Olanzapine-induced vasculitis.
Elderly patients are particularly vulnerable to adverse drug reactions as a result of polypharmacy and metabolic changes associated with aging. We present a case of leukocytoclastic vasculitis induced by olanzapine, a medication commonly used in elderly patients. An 82-year-old woman was admitted to the extended-care center for short-term rehabilitation after prolonged hospitalization for a pulmonary embolism requiring mechanical ventilation. The pulmonary problem resolved, but her hospitalization and subsequent rehabilitation were complicated by agitated delirium, which was treated with olanzapine and modification of contributory factors. At the time of admission to the rehabilitation facility, the patient had been receiving warfarin for 2 weeks and olanzapine for 6 days. On the eighth day after initiation of olanzapine, erythematous skin lesions developed on dependent areas. The international normalized ratio for warfarin was within the acceptable range; however, because warfarin has been associated with subcutaneous bleeding presenting as petechiae and ecchymosis, subcutaneous enoxaparin was substituted for warfarin. The skin lesions continued to worsen over the next week and developed into palpable lesions. Biopsy of the rash revealed leukocytoclastic vasculitis. In the absence of another cause, olanzapine was discontinued and the rash improved significantly. When the agitation recurred, risperidone was initiated, but the patient experienced dizziness with this agent. Olanzapine was resumed and the skin lesions recurred. Olanzapine was then changed to quetiapine, and the skin lesions improved over the next few weeks. Olanzapine is commonly used in elderly patients to control behavioral disturbances associated with dementia, delirium, and other psychiatric disorders. Leukocytoclastic vasculitis is an infrequently reported adverse drug reaction with olanzapine. Its exact pathogenic mechanism is unknown, but both cell-mediated and humoral immunity appear to play important roles. Because drug-induced vasculitis has an identical clinical presentation and identical serologic/pathologic parameters to idiopathic forms of vasculitis, a high index of suspicion is necessary for its accurate diagnosis. Because adverse drug reactions are common in elderly patients taking multiple medications, physicians should be vigilant when starting new medications and should attempt to eliminate unnecessary medications. Clinicians should be aware of the potential for leukocytoclastic vasculitis in association with olanzapine.


Expression analysis of three isoforms of hyaluronan synthase and hyaluronidase in the synovium of knees in osteoarthritis and rheumatoid arthritis by quantitative real-time reverse transcriptase polymerase chain reaction.
Hyaluronan is a major molecule in joint fluid and plays a crucial role in joint motion and the maintenance of joint homeostasis. The concentration and average molecular weight of hyaluronan in the joint fluids are reduced in osteoarthritis and rheumatoid arthritis. To elucidate the underlying mechanism, we analyzed the message expression of three isoforms of hyaluronan synthase and hyaluronidase from knee synovium, using real-time reverse transcriptase polymerase chain reaction. Synovia were obtained from 17 patients with osteoarthritis, 14 patients with rheumatoid arthritis, and 20 healthy control donors. The message expression of hyaluronan synthase-1 and -2 in the synovium of both types of arthritis was significantly less than in the control synovium, whereas that of hyaluronidase-2 in the synovium of both arthritides was significantly greater than in the control synovium. The decreased expression of the messages for hyaluronan synthase-1 and -2 and/or the increased expression of the message for hyaluronidase-2 may be reflected in the reduced concentration and decreased average molecular weight of hyaluronan in the joint fluids of patients with osteoarthritis and rheumatoid arthritis.


Lower airway microbiota in patients with clinically suspected Mycobacterium avium complex lung disease.
The relationship between the lower airway microbiota in humans and respiratory illness has gained attention recently. However, the relationship between nontuberculous mycobacterial lung disease (NTM-LD) and the lower airway microbiota is not fully understood yet. We conducted a study to characterize the lower airway microbiota in Mycobacterium avium complex lung disease (MAC-LD), a representative subclass of the NTM-LD. The subject sample included 25 patients clinically suspected of having mild MAC disease whose condition could not be diagnosed using sputum culture. Upon testing MAC antibodies (anti-glycopeptidolipid (GPL)-core IgA antibodies), mycobacterial culture of bronchoalveolar lavage fluid (BALF), and performing BALF 16S rRNA gene sequencing, we divided the subjects into two groups of patients: those in whom MAC was detected in BALF mycobacterial culture (MAC-LD group) and in whom MAC was not detected in BALF mycobacterial culture (non-MAC-LD group), which was then comparatively examined. BALF mycobacterial culture showed that 9 out of 25 patients were positive for NTM; the detected Mycobacterium was MAC in all. No patients were positive for acid-fast bacteria other than MAC. Eighteen patients were positive for MAC antibodies (anti-glycopeptidolipid (GPL)-core IgA antibodies), including nine patients positive for mycobacterial culture. On BALF 16S rRNA gene sequencing, six patients were positive for the genus Mycobacterium and were culture-positive. Among the 16 patients in the non-MAC-LD group, the genus Pseudomonas was detected by 16S rRNA gene sequencing in 7 patients, 4 among whom were positive for MAC antibodies (anti-GPL-core IgA antibodies). Conversely, the genus Pseudomonas was not detected among the nine patients in the MAC-LD group. Other than the genus Pseudomonas, there was no clear difference in the composition of and no significant difference in the diversity of the bacterial flora between the MAC-LD and non-MAC-LD groups. However, we found that the genus Pseudomonas and MAC tended to exist exclusively.


Phototransformation of selected human-used macrolides in surface water: kinetics, model predictions and degradation pathways.
The phototransformation of clarithromycin and roxithromycin, two human-used macrolide (MLs) antibiotics was investigated in surface waters. Photolysis kinetic data suggest that degradation in water would occur via the direct photolysis of the Fe(III)-MLs complexes. Hydroxyl radicals, singlet oxygen and other photooxidants generated from nitrate ions and from excited chromophores present in humic acids appeared to have only a very limited impact on the overall degradation of MLs under the adopted UV-vis irradiation conditions. A photolysis model applied to the Fe(III)-clarithromycin complex in river water showed that a half-life of 40 days was predicted under clear-sky irradiation in November, 26 days in February, and 10 in May. Direct photolysis could have a limited impact on the environmental concentrations of MLs in rivers, due to a too short water residence time but might be important in shallow lakes and lagoons. Photoinduced degradation of MLs mainly implied changes in the structure of the aglycone, probably leading to their detoxification because the pseudoerythromycin derivatives have very little antimicrobial activity.


The anticalmodulin effect of aflatoxin B1 on purified erythrocyte Ca(2+)-ATPase.
The genotoxic carcinogen aflatoxin B1 (AFB1) inhibited the calmodulin-stimulated membrane-bound (Ca2+Mg2+)-ATPase. Using the purified enzyme, 12 nmoles per ml of AFB1 caused maximum inhibition of 28% and 50%, of the acidic phospholipid-stimulated and calmodulin-activated Ca(2+)-ATPase activity respectively. Treatment of red cell ghosts with increasing concentrations of Triton X-100, a non-ionic detergent caused a progressive loss of both the basal and calmodulin-stimulated Ca(2+)-ATPase activity. The activity of the phospholipid-free, detergent-solubilized enzyme was almost fully restored by phosphatidyl serine (PS) and its sensitivity to calmodulin was restored in the presence of phosphatidyl choline (PC). Analysis of the results obtained using varying concentrations of ATP shows that AFB1 did not affect the Km and Vmax of the unstimulated enzyme whereas these parameters were reduced by about 75% and 50%, respectively, in the presence of calmodulin. Using the product of limited proteolysis by trypsin i.e. the 90 kDa fragment which still retains its calmodulin binding-domain and the 76 kDa fragment which has lost this domain, kinetic studies on the enzyme activity revealed that AFB1 inhibited the calmodulin-activated 90 kDa fragment by about 50% while the 76 kDa was not affected at all by the toxin and calmodulin. The toxin had no significant affect on the basal activity of the 90 kDa limited proteolysis fragment of the enzyme. These observations suggest that AFB1 inhibits the activated Ca(2+)-ATPase by binding to an important site in the calmodulin-binding domain of the enzyme. It seems likely that the toxin binds to tryptophan in the calmodulin-binding domain, thus causing a reduction in the rate at which this domain can interact with Ca(2+)-calmodulin or acidic phospholipids. The implication of these observations is that Ca(2+)-extrusion and other calmodulin-activated enzymes and processes may be slowed down during prolonged exposure to AFB1 because of its anticalmodulin effect.


Asymmetry in histone rotation in forced unwrapping and force quench rewrapping in a nucleosome.
Single molecule pulling experiments have shown that DNA in the nucleosomes unwraps in two stages from the histone protein core (HPC). The first stage, attributed to the rupture of the outer DNA turn, occurs between 3 and 5 pNs, and is reversible. The inner DNA turn ruptures irreversibly at forces between 9 and 15 pNs (or higher) in the second stage. Molecular simulations using the Self-Organized Polymer model capture the experimental findings. The unwrapping of the outer DNA turn is independent of the pulling direction. The rupture of the DNA inner turn depends on the pulling direction and involves overcoming substantial energetic (most likely electrostatic in origin) and kinetic barriers. They arise because the mechanical force has to generate sufficient torque to rotate the HPC by 180°. On the other hand, during the rewrapping process, HPC rotation is stochastic, with force playing no role. The assembly of the outer DNA wrap upon force quench nearly coincides with the unwrapping process, confirming the reversibility of the outer turn rupture. The asymmetry in HPC rotation during unwrapping and rewrapping explains the observed hysteresis in the stretch-release cycles in experiments. We propose experiments to test the prediction that HPC rotation produces kinetic barriers in the unwrapping process.


Transcriptional activation of c-fos and c-jun protooncogenes by serum growth factors in osteoblast-like MC3T3-E1 cells.
The present study was undertaken to clarify the relationship between c-fos and c-jun protooncogene expression and the differentiation and/or proliferation of osteoblasts, using osteoblast-like MC3T3-E1 (E1) cells. c-fos mRNA was barely detectable, whereas c-jun mRNA was constitutively expressed in E1 cells after serum deprivation for 24-72 h. When serum was added, a rapid and transient induction of c-fos and c-jun mRNAs was observed. The c-fos and c-jun mRNAs reached peak levels at 30 minutes, with a rapid disappearance of c-fos mRNA within 3 h and a much slower decrease in c-jun mRNA. The addition of serum together with cycloheximide, an inhibitor of protein synthesis, resulted in the superinduction of both c-fos and c-jun mRNAs. Among various growth factors, PDGF, EGF, and bFGF mimicked the serum effect, whereas IGF-I and TGF-beta failed to induce c-fos and c-jun mRNA. The effects of PDGF, EGF, and bFGF were completely abolished by pretreatment with actinomycin D, an inhibitor of RNA synthesis, suggesting a transcriptional mechanism. Nuclear runoff experiments showed that the transcription rate of c-fos and c-jun protooncogenes was increased by serum and growth factors. The effects of PDGF, EGF, and bFGF were inhibited by H-7 or staurosporine, inhibitors of protein kinase C (PKC), but not by HA1004 with a much weaker inhibitory activity, suggesting the involvement of PKC for the activation of the protooncogenes.(ABSTRACT TRUNCATED AT 250 WORDS)


Wolbachia-induced expression of kenny gene in testes affects male fertility in Drosophila melanogaster.
Wolbachia are Gram-negative endosymbionts that are known to cause embryonic lethality when infected male insects mate with uninfected females or with females carrying a different strain of Wolbachia, a situation characterized as cytoplasmic incompatibility (CI). However, the mechanism of CI is not yet fully understood, although recent studies on Drosophila melanogaster have achieved great progress. Here, we found that Wolbachia infection caused changes in the expressions of several immunity-related genes, including significant upregulation of kenny (key), in the testes of D. melanogaster. Overexpression of key in fly testes led to a significant decrease in egg hatch rates when these flies mate with wild-type females. Wolbachia-infected females could rescue this embryonic lethality. Furthermore, in key overexpressing testes terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling signal was significantly stronger than in the control testes, and the level of reactive oxygen species was significantly increased. Overexpression of key also resulted in alterations of some other immunity-related gene expressions, including the downregulation of Zn72D. Knockdown of Zn72D in fly testes also led to a significant decrease in egg hatch rates. These results suggest that Wolbachia might induce the defect in male host fertility by immunity-related pathways and thus cause an oxidative damage and cell death in male testes.


Inhibition of malate dehydrogenase by thyroxine and structurally related compounds.
The inhibition of pig heart mitochondrial malate dehydrogenase (L-malate: NAD+ oxidoreductase, EC 22.214.171.124) by the thyroxine and structurally related compounds was studied to resolve a longstanding question about the exact nature of the inhibition. Thyroxine, in freshly prepared solution, was found to be a "pure" competitive inhibitor relative to the nucleotide cofactor. Upon standing in diffuse daylight, solutions of thyroxine showed increased ability to inhibit the enzyme, presumably as a result of oxidation of enzyme sulfhydryl groups by free iodine that is released photochemically. This behavior probably accounts for earlier reports of irreversible inactivation by thyroxine. Comment is made on the implications of these findings to the mechanism of thyroid hormmone action.


RNAi-mediated down-regulation of ITPK-2 enhanced inorganic phosphorus and minerals in the transgenic rice.
Phytic acid or Myo-inositol hexakisphosphate is an essential compound for the rice plants. It remains in the form of phytate, a mixed salt of different mineral cations, in the seeds. The phytate breaks down during germination and provides the inorganic phosphorus and mineral ions to the seedlings. However, humans do not get the benefit of those essential ions from rice consumption due to the absence of phytase in the gut. We envisaged down-regulating ITPK, the gene behind the phytic acid biosynthesis so that its low amount would facilitate a greater amount of free mineral ions in the endosperm. Since there are six homologues of rice ITPK, we studied their expression in seeds. Additionally, we undertook an in-silico analysis of the homologous proteins. Considering the results, we selected ITPK-2 for its RNAi-mediated embryo-specific down-regulation to obtain the low phytate rice. We obtained a 37% reduction of phytic acid content accompanied by a nearly three-fold enhancement of inorganic phosphorus in the transgenic seeds. Additionally, the iron and zinc content increased in polished rice grains compared to the wild type. The results also showed that reduced phytic acid content did not affect the germination potential and seedling growth of the transgenic rice.


Analysis of the mechanism underlying the peripheral antinociceptive action of sildenafil in the formalin test.
The mechanism of the antinociceptive action of the phosphodiesterase 5 inhibitor, sildenafil, was assessed in the formalin test. Local peripheral ipsilateral, but not contralateral, administration of sildenafil (50-200 microg/paw) produced a dose-related antinociception during both phases of the formalin test. The local peripheral pretreatment with protein kinase G inhibitor peptide (PKG inhibitor, 0.01-1 microg/paw), charybdotoxin (large- and intermediate-conductance Ca2+-activated K+ channel blocker, 0.01-1 microg/paw), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-2 microg/paw), tolbutamide (ATP-sensitive K+ channel blocker, 12.5-50 microg/paw), and tetraethylammonium (non-selective voltage-dependent K+ channel blocker, 12.5-50 microg/paw), but not 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5-50 microg/paw) or saline, significantly diminished in a dose-dependent manner sildenafil-induced local peripheral antinociception. Given alone, local peripheral administration of inhibitors did not modify formalin-induced nociceptive behavior. Results suggest that sildenafil produces its local peripheral antinociceptive effect via activation of the cyclic GMP-PKG-K+ channel pathway.


Retrograde sulfur flow from glucosinolates to cysteine in Arabidopsis thaliana.
Specialized (secondary) metabolic pathways in plants have long been considered one-way routes of leading primary metabolite precursors to bioactive end products. Conversely, endogenous degradation of such "end" products in plant tissues has been observed following environmental stimuli, including nutrition stress. Therefore, it is of general interest whether specialized metabolites can be reintegrated into primary metabolism to recover the invested resources, especially in the case of nitrogen- or sulfur-rich compounds. Here, we demonstrate that endogenous glucosinolates (GLs), a class of sulfur-rich plant metabolites, are exploited as a sulfur source by the reallocation of sulfur atoms to primary metabolites such as cysteine in Arabidopsis thaliana Tracer experiments using 34S- or deuterium-labeled GLs depicted the catabolic processing of GL breakdown products in which sulfur is mobilized from the thioglucoside group in GL molecules, potentially accompanied by the release of the sulfate group. Moreover, we reveal that beta-glucosidases BGLU28 and BGLU30 are the major myrosinases that initiate sulfur reallocation by hydrolyzing particular GL species, conferring sulfur deficiency tolerance in A. thaliana, especially during early development. The results delineate the physiological function of GL as a sulfur reservoir, in addition to their well-known functions as defense chemicals. Overall, our findings demonstrate the bidirectional interaction between primary and specialized metabolism, which enhances our understanding of the underlying metabolic mechanisms via which plants adapt to their environments.


Kinetics and mechanism of nickel ferrite formation under high temperature ultrasonic treatment.
The effect of simultaneous ultrasonic and thermal treatment on kinetics and mechanism of nickel ferrite formation was studied. It was established that sonication leads to notable increase of the mean rate of this reaction and decrease of effective activation energy from 190+/-5 to 125+/-7 kJ/mol. XRD data show that ultrasonic treatment significantly affects the microstructure of both initial reagent (Fe(2)O(3)) and reaction product (NiFe(2)O(4)) thus promoting formation of well developed reaction zone. A general model of ferrite formation mechanism under high temperature ultrasonic treatment was proposed.


Substrate stereoselectivity and enantiomer/enantiomer interaction in propranolol metabolism in rat liver microsomes.
The substrate stereoselectivity and enantiomer/enantiomer interaction of (S)- and (R)- propranolol for the formation of their metabolites were investigated in rat liver microsomal fractions. The enantiomers of primary metabolites of propranolol, 4-, 5-, 7-hydroxy- and N-desisopropyl-propranolol were separated and assayed by an HPLC method employing a chiral ovomucoid column. Regioselective substrate stereoselectivity (R < S for 4- and 5-hydroxylations; R > S for 7-hydroxylation; R = S for N-desisopropylation) was observed in the formation of propranolol metabolites when the individual enantiomers or a racemic mixture of propranolol were used as substrates. Concentration-dependent metabolic inhibition of propranolol enantiomers by their optical isomers was also observed. In addition, the inhibition of propranolol 4-, 5- and 7-hydroxylations between the enantiomers showed a typical competitive nature. These findings suggested that the propranolol enantiomers competed for the same enzyme, probably a cytochrome P450 isozyme in the CYP2D subfamily.


Injuries associated with mechanical chest compressions and active decompressions after out-of-hospital cardiac arrest: A subgroup analysis of non-survivors from a randomized study.
Both skeletal and visceral injuries are reported after cardiopulmonary resuscitation (CPR). This subgroup analysis of a randomized clinical study describes/compares autopsy documented injury patterns caused by two mechanical, piston-based chest compression devices: standard LUCAS® 2 (control) and LUCAS® 2 with active decompression (AD, intervention) in non-survivors with out-of-hospital cardiac arrest (CA). We compared injuries documented by autopsies (medical/forensic) after control and intervention CPR based on written relatives consent to use patients' data. The pathologists were blinded for the device used. The cause of CA and injuries reported were based on a prespecified study autopsy template. We used Pearson's chi-squared test and logistic regression analysis with an alpha level of 0.05. 221 patients were included in the main study (April 2015-April 2017) and 207 did not survive. Of these, 114 (55%, 64 control and 50 intervention) underwent medical (N = 73) or forensic (N = 41) autopsy. The cause of CA was cardiac 53%, respiratory 17%, overdose/intoxication 14%, ruptured aorta 10%, neurological 1%, and other 5%. There were no differences between control and intervention in the incidence of rib fractures (67% vs 72%; p-value = 0.58), or sternal fractures (44% vs 48%; p-value = 0.65), respectively. The most frequent non-skeletal complication was bleeding (26% of all patients) and intrathoracic was the most common location. Ten of the 114 patients had internal organ injuries, where lungs were most affected. In non-survivors of OHCA patients, the most frequent cause of cardiac arrest was cardiogenic. Skeletal and non-skeletal fractures/injuries were found in both control and intervention groups. Bleeding was the most common non-skeletal complication. Internal organ injuries were rare.


Structural study of two proteins SigE and ORF1 to predict their roles in the biochemical oxidation of sulfur anions via the global sulfur oxidation operon (sox).
Microbial redox reactions involving inorganic sulfur compounds in the environment are one of the major reactions of the global sulfur cycle. These reactions are mediated by phylogenetically diverse prokaryotes containing the sulfur oxidizing gene cluster (sox). The sox gene cluster of alpha-Proteobacteria comprises of at least 15 genes, which form two transcriptional units. Recently two new orfs, which code for proteins named, SigE and ORF1, were identified in Starkeya novella. Sequence analyses reveal that SigE protein has the signature sequence of ECF-type sigma factors and a helix-turn-helix (HTH) DNA binding motif whereas ORF1 is possibly an anti ECF-sigma factor, which also has the signature sequence of the dsr family of sulfate ion binding proteins. We employed homology modeling to construct the three-dimensional structures of these proteins. The model of SigE was docked on to its promoter DNA to investigate the favourable binding modes of the protein. Interactions of SigE with its anti-sigma factor ORF1 were also reported after docking these proteins. We also identified the putative sulfate ion binding residues of ORF1 by docking sulfate ion on to it. Our study provides a rational framework for understanding of the structural as well as the molecular basis of the mechanism of the regulation of sulfur oxidation reactions by SigE and ORF1 proteins via the sox operon.


[Current perspectives on the repackaging and stability of solid oral doses].
Which are the guidelines and scientific aspects for repackaged oral solid medications in France in 2010 whereas it develops? The transient or definitive displacement of the solid oral form from the original atmosphere to enter a repackaging process, sometimes automated, is likely to play a primary role in the controversy. However, the solid oral dose is to be repackaged in materials with defined quality. Considering these data, a review of the literature for determination of conditions for repackaged drug stability according to different international guidelines is presented in this paper. Attention is also paid to the defined conditions ensuring the conservation and handling of theses drugs throughout the repackaging process. However, there is lack of scientific published stability data. Nevertheless, recent alternatives may be proposed to overcome the complexity of studying stability in such conditions. Then, the comparison of the moisture barrier properties of the respective package, a galenic model of hygroscopic molecules, or light sensitive molecules or stability data obtained during the industrial preformulation phase could also secure the list of drugs to be reconditioned. Similarly, a wise precaution will be to get stability data for the industrial blisters and unit doses undergoing the real conditions of the medication use process in hospitals and other healthcare settings. By now, reduction of dispensing errors and improvement of the compliance aid put a different perspective on the problem of repackaged drugs. To date, the pharmacist is advised to carry out its analysis of the risks.


The distribution of the ABO blood groups among diabetes mellitus patients in Qatar.
There is strong evidence in the literature that there is an association between ABO blood group and certain diseases. The aim of this study was to investigate any association between the ABO blood groups and diabetes mellitus (DM) in Qatar. This was a sex-matched case-control study. This study was carried out in the diabetic outpatient clinics and blood bank of the Hamad Medical Corporation (HMC) from April 2011 to December 2012. The study included 1633 diabetic patients and 1650 nondiabetic apparently healthy controls. A total of 2148 adult patients above 18 years of age were selected consecutively from the diabetic clinics of the hospitals and 1633 patients gave consent to take part in this study, thus giving a response rate of 76%. A total of 2150 nondiabetic healthy adults above 18 years of age were recruited from the blood bank and 1650 individuals agreed to take part in this study, giving a response rate of 76.7%. Blood group of the recruited subjects was taken from the database of the Blood Bank, Central laboratory, HMC. The data revealed that the blood group B was significantly more common in diabetic patients as compared with healthy population (25.7% vs. 20.4%; P < 0.001). Blood group O was significantly less common in diabetic patients compared with nondiabetics (38.5% vs. 45.4%; P < 0.001). Among diabetic men, the frequency of only blood group B was significantly higher, while on the contrary among diabetic women the frequency of both A and B (29.7% vs. 24.8%; P = 0.03 and 25.5% vs. 20%; P < 0.009, respectively) were significantly higher as compared with nondiabetic healthy population. The findings in this study suggest that ABO antigens are associated with DM. DM is more common in individuals with blood group B.


Changes in Manufacturing Processes of Biologic Therapies Can Alter the Immunogenicity Profile of the Product.
Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs.


A mathematical model for the liver uptake and excretion of 99mTc-diethyl IDA.
A mathematical model for the liver uptake and excretion of 99mTc-diethyl IDA has been formulated and data from four patient studies have been fitted to the model, resulting in values for the model parameters. The model includes compartments for blood, extravascular space, hepatocytes, bile ducts, and kidneys. The parameter values obtained reflect a rapid exchange between blood and extravascular space and a significant reverse flow of the radiopharmaceutical from the liver to the blood.


The middle layer of lumbar fascia can transmit tensile forces capable of fracturing the lumbar transverse processes: an experimental study.
Transversus abdominis and its aponeurotic attachment to the lumbar transverse processes via the middle layer of lumbar fascia are of proposed clinical and biomechanical importance. Moderate traction on these structures (simulating submaximal contraction of transversus abdominis) is reported to influence segmental motion, but their tensile capacity is unknown and the effects of sudden, maximal traction on these attachments and the transverse processes are uncertain. In 15 embalmed cadaver abdomens, the middle layer of lumbar fascia was isolated, gripped and rapid tension applied in either a lateral or posteroanterior direction (simulating forces that may produce avulsion and traumatic fractures). Peak forces prior to tissue failure were recorded and the gross effects of traction documented. Lumbar transverse process fractures were produced in all specimens; by transverse traction in 50% of tests and posteroanterior force in 80%. In the remainder the middle layer of lumbar fascia was torn. Mean transverse and posteroanterior peak forces reached in the middle layer of lumbar fascia prior to failure were 82 N (range 20-190 N) and 47 N (range 25-70 N), respectively. The middle layer of lumbar fascia can transmit substantial tensile forces to lumbar vertebrae, capable of transverse process fracture under experimental conditions. Tensile capacity is likely to be even greater in-vivo. This suggests transversus abdominis and the middle layer of lumbar fascia can strongly influence vertebral motion, should be incorporated in biomechanical models of the spine and considered as potential contributors to transverse process fractures by avulsion.


Retinoids and cancer.
The early and recent investigations in the field of retinoids and cancer are reviewed. The retinoids, including natural vitamin A compounds and their synthetic analogs, present a new class of substances exerting a prophylactic and a therapeutic effect both in certain experimental tumor models and in certain clinical conditions of preneoplastic and neoplastic lesions. Because of a particular physiological mechanism of action, the retinoids offer a new approach to the cancer problem, which is different from those of surgery, X-ray therapy, conventional chemotherapy, and immunotherapy.


Direct oral anticoagulants for atrial fibrillation in early postoperative valve repair or bioprosthetic replacement.
Despite increased use of direct oral anticoagulants (DOACs), limited evidence guides their use in the early postoperative period after bioprosthetic valve implantation in patients with atrial fibrillation. Our objective was to describe the efficacy and safety of DOACs and warfarin in the first 3 months after surgical bioprosthetic valve replacement or repair in patients with atrial fibrillation. This was a retrospective, registry-informed cohort study of surgical patients who underwent bioprosthetic valve replacement or repair, had concomitant atrial fibrillation and received oral anticoagulation at discharge. The primary efficacy outcome was a composite of death, ischemic stroke, transient ischemic attack, and systemic embolism; the primary safety outcome was a composite of major bleeding. Key secondary outcomes were comparative analyses of primary outcomes, temporal anticoagulation prescribing patterns, and 30-day readmission rates. A total of 1743 patients were included. Of the 570 patients in the DOAC group, 17 (2%) met the composite efficacy outcome and 55 (10%) met the composite safety outcome. Of the 1173 patients receiving warfarin, 41 (3%) and 114 (10%) met the composite efficacy and safety outcomes, respectively. Comparative secondary analysis was not statistically significant for either the efficacy (adjusted odds ratio, 0.85; 95% confidence interval, 0.46-1.55, P = .59) or safety (adjusted odds ratio, 0.94; 95% confidence interval, 0.66-1.34, P = .76) outcomes. The 30-day readmission rates were similar between both groups. Our results suggest DOACs may be safe and effective alternatives to warfarin in the early postoperative period after valve repair or surgical bioprosthetic replacement. Confirmation awaits adequately powered prospective studies.


Emerging Laminin-332‒Dependent and ‒Independent Roles for Integrin α3 in Protumorigenic Signaling.
The epidermal integrin α3β1 promotes skin tumorigenesis in experimental models; yet, the underlying molecular mechanisms remain mostly unclear. In their article, Ramovs et al. (2020a) identify two spatially separated α3β1-dependent signaling branches fostering skin tumor outgrowth. In basal keratinocytes, α3β1/laminin (LN)-332 drives FAK/Src activation, whereas in suprabasal layers, junctional α3β1 and the tetraspanin CD151 mediate signal transducer and protein kinase B (Akt)‒dependent survival that is independent of LN-332 binding.


Teaching Spanish-Speaking Caregivers to Implement EMT en Español: A Small Randomized Trial.
The primary purpose of this study was to examine the effects of using the Teach-Model-Coach-Review approach to teach Spanish-speaking caregivers from low-income households to implement EMT en Español with their young children with language delays. A secondary purpose was to explore the effects of the caregiver-implemented intervention on children's vocabulary. A final and more exploratory goal was to gain insight into caregivers' perceptions of the intervention. 21 caregiver-child dyads participated in the intent-to-treat randomized control trial. Their children were 30-43 months old with language delays. Dyads were randomly assigned to receive 24 caregiver training sessions delivered at home in Spanish or a wait list control group. Pre, post and 3-month follow assessments included observational measures of caregiver-child interactions and child standardized vocabulary assessments. Caregivers completed surveys rating their perception of the intervention. Caregivers in the intervention group had significantly higher percentages of matched turns, expansions, and targets at post-assessment and of expansions and targets at follow-up compared to the control group. Overall, children in the intervention condition had significantly higher receptive vocabulary scores and performed better than children in the control condition on observational measure of their lexical diversity, with moderate effect sizes for most outcomes. Caregivers perceived the intervention as effective and culturally appropriate. Teach-Model-Coach-Review is effective in increasing Spanish-speaking caregivers' use of EMT en Español strategies with their young children with language delays. The intervention also appears to be effective for child vocabulary outcomes and acceptable to caregivers.


IgA endomysium antibody in children with dermatitis herpetiformis treated with gluten-free diet.
The IgA antibody to endomysium of smooth muscle (IgA-EmA) was measured in 32 children with confirmed dermatitis herpetiformis who were eating gluten-free diets. One patient had IgA-EmA before treatment but had a negative test one month later while on the diet. Two so treated for less than one year still had antibody, but of seven children treated for more than one year with gluten-free diet, none had detectable antibody. It was present in 13 of 20 children not adhering to the prescribed diet. The antibody was absent in 4 children with linear IgA bullous dermatosis and 43 children with various skin and intestinal diseases. These findings correspond to those in adults with dermatitis herpetiformis and indicate that IgA-EmA is also a marker for gluten-sensitive enteropathy in children.


Antinociceptive action of tizanidine in mice and rats.
The antinociceptive action of tizanidine [5-chloro-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole], a centrally acting muscle relaxant, was evaluated after subcutaneous or peroral administration in mice and rats. Tizanidine strongly inhibited the writhing response induced by acetic acid, phenyl-p-benzoquinone and acetylcholine in mice, and its potency was found to be greater than that of morphine. Tizanidine showed antinociceptive action like morphine not only in tail pressure and electrical stimulation tests in mice but also in tail-flick tests in mice and rats. The antinociceptive action of tizanidine was unaffected by pretreatment with naloxone. These findings suggest that tizanidine develops relatively strong antinociceptive action by a nonopioid mechanism.


Acridine orange-induced precipitation of mouse testicular sperm cell DNA reveals new patterns of chromatin structure.
Precipitate resulting from interaction between certain intercalators, such as acridine orange (AO), and nucleic acids can be detected by electron microscopy. Formation of precipitate in nuclei of live cells is modulated by chromatin structure. Susceptibility of in situ DNA to precipitation was studied in mouse testicular germ cells during various stages of sperm maturation. DNA in round spermatid chromatin, similar to somatic cell euchromatin, was rather resistant to precipitation; the electron-dense precipitate was granular and randomly distributed. DNA in elongated spermatids was more susceptible to precipitation; the products were in the form of fibers. At early stages of spermatid maturation these fibers were distributed uniformly throughout the entire nucleus. At later stages, the products appeared as approximately 25-nm-thick fibers arranged longitudinally in arrays within the nucleus. With further cell maturation, fibers in the anterior portion of the nucleus appeared to fuse, forming homogeneously dense product. These fibrous products likely represent AO interactions with DNA in chromatin in which transition proteins had replaced histones. Changing patterns of these precipitated fibers likely reflect progressive stages of chromatin condensation, which starts at the center and anterior portion of the nucleus where the fibers coalesce. Mature sperm cell DNA, known to be complexed with protamines, was more resistant to AO-induced precipitation. The data suggest that precipitation induced by AO and monitored by electron microscopy may be a useful probe of nuclear chromatin structure.


Ultrathin polymeric films for interfacial passivation in wide band-gap perovskite solar cells.
Wide band-gap perovskite solar cells have the potential for a relatively high output voltage and resilience in a degradation-inducing environment. Investigating the reasons why high voltages with adequate output power have not been realized yet is an underexplored part in perovskite research although it is of paramount interest for multijunction solar cells. One reason is interfacial carrier recombination that leads to reduced carrier lifetimes and voltage loss. To further improve the Voc of methylammonium lead tri-bromide (MAPbBr3), that has a band-gap of 2.3 eV, interface passivation technique is an important strategy. Here we demonstrate two ultrathin passivation layers consisting of PCBM and PMMA, that can effectively passivate defects at the TiO2/perovskite and perovskite/spiro-OMeTAD interfaces, respectively. In addition, perovskite crystallization was investigated with the established anti-solvent method and the novel flash infrared annealing (FIRA) with and without passivation layers. These modifications significantly suppress interfacial recombination providing a pathway for improved VOC's from 1.27 to 1.41 V using anti solvent and from 1.12 to 1.36 V using FIRA. Furthermore, we obtained more stable devices through passivation after 140 h where the device retained 70% of the initial performance value.


Intussusception caused by an inverted colonic diverticulum: a case report.
Intussusception is an unusual disorder among the complications of diverticula in adults. This study aimed to report intussusception due to an inverted colonic diverticulum. Such a large inverted colonic diverticulum has rarely been reported. A 62-year-old Chinese woman presented to the First Hospital of Jilin University with abdominal pain, vomiting, and bloody stool. Preoperative computed tomography imaging indicated intussusception. The intraoperative diagnosis was consistent with postoperative pathology. Our patient was diagnosed as having an inverted colonic diverticulum near the ileocecal valve with intussusception and intestinal necrosis. Although inverted colonic diverticulum is extremely rare, it should also be considered among the causative factors of intussusception.


Safety and Outcomes of Cardiac Rehabilitation for Patients with Spontaneous Coronary Artery Dissection.
To evaluate the safety and outcomes of aerobic and resistance training in patients undergoing cardiac rehabilitation after spontaneous coronary artery dissection. Eleven patients with spontaneous coronary artery dissection at 2 academic centres were studied retrospectively during cardiac rehabilitation from July 2013 to September 2017. Patients underwent maximal effort exercise testing at enrollment and discharge per institutional protocol. Patients were prescribed individualized exercise regimens based on stress test results, stress management with a behavioural psychologist, and diet counselling with a nutritionist. Resistance training was introduced during weeks 3-5 with close blood pressure monitoring. Ten patients who completed cardiac rehabilitation showed improvements in aerobic exercise capacity and exercise duration. For resistance training, patients increased the total number of resistance exercise modalities, repetitions, or both. After cardiac rehabilitation, significant improvements were found in exercise capacity, Mental Composite Score, Physical Composite Score, anxiety measured by Generalied Anxiety Disorders (GAD-7), and positive affect. During a mean followup of 14 months, no patients had any recurrent dissection or major adverse cardiac events. Cardiac rehabilitation is safe and improves functional status, anxiety, positive affect and quality of life in patients with spontaneous coronary artery dissection. Future studies should explore ways to further improve the psychosocial and functional status of these patients.


Regulation of activation-induced receptor activator of NF-kappaB ligand (RANKL) expression in T cells.
Receptor activator of NF-kappaB ligand (RANKL) is a type II membrane protein of the TNF family and plays a critical role in the regulation of osteoclastogenesis. RANKL expressed on osteoblastic stromal cells has been shown to support osteoclast differentiation originated from hematopoietic precursors. Interestingly, RANKL is also expressed on cells of the immune system including T cells and dendritic cells. We have shown that anti-CD3 could induce RANKL expression in T cell hybridoma A1.1 cells and splenic T cells. RANKL expressed on T cells could effectively induce osteoclast formation from the whole population of murine splenocytes. Furthermore, we have found that the induction of RANKL expression is solely dependent on TCR activation-induced Ca2+ mobilization since its expression can be blocked by cyclosporine A and TMB-8, a Ca2+ mobilization inhibitor. Additionally, treatment of A1.1 cells with ionomycin alone also strongly induces RANKL expression, while phorbol myristate acetate by itself does not. Moreover, although inhibition of c-myc has significant effects on anti-CD3-induced Fas ligand (FasL) expression, we have found that the anti-CD3-induced RANKL expression is independent of c-myc. Surprisingly, in contrast to its inhibitory effect on FasL expression, TGF-beta dramatically increased the expression of anti-CD3-induced RANKL expression. In addition to its potential role in immune responses, RANKL expressed on activated T lymphocytes may provide a mechanism for the communication between the immune and skeletal systems during immune responses and disease states such as rheumatoid arthritis.


Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors.
Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activation of this cellular signaling pathway in a variety of physiologically processes, pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed to inhibit PDE5, the inhibitors show different affinities and specificities against all PDE subtypes. Additionally, they have been shown to induce allosteric structural changes in the protein. These are mostly attributed to their chemical structure and, therefore, binding interactions with PDE catalytic domains. Therefore, understanding how these inhibitors interact with PDE5 and the structural basis of their selectivity is critically important for the design of novel, highly selective PDE5 inhibitors. Here, we review the structure of PDE5, how its function is regulated, and discuss the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity. We also discuss the therapeutic indications of these inhibitors and the potential of repurposing for a wider range of clinical applications.


Pulmonary blastoma.
A primary pulmonary tumour in a four year old boy arising from the subpleural zone of the lung is described. It contains both stromal and epithelial elements at the primary site and in the bony metastases. The combination of the age of the patient, the site of the tumour, the stromal and epithelial elements present in the tumour suggest that this is a true pulmonary blastoma. Electronmicroscopy showed the presence of intranuclear viral particles.


Glycoconjugates in the mucosa of the digestive tract of Cynoscion guatucupa: a histochemical study.
This study addresses the histomorphology, the histochemistry and the distribution of glycoconjugates (GCs) in the mucosa of the digestive tract of the weakfish Cynoscion guatucupa. The histological characterization of the buccopharyngeal cavity and the esophagus revealed that they are lined by a stratified epithelium where the mucosa is thrown into longitudinal folds. The stomach is lined with a simple columnar secretory epithelium with tubular glands. GCs were analyzed using a range of histochemical methods. They were identified as oxidizable vicinal diols; sialic acids and some of their chain variants, C7, C8 or C9; sialic acid residues with O-acyl substitution at C8 or C9; carboxyl groups and sulfate groups. Sugar residues in the oligosaccharide side chains of the GCs were investigated using seven biotinylated lectins. Mucous cells from the contents of the buccopharyngeal cavity, esophagus and stomach evidenced neutral, sulphated and sialylated GCs. The latter were substituted mainly in C8. A moderately strong lectin labeling was observed in mucous cells of the three organs studied. Nonetheless, the apical edge of the gastric gland cells showed a strong positive labeling. The presence of different classes of GCs has been associated with different functions, such as lubrication, protection, inhibition of microorganisms proliferation and ionic regulation.


Pulmonary vein isolation guided by moderate ablation index targets combined with strict procedural endpoints for patients with paroxysmal atrial fibrillation.
Ablation index (AI)-guided radiofrequency ablation has been increasingly used for the treatment of drug-resistant paroxysmal atrial fibrillation (AF),but the optimal AI targets remain to be determined. We aimed to examine the efficacy and safety of catheter ablation guided by moderate AI values but more strict procedural endpoints in patients with paroxysmal AF. We conducted a retrospective review of a consecutive series of patients who received their first AI-guided ablation for paroxysmal AF from 2017 to 2018. The standard procedural protocol recommends AI targets as follows: anterior: 400-450; posterior: 280-330; and roof/inferior wall: 380-430. After circumferential pulmonary vein isolation (PVI), we performed bipolar pacing along the ablation line, adenosine triphosphate (ATP)-provocation, and waited for 30 min to verify PVI. The primary clinical outcome was the rate of freedom from AF recurrence at 12 months. A total of 140 consecutive patients were included. The mean procedure and ablation times were 132.2 ± 30.2 min and 24.2 ± 7.9 min, respectively. The first-pass isolation and final isolation rates were documented in 49.3% and in 100% of the patients, respectively. At 12 months, single-procedure freedom from atrial tachyarrhythmias was observed in 92.1% of patients. No major procedure-related complications were encountered. Moderate AI-guided catheter ablation is highly effective for the treatment of drug-refractory paroxysmal AF in real-world settings. Over 90% of patients achieved single-procedure arrhythmia-free survival at 1 year. The outcome was obtained without major complications and the procedure involved relatively short procedure and ablation times.


The cavity in the hydrophobic core of Myb DNA-binding domain is reserved for DNA recognition and trans-activation.
The DNA-binding domain of Myb consists of three imperfect repeats, R1, R2 and R3, each containing a helix-turn-helix motif variation. Among these repeats, R2 has distinct characteristics with high thermal instability. The NMR structure analysis found a cavity inside the hydrophobic core of R2 but not in R1 or R3. Here, we show that R2 has slow conformational fluctuations, and that a cavity-filling mutation which stabilizes the R2 structure significantly reduces specific Myb DNA-binding activity and trans-activation. Structural observations of the free and DNA-complexed stages suggest that the implied inherent conformational flexibility of R2, associated with the presence of the cavity, could be important for DNA recognition by Myb.


Long non-coding RNA CRNDE suppressing cell proliferation is regulated by DNA methylation in chronic lymphocytic leukemia.
Long non-coding RNA CRNDE and DNA methylation play a vital role in the occurrence and development of chronic lymphocytic leukemia (CLL). This study attempted to investigate the biological role of CRNDE methylation in CLL. The expression and methylation levels of CRNDE in CLL cell lines (MEC-1 and HG3) before or after methylation inhibitor (5-Aza-2'-deoxycytidine, 5-Aza-CdR) treatment was detected by quantitative real-time PCR or methylation-Specific PCR. The relationship among CRNDE, miR-28 and NDRG2 was verified by luciferase reporter assay. The effect of CRNDE overexpression and 5-Aza-CdR treatment on cell proliferation and apoptosis of MEC-1 and HG3 cells were assessed by CCK8 and flow cytomery. Compared with normal B lymphocytes, CRNDE was down-regulated and the methylation level of CRNDE was increased in MEC-1 and HG3 cells. Then, 5-Aza-CdR treatment caused an increase of CRNDE expression in MEC-1 and HG3 cells by demethylation. The overexpression or demethylation of CRNDE inhibited cell proliferation and promoted apoptosis in MEC-1 and HG3 cells by up-regulating CRNDE expression. Moreover, CRNDE functioned as a competing endogenous RNA to repress miR-28, which controlled its down-stream target NDRG2. CRNDE overexpression inhibited cell proliferation and promoted apoptosis via miR-28/NDRG2 axis in CLL. In conclusion, our data elaborated that CRNDE expression was regulated by DNA methylation, and the protective effect of CRNDE on CLL was attributed to the inhibition of proliferation in CLL via miR-28/NDRG2 axis. Thus, this work highlights a novel competing endogenous RNA circuitry involving key regulators of CLL.


Comparison of antibody-dependent cellular cytotoxicity and complement-dependent antibody lysis of herpes simplex virus-infected cells as methods of detecting antiviral antibodies in human sera.
An antibody-dependent cellular cytotoxicity (ADCC) assay was used to detect antibodies to the herpes simplex viruses in humans sera. The assay utilized the release of 51Cr from BHK-21 cells infected with the viruses, hamster peritoneal exudate cells as effector cells, and antiviral antibodies in human sera. The technique was found to be far more sensitive than complement-dependent antibody lysis of infected cells and virus neutralization. The ADCC assay was useful in detecting antibodies in sera that had low titers or no antibodies detectable by other methods. In a sample of 100 sera from university students, 40 were positive by complement-dependent lysis whereas 73 were positive by ADCC. Of 400 sera from women with cervical cancer, 17 did not have detectable antibodies by microneutralization or complement-dependent lysis; however, all sera were positive by ADCC, suggesting that all of the women had been infected in the past with one or both types of herpes simplex virus.


Conformational equilibrium defines the variable induction of the multidrug-binding transcriptional repressor QacR.
QacR, a multidrug-binding transcriptional repressor in pathogenic bacteria Staphylococcus aureus, modulates the transcriptional level of the multidrug transporter gene, qacA, in response to engaging a set of diverse ligands. However, the structural basis that defines the variable induction level remains unknown. Here, we reveal that the conformational equilibrium between the repressive and inducive conformations in QacR defines the induction level of the transporter gene. In addition, the unligated QacR is already partly populated in the inducive conformation, allowing the basal expression of the transporter. We also showed that, in the known constitutively active QacR mutants, the equilibrium is shifted more toward the inducive conformation, even in the unligated state. These results highlight the unexpected structural mechanism, connecting the promiscuous multidrug binding to the variable transcriptional regulation of QacR, which provide clues to dysfunctioning of the multidrug resistance systems.


Photocatalytic CO2 Reductions Catalyzed by meso-(1,10-Phenanthrolin-2-yl)-Porphyrins Having a Rhenium(I) Tricarbonyl Complex.
We have prepared Zn and free-base porphyrins appended with a fac-Re(phen)(CO)3 Br (where phen is 1,10-phenanthroline) at the meso position of the porphyrin, and performed photocatalytic CO2 reduction using porphyrin-Re dyads in the presence of either triethylamine (TEA) or 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole (BIH) as an electron donor. The Zn porphyrin dyad showed a high turnover number for CO production compared with the free-base porphyrin dyad, suggesting that the central Zn ion of porphyrin plays an important role in suppressing electron accumulation on the porphyrin part and achieving high durability of the photocatalytic CO2 reduction using both TEA and BIH. The effect of acids on the CO2 reduction was investigated using the Zn porphyrin-Re dyad and BIH. Acetic acid, a relatively strong Brønsted acid, rapidly causes the porphyrin's color to fade upon irradiation and dramatically decreases CO production, whereas proper weak Brønsted acids such as 2,2,2-trifluoroethanol and phenol enhance the CO2 reduction.


Assessment of activation of the plasma kallikrein-kinin system in frontal and temporal cortex in Alzheimer's disease and vascular dementia.
Decreased cerebral blood flow and blood-brain barrier disruption are features of Alzheimer's disease (AD). The plasma kallikrein-kinin system modulates cerebrovascular tone through release of vasoactive bradykinin (BK). Cerebroventricular infusion of Aβ1-40 enhances BK release, suggesting that the activity of this system may be elevated in AD. We investigated the profile of the activating protease of this system, plasma kallikrein (PK), in frontal and temporal brain tissue from postmortem confirmed cases of AD, vascular dementia (VaD), and controls. Measurements of neuron specific enolase messenger ribonucleic acid (mRNA) and protein were used to adjust for neuronal loss. Adjusted PK mRNA was significantly increased in the frontal cortex in AD, and the frontal and temporal cortex in VaD. Similar trends were seen for PK protein level in AD and VaD. PK activity was significantly increased in the frontal and temporal cortex in AD. Increased PK activity in AD is likely to contribute to increased BK release and may thereby influence cerebral blood flow and vascular permeability.


Transforming Health Experience and Action through Shifting the Narrative on Obesity in Primary Care Encounters.
We sought to understand the impact of primary care conversations about obesity on people's everyday life health experience and practices. Using a dialogic narrative perspective, we examined key moments in three very different clinical encounters, the patients' journals, and follow-up interviews over several weeks. We trace how people living with obesity negotiate narrative alternatives that are offered during clinical dialogue to transform their own narrative and experience of obesity and self. Findings provide pragmatic insights into how providers can play a significant role in shifting narratives about obesity and self and how such co-constructed narratives translate into change and tangible health outcomes in people's lives.


Bariatric/Metabolic Surgery in the Asia-Pacific Region: APMBSS 2018 Survey.
The Asia-Pacific Metabolic and Bariatric Surgery Society (APMBSS) held its congress in Tokyo at the end of March, 2018, and representatives from Asia-Pacific countries presented the current status of bariatric/metabolic surgery in the "National Reports" session. The data are summarized here to show the current status and problems in the Asia-Pacific region in 2017. A questionnaire including data of 2016 and 2017 and consisting of eight general questions was prepared and sent to representatives in 18 Asia-Pacific countries by e-mail before the congress. After the congress, the data were analyzed and summarized. Seventeen of 18 countries responded to the survey. The frequency of obesity (BMI ≥ 30) in the 4 Gulf countries was > 30%, much higher than that in the other countries. In total, 1640 surgeons and 869 institutions were engaging in bariatric/metabolic surgery. In many East and Southeast Asian countries, the indication for bariatric surgery was BMI ≥ 35 or ≥ 37, whereas in many Gulf countries and Australia, it was BMI ≥ 40 or ≥ 35 with obesity-related disease. Ten of the 17 countries (58.8%) but only one of the 5 Southeast Asian countries (20.0%) had public health insurance coverage for bariatric surgery. In 2017, 95,125 patients underwent bariatric/metabolic surgery, with sleeve gastrectomy accounting for 68.0%, bypass surgery for 19.5%, and others for 12.5%. Current problems included public insurance coverage, training system, national registry, and lack of awareness and comprehension. This summary showed that bariatric/metabolic surgery is rapidly developing along with various problems in Asia-Pacific countries.


Mitochondrial mutagenesis in Saccharomyces cerevisiae. III. Nitrous acid.
Nitrous acid (NA) induced mutations efficiently in mitDNA, conferring resistance to erythromycin and weakly induces mit- mutations. In some strains of yeast it also enhanced rho- mutations. The frequencies of nuclear and mitochondrial mutations induced with NA are compared.


Long-term functional and quality of life outcomes in laryngectomized patients after successful voice restoration using tracheoesophageal prostheses.
To assess long-term functional and quality of life (QoL) outcomes and their predictive factors in laryngectomized patients after successful voice restoration using tracheoesophageal prostheses (TEP). This cross-sectional study was conducted in alive and disease-free patients at least 1 year after total laryngectomy ± partial pharyngectomy. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Core (QLQ-C30) and Head and Neck Cancer (QLQ-H&N35) QoL questionnaires, the Voice Handicap Index (VHI-10) questionnaire and the Hospital Anxiety and Depression Scale (HADS). The level of dysphagia was evaluated using the Dysphagia Handicap Index (DHI) and the Dysphagia Outcomes and Severity Scale (DOSS). Predictive factors of these clinical outcomes were determined in univariate and multivariate analysis. A total of 48 patients were included in this study. Long-term QoL and functioning scales scores were all superior to 70%. Main persistent symptoms were fatigue, dyspnea, senses, speech and coughing problems. A DOSS score ≥6, indicating normal/subnormal swallowing function, and a VHI-10 score ≤20, representing light to medium voice disorders, were found in at least 75% of patients. An anxiodepressive disorder (HADS global score ≥ 15) was reported by 15 (31%) patients and represented the main predictor of QoL and voice outcomes. A strong correlation was found between VHI-10 and global QoL scores. After successful voice restoration, laryngectomized patients achieved satisfactory QoL and functional outcomes. Psychological distress was the main determinant of long-term QoL and is therefore of critical importance in the multidisciplinary management of laryngectomized patients.


Parents' experience of the communication process of positivity at newborn screening for metabolic diseases: A qualitative study.
The process of receiving a communication of positivity for metabolic diseases at expanded newborn screening (ENBS) is extremely articulated, involves a variety of actors (parents, maternal and child departments, clinical centres and laboratories) and is open to a variety of outcomes from false positive to true positive cases. Receiving communication of positivity can be highly stressful for parents and requires an adequate communication process to give clear and reliable information without causing excessive worry. This qualitative study describes the parents' experience of receiving a communication of positivity to metabolic diseases at ENBS, and their assessment of the quality of the communication process and steps, with the main aim to identify the process' strengths and weaknesses and to advance tailored recommendations to improve the communication process. Fourteen in-depth, semi-structured phone interviews were conducted with parents whose children resulted positive to the ENBS. As part of the ENBS communication process, parents received a first phone call communication of positivity and a second in-person communication at metabolic clinical centres (MCC). The framework analysis method was used to organize the data and identify emerging themes. Parents were largely dissatisfied with the quality and depth of the information received and with the way the healthcare staff delivered the first communication phone call, which failed to create a caring, empathic and safe setting. Many parents tried to reduce the uncertainty by searching online information or consulting with other providers. Nevertheless, the majority of parents described the in-person visit at MCC as clear, welcoming and reassuring. More efforts are needed to improve the quality of the communication process of the ENBS. Guidelines, recommendations and standard scripts to communicate positivity are needed along with programmes and educational resources to train tailored communication skills.


Diaqua-bis-(5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ato-κN,O)cobalt(II) 3.5-hydrate.
In the title complex, [Co(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)]·3.5H(2)O, the Co(II) cation is six-coordinated by two H(2)pimda(-) ligands (H(3)pimda is 2-propyl-1H-imidazole-4,5-carboxylic acid) and two water mol-ecules in a distorted octa-hedral environment. The crystal structures features a three-dimensional network stabilized by extensive O-H⋯O and N-H⋯O hydrogen bonds. The propyl groups of the ligands are disordered over two sets of sites with refined occupancies of 0.673 (8):0.327 (8) and 0.621 (17):0.379 (17). One of the water mol-ecules is located on a site with half-occupancy.


Lysosomal phosphatidylcholine: bis(monoacylglycero)phosphate acyltransferase: specificity for the sn-1 fatty acid of the donor and co-purification with phospholipase A1.
Positional specificities in donor and acceptor phospholipids of the lysosomal phosphatidylcholine: bis(monoacylglycero)phosphate acyltransferase have been determined. Comparison of the transfer of labelled fatty acid from sn-1 [14C]acyl and sn-2 [14C]acylphosphatidylcholines by extracts of rat liver lysosomes revealed that fatty acids in the sn-1 position were exclusively transferred. Degradation of the acylphosphatidylglycerol product by Rhizopus arrhizus lipase, highly specific for fatty acids esterified to sn-1 or sn-3 positions, indicated that sn-1 or sn-3 rather than sn-2 positions had been acylated. Assays of phospholipase A1, phosphatidylcholine: bis(monoacylglycero)phosphate acyltransferase, the conversion of lysophosphatidylglycerol to bis(monoacylglycero)phosphate and phospholipase A2 were performed at various steps in the purification of lysosomal phospholipase A1. After the penultimate step of chromatofocusing, there was a 1086-fold increase of phospholipase A1 specific activity over the homogenate and this was accompanied by a 11 998-fold increase of phosphatidylcholine: bis(monoacylglycero)phosphate acyltransferase specific activity. A second preparation carried through to the final step of gel-filtration retained a similar ratio of acyltransferase activity. On the other hand, specific activities of phospholipase A2 and of the conversion of lysophosphatidylglycerol to bis(monoacylglycero)phosphate increased to the step where enzyme was solubilized from lysosomes, but were lost from later steps. These findings suggest that phosphatidylcholine: bis(monoacylglycero)phosphate acyltransferase is catalyzed by lysosomal phospholipase A1. The site of acylation in the bis(monoacylglycero)phosphate acceptor appears to be either sn-1 or sn-3. Since the lysosomal extracts did not catalyze the transacylation of phosphatidylglycerol, we conclude that the formation of acylphosphatidylglycerol in lysosomes requires the sequential acylation of lysophosphatidylglycerol to form bis(monoacylglycero)phosphate by an unidentified enzymatic mechanism followed by a transacylation of bis(monoacylglycero)phosphate in either sn-1 or sn-3 position to form acylphosphatidylglycerol which is catalyzed by phospholipase A1.


Shifting to structures in physics and biology: a prophylactic for promiscuous realism.
Within the philosophy of science, the realism debate has been revitalised by the development of forms of structural realism. These urge a shift in focus from the object oriented ontologies that come and go through the history of science to the structures that remain through theory change. Such views have typically been elaborated in the context of theories of physics and are motivated by, first of all, the presence within such theories of mathematical equations that allow straightforward representation of the relevant structures; and secondly, the implications of such theories for the individuality and identity of putative objects. My aim in this paper is to explore the possibility of extending such views to biological theories. An obvious concern is that within the context of the latter it is typically insisted that we cannot find the kinds of highly mathematised structures that structural realism can point to in physics. I shall indicate how the model-theoretic approach to theories might help allay such concerns. Furthermore, issues of identity and individuality also arise within biology. Thus Dupré has recently noted that there exists a 'General Problem of Biological Individuality' which relates to the issue of how one divides 'massively integrated and interconnected' systems into discrete components. In response Dupré advocates a form of 'Promiscuous Realism' that holds, for example, that there is no unique way of dividing the phylogenetic tree into kinds. Instead I shall urge serious consideration of those aspects of the work of Dupré and others that lean towards a structuralist interpretation. By doing so I hope to suggest possible ways in which a structuralist stance might be extended to biology.


Airway nerves: in vitro electrophysiology.
Recording the activity of single airway sensory fibres or neuronal cell bodies in vitro has allowed detailed characterisation of fibre types and membrane properties. Fibre types can be identified by their conduction velocities and further studied by the application of drugs to their receptive field. C-fibres are sensitive to mechanical stimuli and a range of irritant chemicals (bradykinin, capsaicin, low pH, platelet-activating factor), whereas Adelta-fibres are relatively insensitive to chemical stimuli and appear to correlate to the rapidly adapting receptors identified in airways in vivo. Their site of origin also differs: upper airway C-fibres arise predominantly from the jugular ganglion and Adelta-fibres from the jugular and nodose ganglia. Intracellular recording from cell bodies in the ganglia has revealed a calcium-dependent potassium current common to many putative C-fibre cell bodies. This slow after hyperpolarisation current may be inhibited by stimuli that excite and sensitise C-fibres - this could be an important mechanism underlying the sensitisation of C-fibres in airway irritability.


A novel role of alkaline phosphatase in the ERK1/2 dephosphorylation in renal cell carcinoma cell lines: a new plausible therapeutic target.
Extracellular regulated kinase 1/2 (ERK1/2) has been shown to be activated in renal cell carcinoma (RCC). Previously, we have reported aberrant expression/activity of Liver/Bone/Kidney alkaline phosphatase (L/B/K ALP) in RCC. The present study was conducted to find out whether L/B/K ALP has any role in the dephosphorylation of ERK1/2 in renal cancer cell lines. Two renal cancer cell lines viz. ACHN and A498 were transfected with full length L/B/K ALP cDNA. ALP expression/activity and ERK1/2 phosphorylation were evaluated. Increased L/B/K ALP expression/activity was associated with significantly reduced (P = 0.001) phosphorylation status of ERK1/2 in ALP cDNA transfected cells in comparison to that of control. This is the first study that suggests deactivation of ERK1/2 by stimulation of ALP in renal cancer cell lines which can be used as a therapeutic target of RCC.


Netrin-4 activates endothelial integrin {alpha}6{beta}1.
Netrin-4 regulates vascular development. Identity of netrin-4 endothelial receptor and its subsequent cell functions is controversial. We previously demonstrated that the inhibition of netrin-1 canonical receptors, Unc5B and neogenin, expressed by lymphatic endothelial cells, do not suppress netrin-4-induced cell signaling and functions. Netrin family members were shown to signal through a range of receptors, including integrins (such as α3β1, α6β1, and α6β4) in nonendothelial cells. We tested whether integrins are netrin-4 receptors in the endothelium. The α6β1 integrin is expressed by endothelial cells, and binds netrin-4 in a dose-dependent manner. Inhibition of α6 or β1 integrin subunits suppresses netrin-4-induced endothelial cell migration, adhesion, and focal adhesion contact. Netrin-4-stimulated phosphorylation of Src kinase family, effectors of endothelial cell migration, is also abolished by α6 or β1 inhibition. Finally, netrin-4 and α6β1 integrin expression colocalize in mouse embryonic, intestine, and tumor vasculature. The α6β1 integrin is a netrin-4 receptor in lymphatic endothelium and consequently represents a potential target to inhibit netrin-4-induced metastatic dissemination.


A national assessment of legacy versus new generation Medicaid data.
To compare the performance of Medicaid legacy, Medicaid new generation, and Medicare claims on data analytic tasks. Medicaid Analytic eXtract (MAX) claims (legacy) of 100% beneficiaries in 2011 (all states except Idaho), 2012 (all states), 2013 (28 states), and 2014 (17 states); 2016 Transformed Medicaid Statistical Information System Analytic Files (TAF) claims (new generation) of 100% beneficiaries from all states; Medicare claims of 20% beneficiaries in 2011-2014, 2016. We focused on the chain of events that starts with an out-of-hospital medical emergency and ends with hospital death or survival to discharge. We developed six data quality indicators to assess ambulance variables; linkage between claims; external cause of injury code reporting; and death reporting on hospital discharge status codes. For the latter, we estimated injury severity and modeled its association with death in the Medicare population. We used the model to compare reported versus expected deaths by injury severity in the Medicaid population. Datasets were compared by state and fee-for-service versus managed care. Medicare and Medicaid beneficiaries with emergency ambulance transports. Medicare claims had high performance across indicators and states; MAX claims substantially underperformed on multiple indicators in most states. For example, most states reported external cause codes for over 90% of Medicare but less than 15% of Medicaid injury cases. Medicaid fee-for-service did not consistently perform better than Medicaid managed care. Compared with MAX, TAF claims performed significantly better on some indicators but continued to have poor external cause code reporting. Finally, MAX and TAF managed care records reported deaths at discharge in the range of expected deaths; however, fee-for-service claims might have underreported high-severity injury deaths. New generation Medicaid claims performed better than legacy claims on some indicators, but much more improvement is needed to allow high-quality policy analysis.


The effects of diabetes self-management interventions on physiological outcomes in people living with diabetes in Africa: A systematic review and meta-analysis.
To examine the effects of diabetes self-management interventions on physiological outcomes among people living with diabetes in Africa compared with patients receiving usual care. Relevant databases including PubMed, CINAHL Complete, Scopus, the Cochrane Library and Google Scholar were searched from inception to 28 September 2019, for randomised controlled trials (RCTs) involving adults living with diabetes in Africa. Nine RCTs were included in the review, and the quality of the studies was assessed using Cochrane's collaboration risk of bias tools. A meta-analysis of the outcomes showed the significant effects of diabetes self-management interventions on blood pressure, total cholesterol and body mass index, whereas non-significant and inconclusive results were obtained for waist circumference and glycosylated haemoglobin, respectively. The diabetes self-management interventions (DSM) effectively improved many physiological outcomes, but their effectiveness in HbA1c was inconclusive, suggesting a need for modifications in DSM interventions for African people living with diabetes.


Monitoring of degradation of porous silicon photonic crystals using digital photography.
We report the monitoring of porous silicon (pSi) degradation in aqueous solutions using a consumer-grade digital camera. To facilitate optical monitoring, the pSi samples were prepared as one-dimensional photonic crystals (rugate filters) by electrochemical etching of highly doped p-type Si wafers using a periodic etch waveform. Two pSi formulations, representing chemistries relevant for self-reporting drug delivery applications, were tested: freshly etched pSi (fpSi) and fpSi coated with the biodegradable polymer chitosan (pSi-ch). Accelerated degradation of the samples in an ethanol-containing pH 10 aqueous basic buffer was monitored in situ by digital imaging with a consumer-grade digital camera with simultaneous optical reflectance spectrophotometric point measurements. As the nanostructured porous silicon matrix dissolved, a hypsochromic shift in the wavelength of the rugate reflectance peak resulted in visible color changes from red to green. While the H coordinate in the hue, saturation, and value (HSV) color space calculated using the as-acquired photographs was a good monitor of degradation at short times (t < 100 min), it was not a useful monitor of sample degradation at longer times since it was influenced by reflections of the broad spectral output of the lamp as well as from the narrow rugate reflectance band. A monotonic relationship was observed between the wavelength of the rugate reflectance peak and an H parameter value calculated from the average red-green-blue (RGB) values of each image by first independently normalizing each channel (R, G, and B) using their maximum and minimum value over the time course of the degradation process. Spectrophotometric measurements and digital image analysis using this H parameter gave consistent relative stabilities of the samples as fpSi > pSi-ch.


Steroid hormones in the aquatic environment.
Steroid hormones are extremely important natural hormones in all vertebrates. They control a wide range of physiological processes, including osmoregulation, sexual maturity, reproduction and stress responses. In addition, many synthetic steroid hormones are in widespread and general use, both as human and veterinary pharmaceuticals. Recent advances in environmental analytical chemistry have enabled concentrations of steroid hormones in rivers to be determined. Many different steroid hormones, both natural and synthetic, including transformation products, have been identified and quantified, demonstrating that they are widespread aquatic contaminants. Laboratory ecotoxicology experiments, mainly conducted with fish, but also amphibians, have shown that some steroid hormones, both natural and synthetic, can adversely affect reproduction when present in the water at extremely low concentrations: even sub-ng/L. Recent research has demonstrated that mixtures of different steroid hormones can inhibit reproduction even when each individual hormone is present at a concentration below which it would not invoke a measurable effect on its own. Limited field studies have supported the conclusions of the laboratory studies that steroid hormones may be environmental pollutants of significant concern. Further research is required to identify the main sources of steroid hormones entering the aquatic environment, better describe the complex mixtures of steroid hormones now known to be ubiquitously present, and determine the impacts of environmentally-realistic mixtures of steroid hormones on aquatic vertebrates, especially fish. Only once that research is completed can a robust aquatic risk assessment of steroid hormones be concluded.


Enhanced expression of tubulin-specific chaperone protein A, mitochondrial ribosomal protein S27, and the DNA excision repair protein XPACCH in the song system of juvenile male zebra finches.
Recent evidence suggests that sexual dimorphisms in the zebra finch song system and behavior arise due to factors intrinsic to the brain, rather than being solely organized by circulating steroid hormones. The present study examined expression of 10 sex chromosome genes in the song system of 25-day-old zebra finches in an attempt to further elucidate these factors. Increased expression in males was confirmed for nine of the genes by real-time qPCR using cDNA from individual whole telecephalons. In situ hybridization at the same age revealed specific, male-enhanced mRNA for three of the nine genes in one or more song control nuclei. These genes encode tubulin-specific chaperone A, mitochondrial ribosomal protein S27, and a DNA repair protein XPACCH. Based on what is currently known about these proteins' functions and their localization to particular components of the song circuit, we hypothesize that they each may be involved in specific aspects of masculinization.


Osteopontin regulates the proliferation of rat aortic smooth muscle cells in response to gingipains treatment.
The present study aimed to explore the possible effects of osteopontin (OPN) in the proliferation of rat aortic smooth muscle cells (RASMCs) stimulated by gingipains. The proliferation of RASMCs in response to active gingipains treatment was evaluated by CCK-8 assay. OPN siRNA was designed, constructed and transfected into RASMCs at different concentrations. The cell cycle of RASMCs was analyzed by flow cytometry. OPN, α-SMA and calponin expression were examined by real-time PCR and western blot analysis. Gingipains promoted the proliferation of RASMCs and OPN expression. With siRNA-mediated OPN expression knockdown, the cell cycle of RASMCs was blocked in the G0/G1 phase. Furthermore, the expression of specific differentiation markers, α-SMA and calponin, also decreased. These results demonstrate that OPN has an impact on the proliferation and differentiation of RASMCs stimulated by gingipains.


Early Postoperative Pain After Total Knee Arthroplasty Is Associated With Subsequent Poorer Functional Outcomes and Lower Satisfaction.
There are few studies investigating the effects of acute postoperative pain on functional outcomes after total knee arthroplasty (TKA). The aims of this study are to identify perioperative factors associated with increased early postoperative pain and investigate the effects of acute postoperative day 1 and 2 pain on outcomes at 6 months and 2 years post-TKA. 1041 unilateral TKA patients were included in this retrospective cohort study. Patients were categorized into minor (visual analog scale: VAS <5) and major (VAS ≥5) pain groups based on postoperative day 1/2 VAS scores. Patients were assessed preoperatively, at 6 months and 2 years using Knee Society Knee Score and Function Scores (KSFS), Oxford Knee Score (OKS), SF-36 physical and mental component score (SF-36 PCS), expectation and satisfaction scores. Perioperative variables including age, gender, race, body mass index, American Society of Anesthesiologist status, type of anesthesia, and presence of caregiver were analyzed as predictors of postoperative acute pain. Wilcoxon two-sample test was used to analyze outcomes significantly associated with "major pain." Multiple logistic regression was used to identify predictors of "major pain." Patients with "minor pain" had significantly better KSFS, Knee Society Knee Score, OKS, and SF-36 PCS scores at 6 months and significantly better KSFS, OKS, SF-36 PCS, and satisfaction at 2 years (P < .05). A significantly higher percentage of patients with "minor pain" met the minimal clinically important difference for SF-36 PCS at 6 months and KSFS at 2 years (P < .05). Women, Indian/Malay race, higher BMI, and use of general over regional anesthesia were independent predictors of getting "major pain" (P < .05). Patients should be counseled about risk factors of postoperative pain to manage preoperative expectations of surgery. Patients should be managed adequately using multimodal pain protocols to improve subsequent functional outcomes while avoiding unnecessary opioid use.


The actions of polynucleotides on effector stage cloned murine T-helper cells differ in each subset and depend on antigen concentration.
Polynucleotides enhance T-helper (Th) cell-mediated humoral immune responses in naive resting Th cells, B cells, and antigen-presenting cells (APC) from unprimed mouse spleen. If polynucleotides augment Th cell functions independent of the activation stage of Th cells, then polynucleotides may cause hyperimmune responses. In this study we examined the effects of polynucleotides on effector-stage murine Th cell clones in vitro. The A.E7 clone (primed with pigeon cytochrome C, origin: B10.A mice) and CDC35 clone (primed with rabbit gamma-globulin, origin: DBA/2 mice) were used as representative type 1 (Th1) and type 2 (Th2) Th cells, respectively. Th clones were stimulated with antigen (Ag) in polynucleotide-supplemented or control cultures in the presence of syngeneic spleen cells (either CD4- or irradiated). The number of antibody (Ab)-secreting cells was counted to measure T-dependent Ab production. Production of interferon-gamma (IFNgamma) for the Th1 clone and interleukin-5 (IL-5) for the Th2 clone were measured. Without Ag stimulation, cytokine production and the number of Ab-secreting cells formed were very low and not altered by polynucleotides. With suboptimal Ag challenges provided by Ag-primed spleen cells, polynucleotides enhanced IFNgamma production by the Th1 clone, while they suppressed Th1 clone-mediated Ab production and IL-5 production by the Th2 clone. Polynucleotides did not alter Th2 clone-mediated Ab production. These actions of polynucleotides appeared to be dose-dependent. With optimal Ag challenges, polynucleotides did not affect our measures of Th cell activation. Polynucleotide action in vitro on effector-stage Th cell clones differed in each Th cell subset and depended on Ag concentration.


Imaging the Influence of Red Blood Cell Docosahexaenoic Acid Status on the Expression of the 18 kDa Translocator Protein in the Brain: A [11C]PBR28 Positron Emission Tomography Study in Young Healthy Men.
Docosahexaenoic acid (DHA) shows anti-inflammatory/proresolution effects in the brain. Higher red blood cell (RBC) DHA in humans is associated with improved cognitive performance and a lower risk for suicide. Here, we hypothesized that binding to the 18 kDa translocator protein (TSPO), a proxy for microglia levels, will be higher in individuals with low DHA relative to high DHA levels. We also postulated that higher TSPO would predict poor cognitive performance and impaired stress resilience. RBC DHA screening was performed in 320 healthy males. [11C]PBR28 positron emission tomography was used to measure binding to TSPO in 38 and 32 males in the lowest and highest RBC DHA quartiles. Volumes of distribution expressed relative to total plasma ligand concentration (VT) was derived using an arterial input function-based kinetic analysis in 14 brain regions. [11C]PBR28 VT was significantly lower (by 12% and 20% in C/T and C/C rs6971 genotypes) in males with low RBC DHA than in males with high RBC DHA. Regional VT was correlated positively and negatively with RBC DHA and serum triglycerides, respectively. No relationships between VT and cognitive performance or stress resilience measures were present. Contrary to our hypothesis, we found lower TSPO binding in low-DHA than in high-DHA subjects. It is unclear as to whether low TSPO binding reflects differences in microglia levels and/or triglyceride metabolism in this study. Future studies with specific targets are necessary to confirm the effect of DHA on microglia. These results underscore the need to consider lipid parameters as a factor when interpreting TSPO positron emission tomography clinical findings.


Help yourself by helping others: self-interest in appeals for Russian famine relief, 1921-23.
The hypothesis of psychological egoism is a commonplace in disciplines like economics, psychology, and biology. As an explanatory model it includes prosocial behaviour such as providing aid for distant strangers. But the inclusion of self-interest in humanitarian appeals can prove difficult because the moral economy of charitable work is regulated by different standards than the liberal market economy. This paper analyses the use of self-interest in appeals for humanitarian aid during the Russian famine of 1921-23 through the lens of modern philanthropic studies, while simultaneously assessing theories of philanthropic behaviour from a historical perspective. It points out the need for the systematic inclusion of historical experience in philanthropic research and concludes that the specific conditions surrounding the international campaign favoured the widespread use of appeals to donors' self-interest. An ideal-typical categorisation of such appeals into four groups-national, economic, group-specific, and psychological-is proposed as an analytical tool for similar studies.


FNAIT pathogenesis determined by serial analysis of three subsequent pregnancies of a woman with severe fetal and neonatal alloimmune thrombocytopenia (FNAIT) with anti-HPA-4b and anti-HPA-5b alloantibodies in the first sibling.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by anti-HPA alloantibody, and anti-HPA-4b is the most common cause in Japanese. Anti-HPA-5b is frequently detected in pregnant women, but it is still controversial whether anti-HPA-5b causes severe FNAIT. A Japanese woman with anti-HPA-4b and anti-HPA-5b alloantibodies delivered a baby with severe FNAIT who was both HPA-4b and HPA-5b incompatible. We carefully monitored the patient's following three pregnancies (the second and the fourth siblings were HPA-4b incompatible and HPA-5b compatible; the third sibling was both HPA-4b and HPA-5b compatible). FNAIT was not observed in all three siblings, although a modest decrease in cord blood platelet count was observed in the HPA-4b incompatible siblings compared to the HPA-4b compatible sibling. Serial monitoring of anti-HPA titer showed that anti-HPA-4b markedly decreased in late pregnancy and recovered after delivery of the HPA-4b incompatible siblings, but these decreases were not observed during the mother's pregnancy with the HPA-4b compatible sibling. In contrast, anti-HPA-5b remained at a high titer during pregnancy with all three siblings. Our data indicate that dynamic changes of anti-HPA-4b occur during pregnancy and strongly suggest that anti-HPA-5b was mainly responsible for severe FNAIT in this case.


Motor versus somatosensory evoked potential changes after acute experimental spinal cord injury in rats.
In this study, averaged cortical somatosensory evoked potentials (SEP) after sciatic nerve stimulation, and lower extremity muscle responses after motor cortex stimulation (MEP) were compared in rats. 10 animals served as light (25 g-cm) and 10 animals as severe (80 g-cm) acute spinal cord injury group after weight dropping trauma. After the initial loss of components, both SEP and MEP recovered in most cases in the light injury group. In the severe injury group, however, no recovery was observed in cortical SEPs, while the muscle MEP recovered in some animals. Light spinal cord injury had little effect on muscle MEPs and caused a paradoxical amplitude increase in some MEP recordings. Latency values of muscle MEPs did not show great changes after either kind of injury, while cortical SEP latency was considerably delayed. In this model cortical SEPs were more sensitive to light spinal cord injury than muscle MEPs after single electrical cortical stimuli. Severe spinal cord injury caused amplitude changes or loss of waves from both SEP and MEP.


Spectroscopic studies on covalent functionalization of single-walled carbon nanotubes with glycine.
Single-walled carbon nanotubes (SWCNTs) have a great potential in a wide range of applications, but faces limitation in terms of dispersion feasibility. The functionalization process of SWCNTs with the amino acid, glycine involves oxidation reaction using a mild aqueous acid mixture of HNO3 and H2SO4 (1:3), via ultrasonication technique and the resulted oxidized SWCNTs were again treated with the amino acid glycine suspension. The resulted glycine functionalized carbon nanotubes have been characterized by XRD, UV-Vis, FTIR, EPR, SEM, and EDX, spectroscopic techniques. The enhanced XRD peak (002) intensity was observed for glycine functionalized SWCNTs compared with oxidized SWCNTs, which is likely due to sample purification by acid washing. The red shift was observed in the UV-Vis spectra of glycine functionalized SWCNTs, which reveals that the covalent bond formation between glycine molecule and SWCNTs. The functional groups of oxidized SWCNTs and glycine functionalized SWCNTs were identified and assigned. EPR results indicate that the unpaired electron undergoes reduction process in glycine functionalized SWCNTs. SEM images show that the increase in the diameter of the SWCNTs was observed for glycine functionalized SWCNTs, which indicates that the adsorption of glycine molecule on the sidewalls of oxidized SWCNTs. EDX elemental micro analysis confirms that the nitrogen element exists in glycine functionalized SWCNTs. The functionalization has been chosen due to CONH bioactive sites in glycine functionalized SWCNTs for future applications.


Introduction to Organizational Psycholinguistics.
The paper introduces organizational psycholinguistics as an approach to professional communication i.e., the communication in organizations. The author systematizes a number of theories and concepts as a methodological basis of organizational psycholinguistics. The organizational psycholinguistics methodology is based on Theory of Speech Activity. Organizational psycholinguistics analyzes the communication aimed at a joint activity organization. At the same time, speech activity itself is an activity towards an independent goal to modify a partner's psychic state to involve him/her in a joint activity. The article describes goals, objects, subjects, tasks of the organizational psycholinguistics. The author indicates the methods used in the organizational psycholinguistic research and outlines prospects for further research in this field.


Effect of gene location on the evolutionary rate of amino acid substitutions in herpes simplex virus proteins.
In an effort to understand the organization of genes in the herpes simplex virus (HSV-1) genome, I tested the idea that the location of a gene may be related to the evolutionary rate of amino acid sequence variation in the encoded protein. A measure of protein sequence divergence was calculated for homologous proteins in the UL region of six alphaherpesviruses including HSV-1, and this parameter was plotted against position in the HSV-1 genome. The results revealed a cluster of highly conserved proteins (UL27-UL33) encoded near the middle of UL. A similar analysis was restricted to HSV-1 and HSV-2 permitting an examination of U(S) proteins and proteins encoded in repeated regions at the segment ends. This analysis showed that U(S) proteins as a group are more highly divergent than those encoded in UL. A high degree of divergence was also observed in proteins coded at the segment ends including RL1 (gamma(1)34.5), RL2 (alpha0), UL1 (glycoprotein L), UL56, U(S)1, and U(S)12. It is suggested that conserved proteins UL27-UL33 are encoded near the middle of UL to take advantage of a low local mutation rate. Highly divergent proteins are suggested to be encoded selectively in U(S) because of a comparatively rapid evolutionary rate with which genes can be introduced and removed from S in response to environmental variation.


Enhancement of Methylene Blue Photodegradation Rate Using Laser Synthesized Ag-Doped ZnO Nanoparticles.
In this work, Ag-doped ZnO nanoparticles are obtained via pulsed laser ablation of the Ag-coated ZnO target in water. The ratio of Ag dopant in ZnO nanoparticles strongly depends on the thickness of the Ag layer at the ZnO target. Synthesized nanoparticles were characterized by XRD, XPS, SEM, EDS, ICP-OES, and UV-VIS spectrophotometry to obtain their crystal structure, elemental composition, morphology and size distribution, mass concentration, and optical properties, respectively. The photocatalytic studies showed photodegradation of methylene blue (MB) under UV irradiation. Different ratios of Ag dopant in ZnO nanoparticles influence the photodegradation rate. The ZnO nanoparticles doped with 0.32% silver show the most efficient photodegradation rate, with the chemical reaction constant of 0.0233 min-1. It exhibits an almost twice as large photodegradation rate compared to pure ZnO nanoparticles, showing the doping effect on the photocatalytic activity.


Comparison of hypoxanthine, lactate, and ECG signs as indicators of hypoxia.
High altitude-induced hypoxemia in 26 young adults was used to compared hypoxia parameters such as blood lactate, hypoxia-induced electrocardiogram signs, and the recently proposed plasma hypoxanthine concentration. At a PaO2 of 30 mm Hg, no elevation in hypoxanthine and small increase in lactate was observed. Minimal leg exercise was added to further increase hypoxic during hypoxemia. A significant increase in lactate and considerable ST-T depression in electrocardiogram indicated hypoxia, but no change in plasma hypoxanthine was found. Work-dependent hyperventilation as a main cause of lactate elevation was excluded. Blockade of hypoxanthine breakdown by allopurinol in vivo increased plasma hypoxanthine levels, but hypoxemia with or without leg exercise failed to consistently increase this level further. Elevations of blood lactate above the normal range were found at a PaO2 of 30 mm Hg and below.