Histopathological and Serological Analysis of Aborted Ewes and Neonatal Death with Toxoplasma gondii in Duhok City, Kurdistan-Iraq.
This study was carried out on seven flocks of ewes suffered from late abortion and neonatal mortality with the prevalence rate of infection reported as 13.95%. The blood and tissue samples were collected from the aborted ewes in several flocks of Duhok province, Kurdistan Region, Iraq. Serological analysis indicated that all the aborted ewes were confirmed positive for agglutination to Toxoplasma gondii (T. gondii)antibody. The investigation of the aborted fetuses showed the blood-stained fluid in the thoracic and abdominal cavity. Most of the aborted fetuses had also enlarged, congested, and friable livers and lungs. The placenta was swollen, reddish, and friable, and its cotyledons also spotted with whitish foci. T. gondii tachyzoites were also demonstrated in the placental sections of some aborted ewes. Severe congestion, necrosis, and infiltration of multinucleated cells were the most predominant histopathological changes of the aborted fetuses, as well as presented tissue cysts, tachyzoites, and bradyzoites in the liver, brain, heart, and lung. There were also several clusters of dark purple banana-shaped T. gondii tachyzoites within the brain and heart tissues in most of the examined aborted fetuses in different flocks. T. gondii tachyzoites were also detected from the peritoneal ascites of mice inoculated experimentally 12 days following the infection. Moreover, T. gondii tissue cysts were detected from the impression smears of the mice brains 32 days after the infection. Accordingly, the demonstration of T. gondii in Giemsa-stained impression smears associated with characteristic histopathological changes of different organs is a great fundamental method for the diagnosis of T. gondii in aborted cases.


Lack of association between the hSKCa3 channel gene CAG polymorphism and schizophrenia.
Genetic anticipation, a phenomenon characterized by increased severity of symptoms and earlier age at onset of a disease in successive generations, is believed to be present in schizophrenia. In several neurodegenerative diseases showing anticipation, the mutation causing the disease is an expanded trinucleotide repeat. Therefore, genes containing trinucleotide repeats prone to expansion have become a suitable family of candidate genes in schizophrenia. A human calcium-activated potassium channel gene (hSKCa3), possibly mapping to chromosome 22q11-13, a region previously linked to schizophrenia, was recently described. This gene contains two contiguous expressed CAG repeat stretches. Recently, long allelic variants of one of these CAG repeats were found to be overrepresented in schizophrenic patients compared to normal controls. In this study we attempted to replicate this result and to study the relationship between the length of this CAG repeat on the one hand and the severity and age at onset of the disease on the other hand. No association with the disease or correlation with the severity of schizophrenia was identified. In addition, hSKCa3 was mapped to chromosome 1. Our results do not support the involvement of this particular CAG repeat-containing gene in schizophrenia.


Pediatric obesity epidemiology.
To provide updated summary of recently published data regarding pediatric obesity epidemiology. There is a burgeoning literature of pediatric obesity epidemiology, with type 2 diabetes trends serving as the harbinger for obesity related diseases in children. The National Health and Nutrition Examination Survey and Pediatric Nutrition Surveillance System report a tripling of the prevalence of BMI at least 95% (obesity) among US school-age children and adolescents over the past three decades. Recent updates provide insight into infants and toddler obesity and explore the impact of ethnicity, socioeconomic status, school setting and geographic variations. International data confirm similar upward shifts in pediatric BMI distribution, especially in countries undergoing economic transitions favoring industrialized, western urban lifestyles. The health and financial consequences of this epidemic are a complex global public health dilemma. International efforts are underway to reverse these obesity trends. On-going analysis of obesity prevalence and exploration of potential causal associations are required to implement and assess the effectiveness of interventions and policies.


[A case of xanthogranulomatous pyelonephritis--an experience of echo-guided aspiration biopsy for the diagnosis].
Xanthogranulomatous pyelonephritis is a rare disease of the kidney. The pre-operative diagnosis of this disease is usually very difficult. Recently, echo-guided aspiration biopsy has been suggested for the differential diagnosis of the renal mass. We experienced a case of xanthogranulomatous pyelonephritis and performed echo-guided aspiration biopsy. A 57-year-old female was admitted to our hospital with complaints of upper abdominal pain and right lumbago. Judging from the findings obtained by intravenous pyelography, computed tomographic scan, ultrasonography and angiography, the lesion was a right renal inflammatory mass but renal tumor could not be denied. Because clear cell carcinoma was suspected from the results of echo-guided aspiration biopsy, right radical nephrectomy was performed. However, the resected kidney was diagnosed to be xanthogranulomatous pyelonephritis. Post-operative course was uneventful.


Transcriptional regulation of the phosphoenolpyruvate carboxykinase gene by cooperation between hepatic nuclear factors.
To study the transcriptional regulation of the liver gluconeogenic phenotype, the underdifferentiated mouse Hepa-1c1c7 (Hepa) hepatoma cell line was used. These cells mimicked the fetal liver by appreciably expressing the alpha-fetoprotein and albumin genes but not the phosphoenolpyruvate carboxykinase (PEPCK) gene. Unlike the fetal liver, however, Hepa cells failed to express the early-expressed factors hepatocyte nuclear factor 1 alpha (HNF-1 alpha) and HNF-4 and the late-expressed factor C/EBP alpha, thereby providing a suitable system for examining possible cooperation between these factors in the transcriptional regulation of the PEPCK gene. Transient transfection assays of a chimeric PEPCK-chloramphenicol acetyltransferase construct showed a residual PEPCK promoter activity in the Hepa cell line, which was slightly stimulated by cotransfection with a single transcription factor from either the C/EBP family or HNF-1 alpha but not at all affected by cotransfection of HNF-4. In contrast, cotransfection of the PEPCK construct with members from the C/EBP family plus HNF-1 alpha resulted in a synergistic stimulation of the PEPCK promoter activity. This synergistic effect depended on the presence in the PEPCK promoter region of the HNF-1 recognition sequence and on the presence of two C/EBP recognition sequences. The results demonstrate a requirement for coexistence and cooperation between early and late liver-enriched transcription factors in the transcriptional regulation of the PEPCK gene. In addition, the results suggest redundancy between members of the C/EBP family of transcription factors in the regulation of PEPCK gene expression.


Adaptation of Circadian Neuronal Network to Photoperiod in High-Latitude European Drosophilids.
The genus Drosophila contains over 2,000 species that, stemming from a common ancestor in the Old World Tropics, populate today very different environments [1, 2] (reviewed in [3]). We found significant differences in the activity pattern of Drosophila species belonging to the holarctic virilis group, i.e., D. ezoana and D. littoralis, collected in Northern Europe, compared to that of the cosmopolitan D. melanogaster, collected close to the equator. These behavioral differences might have been of adaptive significance for colonizing high-latitude habitats and hence adjust to long photoperiods. Most interestingly, the flies' locomotor activity correlates with the neurochemistry of their circadian clock network, which differs between low and high latitude for the expression pattern of the blue light photopigment cryptochrome (CRY) and the neuropeptide Pigment-dispersing factor (PDF) [4-6]. In D. melanogaster, CRY and PDF are known to modulate the timing of activity and to maintain robust rhythmicity under constant conditions [7-11]. We could partly simulate the rhythmic behavior of the high-latitude virilis group species by mimicking their CRY/PDF expression patterns in a laboratory strain of D. melanogaster. We therefore suggest that these alterations in the CRY/PDF clock neurochemistry might have allowed the virilis group species to colonize high-latitude environments.


Enhanced perchloroethene dechlorination by humic acids via increasing the dehalogenase activity of Dehalococcoides strains.
Perchloroethene (PCE) is a widely used chlorinated solvent. PCE is toxic to humans and has been identified as an environmental contaminant at thousands of sites worldwide. Several Dehalococcoides mccartyi strains can transform PCE to ethene, and thus contribute to bioremediation of contaminated sites. Humic acids (HA) are ubiquitous redox-active compounds of natural aquatic and soil systems and have been intensively studied because of their effect in electron transfer. In this study, we observed the dechlorination of PCE was accelerated by HA in mixed cultures containing Dehalococcoides strains. Anthraquinone-2,6-disulfonic acid (AQDS), a humic acid analogue, inhibited PCE dechlorination in our cultures and thus induced an opposite effect on PCE dehalogenation than HA. We observed the same effect on PCE dechlorination with the pure culture of Dehalococcoides mccartyi strain CBDB1. Not only in mixed cultures but also in pure cultures, growth of Dehalococcoides was not influenced by HA but inhibited by AQDS. Enzymatic activity tests confirmed the dehalogenating activity of strain CBDB1 was increased by HA, especially when using hydrogen as electron donor. We conclude that HA enhanced PCE dechlorination by increasing the reaction speed between hydrogen and the dehalogenase enzyme rather than acting as electron shuttle through its quinone moieties.


A randomized, double-blind, placebo-controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults.
The cognitive and mood effects of levetiracetam (LEV) in older adults are not known. This study compared the cognitive and mood effects of LEV to placebo in healthy older adults. Cognitive, mood, and balance variables were compared between LEV and placebo using a randomized, double-blind, placebo-controlled crossover study with two 5-week treatment periods. Healthy volunteers (n = 20) aged 65-80 (mean age 72.4) received either LEV or placebo in which the LEV target dose was 1,000 mg/day. Volunteers, aged 65-80, were without epilepsy to limit potentially confounding the impact of seizures and/or underlying neuropathology on outcomes. LEV was initiated at 250 mg twice a day for 2 weeks, then increased to 500 mg twice a day for 2 weeks, and then tapered to 250 mg twice a day for 1 week. This was randomized with placebo for the two treatment arms. Measures included standardized neuropsychological, mood, and balance tests yielding 32 variables. Balance was assessed using subjective report (e.g., A-B neurotoxicity scale) and objective data (e.g., Berg Balance Scale). Average LEV serum concentration was 16.9 (standard deviation [SD} 7.7). Repeated-measures analysis of variance (ANOVA) found no differences between LEV and placebo phases for 29 (90.6%) of 32 variables including no change in balance. Performance on LEV was better than placebo on a visual memory (MCG Complex Figure Recall; p = 0.007) and two attention tests (Trail Making Test, Part A, p = 0.009; Stroop Interference, p = 0.004). There was a trend for greater irritability and fatigue (POMS Anger and Fatigue) during the LEV phase (p = 0.029, p = 0.035). Effect-size changes were generally small (Cohen d < 0.5). LEV was well tolerated in this elderly population in terms of cognition, mood, and balance. When anticonvulsant medication is indicated for older adults, LEV has pharmacokinetic advantages, and these data indicate no adverse impact on cognition or balance.


Quantitative determination of saccharides in dietary glyconutritional products by anion-exchange liquid chromatography with integrated pulsed amperometric detection.
A new technique for the assay of carbohydrates is described in which separation and quantification of neutral saccharides, aminosaccharides, glycuronic acids, and disaccharides may be accomplished in less than 50 min of total run time. This method involves optimized anion-exchange liquid chromatography coupled with integrated pulse amperometric detection. Complex carbohydrates from various sources, including dietary supplements, were hydrolyzed in a dilute solution of trifluoroacetic acid, freeze-dried, and reconstituted in water containing 2-deoxygalactose as the internal standard. The solution was filtered and separated on CarboPac PA20 column. The eluted saccharides were detected by oxidation on a gold electrode with quadruple-pulsed integrated amperometry. The calibration plots for the saccharides were linear with an average correlation coefficient of 0.999. Method precision regarding peak retention time and resolution used in the peak identifications was verified. With this method, previously difficult-to-separate saccharides, such as galactosamine, glucosamine, and N-acetylglucosamine, were successfully resolved from the neutral saccharides rhamnose, arabinose, and galactose. Mannose was also resolved from xylose, and de-acetylation of aminosaccharides prior to separation was not necessary. This technique provides an accurate and efficient means to assay carbohydrates in dietary supplements, which new federal regulations will soon mandate.


AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women.
The amino acid glutamate opens cation permeable ion channels, the iGlu receptors. These ion channels are abundantly expressed in the mammalian brain where glutamate is the main excitatory neurotransmitter. The neurotransmitters and their receptors are being increasingly detected in the cells of immune system. Here we examined the expression of the 18 known subunits of the iGlu receptors families; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, N-methyl-d-aspartate (NMDA) and delta in human peripheral blood mononuclear cells (PBMCs). We compared the expression of the subunits between four groups: men, non-pregnant women, healthy pregnant women and depressed pregnant women. Out of 18 subunits of the iGlu receptors, mRNAs for 11 subunits were detected in PBMCs from men and non-pregnant women; AMPA: GluA3, GluA4, kainate: GluK2, GluK4, GluK5, NMDA: GluN1, GluN2C, GluN2D, GluN3A, GluN3B, and delta: GluD1. In the healthy and the depressed pregnant women, in addition, the delta GluD2 subunit was identified. The mRNAs for GluK4, GluK5, GluN2C and GluN2D were expressed at a higher level than other subunits. Gender, pregnancy or depression during pregnancy altered the expression of GluA3, GluK4, GluN2D, GluN3B and GluD1 iGlu subunit mRNAs. The greatest changes recorded were the lower GluA3 and GluK4 mRNA levels in pregnant women and the higher GluN2D mRNA level in healthy but not in depressed pregnant women as compared to non-pregnant individuals. Using subunit specific antibodies, the GluK4, GluK5, GluN1, GluN2C and GluN2D subunit proteins were identified in the PBMCs. The results show expression of specific iGlu receptor subunit in the PBMCs and support the idea of physiology-driven changes of iGlu receptors subtypes in the immune cells.


Acute renovascular hypertension in conscious dogs. Interaction of the renin-angiotensin system and sympathetic nervous system in systemic hemodynamics and regional blood flow responses.
The effects of acute renovascular hypertension on the sympathetic nervous system, regional blood flow and cardiac function were studied in conscious dogs submitted to renal artery occlusion by inflation of a cuff implanted previously around one renal artery. We then compared the alterations in plasma renin and catecholamine levels and in the various hemodynamic parameters induced by those maneuvers in intact dogs, to those in dogs pretreated with alpha- and beta-adrenergic receptor blockers. Subsequently, the converting enzyme inhibitor teprotide was administered to inhibit angiotensin formation in both experiments. Our results suggest that both the renin-angiotensin system and the sympathetic system contribute to the rise in blood pressure. The hemodynamic changes and alterations in regional blood flows accompanying this acute hypertension appear to be due mostly to the increase in plasma angiotensin, since prior adrenoceptor blockade only attenuated their magnitude but did not alter their direction. However, angiotensin-induced coronary vasoconstriction was observed only in adrenergically blocked but not intact animals, probably because of the protective effect of baroreceptor-mediated reflex sympathetic coronary vasodilation.


Bead injection ELISA for the determination of antibodies implicated in type 1 diabetes mellitus.
This work introduces a novel analytical method for the detection and study of GAD65 autoantibodies, which have been implicated in the onset of type 1 diabetes. There is a clinical need for a rapid and automated assay for GAD65 autoantibodies. Therefore, this method was designed to exploit the advantages of bead injection (BI) analysis for enzyme-linked immunosorbent assays (ELISA). BI ELISA is a microscale technique that uses enzyme labeled secondary antibodies to detect the capture of target antibodies on immobilized antigen in the flow cell of the lab-on-valve (LOV) manifold. A detection limit of 20 ng mL(-1) of GAD65 monoclonal antibody 144 compares favorably with the sensitivity and precision of a standard ELISA currently employed to detect GAD65 autoantibodies. Compared to the standard ELISA protocol, BI ELISA offers a significantly reduced assay time and complete automation of solution handling and detection.


Increased serum clearance of oligomannose species present on a human IgG1 molecule.
The role of Fc glycans on clearance of IgG molecule has been examined by various groups in experiments where specific glycans have been enriched or the entire spectrum of glycans was studied after administration in pre-clinical or clinical pharmacokinetic (PK) studies. The overall conclusions from these studies are inconsistent, which may result from differences in antibody structure or experimental design. In the present study a well-characterized recombinant monoclonal IgG1 molecule (mAb-1) was analyzed from serum samples obtained from a human PK study. mAb-1 was recovered from serum using its ligand cross-linked to Sepharose beads. The overall purity and recovery of all isoforms were carefully evaluated using a variety of methods. Glycans were then enzymatically cleaved, labeled using 2-aminobenzamide and analyzed by normal phase high performance liquid chromatography. The assays for recovering mAb-1 from serum and subsequent glycan analysis were rigorously qualified at a lower limit of quantitation of 15 μg/mL, thus permitting analysis to day 14 of the clinical PK study. Eight glycans were monitored and classified into two groups: (1) the oligomannose type structures (M5, M6 and M7) and (2) fucosylated biantennary oligosaccharides (FBO) structures (NGA2F, NA1F, NA2F, NA1F-GlcNAc and NGA2F-GlcNAc). We observed that the oligomannose species were cleared at a much faster rate (40%) than FBOs and conclude that high mannose species should be carefully monitored and controlled as they may affect PK of the therapeutic; they should thus be considered an important quality attribute. These observations were only possible through the application of rigorous analytical methods that we believe will need to be employed when comparing innovator and biosimilar molecules.


Curing myeloma at last: defining criteria and providing the evidence.
Does the dogma that multiple myeloma is incurable still hold?. The genomic chaos and resulting resistance to apoptosis of myeloma, long considered an obstacle to cure, formed the basis of Total Therapy (TT) program. The TT approach uses all myeloma-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. Long-term follow-up of 1202 patients (TT1: n = 231, median follow-up: 21 years; TT2: 668, median follow-up: 12 years; TT3a: n = 303, median follow-up: 9 years) permitted investigation of whether progression-free survival (PFS) and complete response (CR) duration were consistent with curability, ie observation of plateaus in Kaplan-Meier plots for PFS and CR duration. In the subset of 627 patients with plasma cell gene expression profiling data, cure plateaus were apparent at 5 years in the 14% with high-risk myeloma compared with 10 years in the remainder with low-risk disease. A parametric model based on PFS and CR duration supported an increase in curability: 10-year PFS and CR estimates increased from 8.8%/17.9% in TT1 to 15.5%/28.2% in TT2's control arm to 25.1%/35.6% in TT2's thalidomide arm and to 32.9%/48.8% in TT3a. Toward developing novel therapies, we recommend a concerted focus on patients with high-risk myeloma whose outcome has not been advanced.


Enrollment and Retention of Men and Women in Health Services Research and Development Trials.
Sex- and gender-specific science is essential to inform patient-centered, evidence-based care. Developing such evidence requires adequate inclusion of both women and men in trials. We sought to describe study participation of women and men in Department of Veterans Affairs Health Services Research and Development trials. We identified recent health services research trials from one Health Services Research and Development Center of Innovation and compared the participation of women and men from trial recruitment to study completion. We also calculated the participation to prevalence ratio (PPR) by sex for each trial. We included eight trials that started recruitment between 2011 and 2014. Only one study purposefully attempted to boost the recruitment of women. Overall, the PPR for women ranged from 0.2 to 4.5, with seven studies having a PPR of greater than 1, indicating that women participated in these trials at proportions greater than their prevalence in the disease population within the Department of Veterans Affairs. The PPR for men ranged from 0.8 to 1.1. Retention was best with those studies that used administrative data for final outcomes assessment. No studies provided results stratified by sex or conducted analyses to explore treatment effect by sex. At a single site, women participated in Health Services Research and Development trials at similar or greater rates to men without cross-study efforts to enrich the recruitment or retention of women. Adding strategic recruitment approaches could further boost the proportion of women in Department of Veterans Affairs trials and enable adequately powered sex-based analyses.


Cyanoacrylate glue in the repair of retinal detachment associated with posterior retinal breaks in infants and children.
To share the authors' experience with cyanoacrylate glue in posterior retinal breaks associated with retinal detachments in infants and children. A retrospective study was performed of four consecutive pediatric patients who underwent vitreoretinal surgery for retinal detachment associated with posterior retinal breaks, for which cyanoacrylate glue was used. In three of the four patients, successful retinal reattachment with visual function was achieved by vitreoretinal surgery and cyanoacrylate placed on the apposed edges of posterior retinal breaks or used to plug a break (postoperative follow-up was 1.5-2 years). In two successful cases, the glue was applied onto the break while the retina was detached, which resulted in closure of the retinal breaks and reattachment of the retina in both cases. Cyanoacrylate creates a permanent closure of retinal breaks and may be useful in select cases of infant retinal detachment with posterior retinal breaks in which current available treatment failed or would fail.


The Interactions Between Three Typical PPCPs and LDH.
With a layered structure, layered double hydroxide (LDH) has potential applications in remediation of anionic contaminants, which has been a hot topic for recent years. In this study, a Cl type Mg-Al hydrotalcite (Cl-LDH) was prepared by a co-precipitation method. The adsorption process of three pharmaceuticals and personal care products (PPCPs) [tetracycline (TC), diclofenac sodium (DF), chloramphenicol (CAP)] by Cl-LDH was investigated by X-ray diffraction (XRD), Zeta potential, dynamic light scattering (DLS), BET, Fourier transform infrared (FTIR) spectroscopy, and molecular dynamics simulation. The results showed that the adsorption equilibrium of TC and DF could be reached in 120 min, and the maximum adsorption capacity of the TC and DF were 1.85 and 0.95 mmol/g, respectively. The isothermal adsorption model of TC was fitted with the Freundlich adsorption model, and the isothermal adsorption model of DF was fitted with the Langmuir adsorption model. The adsorption dynamics of TC and DF followed the pseudo-second-order model. The adsorption mechanisms of the three PPCPs into Cl-LDH were different based on the experimental results and molecular dynamics simulation. The TC adsorption on Cl-LDH was accompanied by the electrostatic interactions between the negative charge of TC and the positive charge of Cl-LDH. The uptake of DF was attributed to anion exchange and electrostatic interaction. Cl-LDH does not adsorb CAP due to no electrostatic interaction. The molecular dynamic simulation further confirmed different configurations of three selected PPCPs, which were ultimately responsible for the uptake of PPCPs on Cl-LDH.


Trovafloxacin in treatment of rabbits with experimental meningitis caused by high-level penicillin-resistant Streptococcus pneumoniae.
The fluoroquinolone trovafloxacin was bactericidal (0.47 +/- 0.23 delta log10 CFU/ml x h after 10 mg/kg of body weight and 0.78 +/- 0.15 delta log10 CFU/ml x h after 30 mg/kg) in the treatment of experimental meningitis caused by a highly penicillin-resistant (MIC and minimum bactericidal concentration = 4 and 4 microg/ml) strain of Streptococcus pneumoniae. Combinations with ampicillin and rifampin were indifferent compared to single drugs.


Atomically Dispersed Mn for Electrochemical CO2 Reduction with Tunable Performance.
Electrochemical CO2 reduction (ECR) is recognized as a sustainable and promising approach for the production of high-value chemicals. To facilitate widespread application of this technology, the design and construction of efficient cathodic electrocatalysts is critically important. Here we report the synthesis of atomically dispersed manganese on nitrogen-doped porous carbon (Mn SAs/NC) using a facile and scalable annealing method for catalyzing the ECR reaction. The as-obtained Mn SAs/NC delivers high activity and selectivity toward CO formation with a faradaic efficiency of 80.5±0.6%, over 5 times that of bare NC. The high activity is preserved even after 10 h of continuous polarization. The catalytic properties of our cost-effective Mn SAs/NC catalyst are readily tuned by regulating the nitrogen configurations and the percentage of Mn SAs via modulation of the nitrogen precursor and the thermal treatment conditions.


Characterization of pyruvate kinase from the liver of a patient with aberrant erythrocyte pyruvate kinase, PK Nagasaki.
The characterization of the L-type PK were made of PK extracted from the liver of a patient with congenital hemolytic anemia associated with an erythrocyte PK variant, PK Nagasaki. The L-type PK of PK Nagasaki showed the following parameters: slow migration on electrophoresis, high Km for PEP without F-1,6-P2, less activation by F-1,6-P2, normal Km for ADP, high utilization of UDP, acidic pH optimum, and instability to urea and heat. These tests served to differentiate this L-type PK variant from the other variants previously reported. At the same time, both the Km for PEP with F-1,6-P2 saturation and the electrophoretic mobility of L-type PK were found to be different from those of the erythrocyte PK and PK Nagasaki. Though the liver cell, with regard to L-type PK, has only the less functional and less stable mutant L-type PK there is no evidence of liver dysfunction or damage, although there is chronic hemolytic anemia.


[Current status and prospects of immunotherapy for castration-resistant prostate cancer].
Surgery, radiation and chemotherapy are three major therapies for cancer. But now, hope is being gathered in immunotherapy as a treatment for fourth. Immunotherapy has been done than before, but they are non-specific immunotherapy. Those that have become hot topics are specific immunotherapies targeting certain molecules or antigens. In this chapter, current status and prospects of immunotherapy for castration-resistant prostate cancer (CRPC) are described. As concrete examples, Sipuleucel-T(Provenge), GVAX, PROSTVAC-VF, Ipilimumab (anti-CTLA-4 mAb), anti-PD-1 mAb and anti-PSMA mAb are cited. As a result, it is not obtained results which therapy also satisfactory at present. Because of its uncertainties we are in the developmental stages of this therapy and improved outcomes might be achievable.


Effect of glycyrrhizin on CYP2C19 and CYP3A4 activity in healthy volunteers with different CYP2C19 genotypes.
The objective of this study was to investigate the interaction between glycyrrhizin and omeprazole and observe the effects of glycyrrhizin on CYP2C19 and CYP3A4 activities in healthy Chinese male volunteers with different CYP2C19 genotypes. Eighteen healthy subjects (six CYP2C19*1/*1, five CYP2C19*1/*2, one CYP2C19*1/*3, five CYP2C19*2/*2 and one CYP2C19*2/*3) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or glycyrrhizin salt tablet 150 mg twice daily for 14 consecutive days. The pharmacokinetics of omeprazole (20 mg orally on day 15) was determined for up to 12 h following administration by high-performance liquid chromatography. After 14-day treatment of glycyrrhizin, plasma omeprazole significantly decreased, and those of omeprazole sulfone significantly increased. However, plasma concenetrations of 5-hydroxyomeprazole did not significantly change. The ratio of AUC(0-infinity) of omeprazole to omeprazole sulfone decreased by 43.93% + or - 13.56% (p = 0.009) in CYP2C19*1/*1, 44.85% + or - 14.84% (p = 0.002) in CYP2C19*1/*2 or *3 and 36.16% + or - 7.52% (p < 0.001) in CYP2C19*2/*2 or *3 while those of omeprazole to 5-hydroxyomeprazole did not change significantly in all three genotypes. No significant differences in glycyrrhizin response were found among CYP2C19 genotypes. Glycyrrhizin induces CYP3A4-catalyzed sulfoxidation of omeprazole and leads to decreased omeprazole plasma concentrations, but has no significant impact on CYP2C19-dependent hydroxylation of omeprazole.


Patient age, histologic features, and length of survival in patients with glioblastoma multiforme.
Histologic sections from 71 patients with glioblastoma multiforme were reviewed to identify histologic prognostic factors and to explain the significantly shorter survival in older patients. Slides were studied for 14 histologic variables from a group of 35 patients aged less 45 years and from 36 patients aged 65 years or more. The relation of these histologic factors to the length of survival and age group was then investigated. The results document the marked histologic and cytologic heterogeneity of the glioblastoma and reaffirm the importance of necrosis as a prognostic factor. The results further suggest that patients whose glioblastomas contained microcysts, pseudopalisading, cells with astrocytic differentiation, and large areas of better differentiated glioma, did better than those patients whose lesions were homogeneously composed of small cells or whose lesion had a small median nuclear size. The study reaffirmed the strong (P less than 0.0001) negative relationship between advancing age and duration of postoperative survival. The presence of necrosis, a smaller standard deviation of nuclear size, the extent of vascular proliferation, the absence of well differentiated neoplastic fibrillary astrocytes, and neoplasms composed homogeneously of small cells were related to patient age and offered a possible explanation for at least part of the observed age effect. However, the strong relation between age and survival remained significant when adjusted for other variables, and the effect of age must rest largely on factors other than those detected in this morphologic study.


[A new case of idiopathic carpo-tarsal osteolysis with Bartter's syndrome (case report and short review of the literature)].
The author gives in connection with the description of the case of an idiopathic carpo-tarsal osteolysis of a six year old female patient a short literary review of this rare disease. The nephropathy previously frequently observed in the cases described appeared in the form of a typical Bartter's syndrome, this connection was not yet observed before.


Extrinsic and intrinsic signals converge on the Runx1/CBFβ transcription factor for nonpeptidergic nociceptor maturation.
The generation of diverse neuronal subtypes involves specification of neural progenitors and, subsequently, postmitotic neuronal differentiation, a relatively poorly understood process. Here, we describe a mechanism whereby the neurotrophic factor NGF and the transcription factor Runx1 coordinate postmitotic differentiation of nonpeptidergic nociceptors, a major nociceptor subtype. We show that the integrity of a Runx1/CBFβ holocomplex is crucial for NGF-dependent nonpeptidergic nociceptor maturation. NGF signals through the ERK/MAPK pathway to promote expression of Cbfb but not Runx1 prior to maturation of nonpeptidergic nociceptors. In contrast, transcriptional initiation of Runx1 in nonpeptidergic nociceptor precursors is dependent on the homeodomain transcription factor Islet1, which is largely dispensable for Cbfb expression. Thus, an NGF/TrkA-MAPK-CBFβ pathway converges with Islet1-Runx1 signaling to promote Runx1/CBFβ holocomplex formation and nonpeptidergic nociceptor maturation. Convergence of extrinsic and intrinsic signals to control heterodimeric transcription factor complex formation provides a robust mechanism for postmitotic neuronal subtype specification.


Localized eruptive porokeratosis in pediatric patients following treatment of acute leukemia.
Porokeratosis is a rare diagnosis in the pediatric population, and eruptive disease has been documented prior in patients with history of stem cell transplantation. Comparing various porokeratosis eruptions between patients can be difficult due to limitations in current classification and nomenclature. Here, we discuss a single-institution case series of three children who developed porokeratosis following hematopoietic stem cell transplantation for acute leukemia, and we propose that this presentation be termed localized eruptive porokeratosis (LEP). We present the distinguishing features of this variant by discussing the shortcomings in current nomenclature and also examine the association between porokeratosis and hematopoietic stem cell transplantation in the pediatric population.


Experimental observation of photochemically induced oxygen depletion in perfused cells undergoing photodynamic therapy.
This report presents a non invasive method for studying oxygen consumption during photodynamic therapy in cultured cells. The oxygen partial pressure of perfusion medium flowing through cells cultured on microcarrier beads, was investigated before, during and after treatment. Pheophorbide a was used as a sensitiser. Time-dependent measurements demonstrate photochemical oxygen depletion induced by photosensitized reactions, followed by an oxygen pressure increase were attributed to a reduction in the cells' metabolism.


Selenium and cardiovascular disease.
For humans, ecological and epidemiological results are reported that show a relationship between the serum selenium concentration and cardiovascular disease in populations where low serum selenium concentrations are found, e.g., in Eastern Finland. From clinical studies done in Germany (FRG and GDR), Finland, and Sweden, subnormal serum selenium and partially whole blood selenium concentrations are reported in patients with acute myocardial infarction. For patients with coronary arteriosclerosis, subnormal serum selenium concentrations are reported from the USA and Germany and subnormal whole blood selenium concentrations from Germany. Subnormal serum and subnormal whole blood selenium concentrations of patients with cardiomyopathy are reported from non Keshan disease affected areas in Germany, France, and China. In selenium deficiency, an accumulation of lipid peroxides in the heart may occur, especially under ischemic conditions and if ischemic tissue is reperfused. Lipid peroxides in the heart may damage the cell membrane and may lead to an impaired calcium transport with an uncontrolled calcium accumulation in the cell. This may result in an activation of phospholipids, and, in consequence, to an enhanced formation of arachidonic acid. An increased concentration of lipid peroxides owing to selenium deficiency may shift the prostaglandin synthesis from prostacyclin to thromboxane, causing enhanced blood pressure and platelet aggregability. From animal experiments, it is known that selenium protects against cardiotoxic elements, cardiotoxic xenobiotics, and viral infections that affect the heart. Selenium deficiency may also be a secondary factor in the causation of hypertension and myocardial ischemia.


[Cytogenetic changes and their prognostic significance in elderly acute myeloid leukemia].
Cytogenetic analyses were performed in 72 acute myeloid leukemia (AML) patients > or = 60 years old. Karyotype was normal in 35 (48.6%) patients (group III). 3 patients (4.2%) had favourable karyotype with t(15;17) as an isolated aberration (group IV). 21 patients (29.2%) had adverse karyotypes (group I) and 13 (18%) had intermediate karyotypes (group II). Adverse karyotypes were simple (< 3 aberrations), with add 3q, 5q-, 7q-, in 5 persons, and complex (> or = 3 aberrations) in 16. Karyotypes of 14 patients from the latter group contained > or = 5 aberrations. Laboratory and clinical data were comparable between groups with > or = 3 and with > or = 5 changes. In more than 2/3 complex karyotypes chromosome 5 and 7 aberrations also were found. AML clinical course of group II patients was more similar to that of group I than of groups III and IV. A frequency of complete remissions differed statistically between group I and the others and a frequency of complete and partial remissions together--between I + II and III + IV groups. Overall survival time differed statistically between all groups. There were significantly more patients with secondary AML in groups I and II than in group III. Analysis according to FAB did not show prognostic significance of this classification. Authors conclude that cytogenetics have a fundamental prognostic importance in AML of the elderly and should be taken into account in establishing therapeutic strategies.


Therapy of Dysphagia by Prolonged Pharyngeal Electrical Stimulation (Phagenyx) in a Patient with Brainstem Infarction.
Dysphagia after stroke impacts quality of life and is a risk factor for respiratory infections. Patients frequently require prophylactic measures including nasogastric tube or percutaneous endoscopic gastrostomy. Until recently, therapy for dysphagia was limited to training with a speech and language specialist. Intraluminal pharyngeal electrical stimulation (PES) is a new technique that stimulates the pharyngeal sensory afferents to the higher swallowing center in cortex. The clinical trials published to date involved stimulation for 10 minutes over three days. We present a case of brainstem infarction with severe dysphagia in a 53-year-old woman with preserved cognitive functions. For airway protection, she had a surgical tracheotomy. The initial swallowing training achieved slight improvements, but stagnated after three months so PES was tried. Under good PES tube tolerance, a prolonged and repeated stimulation protocol was administered, with the main purpose of relieving her of the tracheal tube. Although the swallowing improved, she stayed tube-dependent with minimal attempts with puréed food during therapy, and could not be decannulated. Further studies are required to assess the value of this promising approach for the treatment of dysphagia.


Dysphagia lusoria: a little-known cause of dysphagia.
It is referred the case report of an 82-year-old female was referred for the evaluation of progressive esophageal dysphagia of a six month duration, with a recent weight loss of 10% of the normal corporal weight over a six month period. The patient reported solid food dysphagia that required liquids to facilitate food progression and denied food impaction.


Impact of osmotic and matric water stress on germination, growth, mycelial water potentials and endogenous accumulation of sugars and sugar alcohols in Fusarium graminearum.
Studies were conducted to determine the effect of osmotic (NaCl, glycerol) and matric (PEG 8000) water stress on temporal germination and growth of two F. graminearum strains over the water potential range of -0.7 to -14.0 MPa at 15 and 25 C. The effect on endogenous water potentials and accumulation of sugars and sugar alcohols also were measured. For both strains, germination occurred rapidly over the same range of osmotic or matric potential of -0.7 to -5.6 MPa after 4-6 h incubation. At lower osmotic and matric potentials (-7.0 to -8.4 MPa), there was a lag of up to 24 h before germination. Optimum germ-tube extension occurred between -0.7 and -1.4 MPa for both strains but varied with the solute used. Growth was optimal at -1.4 MPa and 25 C in response to matric stress, with the minimum being about -8.0 and -11.2 MPa at 15 and 25 C, respectively. In contrast, F. graminearum grew fastest at -0.7 MPa and was more tolerant of solute stress modified with either glycerol or NaCl with a minimum of about -14.0 MPa at 15 and 25 C. A decrease in the osmotic/matric water potential of the media caused a large decrease in the mycelial water potential (Ψ(c)) as measured by thermocouple psychrometry. In general, the concentration of total sugar alcohols in mycelia increased as osmotic and matric potential were reduced to -1.2 MPa. However, this increase was more evident in mycelia from glycerol-amended media. The quality of the major sugar alcohol accumulated depended on the solute used to generate the water stress. The major compounds accumulated were glycerol and arabitol on osmotically modified media and arabitol on matrically modified media. In response to matric stress, the concentration of trehalose in colonies generally was higher in the case of osmotic stress. In each water-stress treatment there was a good correlation between Ψ(c) and total sugar alcohol content.


Ab initio based potential energy surface and kinetics study of the OH + NH3 hydrogen abstraction reaction.
A full-dimensional analytical potential energy surface (PES) for the OH + NH3 → H2O + NH2 gas-phase reaction was developed based exclusively on high-level ab initio calculations. This reaction presents a very complicated shape with wells along the reaction path. Using a wide spectrum of properties of the reactive system (equilibrium geometries, vibrational frequencies, and relative energies of the stationary points, topology of the reaction path, and points on the reaction swath) as reference, the resulting analytical PES reproduces reasonably well the input ab initio information obtained at the coupled-cluster single double triple (CCSD(T)) = FULL/aug-cc-pVTZ//CCSD(T) = FC/cc-pVTZ single point level, which represents a severe test of the new surface. As a first application, on this analytical PES we perform an extensive kinetics study using variational transition-state theory with semiclassical transmission coefficients over a wide temperature range, 200-2000 K. The forward rate constants reproduce the experimental measurements, while the reverse ones are slightly underestimated. However, the detailed analysis of the experimental equilibrium constants (from which the reverse rate constants are obtained) permits us to conclude that the experimental reverse rate constants must be re-evaluated. Another severe test of the new surface is the analysis of the kinetic isotope effects (KIEs), which were not included in the fitting procedure. The KIEs reproduce the values obtained from ab initio calculations in the common temperature range, although unfortunately no experimental information is available for comparison.


Immunogenic properties of the small chain HA2 of the haemagglutinin of influenza viruses.
The small chain of influenza virus haemagglutinin, HA2 was isolated by a selective enzymic removal of HA1 or by preparative SDS-polyacrylamide gel electrophoresis. Anti-HA2 specific antisera and monoclonal antibodies were subtype-specific in immunodiffusion tests and radioimmunoassays. These antibodies did not inhibit haemagglutination or haemolysis, did not prevent virus release, did not neutralize infectivity, and HA2 did not induce a protective immunity. HA2-specific antigenic determinants could not be demonstrated on the surface of infected cells. Lymphocytes from pre-immunized mice could not be stimulated by HA2 to exert a cytotoxic effect.


Effect of obesity on insulin signaling through JAK2 in rat aorta.
Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.


Activation of an Mg2+-dependent DNA endonuclease of avian myeloblastosis virus alpha beta DNA polymerase by in vitro proteolytic cleavage.
Partial chymotryptic digestion of purified avian myeloblastosis virus alpha beta DNA polymerase resulted in the activation of a Mg2+-dependent DNA endonuclease activity. Incubation of the polymerase-protease mixture in the presence of super-coiled DNA and Mg2+ permitted detection of the cleaved polymerase fragment possessing DNA nicking activity. Protease digestion conditions were established permitting selective cleavage of beta to alpha, which contained DNA polymerase and RNase H activity and to a family of polypeptides ranging in size from 30,000 to 34,000 daltons. These latter beta-unique fragments were purified by polyuridylate-Sepharose 4B chromatography and were shown to contain both DNA binding and DNA endonuclease activities. We have demonstrated that this group of polymerase fragments derived by chymotryptic digestion of alpha beta DNA polymerase is similar to the in vivo-isolated avian myeloblastosis virus p32pol in size, sequence, and DNA endonuclease activity.


Building Capacity for Behavioral Health Services and Clinical Research in a Rural Primary Care Clinic: A Case Study.
Integrating sustainable, evidence-based, and collaborative depression screening and follow-up treatment into primary care clinics is a significant challenge in health care. In this article a case study approach is used to describe the process of building capacity for a depression screening program in a rural federally qualified health center (FQHC). A conceptual framework addressing the clinical, operational, and financial perspectives of a primary care setting is applied restrospectively to identify 1) the barriers and facilitating factors associated with integrating a depression screening program into standard practice and 2) how the program was leveraged to conduct clinical research to improve self-management in patients with diabetes and elevated depressive symptoms.


Pediatric leg ulcers: going out on a limb for the diagnosis.
This article exhibits the most common differential diagnoses for pediatric leg ulcers and contrasts the etiologies with the adult population. The diagnoses are further categorized into hematologic, infectious, genodermatoses, and autoimmune etiologies to help the dermatologist deduce the accurate diagnosis in this unique patient population.


[Influence of age on laparoscopic colposacropexy].
To evaluate the influence of age on laparoscopic colposacropexy (LCS) outcome and complications for pelvic organ prolapse. A retrospective and comparative study of 105 patients who underwent standard LCS for Baden-Walker graded pelvic organ prolapse from February 2002 to March 2015. They were categorized into two groups according to age. Group 1 consisted in ≤ 50 years old patients and included 55 women. Group 2 included 50 women who were ≥ 60 years old. Outcomes and complications were compared in both groups. Previous history of abdominal surgery or surgery for pelvic floor disorders was significantly greater in group 2 (43.6 vs 70%). There was no significant difference regarding urinary stress incontinence, urge incontinence or severe organ prolapse between groups (47.2 vs 36%; 1.8 vs 8% and 90.9 vs 92% for Groups 1 and 2 respectively). Although a statistically significant greater proportion of vaginal vault prolapse was present in the elderly group (16.3 vs 38%), the same LCS surgical technique was used in both groups of patients. Despite operating time was significantly greater in the younger group (205.8 ± 53.4 minutes in Group 1 vs 182 ± 42.3 minutes in Group 2), hospital stay was similar in both groups (2.9 ± 1.1 days vs 3.0 ± 1.9 days in group 1 and group 2 respectively). Postoperative complications were not severe and there were no clinically significant differences between groups (20 vs 14%). We found no statistically differences between groups when comparing cure rates (87 vs 92%) in groups 1 and 2 respectively, patient satisfaction and postoperative anatomical findings. LCS has shown excellent cure rates in both young and elder female patients with pelvic organ prolapse.


Meira siamensis sp. nov., a novel anamorphic ustilaginomycetous yeast species isolated from the vetiver grass phylloplane.
Two strains, DMKU-LV83 and DMKU-LV85, of a novel yeast species were isolated from the phylloplane of vetiver grass collected in Thailand by plating of leaf washings. Analysis of the sequences of the D1/D2 region of the large subunit (LSU) rRNA gene showed that the two strains represent a single novel species and most closely related to Meira miltonrushii. However, the novel species differed from the type strain of M. miltonrushii (MCA 3882T) by 5.5 % nucleotide substitutions in the D1/D2 region and 8.9 % nucleotide substitutions in the ITS region. The phylogenetic analysis based on the D1/D2 region of the LSU rRNA gene confirmed the placement of the novel species in the Meira clade and its close affinity with M. miltonrushii. Therefore, the species Meira siamensis sp. nov. is proposed. The type strain is DMKU-LV83T (=CBS 12860T=BCC 61180T).


Infection of brain microglial cells by human immunodeficiency virus type 1 is CD4 dependent.
In the central nervous system of AIDS patients, human immunodeficiency virus (HIV) infects primarily microglia, a cell type of bone marrow origin. Moreover, microglial cells isolated from adult human brain support the replication of macrophage-adapted strains of HIV type 1 (HIV-1) (B.A. Watkins, H.H. Dorn, W.B. Kelly, R.C. Armstrong, B. Potts, F. Michaels, C.V. Kufta, and M. Dubois-Dalcq, Science 249:549-553, 1990). To determine whether the CD4 receptor, which is expressed in brain, mediates the entry of HIV-1 in microglial cells, we analyzed CD4 transcript expression in cultured microglia using highly sensitive polymerase chain reaction detection of cDNAs synthesized from RNA. With this method, CD4 transcripts could be detected in cultured microglia--as well as in various human brain regions and cultured macrophages used as positive controls--along with transcripts for the LDL and Fc receptors which are characteristic of cells of the macrophage lineage. We then attempted to block viral entry into microglial cells using anti-CD4 antibodies or soluble CD4 (sCD4), which recognize binding sites on CD4 and HIV-1 glycoprotein gp120, respectively. Cultures were pretreated with blocking antibodies (Leu-3a, OKT4A) or virus was preincubated with sCD4 prior to infection with HIV-1 strain AD87(M) or BaL. With either viral strain, these treatments resulted in the prevention of infection or significant and dose-dependent reduction in the number of infected cells and in the levels of reverse transcriptase or p24 antigen released in the medium. Thus, brain-derived microglial cells, which are the primary target of HIV-1 infection in the brain, express the CD4 receptor and this receptor is effectively used for viral entry in vitro.


Role of Streptococcus pneumoniae in hospitalization for acute community-acquired pneumonia associated with culture-confirmed Mycobacterium tuberculosis in children: a pneumococcal conjugate vaccine probe study.
African children hospitalized with symptoms of severe acute pneumonia, which resolves following empiric antibiotic therapy, are sometimes identified to have underlying culture-confirmed pulmonary tuberculosis (PTB). Experimental studies suggest Mycobacterium tuberculosis infection predisposes to Streptococcus pneumoniae infection; however, diagnostic limitations make it difficult to quantify this association in children. We aimed to probe the extent of pneumococcal coinfection in children with PTB, using a vaccine-probe design study. A post hoc analysis of PTB cases occurring among 39,836 participants in a phase III randomized, double-blind placebo-controlled 9-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV9) trial in South Africa was undertaken. Hospitalization for PTB occurring during the 5.3 years of follow-up were identified and categorized as culture-confirmed PTB or probable/possible-PTB. The incidence rates of hospitalized PTB were compared between PCV9 vaccinees and placebo recipients. Hospitalization for culture-confirmed PTB was 43.4% (95% CI, 9.7%–65.1%) less likely among vaccinees (n = 30) compared with placebo recipients (n = 53), incidence, 20 versus 35 per 100,000 child-years of follow-up (P = 0.0117). In HIV-infected children, culture-confirmed PTB was 47.3% (95% CI, 8.6%–69.6%) less likely among vaccinees (n = 19) compared with placebo recipients (n = 36), P = 0.0203. The incidence of possible/probable PTB did not differ by vaccination status. This vaccine-probe design study suggests that in a setting with high HIV and TB prevalence, culture-confirmed PTB in African children, which frequently presents with symptoms of acute pneumonia, is probably associated with superimposed pneumococcal pneumonia. Children admitted with pneumonia in these settings should be investigated for underlying PTB.


Mitophagy in Traumatic Brain Injury: A New Target for Therapeutic Intervention.
Traumatic brain injury (TBI) contributes to death, and disability worldwide more than any other traumatic insult and damage to cellular components including mitochondria leads to the impairment of cellular functions and brain function. In neurons, mitophagy, autophagy-mediated degradation of damaged mitochondria, is a key process in cellular quality control including mitochondrial homeostasis and energy supply and plays a fundamental role in neuronal survival and health. Conversely, defective mitophagy leads to the accumulation of damaged mitochondria and cellular dysfunction, contributing to inflammation, oxidative stress, and neuronal cell death. Therefore, an extensive characterization of mitophagy-related protective mechanisms, taking into account the complex mechanisms by which each molecular player is connected to the others, may provide a rationale for the development of new therapeutic strategies in TBI patients. Here, we discuss the contribution of defective mitophagy in TBI, and the underlying molecular mechanisms of mitophagy in inflammation, oxidative stress, and neuronal cell death highlight novel therapeutics based on newly discovered mitophagy-inducing strategies.


Structure of Rubisco from Arabidopsis thaliana in complex with 2-carboxyarabinitol-1,5-bisphosphate.
The crystal structure of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) from Arabidopsis thaliana is reported at 1.5 Å resolution. In light of the importance of A. thaliana as a model organism for understanding higher plant biology, and the pivotal role of Rubisco in photosynthetic carbon assimilation, there has been a notable absence of an A. thaliana Rubisco crystal structure. A. thaliana Rubisco is an L8S8 hexadecamer comprising eight plastome-encoded catalytic large (L) subunits and eight nuclear-encoded small (S) subunits. A. thaliana produces four distinct small-subunit isoforms (RbcS1A, RbcS1B, RbcS2B and RbcS3B), and this crystal structure provides a snapshot of A. thaliana Rubisco containing the low-abundance RbcS3B small-subunit isoform. Crystals were obtained in the presence of the transition-state analogue 2-carboxy-D-arabinitol-1,5-bisphosphate. A. thaliana Rubisco shares the overall fold characteristic of higher plant Rubiscos, but exhibits an interesting disparity between sequence and structural relatedness to other Rubisco isoforms. These results provide the structural framework to understand A. thaliana Rubisco and the potential catalytic differences that could be conferred by alternative A. thaliana Rubisco small-subunit isoforms.


Laser-driven acoustic desorption of organic molecules from back-irradiated solid foils.
Laser-induced acoustic desorption (LIAD) from thin metal foils is a promising technique for gentle and efficient volatilization of intact organic molecules from surfaces of solid substrates. Using the single-photon ionization method combined with time-of-flight mass spectrometry, we have examined the neutral component of the desorbed flux in LIAD and compared it to that from direct laser desorption. These basic studies of LIAD, conducted for molecules of various organic dyes (rhodamine B, fluorescein, anthracene, coumarin, BBQ), have demonstrated detection of intact parent molecules of the analyte even at its surface concentrations corresponding to a submonolayer coating. In some cases (rhodamine B, fluorescein, BBQ), the parent molecular ion peak was accompanied by a few fragmentation peaks of comparable intensity, whereas for others, only peaks corresponding to intact parent molecules were detected. At all measured desorbing laser intensities (from 100 to 500 MW/cm2), the total amount of desorbed parent molecules depended exponentially on the laser intensity. Translational velocities of the desorbed intact molecules, determined for the first time in this work, were of the order of hundreds of meters per second, less than what has been observed in our experiments for direct laser desorption, but substantially greater than the possible perpendicular velocity of the substrate foil surface due to laser-generated acoustic waves. Moreover, these velocities did not depend on the desorbing laser intensity, which implies the presence of a more sophisticated mechanism of energy transfer than direct mechanical or thermal coupling between the laser pulse and the adsorbed molecules. Also, the total flux of desorbed intact molecules as a function of the total number of desorbing laser pulses, striking the same point on the target, decayed following a power law rather than an exponential function, as would have been predicted by the shake-off model. To summarize, the results of our experiments indicate that the LIAD phenomenon cannot be described in terms of simple mechanical shake-off or direct laser desorption. Rather, they suggest that multistep energy-transfer processes are involved. Two possible (and not mutually exclusive) qualitative mechanisms of LIAD that are based on formation of nonequilibrium energy states in the adsorbate-substrate system are proposed and discussed.


Cutaneous melanoma in the elderly: epidemiology, prognosis and treatment.
The incidence and mortality of cutaneous melanoma (CM) has increased over the last decades in fair-skinned populations. Incidence and mortality, as well as rates of increase, have been significantly higher in elderly people compared with younger age groups. Lower survival rates from CM among elderly are mainly the result of late diagnosis of tumors with dismal prognostic features. Expansion of current preventive strategies to include older age groups is therefore warranted. Despite differences in clinical presentation and pathological characteristics of CM in the elderly, there is no evidence that primary surgical treatment should differ from that proposed generally for melanoma. However, the rate of positive sentinel node dissection decreases with age, even though overall survival is shorter in older patients, a paradox that remains to be explained. The use of adjuvant treatment with interferon-alpha in elderly patients requires careful discussion of the risks and benefits, especially when serious illness coexists. For metastatic melanoma, complete metastasectomy is the only treatment associated with benefit for overall survival. However, careful selection of surgical oncogeriatric candidates is necessary, probably with the use of tools to provide a comprehensive geriatric assessment, to identify patients more likely to benefit from this treatment. In the absence of any effective systemic treatment for disseminated CM, new therapeutic agents are urgently needed. Practical means to improve accrual of older patients in clinical trials are necessary to provide better evidence for their treatment.


Protein arginine methyltransferase 6 specifically methylates the nonhistone chromatin protein HMGA1a.
The HMGA family proteins HMGA1a and HMGA1b are nuclear nonhistone species implicated in a wide range of cellular processes including inducible gene transcription, modulation of chromosome structure through nucleosome and chromosome remodeling, and neoplastic transformation. HMGA proteins are highly modified, and changes in their phosphorylation states have been correlated with the phase of the cell cycle and changes in their transcriptional activity. HMGA1a is also methylated in the first DNA-binding AT-hook at Arg25 and other sites, although the enzyme or enzymes responsible have not been identified. We demonstrate here that a GST fusion of protein arginine methyltransferase 6 (PRMT6) specifically methylates full-length recombinant HMGA1a protein in vitro. Although GST fusions of PRMT1 and PRMT3 were also capable of methylating the full-length HMGA1a polypeptide, they recognize its proteolytic degradation products much better. GST fusions of PRMT4 or PRMT7 were unable to methylate the full-length protein or its degradation products. We conclude that PRMT6 is a good candidate for the endogenous enzyme responsible for HGMA1a methylation.


Multiple Ligament Reconstruction for Absent Cruciate and a Congenital Short Femur Case Report and Review of the Literature.
Congenital short femur syndrome is a rare condition affecting about 0.017 of every 1,000 births. Patients frequently have ligamentous abnormalities, most frequently aplastic or hypoplastic cruciate ligaments. Advances in limb lengthening procedures have increased movement expectations for these patients, thus necessitating surgical treatment for their ligamentous abnormalities. An individual case is presented, including history, physical exam, and imaging demonstrating both the short femur and absent cruciate ligaments. A surgical reconstruction technique of the anterior cruciate ligament, posterior cruciate ligament, and posterolateral corner is described. At 1-year follow-up, the patient had 0° to 135° of ROM. He reported no pain but mild swelling experienced during squatting. His knee continues to be stable in all planes with a grade 1A Lachman exam and a grade 1 posterior drawer with no posterolateral corner laxity.


Pathologic examination of the sentinel lymph node.
One of the most important prognostic indicators in patients with malignant melanoma is lymph node status. While the five-year survival of stage I and II patients (without clinical adenopathy) is approximately 80 percent, this drops to 36-50 percent in patients with clinical or microscopic lymph node involvement. Other factors within lymph node specimens which affect disease-free and overall survival are the number of positive nodes (1 vs. 1-3 vs. 4 or greater) and the presence of extracapsular extension. Recently, the technique of sentinel lymphadenectomy has been developed to facilitate detection of metastatic disease in regional lymph nodes. Successful completion of this procedure requires a specialized but multidisciplinary approach, utilizing the surgeon, oncologist, nuclear radiologist, and pathologist. The pathologist's role is pivotal in this process, because identification of melanoma metastasis in the sentinel lymph node(s) is not only an important prognostic indicator but also dictates whether the patient will receive further surgery and adjuvant chemotherapy. Therefore, the goal of the pathologist in examining the sentinel lymph node is to maximize identification of nodal metastases of malignant melanoma. This is accomplished by following a standard protocol which fully utilizes all tissue submitted in concert with commonly available immunohistochemical techniques.


Interleukin-17 promotes the development of cisplatin resistance in colorectal cancer.
Cisplatin (DDP)-based anticancer therapy is an important chemotherapeutic strategy for the treatment of colorectal cancer. However, its beneficial effect is largely compromised by adverse reactions, and more importantly, by the development of drug resistance. Therefore, it is crucial to determine the potential mechanism underlying the development of DDP resistance in colorectal cancer. Interleukin-17 (IL-17) is a proinflammatory cytokine that has been found to serve an important role in the host defense during cancer development. It has been suggested that IL-17 is key to promoting the development of resistance to DDP in several major types of cancer. However, the role of IL-17 in DDP resistance in colorectal cancer has not been extensively investigated. In the present study, it was observed that IL-17 was significantly upregulated in colorectal tumor samples, compared with the adjacent tissues. Furthermore, IL-17 was found to promote the viability of HCT116 colorectal cells treated with DDP, whilst blocking IL-17 signaling leading to HCT116 cell apoptosis. IL-17 was also shown to regulate the expression of several apoptosis-related proteins, including phosphorylated-protein kinase B (p-Akt), apoptosis regulator BAX (Bax), apoptosis regulator Bcl-2 (Bcl-2) and serine/threonine-protein kinase mTOR (mTOR). These findings indicated that IL-17 facilitates the development of DDP resistance in colorectal cancer by inhibiting cancer cell apoptosis through targeting p-Akt, Bax, Bcl-2 and mTOR. Overall, the findings of the present study suggest that a combination of DDP and an IL-17 inhibitor may prove to be a highly efficient strategy for colorectal cancer treatment.


Genomics and transcriptomic alterations of the glutamate receptors in acute myeloid leukemia.
Glutamine and glutamate have been widely explored as potential therapeutic targets in acute myeloid leukemia (AML). In addition to its bioenergetic role in leukemia cell proliferation, L-glutamate is a neurotransmitter that acts on glutamate receptors. However, the role of glutamate receptors in AML is largely understudied. Here, we comprehensively analyze the genomic and transcriptomic alterations of glutamate receptor genes in AML using publicly available data. We investigated the frequency of mutations in the glutamate receptor genes and whether an association exist between the presence of these mutations and clinical and molecular characteristics or patient's clinical outcome. We also assessed the dysregulation of glutamate receptor gene expression in AML with and without mutations and whether gene dysregulation is associated with clinical outcomes. We found that 29 (14.5%) of 200 patients with AML had a mutation in at least one glutamate receptor gene. The DNMT3A mutations were significantly more frequent in patients with mutations in at least one glutamate receptor gene compared with patients without mutations (13 of 29 [44.8%] vs. 41 of 171 [23.9%], p value: 0.02). Notably, patients with mutations in at least one glutamate receptor gene survived shorter than patients without mutations; however, the results did not reach statistical significance (overall survival: 15.5 vs. 19.0 months; p value: 0.10). Mutations in the glutamate receptor genes were not associated with changes in gene expression and the transcriptomic levels of glutamate receptor genes were not associated with clinical outcome.


Application of Long Noncoding RNAs in Osteosarcoma: Biomarkers and Therapeutic Targets.
Osteosarcoma is the most common primary bone malignancy in children and adolescents. Although improvements in therapeutic strategies were achieved, the outcome remains poor for most patients with metastatic or recurrent osteosarcoma. Therefore, it is imperative to identify novel and effective prognostic biomarker and therapeutic targets for the disease. Long noncoding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts >200 nucleotides that lack protein coding potential. Many lncRNAs are deregulated in cancer and are important regulators for malignancies. Nine lncRNAs (91H, BCAR4, FGFR3-AS1, HIF2PUT, HOTTIP, HULC, MALAT-1, TUG1, UCA1) are upregulated and considered oncogenic for osteosarcoma. Loc285194 and MEG3 are two lncRNAs downregulated and as tumor suppressor for the disease. Moreover, the expressions of LINC00161 and ODRUL are associated with chemo-resistance of osteosarcoma. The mechanisms for these lncRNAs in regulating development of osteosarcoma are diverse, e.g. ceRNA, Wnt/β-catenin pathway, etc. The lncRNAs identified may serve as potential biomarkers or therapeutic targets for osteosarcoma.


Radiomic markers of intracerebral hemorrhage expansion on non-contrast CT: independent validation and comparison with visual markers.
To devise and validate radiomic signatures of impending hematoma expansion (HE) based on admission non-contrast head computed tomography (CT) of patients with intracerebral hemorrhage (ICH). Utilizing a large multicentric clinical trial dataset of hypertensive patients with spontaneous supratentorial ICH, we developed signatures predictive of HE in a discovery cohort (n = 449) and confirmed their performance in an independent validation cohort (n = 448). In addition to n = 1,130 radiomic features, n = 6 clinical variables associated with HE, n = 8 previously defined visual markers of HE, the BAT score, and combinations thereof served as candidate variable sets for signatures. The area under the receiver operating characteristic curve (AUC) quantified signatures' performance. A signature combining select radiomic features and clinical variables attained the highest AUC (95% confidence interval) of 0.67 (0.61-0.72) and 0.64 (0.59-0.70) in the discovery and independent validation cohort, respectively, significantly outperforming the clinical (pdiscovery = 0.02, pvalidation = 0.01) and visual signature (pdiscovery = 0.03, pvalidation = 0.01) as well as the BAT score (pdiscovery < 0.001, pvalidation < 0.001). Adding visual markers to radiomic features failed to improve prediction performance. All signatures were significantly (p < 0.001) correlated with functional outcome at 3-months, underlining their prognostic relevance. Radiomic features of ICH on admission non-contrast head CT can predict impending HE with stable generalizability; and combining radiomic with clinical predictors yielded the highest predictive value. By enabling selective anti-expansion treatment of patients at elevated risk of HE in future clinical trials, the proposed markers may increase therapeutic efficacy, and ultimately improve outcomes.


Deep-learning based super-resolution for 3D isotropic coronary MR angiography in less than a minute.
To develop and evaluate a novel and generalizable super-resolution (SR) deep-learning framework for motion-compensated isotropic 3D coronary MR angiography (CMRA), which allows free-breathing acquisitions in less than a minute. Undersampled motion-corrected reconstructions have enabled free-breathing isotropic 3D CMRA in ~5-10 min acquisition times. In this work, we propose a deep-learning-based SR framework, combined with non-rigid respiratory motion compensation, to shorten the acquisition time to less than 1 min. A generative adversarial network (GAN) is proposed consisting of two cascaded Enhanced Deep Residual Network generator, a trainable discriminator, and a perceptual loss network. A 16-fold increase in spatial resolution is achieved by reconstructing a high-resolution (HR) isotropic CMRA (0.9 mm3 or 1.2 mm3 ) from a low-resolution (LR) anisotropic CMRA (0.9 × 3.6 × 3.6 mm3 or 1.2 × 4.8 × 4.8 mm3 ). The impact and generalization of the proposed SRGAN approach to different input resolutions and operation on image and patch-level is investigated. SRGAN was evaluated on a retrospective downsampled cohort of 50 patients and on 16 prospective patients that were scanned with LR-CMRA in ~50 s under free-breathing. Vessel sharpness and length of the coronary arteries from the SR-CMRA is compared against the HR-CMRA. SR-CMRA showed statistically significant (P < .001) improved vessel sharpness 34.1% ± 12.3% and length 41.5% ± 8.1% compared with LR-CMRA. Good generalization to input resolution and image/patch-level processing was found. SR-CMRA enabled recovery of coronary stenosis similar to HR-CMRA with comparable qualitative performance. The proposed SR-CMRA provides a 16-fold increase in spatial resolution with comparable image quality to HR-CMRA while reducing the predictable scan time to <1 min.


Multiresidue method for the analysis of multiclass pesticides in agricultural products by gas chromatography-tandem mass spectrometry.
A multiresidue method is described for determining 55 organophosphorus and organochlorinated compounds and pyrethroids commonly used in crop protection. Pesticide residues are extracted from samples with a mixture of ethyl acetate and sodium sulfate, obtaining a final preconcentration of I mg sample (ml extract)(-1). No additional clean-up steps are necessary. Analysis is performed by gas chromatography by using a combination of positive chemical ionisation (PCI) and electron impact (EI) ionisation modes and tandem mass spectrometry (GC-PCI/EI-MS-MS). Good sensitivity and selectivity of the method are obtained with limits of detection (LODs) ranging from 0.07 to 4.21 microg kg(-1) in all the cases, except for methamidophos, permethrin, cypermethrin and difenconazol. Average recoveries between 52 and 114% are obtained and good linearity is observed in the studied ranges (r > or = 0.994). The RSD values are < or = 29% in all the cases. The method has been applied to the analysis of 178 vegetable samples, as a part of the monitoring programme of the Association of Producers and Exporters of Fruits and Vegetables of Almería (COEXPHAL) and quality control systems applied during the assays have demonstrated a good performance and stability with time.


[Improvement in diabetes control by treatment with bezafibrate].
380 diabetic patients with hyperlipidaemia and undergoing treatment with sulphonylureas or insulin were given 200 mg bezafibrate t.i.d for 3 months after a control period of 4 weeks. After cessation of treatment a follow-up examination was performed a further 4 weeks later. 194 treatment centres took part in the investigation. Total cholesterol fell by 17%, triglycerides by 36% and HDL-cholesterol rose by 15% during the treatment period. In addition, a glucose-lowering effect was seen which led to a definite improvement in the control of diabetes both with glibenclamide and with insulin. The degree of glucose reduction was most marked in moderately or poorly controlled diabetics. There was no correlation between the triglyceride reduction and the glucose reduction. After cessation of bezafibrate treatment the cholesterol, triglyceride and fasting glucose increased again and the HDL-cholesterol diminished. However, they did not reach pretreatment values. Bezafibrate was well tolerated, hypoglycaemia or hypoglycaemic reactions were not observed.


Characterization of the Hallé SSPE measles virus isolate.
The Hallé subacute sclerosing panencephalitis (SSPE) measles virus isolate and its plaque-purified progeny were investigated to determine whether any unusual properties could be associated with its ability to cause persistent infection. Three types of plaque-purified progeny were isolated. One population appeared to be similar in biological and biochemical properties to laboratory-adapted measles virus and had the ability to induce syncytia (syn+). A second population (syn-) plaqued more efficiently at 39 degrees C than at 33 degrees C, did not cause normal cell fusion at either temperature, and produced particles that interfered with the replication of other measles virus isolates in vivo and in vitro. This syn- virus was further plaque-purified to eliminate the interfering particles, producing the syn- P2 virus. This virus also plaqued more efficiently at 39 degrees C than at 33 degrees C, but caused cell fusion only at 39 degrees C. Both syn- viruses and the parental virus were significantly less virulent in vivo than the syn+ virus and caused a more prolonged infection. Biochemical analysis showed that the syn- P2 population produced particles that banded at two different densities in potassium tartrate gradients; both densities were less than those of the standard laboratory measles virus and the syn+ virus. Although the syn- P2 virus did not cause cell fusion at 33 degrees C, [35S]methionine labelling demonstrated that the haemolysin/cell fusion protein was present in syn- P2 virions. The production of interfering particles, the inability to cause cell fusion at 33 degrees C, and the cold-sensitive nature of the syn- population appear to play a role in the ability of the Hallé SSPE virus to establish persistent infection.


Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain-gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3-V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus, were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain-gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes.


Contextualizing gender disparities in online teaching evaluations for professors.
Student evaluation of teaching (SET) is widely used to assess teaching effectiveness in higher education and can significantly influence professors' career outcomes. Although earlier evidence suggests SET may suffer from biases due to the gender of professors, there is a lack of large-scale examination to understand how and why gender disparities occur in SET. This study aims to address this gap in SET by analyzing approximately 9 million SET reviews from RateMyProfessors.com under the theoretical frameworks of role congruity theory and shifting standards theory. Our multiple linear regression analysis of the SET numerical ratings confirms that women professors are generally rated lower than men in many fields. Using the Dunning log-likelihood test, we show that words used in student comments vary by the gender of professors. We then use BERTopic to extract the most frequent topics from one- and five-star reviews. Our regression analysis based on the topics reveals that the probabilities of specific topics appearing in SET comments are significantly associated with professors' genders, which aligns with gender role expectations. Furtherly, sentiment analysis indicates that women professors' comments are more positively or negatively polarized than men's across most extracted topics, suggesting students' evaluative standards are subject to professors' gender. These findings contextualize the gender gap in SET ratings and caution the usage of SET in related decision-making to avoid potential systematic biases towards women professors.


[Blood component replacement in bone marrow aplasia in patients after aggressive chemotherapy for malignant hematologic diseases].
Aggressive chemotherapy of malignant haematological diseases causes long-term aplasia of bone marrow and it is necessary to supplement blood elements repeatedly. When procuring blood derivates frequently dramatic situations develop. In an attempt to prevent alloimmunization of the patient by careful selection of the donor the time interval between indication and administration of the transfusion is prolonged. The objective of the present work was to attempt an estimate, as regards time and amount, for transfusion of blood derivates. The authors analyzed 100 cycles of aggressive chemotherapy with regard to changes of the haemogram. The group was divided arbitrarily with regard to the initial value of different components of the haemogram and for these portions of the group a time schedule of check-up examinations of the haemogram and of the assumed time of indication of transfusion of blood derivates was elaborated. In patients with an initial values of red blood cells above 3.5 x 10(12)/l the first transfusion is usually needed on the 8th day after the beginning of chemotherapy, in patients with a values lower than 3.0 x 10(12)/l after the initial supplementation a further drop may be expected already on the 4th day. Indication of replacement of thrombocytes can be expected in patients with an initial thrombocyte value above 120 x 10(9)/l cca on the 8th day, in patients with an initial thrombocyte value of 30 x 10(9)/l after initial replacement indication of another transfusion can be anticipated already on the 4th day after the beginning of chemotherapy.


Using Artificial Intelligence to Diagnose Osteoporotic Vertebral Fractures on Plain Radiographs.
Osteoporotic vertebral fracture (OVF) is a risk factor for morbidity and mortality in elderly population, and accurate diagnosis is important for improving treatment outcomes. OVF diagnosis suffers from high misdiagnosis and underdiagnosis rates, as well as high workload. Deep learning methods applied to plain radiographs, a simple, fast, and inexpensive examination, might solve this problem. We developed and validated a deep-learning-based vertebral fracture diagnostic system using area loss ratio, which assisted a multitasking network to perform skeletal position detection and segmentation and identify and grade vertebral fractures. As the training set and internal validation set, we used 11,397 plain radiographs from six community centers in Shanghai. For the external validation set, 1276 participants were recruited from the outpatient clinic of the Shanghai Sixth People's Hospital (1276 plain radiographs). Radiologists performed all X-ray images and used the Genant semiquantitative tool for fracture diagnosis and grading as the ground truth data. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were used to evaluate diagnostic performance. The AI_OVF_SH system demonstrated high accuracy and computational speed in skeletal position detection and segmentation. In the internal validation set, the accuracy, sensitivity, and specificity with the AI_OVF_SH model were 97.41%, 84.08%, and 97.25%, respectively, for all fractures. The sensitivity and specificity for moderate fractures were 88.55% and 99.74%, respectively, and for severe fractures, they were 92.30% and 99.92%. In the external validation set, the accuracy, sensitivity, and specificity for all fractures were 96.85%, 83.35%, and 94.70%, respectively. For moderate fractures, the sensitivity and specificity were 85.61% and 99.85%, respectively, and 93.46% and 99.92% for severe fractures. Therefore, the AI_OVF_SH system is an efficient tool to assist radiologists and clinicians to improve the diagnosing of vertebral fractures. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Identifying Continuous Quality Improvement Priorities in Maternal, Infant, and Early Childhood Home Visiting.
The purpose of this article was to describe a methodology to identify continuous quality improvement (CQI) priorities for one state's Maternal, Infant, and Early Childhood Home Visiting program from among the 40 required constructs associated with 6 program benchmarks. The authors discuss how the methodology provided consensus on system CQI quality measure priorities and describe variation among the 3 service delivery models used within the state. Q-sort methodology was used by home visiting (HV) service delivery providers (home visitors) to prioritize HV quality measures for the overall state HV system as well as their service delivery model. There was general consensus overall and among the service delivery models on CQI quality measure priorities, although some variation was observed. Measures associated with Maternal, Infant, and Early Childhood Home Visiting benchmark 1, Improved Maternal and Newborn Health, and benchmark 3, Improvement in School Readiness and Achievement, were the highest ranked. The Q-sort exercise allowed home visitors an opportunity to examine priorities within their service delivery model as well as for the overall First Teacher HV system. Participants engaged in meaningful discussions regarding how and why they selected specific quality measures and developed a greater awareness and understanding of a systems approach to HV within the state. The Q-sort methodology presented in this article can easily be replicated by other states to identify CQI priorities at the local and state levels and can be used effectively in states that use a single HV service delivery model or those that implement multiple evidence-based models for HV service delivery.


Anatomy of the sense of touch in sea otters: Cutaneous mechanoreceptors and structural features of glabrous skin.
Sea otters (Enhydra lutris) demonstrate rapid, accurate tactile abilities using their paws and facial vibrissae. Anatomical investigations of neural organization in the vibrissal bed and somatosensory cortex coincide with measured sensitivity, but no studies describe sensory receptors in the paws or other regions of glabrous (i.e., hairless) skin. In this study, we use histology to assess the presence, density, and distribution of mechanoreceptors in the glabrous skin of sea otters: paws, rhinarium, lips, and flipper digits, and we use scanning electron microscopy to describe skin-surface texture and its potential effect on the transduction of mechanical stimuli. Our results confirm the presence of Merkel cells and Pacinian corpuscles, but not Meissner corpuscles, in all sea otter glabrous skin. The paws showed the highest density of Merkel cells and Pacinian corpuscles. Within the paw, relative densities of mechanoreceptor types were highest in the distal metacarpal pad and digits, which suggests that the distal paw is a tactile fovea for sea otters. In addition to the highest receptor density, the paw displayed the thickest epidermis. Rete ridges (epidermal projections into the dermis) and dermal papillae (dermal projections into the epidermis) were developed across all glabrous skin. These quantitative and qualitative descriptions of neural organization and physical features, combined with previous behavioral results, contribute to our understanding of how structure relates to function in the tactile modality. Our findings coincide with behavioral observations of sea otters, which use touch to maintain thermoregulatory integrity of their fur, explore objects, and capture visually cryptic prey.


Effects of subsidy quality on reciprocal subsidies: how leaf litter species changes frog biomass export.
Spatial subsidies are resources transferred from one ecosystem to another and which can greatly affect recipient systems. Increased subsidy quantity is known to increase these effects, but subsidy quality is likely also important. We examined the effects of leaf litter quality (varying in nutrient and tannin content) in pond mesocosms on gray treefrog (Hyla versicolor) biomass export, as well as water quality and ecosystem processes. We used litter from three different tree species native to Missouri [white oak (Quercus alba), northern red oak (Quercus rubra), and sugar maple (Acer saccharum)], one non-native tree [white pine (Pinus strobus)], and a common aquatic grass [prairie cordgrass (Spartina pectinata)]. We found that leaf litter species affected almost every variable we measured. Gray treefrog biomass export was greatest in mesocosms with grass litter and lowest with white oak litter. Differences in biomass export were affected by high tannin concentrations (or possibly the correlated variable, dissolved oxygen) via their effects on survival, and by primary production, which altered mean body mass. Effects of litter species could often be traced back to the characteristics of the litter itself: leaf nitrogen, phosphorus, and tannin content, which highlights the importance of plant functional traits in affecting aquatic ecosystems. This work and others stress that changes in forest species composition could greatly influence aquatic systems and aquatic-terrestrial linkages.


Understanding tricuspid valve remodelling in atrial fibrillation using three-dimensional echocardiography.
Atrial fibrillation (AF) has been associated with tricuspid annulus (TA) dilation in patients with severe functional tricuspid regurgitation (TR); however, the impact of AF is less clear in patients without severe TR. Our aim was to characterize TA remodelling in patients with AF in the absence of severe TR using 3D transoesophageal echocardiography (TOE). Ninety patients underwent clinically indicated transthoracic and TOE: non-structural (NS)-AF (n = 30); AF with left heart disease (LHD) (n = 30), and controls in sinus rhythm (n = 30). Three-dimensional TOE datasets were analysed to measure TA dimensions using novel dedicated tricuspid valve software. The NS-AF group showed biatrial dilatation and normal right ventricular (RV) size with decreased longitudinal function compared to controls, whereas the LHD-AF group showed biatrial dilatation, RV enlargement, decreased biventricular function, and higher systolic pulmonary artery pressure compared with the other groups. Indexed TA area, minimum diameter, maximum diameter, and total perimeter were significantly larger in the NS-AF group than in controls (measurements in end-diastole: 6.4 ± 1.1 vs. 5.0 ± 0.6 cm2/m2, 1.8 ± 0.3 vs. 1.6 ± 0.2 cm/m2, 2.1 ± 0.3 vs. 1.9 ± 0.2 cm/m2, and 6.6 ± 0.9 vs. 5.9 ± 0.7 cm/m2, respectively, all P < 0.05). There was no significant difference in any indexed TA parameter between AF groups. TA circularity index (ratio between minimum and maximal diameters) and TA fractional area change between end-diastole and end-systole were no different among the three groups. AF is associated with right atrial and tricuspid annular remodelling independent of the presence of LHD in patients with intrinsically normal tricuspid leaflets without severe TR.


[Geographic aspects in the allocation of kidney transplants in Switzerland].
By tradition kidney transplants in Switzerland are allocated to recipients on a regional basis. Since multi-organ donation became routine, teams traveling all over Switzerland have been accused of harvesting not only the livers but at the same time kidneys, thus withholding such kidneys from regional recipients. In order to investigate this suspicion, we analyzed the place of residence of all kidney donors and recipients during a twelve months' period. Shipping for reasons of matching was not analyzed. We found only minor imbalances between the six transplant centers. We conclude that the allocation of kidney transplants in Switzerland is satisfactory from a geographical point of view. The analysis of donor hospitals, however, shows intense organ recruitment in the referred area of Zurich. In other regions, abstinence from organ recruitment outside the transplant centers is evident. To increase organ availability, the motivation and collaboration of hospitals outside transplant centers needs to be improved.


Cation Diffusion in Compacted Clay: A Pore-Scale View.
Cation diffusion through compacted clays is of great interest due to its potential for buffer materials for waste disposal. The importance of the electrokinetic effect on cationic tracer diffusion is investigated by using pore-scale simulations to consider the influence from the electrokinetic properties and topology of clays. It is indicated that the normalized volume charge density has a significant impact on the cationic diffusion. In clays with a large normalized volume charge density, the electrical double layer has the major impact on cationic diffusion. When the ion strength of the pore solution is constant, the flux from the electromigration term can be negligible. However, once an ion strength gradient is added, the electromigration process should be considered carefully due to its non-negligible role to balance the alteration of total flux. The present study could help improve the understanding of the transport mechanism of simple cationic tracers in compacted clays.


S-Allylmercapro-N-Acetylcysteine Attenuates the Oxidation-Induced Lens Opacification and Retinal Pigment Epithelial Cell Death In Vitro.
The capacity of S-Allylmercapto-N-acetylcysteine (ASSNAC) to protect human retinal pigment epithelial (RPE) cells (line ARPE-19) and porcine lenses from oxidative stress was studied. Confluent ARPE-19 cultures were incubated with ASSNAC or N-acetyl-cysteine (NAC) followed by exposure to oxidants and glutathione level and cell survival were determined. Porcine lenses were incubated with ASSNAC and then exposed to H₂O₂ followed by lens opacity measurement and determination of glutathione (reduced (GSH) and oxidized (GSSG)) in isolated lens adhering epithelial cells (lens capsule) and fiber cells consisting the lens cortex and nucleus (lens core). In ARPE-19 cultures, ASSNAC (0.2 mM; 24 h) increased glutathione level by 2⁻2.5-fold with significantly higher increase in GSH compared to NAC treated cultures. Similarly, ex-vivo exposure of lenses to ASSNAC (1 mM) significantly reduced the GSSG level and prevented H₂O₂ (0.5 mM)-induced lens opacification. These results demonstrate that ASSNAC up-regulates glutathione level in RPE cells and protects them from oxidative stress-induced cell death as well as protects lenses from oxidative stress-induced opacity. Further validation of these results in animal models may suggest a potential use for ASSNAC as a protective therapy in retinal degenerative diseases as well as in attenuation of oxidative stress-induced lens opacity.