilized by the balance between the expansive interstitial pressure and inward pull by the subepithelial supportive meshwork. This hypothesis explains the hitherto neglected fact that the intestinal epithelium possesses wide intercellular spaces only in the villi, and accounts for the counterforce against the perpendicular smooth muscle cells, which are supposed to contract the intestinal villi.


Human alpha-fetoprotein-fatty acid interaction.
Human alpha-fetoprotein (AFP) is able to bind arachidonic acid with high affinity Ka = 10(7)M-1 and a limited number of binding sites NS = 3. Thirty different fatty acids were tested by competition using labelled arachidonic acid as tracer. This experiment demonstrated a great specificity for the fatty acid-AFP interaction. Only polyunsaturated long chain fatty acids were able to bind to AFP with high affinity. The metabolic products of arachidonic acid i.e. prostaglandins presented no affinity for the AFP molecule.


Structural dynamics and interactions of Xeroderma pigmentosum complementation group A (XPA98-210) with damaged DNA.
Nucleotide excision repair (NER) in higher organisms repair massive DNA abrasions caused by ultraviolet rays, and various mutagens, where Xeroderma pigmentosum group A (XPA) protein is known to be involved in damage recognition step. Any mutations in XPA cause classical Xeroderma pigmentosum disease. The extent to which XPA is required in the NER is still unclear. Here, we present the comparative study on the structural and conformational changes in globular DNA binding domain of XPA98-210 in DNA bound and DNA free state. Atomistic molecular dynamics simulation was carried out for both XPA98-210 systems using AMBER force fields. We observed that XPA98-210 in presence of damaged DNA exhibited more structural changes compared to XPA98-210 in its free form. When XPA is in contact with DNA, we found marked stability of the complex due to the formation of characteristic longer antiparallel β-sheets consisting mainly lysine residues.


Evaluation on an ergonomic design of functional clothing for wheelchair users.
Researchers have pointed out that people with physical disabilities find it difficult to obtain suitable clothing. In this study a set of wheelchair user oriented functional clothing was designed. Attention was paid to the wheelchair users' daily living activities related with clothing. An evaluating system combined with sports tournament and rehabilitation medicine was introduced to assess the new designed clothing. Six wheelchair users (3 males and 3 females) were invited to wear the clothing. A set of normal functional clothing was employed as a comparison (Control). The time required to complete three different daily living activities, i.e. dressing and undressing, going to toilet and bathing were recorded. Results showed that with the new clothing wheelchair users' competence of managing toilet was increased by 52.9%. The time needed for toilet was reduced by 45.7%. Their capability of managing dressing and undressing was improved by 24.6%. The study indicated that the newly designed clothing could facilitate wheelchair users' daily living activities related with clothing.


Randomized trial of laryngeal mask airway versus endotracheal intubation for surfactant delivery.
To compare the effectiveness of surfactant delivery via endotracheal tube (ETT) using an intubation-surfactant-rapid extubation approach with premedication) vs laryngeal mask airway (LMA) in preventing the need for mechanical ventilation in preterm neonates with moderate respiratory distress syndrome (RDS). Moderately preterm infants diagnosed with RDS, receiving nasal continuous positive airway pressure with FiO2 0.30 to 0.60, were randomized to two groups at age 3 to 48 h. Those in the ETT group were intubated following premedication with atropine and morphine, whereas the LMA group received only atropine. Both groups received calfactant before a planned reinstitution of nasal continuous positive airway pressure, and had equivalent pre-specified criteria for subsequent mechanical ventilation and surfactant retreatment. The primary outcome was failure of surfactant treatment strategy to avoid mechanical ventilation; we differentiated early from late failures to assess the contribution of potential mechanisms such as respiratory depression versus less-effective surfactant delivery. Secondary outcomes addressed efficacy and safety end points. Sixty-one patients were randomized, one excluded and 30 analyzed in each group, with similar baseline characteristics. Failure rate was 77% in the ETT group and 30% in the LMA group (P<0.001). The difference was related to early failure, as late failure rates did not differ between groups. FiO2 decrease after surfactant and rates of adverse events were similar between groups. Surfactant therapy through an LMA decreases the proportion of newborns with moderate RDS who require mechanical ventilation, when compared with a standard endotracheal intubation procedure with sedation. The efficacy of surfactant in decreasing RDS severity appears similar with both methods. Morphine premedication likely contributed to early post-surfactant failures.


Identity of gonadotropin-releasing hormone in passerine birds: comparison of GnRH in song sparrow (Melospiza melodia) and starling (Sturnus vulgaris) with five vertebrate GnRHs.
Gonadotropin-releasing hormone (GnRH) was detected in the brains of passerine birds, a recently evolved and diverse avian group. The molecular forms of GnRH in two species of birds under breeding conditions were deduced using methods of HPLC and immunology. The brain extracts of song sparrows (Melospiza melodia) contained a form of GnRH identified as chicken I GnRH-like peptide by its HPLC elution pattern and cross-reactivity with four antisera. In contrast, starling (Sturnus vulgaris) brain extracts showed molecular heterogeneity of GnRH forms; equal amounts of chicken I and chicken II GnRH-like peptides were present. Neither bird contained GnRH that could be identified as mammalian, salmon, or lamprey GnRH. Chicken II GnRH-like peptide may not have evolved after the separation of the song sparrow and starling as both peptides are found in chicken, a more primitive bird. The possibility remains that different stages of the life cycle are associated with the expression of these GnRH-like peptides or their ratio. Only determination of the primary structure will establish whether our chromatographic and immunological evidence is correct that chicken I and II GnRH are present in passerine birds and have been conserved in representatives throughout the reptiles and birds. Starlings can be added now to the growing list of submammalian species that express multiple forms of GnRH in their brains.


Safety, functional properties and technological performance in whey-based media of probiotic candidates from human breast milk.
We aimed at isolating and characterising microorganisms present in human breast milk with probiotic potential. In an 8-week postpartum sampling period, two strains of bifidobacteria (Bifidobacterium longum LM7a and Bifidobacterium dentium LM8a') and four strains of lactobacilli were isolated, all during the first 4-week postpartum. B. longum LM7a and B. dentium LM8a', together with four strains previously isolated from breast milk (Bifidobacterium lactis INL1, INL2, INL4 and INL5), were considered for further studies. Susceptibility of the strains to tetracycline, erythromycin, clindamycin, streptomycin, vancomycin and chloramphenicol was evaluated and the isolates exhibited, in general, the same properties as previously reported for bifidobacteria. All isolates showed low hydrophobicity and B. lactis and B. longum strains had satisfactory resistance to gastric digestion and bile shock, but not to pancreatin. B. lactis INL1, B. longum LM7a and B. dentium LM8a' were selected for some comparative technological studies. In particular, B. lactis INL1 displayed technological potential, with satisfactory growth in cheese whey-based media in biofermentor and resistance to freeze-drying, accelerated storage conditions and simulated gastric digestion.


Epigenetics: a way to understand the origin and biology of testicular germ cell tumors.
Testicular germ cell tumors are neoplasms carrying two unique features. First, testicular germ cell tumors have a pluripotential nature and show protean histology ranging from that of germ cells to embryonal and differentiated somatic cells. Therefore, testicular germ cell tumors are interesting resources positioned at a crossroad in developmental and neoplastic processes. The second unique feature of testicular germ cell tumors is their exquisite sensitivity to cisplatin-based chemotherapy. This review summarizes recent research progress in the epigenetics of testicular germ cell tumors in an attempt to explain the abovementioned biological and clinical characteristics of testicular germ cell tumors.


Acute abdominal emergencies in patients on long-term ambulatory peritoneal dialysis.
To review intercurrent abdominal emergencies in patients receiving long-term peritoneal dialysis on an ambulatory basis. A chart review. Tertiary care referral centre. Seven patients receiving long-term peritoneal dialysis, who suffered an acute abdominal emergency during a 7-year study period. Laparotomy with appropriate management depending on the findings. Antibiotic therapy and dialysate culture. In all patients the acute abdominal process involved the colon: five patients had perforated diverticulitis and two had ischemic colitis. The death rate overall was 57%. Peritonitis in these patients was difficult to differentiate from the peritonitis that occurs commonly in patients on long-term peritoneal dialysis. As a result there was a delay in the initiation of therapy ranging from 2 to 27 days. Coincidental abdominal emergency should be considered when patients receiving long-term peritoneal dialysis on an ambulatory basis present with peritonitis that does not respond to established antibiotic protocols and when culture results show evidence of multiple enteric organisms.


An evaluation of costs and benefits of a vehicle periodic inspection scheme with six-monthly inspections compared to annual inspections.
Although previous research suggests that safety benefits accrue from periodic vehicle inspection programmes, little consideration has been given to whether the benefits are sufficient to justify the often considerable costs of such schemes. Methodological barriers impede many attempts to evaluate the overall safety benefits of periodic vehicle inspection schemes, including this study, which did not attempt to evaluate the New Zealand warrant of fitness scheme as a whole. Instead, this study evaluated one aspect of the scheme: the effects of doubling the inspection frequency, from annual to biannual, when the vehicle reaches six years of age. In particular, reductions in safety-related vehicle faults were estimated together with the value of the safety benefits compared to the costs. When merged crash data, licensing data and roadworthiness inspection data were analysed, there were estimated to be improvements in injury crash involvement rates and prevalence of safety-related faults of respectively 8% (95% CI 0.4-15%) and 13.5% (95% CI 12.8-14.2%) associated with the increase from annual to 6-monthly inspections. The wide confidence interval for the drop in crash rate shows considerably statistical uncertainty about the precise size of the drop. Even assuming that this proportion of vehicle faults prevented by doubling the inspection frequency could be maintained over the vehicle age range 7-20 years, the safety benefits are very unlikely to exceed the additional costs of the 6-monthly inspections to the motorists, valued at $NZ 500 million annually excluding the overall costs of administering the scheme. The New Zealand warrant of fitness scheme as a whole cannot be robustly evaluated using the analysis approach used here, but the safety benefits would need to be substantial--yielding an unlikely 12% reduction in injury crashes--for benefits to equal costs.


Designing the invisible architecture of your hospital.
Before building or remodeling a hospital, architects develop a complete set of blueprints. That same sort of detailed attention should be given to the "invisible architecture" of core values, corporate culture, and emotional attitude because this has a much greater impact on the patient and employee experience than do the bricks and mortar.


Integrating fish scale and bone isotopic compositions for 'deep time' retrospective studies.
Isotopic studies of archived fish scales have tremendous potential to develop long-term retrospectives that provide important insights into how humans have altered aquatic ecosystems. However, fish specimens in museum archives and other repositories typically date to time periods when the impacts of industrial societies may have already caused profound environmental changes. Archaeological fish bones offer an opportunity to bridge this key temporal gap by providing samples spanning from the recent past to as far back as the Pleistocene. Collagen is the primary protein component of both fish scale and bone, but the comparability of isotopic compositions from these tissues has not been established experimentally. To lay the framework for integrating isotopic datasets from these tissues, we compare δ13C and δ15N of bone and scale collagen, as well as other tissues, from fish with life-time controlled diets. Results show that while there is no difference in δ13C between scale and bone collagen, there may be a very slight but meaningful inter-tissue offset in δ15N (<0.3‰). We discuss potential sources of δ15N variation in scale and bone collagen measurements. Because there is no difference in scale and bone δ13C, and the observed offset in δ15N is very small (less than analytical uncertainty in many studies), our findings demonstrate that collagen isotopic compositions from these tissues should be directly comparable when integrating datasets from modern and ancient samples to build more powerful, millennium-scale isotopic times series. In linking isotopic compositions of collagen from modern, historical (scales), and archaeological (bones) fish, our findings open the way for more nuanced contextualization of how ecosystems functioned prior to large-scale exploitation and how they have responded to mounting anthropogenic pressures in the intervening centuries.


Distribution of vehicular pollutants in street canyons of Varanasi, India: a different case.
In present study horizontal and vertical distribution of traffic-related pollutants (CO and SO(2)) within the street canyons in (CO and SO(2)) Varanasi, India was monitored. The results showed that average horizontal profiles of traffic-related pollutant concentrations within street canyon at leeward side were approximately same as that of windward side. However, the vertical concentration of both the pollutants decreases with height above the ground and study indicated that CO and SO(2) concentrations at different heights below the roof showed clear vertical self-gradient. CO and SO(2) concentration decreased with height and the minimum value occurred at the roof. It was concluded from the observed results that pollutants from vehicular exhaust emissions in the street canyon of Varanasi were evenly distributed. This result may be due to the fact that wind vortices are not formed. Therefore, urban planners can use this type of streets so that there is proper ventilation and dispersal of pollutants.


Regulation of the F conjugation genes studied by hybridization and tra-lacZ fusion.
Hybridization experiments and tra-lacZ fusions were used to obtain further insight into the complex series of control systems that affect F conjugation. We confirmed that the regular IncF FinOP control system represses transcription of traJ, and found that the traJ product is required for transcription of traM as well as of the traY-Z operon. The chromosomal sfrA gene product may be required to prevent premature termination of traJ transcription, while the sfrB gene product prevents premature termination at two sites within the traY-Z operon. The FinQ inhibition system determined by several IncI plasmids caused termination at three different sites in the operon, and that of JR66a at one further site. JR66a and R485 strongly inhibit F transfer, but have weak, or no (respectively) effects on transcription: they may inhibit function of one or more transfer gene products.


Retracted: Analysis of the Relationship between Scleritis and T Cell Activation in Patients with Hepatocellular Carcinoma Treated with PD-1 Carrelizumab.
[This retracts the article DOI: 10.1155/2022/4853481.].


[The effect of microwave radiation on the levels of MDA and the activity of SOD of nasopharyngeal carcinoma cells].
To study the effect of microwave radiation on the levels of malondialdehyde (MDIA) and activity of superoxide dismutase (SOD) of Nasopharyngeal carcinoma cells. The experiment were divided into four groups included control, 10, 20 and 30 mW/cm2 groups. The methods, such as TBA colorimetric assay and modified NBT hydroxylamine method, were used to detect the effect of microwave radiation on the levels of MDA and activity of SOD of nasopharyngeal carcinoma cells. With increase of microwave radiation, TBA assay showed that the levels of MAD were 1.4 and 3.5 times in 20 mW/cm2 group and 30 mW/cm2 group respectively compared with control group, there were significant differences among them (P < 0.05). NBT method shows that the activity of SOD were 68.2%, 46.2% and 36.0% of 10, 20 and 30 mW/cm2 groups respectively compared with control group, there were significant differences among them too (P < 0.01). Microwave Radiation could up-regulate the levels of MAD) while down-regulate the SOD activity.


Biologically relevant metal ion-dependent hydroxyl radical generation. An update.
Transition metal ions, especially iron, appear to be important mediators of oxidative damage in vivo. Iron(II) reacts with H2O2 to give more-reactive radicals. On the basis of ESR spin-trapping data with DMPO, supported by aromatic hydroxylation studies and patterns of DNA base modification, it is concluded that hydroxyl radical (OH.) is likely to be the major damaging species formed in Fenton Systems under biologically-relevant conditions (which include iron concentrations no higher than the micromolar range). Although reactive oxo-iron species (such as ferryl and perferryl) may also be important, direct chemical evidence for their formation and identity in biologically relevant Fenton systems is currently lacking. Studies at alkaline pH values show that iron(IV) and iron(V) species are highly oxidizing under those reaction conditions, with a pattern of reactivity different from that of OH..


Involvement of alpha-calcitonin gene-related peptide in monophosphoryl lipid A-induced delayed preconditioning in rat hearts.
Recent study has shown that monophosphoryl lipid A-induced delayed preconditioning enhanced preservation with cardioplegia and that the protective effects of monophosphoryl lipid A were related to stimulation of calcitonin gene-related peptide (CGRP) release. The purpose of the present study was to explore whether the elevated release of CGRP induced by monophosphoryl lipid A is secondary to stimulation of CGRP synthesis via the nitric oxide (NO) pathway and to characterize the isoform of CGRP. Sprague-Dawley rats were pretreated with monophosphoryl lipid A 24 h before the experiment, and then the left main coronary artery of rat hearts was subjected to 1 h occlusion followed by 3 h reperfusion. Infarct size, plasma creatine kinase activity, the plasma level of CGRP, and the expression of CGRP isoforms (alpha- and beta-CGRP) mRNA in lumbar dorsal root ganglia were measured. Pretreatment with monophosphoryl lipid A (500 microg/kg, i.p.) significantly reduced infarct size and creatine kinase release. Monophosphoryl lipid A caused a significant increase in the expression of alpha-CGRP mRNA, but not of beta-CGRP mRNA, concomitantly with an increase in plasma concentrations of CGRP, and the increased level of CGRP expression happened before stimulation of CGRP release. The effect of monophosphoryl lipid A was completely abolished by pretreatment with L-nitroarginine methyl ester (L-NAME, 10 mg/kg, i.p.), an inhibitor of NO synthase or capsaicin (50 mg/kg, s.c.), which selectively depletes transmitters in capsaicin-sensitive sensory nerves. The results suggest that the delayed cardioprotection afforded by monophosphoryl lipid A involves the synthesis and release of CGRP via the NO pathway, and that the protection is mainly mediated by the alpha-CGRP isoform.


Psychobiology of food preferences.
Investigations with laboratory animals can reveal much about the basic psychobiological determinants of food preference and diet-induced overeating. When offered a choice of foods, rats typically prefer high-fat and/or high-sugar food items over their nutritionally balanced chow diet. In addition, they may increase their total energy intake by 20-40% and consequently develop mild to moderate obesity. The role of flavor and postingestive nutritional actions on the preference for and overconsumption of fat- and sugar-rich foods has been questioned. To evaluate flavor and nutritional effects independently, recent studies have used self-regulated intragastric feeding paradigms. The results indicate that enhancing the flavor of food can significantly increase energy intake when nutrient composition is held constant. Similarly, changes in nutrient composition (ie fat-carbohydrate ratio) can significantly influence energy intake when flavor is held constant. In addition, postingestive nutrient actions can significantly alter flavor preferences through a conditioning process as function of nutrient type and concentration. Thus, food preferences and overeating result from interactions between the orosensory and nutritional properties of food.


Efficacy and safety of skin-adhesive low-level light therapy for overactive bladder: a Phase III study.
Overactive bladder (OAB) is a common condition that remains challenging to treat. We hypothesized that skin-adhesive low-level light therapy (LLLT) would be an effective treatment for OAB caused by bladder muscle contraction. Accordingly, we aimed to evaluate the efficacy and safety of an LLLT device for the treatment of OAB. This prospective, randomized, double-blind, placebo-controlled, multicenter trial included patients with a clinical diagnosis of OAB who were treated at either of two university hospitals. Patients were instructed to apply an LLLT device (Color DNA-WSF) or a sham device at home three times daily for 12 weeks. The primary outcome was the change in the mean daily number of urge urinary incontinence (UUI) episodes between baseline and 12 weeks. The secondary outcomes were the mean changes in incontinence, voiding, and nocturia episodes from baseline and the likelihood of achieving a > 50% reduction in UUI and incontinence episodes after 12 weeks. All patients completed the Overactive Bladder Symptom Score (OABSS), Urogenital Distress Inventory-6 (UDI-6), and Impact Urinary Incontinence-7 (IIQ-7) questionnaires. Safety parameters included treatment-emergent adverse events. Compared with those in the sham group, the numbers of UUI and urinary incontinence episodes in the LLLT group were significantly decreased at week 12 (UUI, (-1.0 ± 1.7 vs. -0.4 ± 2.5, P = 0.003; urinary incontinence, -1.1 ± 1.9 vs. -0.5 ± 2.9, P=0.002). Furthermore, the OABSS, UDI-6, and IIQ-7 scores at week 12 tended to be better in the LLLT group than in the sham group. The incidence of device-related treatment-emergent adverse events was similar between groups. LLLT may be clinically useful and safe for the treatment of OAB.


Which teen mothers choose Norplant?
The objective of this study was to determine if there are sociodemographic differences between adolescent mothers who choose to use Norplant after delivery and those who do not. We hypothesized that those adolescent mothers who are at highest risk for repeat adolescent pregnancy are least likely to select Norplant as a postpartum contraceptive. We prospectively compared the prevalence of epidemiologic risk factors for repeat adolescent pregnancy in a group of 187 consecutively delivered 13-18-year-olds who were enrolled in a comprehensive, multidisciplinary, adolescent-oriented maternity program. The study subjects were interviewed at delivery; 100 subsequently had a Norplant inserted (Norplant users). Student's t-tests and chi-square analyses were used to compare Norplant users and refusers. We found no statistically significant differences between Norplant users and refusers with regard to: age, race, Medicaid, or marital or school status. Compared to Norplant refusers, Norplant users were less likely to be primiparous (79% compared to 90%; p = .04) and more likely to have poor school grades (20% compared to 7%; p = .001). Norplant users were more likely to state that they had had trouble remembering to use contraceptives in the past (32% compared to 14%; p = .005). These data do not support the study hypothesis and are encouraging because they suggest that Norplant may reduce repeat pregnancy among adolescent parents.


Cell differentiation through tissue elasticity-coupled, myosin-driven remodeling.
Cells may lack eyes to see and ears to hear, but cells do seem to have a sense of 'touch' that allows them to feel their microenvironment. This is achieved in part through contractility coupled adhesion to physically flexible 'soft' tissue. Here we summarize some of the known variations in elasticity of solid tissue and review some of the long-term effects of cells 'feeling' this elasticity, focusing on differentiation processes of both committed cell types and stem cells. We then highlight what is known of molecular remodeling in cells under stress on short time scales. Key roles for forces generated by ubiquitous and essential myosin-II motors in feedback remodeling are emphasized throughout.


Sequential delithiation behavior and structural rearrangement of a nanoscale composite-structured Li1.2Ni0.2Mn0.6O2 during charge-discharge cycles.
Lithium- and manganese-rich layered oxides (LMRs) are promising positive electrode materials for next-generation rechargeable lithium-ion batteries. Herein, the structural evolution of Li1.2Ni0.2Mn0.6O2 during the initial charge-discharge cycle was examined using synchrotron-radiation X-ray diffraction, X-ray absorption spectroscopy, and nuclear magnetic resonance spectroscopy to elucidate the unique delithiation behavior. The pristine material contained a composite layered structure composed of Ni-free and Ni-doped Li2MnO3 and LiMO2 (M = Ni, Mn) nanoscale domains, and Li ions were sequentially and inhomogeneously extracted from the composite structure. Delithiation from the LiMO2 domain was observed in the potential slope region associated with the Ni2+/Ni4+ redox couple. Li ions were then extracted from the Li2MnO3 domain during the potential plateau and remained mostly in the Ni-doped Li2MnO3 domain at 4.8 V. In addition, structural transformation into a spinel-like phase was partly observed, which is associated with oxygen loss and cation migration within the Li2MnO3 domain. During Li intercalation, cation remigration and mixing resulted in a domainless layered structure with a chemical composition similar to that of LiNi0.25Mn0.75O2. After the structural activation, the Li ions were reversibly extracted from the newly formed domainless structure.


Diagnosis consensus among endodontic specialists and general practitioners: An international survey and a proposed modification to the current diagnostic terminology.
This survey aimed to determine the consensus amongst endodontic specialists in North America and practitioners worldwide to diagnose the pulp and periapical conditions of selected case scenarios encountered in daily practice using the American Association of Endodontists (AAE) pulpal and periapical diagnostic terms. Secondly, an attempt was made to suggest modifications in terms accordingly. A survey designed by two endodontic educators was sent to endodontists in North America and clinicians worldwide through an electronic database. The survey included socio-demographic questions followed by the clinical and radiographic presentations of four clinical scenarios. The participants were then requested to provide the pulpal and the periapical diagnosis of 11 teeth presented in these cases (22 answers in total/participant) using the AAE diagnostic terminology. Cases were designed to include 12 pulpal/periapical conditions as control (non-controversial conditions) and ten so-called controversial conditions. A proportion threshold of 10% was required for any diagnostic term to be reported in this survey. The participants were divided into two groups based on the region of endodontic training and/or practice to 'Specialised North American' or 'International Practitioners,' and their results were statistically compared using chi-squared tests (p < .05). The survey included 421 participants. 74% were endodontists, and 46.1% were amongst the 'Specialised North American' group and 53.9% amongst the 'International Practitioners'. Eleven of 12 control conditions had an almost complete agreement amongst the participants regarding the diagnostic terms selected, ranging between 82% and 96%, with no other diagnostic term exceeding the 10% threshold. All the controversial conditions yielded more than one diagnostic term selected/condition that exceeded the 10% threshold for groups ('Specialised North American' and 'International practitioners'). There were no differences in the diagnostic terms selected between the two groups; however, the weight for each term varied between the groups in some cases. There is a lack of consensus amongst clinicians, regardless of their training and region of practice, on the appropriate diagnostic terms to be used in particular clinical conditions. More diagnostic terms and modifications in the current terms may be required to establish a more reliable diagnostic terminology.


The effects of freezing on the tensile properties of repaired porcine flexor tendon.
When conducting complex testing of tendon repairs, it is essential that the samples are adequately preserved to prevent degradation. Freezing of samples is the most convenient method of preservation; however, there is no evidence in the literature to prove that freezing tendon before or after repair is acceptable. We aimed to prove that freezing tendons does not significantly alter the results of linear load-to-failure testing of tendon repairs. After a power study, 150 tendons were harvested from porcine forelimbs and randomized into 5 groups of 30 tendons. After division, tendons were repaired using a Pennington modified core technique with a Silfverskiöld peripheral cross-stitch. Tendons in group 1 were divided, repaired, and tested within 3 hours postmortem. Tendons in group 2 were refrigerated at 4 degrees C for 24 hours prior to repair and testing. Tendons in group 3 were frozen at -25 degrees C for 3 months prior to repair and testing. Tendons in group 4 were frozen at -25 degrees C for 6 months prior to repair and testing. Tendons in group 5 were frozen at -25 degrees C for 6 months, repaired, refrozen for 1 month, and then tested. All repairs were linear load tested to ascertain the ultimate strength and force to produce 3-mm gap in the repair. Analysis of variance analysis of the results did not demonstrate any significant differences between groups. Freezing tendons both before and after suture repair is an acceptable method of preservation when investigating the force to produce 3-mm gap and ultimate strength of tendon repairs.