Matrix metalloproteinase levels in early HIV infection and relation to in vivo brain status.
Matrix metalloproteinases (MMPs) have been implicated in human immunodeficiency virus (HIV)-associated neurological injury; however, this relationship has not been studied early in infection. Plasma levels of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-10 measured using Luminex technology (Austin, TX, USA) were compared in 52 HIV and 21 seronegative participants of the Chicago Early HIV Infection study. MMP levels were also examined in HIV subgroups defined by antibody reactivity, viremia, and antiretroviral status, as well as in available cerebrospinal fluid (CSF) samples (n = 9). MMPs were evaluated for patterns of relationship to cognitive function and to quantitative magnetic resonance measurements of the brain derived in vivo. Plasma MMP-2 levels were significantly reduced in early HIV infection and correlated with altered white matter integrity and atrophic brain changes. MMP-9 levels were higher in the treated subgroup than in the naïve HIV subgroup. Only MMP-2 and MMP-9 were detected in the CSF; CSF MMP-2 correlated with white matter integrity and with volumetric changes in basal ganglia. Relationships with cognitive function were also identified. MMP-2 levels in plasma and in CSF correspond to early changes in brain structure and function. These findings establish a link between MMPs and neurological status previously unidentified in early HIV infection.


Cloning of a cDNA encoding MAP1B in rat brain: regulation of mRNA levels during development.
This article describes the isolation of a microtubule-associated protein 1B (MAP1B) cDNA clone from a rat brain lambda gt11 library and the study of MAP1B mRNA expression during brain development. On Northern blots, the cDNA hybridized with an mRNA of greater than 10 kilobases which was present only in the brain. The identity of the cDNA was confirmed by the characterization of the antiserum against the fusion protein, and also by comparing both the original antibody and the anti-fusion protein antiserum with a panel of well-studied monoclonal antibodies against different forms of MAP1 and MAP2. The regulation of MAP1B mRNA during development was studied in whole brain, cerebral cortex, hypothalamus, brainstem, and olfactory bulbs. The steady-state levels of MAP1B mRNA in all tissues examined were relatively low in the adult compared to developing brains. This decrease varied in different brain regions, and its time course appeared to coincide with the pattern of postnatal developmental and morphological events. The developmental patterns of the MAP1B mRNA and protein in the brain were similar, suggesting that expression of this protein is under transcriptional control. The RNA blots were also probed with beta-actin and beta-tubulin to compare the levels of MAP1B mRNA with other cytoskeletal elements and as controls for the quality of the RNA.


Congenital tuberculosis presenting as cutaneous disease in a premature infant.
We report a premature neonate who developed bizarre multiple skin lesions after being cured from hyaline membrane disease. These lesions were thought initially as multiple abscesses at the puncture sites, which did not respond to the conventional antibiotics. Biopsy of the skin lesion was of great importance in reaching the diagnosis of congenital tuberculosis as cutaneous disease.


Uptake of 5-hydroxytryptamine by isolated platelets in childhood schizophrenia and autism.
Previous work indicated a platelet abnormality in the in vitro accumulation of serotonin in childhood schizophrenia, especially infantile autism. The present report validates this further in cases of infantile autism and shows that the abnormality seems to be due to the platelets. The defect is apparently associated with the platelet and not the plasma.


Serum uromodulin in dogs with chronic kidney disease.
Serum uromodulin concentration has been described as a novel biomarker of chronic kidney disease (CKD) in humans but not dogs. To evaluate the serum uromodulin concentration in dogs with CKD and assess its diagnostic performance in distinguishing dogs with CKD from healthy dogs. Forty-nine dogs with CKD (International Renal Interest Society [IRIS] Stage 1, n = 23; Stage 2, n = 20; Stage 3-4, n = 6) and 25 healthy controls. Prospective, observational study. Serum uromodulin concentration was measured using a canine-specific enzyme-linked immunosorbent assay (ELISA), and its correlation with conventional renal markers was analyzed. Serum uromodulin concentrations were significantly lower in the CKD group than in the control group (P < .001), but no significant difference was observed among stages of CKD. A negative correlation was observed between serum uromodulin concentration and conventional renal markers (blood urea nitrogen concentration, r = -.60, P < .0001; serum creatinine concentration, r = -.46, P < .0001; serum symmetric dimethylarginine concentration [SDMA], r = -.65, P < .0001). In receiver operating characteristic analysis, the area under the curve (AUC) of uromodulin (AUC, 0.97; 95% confidence interval [CI], 0.94-1.00) was higher than that of SDMA (AUC, 0.87; 95% CI, 0.79-0.95) for CKD diagnosis (P = .01). The AUC of uromodulin (AUC, 0.95; 95% CI, 0.89-1.00) also was higher than that of SDMA (AUC, 0.72; 95% CI, 0.58-0.87) in distinguishing dogs with Stage 1 CKD from controls (P = .001). Serum uromodulin concentration is decreased in dogs with CKD. Thus, serum uromodulin may be a valuable diagnostic marker for CKD in dogs, particularly in identifying early-stage CKD.


Genome-wide identification and characterization of bZIP gene family and cloning of candidate genes for anthocyanin biosynthesis in pomegranate (Punica granatum).
The basic leucine zipper (bZIP) transcription factor is one of the most abundant and conserved gene families in eukaryotes. In addition to participating in plant development and growth, bZIP transcription factors play crucial roles in various abiotic stress responses and anthocyanin accumulation. Up to now, analysis of bZIP gene family members in pomegranate (Punica granatum) has not been reported. Three published pomegranate genome sequences provide valuable resources for further gene function analysis. Using bioinformatics analysis, 65 PgbZIPs were identified and analyzed from the 'Taishanhong' pomegranate genome. We divided them into 13 groups (A, B, C, D, E, F, G, H, I, J, K, M, and S) according to the phylogenetic relationship with those of Arabidopsis, each containing a different number of genes. The regularity of exon/intron number and distribution was consistent with the classification of groups in the evolutionary tree. Transcriptome analysis of different tissues showed that members of the PgbZIP gene family were differentially expressed in different developmental stages and tissues of pomegranate. Among them, we selected PgbZIP16 and PgbZIP34 as candidate genes which affect anthocyanin accumulation. The full-length CDS region of PgbZIP16 and PgbZIP34 were cloned from pomegranate petals by homologous cloning technique, encoding 170 and 174 amino acids, which were 510 bp and 522 bp, respectively. Subcellular localization assays suggested that both PgbZIP16 and PgbZIP34 were nucleus-localized. Real-time quantitative PCR (qPCR) was used to explore the expression of PgbZIP16 and PgbZIP34 in the petals of three kinds of ornamental pomegranates at the full flowering stage. The results demonstrated that the expression of PgbZIP16 in red petals was 5.83 times of that in white petals, while PgbZIP34 was 3.9 times. The results of transient expression in tobacco showed that consistent trends were observed in anthocyanin concentration and expression levels of related genes, which both increased and then decreased. Both PgbZIP16 and PgbZIP34 could promote anthocyanin accumulation in tobacco leaves. We obtained transgenic strains overexpressing PgbZIP16, and the histochemical staining for GUS activity showed that overexpressed PgbZIP16 seedlings were expressed in the stem. Transgenic experiments indicated that overexpression of PgbZIP16 significantly upregulated UF3GT, ANS and DFR genes in Arabidopsis and enhanced anthocyanin accumulation. The whole genome identification, gene structure, phylogeny, gene cloning, subcellular location and functional verification of the pomegranate bZIP gene family provide a theoretical foundation for the functional study of the PgbZIP gene family and candidate genes for anthocyanin biosynthesis.


Successful treatment of ankylosing spondylitis with alternative and complementary medicine withdrawal of adalimumab treatment.
Current treatment strategies for ankylosing spondylitis (AS) include adalimumab and other biological drugs. However, treatment failures and side effects are commonly observed. This report documents the successful use of supplements and dietary changes to treat a patient with AS after cessation of adalimumab therapy. A 38-year-old human leukocyte antigen B27 positive female patient with AS showed no improvement when treated with a non-steroidal anti-inflammatory drug. The patient then began adalimumab therapy with some success; however, after nine months, she developed a disseminated and refractory Molluscum contagiosum infection. Adalimumab was withdrawn, and the patient started taking supplements, while adopting an anti-inflammatory diet (dairy-free, gluten-free, and sugar-free). Normalization of inflammatory markers was achieved after two months, and magnetic resonance imaging of the sacroiliac revealed a notable physical improvement.


Adjustment to intermittent access in rats drinking saccharin: II. Adjustment of lapping rate.
Hungary rats were permitted to drink saccharin under conditions in which (a) the drinking spout was available continuously, or (b) it was withdrawn during alternate 30-sec periods. Rats adjust to such constraint by increasing their integrated lap rate (laps/min). We show that one way in which they do this is to lap at a higher rate within bursts of lapping. This faster lapping is not an artifact of forced interruptions and resumptions. It cannot only be maintained over a drinking session, but also initiated midway through the session if restricted access is imposed then. Therefore, the period of the lapping cycle can be adjusted, within limits, in response to situational constraints on access to the fluid.


Analysis for fractional dynamics of Ebola virus model.
Ebola virus is very challenging problem of the world. The main purpose of this work is to study fractional Ebola virus model. An efficient computational method based on iterative scheme is proposed to solve fractional Ebola model numerically. Stability of proposed method is also discussed. Efficiency of proposed method is shown by listing CPU time. Proposed computational method will work for long time domain. Numerical results are presented graphically. The main reason for using this technique is low computational cost and high accuracy. It is also shown how the approximate solution varies for fractional and integer order Ebola virus model.


Harsh Environments, Life History Strategies, and Adjustment: A Longitudinal Study of Oregon Youth.
We modeled the effects of harsh environments in childhood on adjustment in early emerging adulthood, through parenting style and the development of fast Life History Strategies (LHS; risky beliefs and behaviors) in adolescence. Participants were from the Oregon Youth Substance Use Project (N = 988; 85.7% White). Five cohorts of children in Grades 1-5 at recruitment were assessed through one-year post high school. Greater environmental harshness (neighborhood quality and family poverty) in Grades 1-6 predicted less parental investment at Grade 8. This parenting style was related to the development of fast LHS (favorable beliefs about substance users and willingness to use substances at Grade 9, and engagement in substance use and risky sexual behavior assessed across Grades 10-12). The indirect path from harsh environment through parenting and LHS to (less) psychological adjustment (indicated by lower life satisfaction, self-rated health, trait sociability, and higher depression) was significant (indirect effect -.024, p = .011, 95% CI = -.043, -.006.). This chain of development was comparable to that found by Gibbons et al. (2012) for an African-American sample that, unlike the present study, included perceived racial discrimination in the assessment of harsh environment.


[Chronic obstructive pulmonary disease: pathophysiology, diagnosis, and therapy].
Chronic obstructive pulmonary disease (COPD), a complex disease triggered mostly by exposure to cigarette smoke, is a leading cause of morbidity and mortality worldwide, leading not only to pulmonary damage but also to systemic impairment. There is growing awareness of systemic inflammation and cardiovascular, neurologic, psychiatric, and endocrine comorbidities associated with COPD. The diagnosis of CODP is based upon the clinical presentation, measurement of the pulmonary function, investigation of comorbidities and exclusion of differential diagnoses. COPD is a heterogeneous disease including various phenotypes. A number of drugs reduce or alleviate symptoms, increase exercise capacity, or reduce the number and severity of exacerbations. Non-pharmacologic measures such as smoking cessation, nutritional support, long term oxygen therapy, physiotherapy, rehabilitation, lung volume reduction and lung transplantation may be available for appropriate patients and can improve health status.


The "crush and aspiration" technique for debridement of the aortic annulus revisited.
An effective technique for the debridement of the aortic annulus using a needle holder to crush the calcify nodules, follow by the immediate aspiration of the pulverized material using a Yankauer suction device is reported.


Prevalence of depression and anxiety in end-stage renal disease: A survey of patients undergoing hemodialysis.
Dialysis is a lifelong treatment required by end stage renal disease patients who are not able to undergo renal transplantation. Dialysis impacts the patients' quality of life drastically, increasing the risk of mortality. Depression and anxiety are commonly reported among dialysis patients, but their prevalence and correlates vary by sociocultural context. The aim of this study is to examine the prevalence of anxiety and depression and associated factors among patients receiving hemodialysis at a major tertiary referral medical center in Lebanon that receives patients from all over the country. A cross-sectional, descriptive design was used. Ninety patients receiving hemodialysis were targeted using convenience sampling, with a final sample size of 83 patients. The patients were interviewed while undergoing their dialysis session using the Hospital Anxiety and Depression Scale, and asked demographic and clinical questions. The majority of participants were married men over 60 years of age; 48% achieved high school education. Depression was prevalent in 40.8% and anxiety in 39.6%, with 20 patients (24.1%) having both conditions. Although 24.1% self-reported anxiety symptoms, only 2.4% were taking anxiolytics. Illiterate patients had significantly higher depression scores than those with higher levels of education (p = 0.021). Patients who were living with their family had higher anxiety scores than those living alone (p = 0.014). Anxiety and depression are underdiagnosed and undertreated in Lebanese dialysis patients. Screening and appropriate referral to mental health specialists are needed.


Factors for Predicting the Therapeutic Efficacy of Laryngeal Contact Granuloma.
To explore the factors affecting the therapeutic efficacy of laryngeal contact granuloma. The clinical data of 534 patients with laryngeal contact granuloma treated in our hospital from April 2014 to December 2019 were studied. The multivariable logistic regression was performed to find the risk factors influencing the treatment efficacy. Multivariable logistic regression showed that factors related to therapeutic efficacy were granuloma size (P = 0.0006) and gender (P = 0.0299) in conservative treatment group; laryngopharyngeal reflux (P = 0.0115), cough (P = 0.0124), and previous surgical history (P < 0.001) in combined treatment group. The surgical treatment had the worst therapeutic efficacy compared with combined treatment and conservative treatment. In the larger granuloma size subgroup, combined treatment showed better results than conservative treatment. Granuloma size and gender affect the therapeutic efficacy of conservative treatment. Previous surgical history, laryngopharyngeal reflux, and cough affect the therapeutic efficacy of combined treatment. Combined treatment is better than conservative treatment alone and surgical treatment shows the worst efficacy.


Spinal neurons that contain gastrin-releasing peptide seldom express Fos or phosphorylate extracellular signal-regulated kinases in response to intradermal chloroquine.
Gastrin-releasing peptide (GRP) is thought to play a role in the itch evoked by intradermal injection of chloroquine. Although some early studies suggested that GRP was expressed in pruriceptive primary afferents, it is now thought that GRP in the spinal cord is derived mainly from a population of excitatory interneurons in lamina II, and it has been suggested that these are involved in the itch pathway. To test this hypothesis, we used the transcription factor Fos and phosphorylation of extracellular signal-regulated kinases (ERK) to look for evidence that interneurons expressing GRP were activated following intradermal injection of chloroquine into the calf, in mice that express enhanced green fluorescent protein (EGFP) in these cells. Injection of chloroquine resulted in numerous Fos- or phospho-ERK (pERK) positive cells in the somatotopically appropriate part of the superficial dorsal horn. The proportion of all neurons in this region that showed Fos or pERK was 18% and 21%, respectively. However, among the GRP-EGFP, only 7% were Fos-positive and 3% were pERK-positive. As such, GRP-EGFP cells were significantly less likely than other neurons to express Fos or to phosphorylate ERK. Both expression of Fos and phosphorylation of ERK can be used to identify dorsal horn neurons activated by chloroquine injection. However, these results do not support the hypothesis that interneurons expressing GRP are critical components in the itch pathway.


In vitro studies of the metabolic pathway from 8-COOH porphyrins to 4-COOH porphyrins.
The authors report the experiments about incubation of uroporphyrinogen with sonified fibroblasts of normal individuals and prophyrics and present the hypothesis of the absence of deficiency in the activity of uroporphyrinogendecarboxylase.


Peripherally induced brain tissue-resident memory CD8+ T cells mediate protection against CNS infection.
The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (TRM) CD8+ T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain TRM cells. We show that peripheral infections generate antigen-specific CD8+ memory T cells in the brain that adopt a unique TRM signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain TRM cells was revealed by intravital imaging. Notably, peripherally induced brain TRM cells showed evidence of rapid activation and enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain TRM cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.


A method for assessing alertness fluctuations from EEG spectra.
The object of the study was to develop a method for automatic evaluation of the vigilance level using the EEG frequency pattern. Forty-one EEG records were selected as training material, being considered representative of either a fully alert EEG, or sleep stage I. In the same epochs, 22 different variables based on EEG spectral analysis were calculated. Multiple regression analysis was applied to determine the correlation between the spectral values and the assigned levels of vigilance. The coefficients obtained were applied to the spectral values of 265 epochs belonging to another set of tracings, for estimation of the vigilance level. The correlation between the automatic and visual finding was 0.89 in the training material and 0.86 in the test material. The method can be used to evaluate the mean vigilance level and its variance, rhythmicity and trend during the examination. The preliminary results suggest that objective measurement of alertness can be of value in many applications, such as in pharmacological research, in evaluation of certain psychic symptoms and in working environment studies.


[Effect of physical load on cholesterol content in different classes of lipoproteins of blood serum and their decomposition].
An increase in the amount of cholesterol is established in blood serum high-density lipoproteins of rabbits which were subjected to moderate physical loads. Under these conditions an accelerated decay was also observed for lipoproteins of very low and low density.


Irisin/FNDC5 inhibits the epithelial-mesenchymal transition of epithelial ovarian cancer cells via the PI3K/Akt pathway.
This study explored the role of irisin/fibronectin type III domain-containing protein 5 (FNDC5) in epithelial ovarian cancer and investigated its underlying mechanisms. Immunohistochemistry was performed to analyze the expression of irisin/FNDC5 in epithelial ovarian cancer and normal ovarian tissues. Cell Counting Kit-8, transwell, and wound-healing assays were performed to examine the effect of irisin on the viability, migration, and invasion of ovarian cancer cells, respectively. Western blotting was used to detect the changes of epithelial-mesenchymal transition (EMT)-related proteins and phosphatidylinositol 3-kinase (PI3K)/Akt pathway proteins. Ovarian cancer cells were treated in vitro with the PI3K agonist (740Y-P) in combination with irisin to explore the mechanism of irisin in ovarian cancer. The expression of irisin/FNDC5 in epithelial ovarian cancer tissue was significantly higher than that in normal ovarian tissues, and the expression in late stage patients with lymph node metastasis was lower than that in early stage patients without metastasis. Irisin inhibited the proliferation, invasion, and migration of epithelial ovarian cancer cells, down-regulated phosphorylated Akt, and inhibited EMT progression. The PI3K agonist, 740Y-P, partially reversed the effects of irisin on the invasion, migration, and EMT of ovarian cancer cells. These findings show that irisin/FNDC5 was highly expressed in ovarian cancer tissues, which may regulate the EMT through the PI3K/Akt signaling pathway and inhibit the proliferation, invasion, and migration of epithelial ovarian cancer.


A Comparative Study Between Uncemented and Hybrid Total Hip Arthroplasty in Octogenarians.
The aim of this prospective cohort study is to evaluate the outcome of octogenarian patients undergoing uncemented total hip arthroplasty (THA) with a control group of similarly aged patients undergoing hybrid THA with a minimum 5-year follow-up. Clinical outcomes including intraoperative and postoperative complications, blood transfusion, revision rate, and mortality were recorded. Radiological analysis of preoperative and postoperative radiographs assessed bone quality, implant fixation, and any subsequent loosening. One hundred forty-three patients (mean age 86.2 years) were enrolled in the study. Seventy-six patients underwent uncemented THA and 67 underwent hybrid THA. The uncemented cohort had a significantly lower intraoperative complication rate (P = .017) and also a lower transfusion rate (P = .002). Mean hospital stay (P = .27) was comparable between the 2 groups. Two patients underwent revision surgery in each cohort. Our study demonstrates that uncemented THA is safe for the octogenarian patient and we recommend that age should not be a barrier to the choice of implant. However, intraoperative assessment of bone quality should guide surgeons to the optimum decision regarding uncemented and hybrid implants. 3.


Pancreatic disorders in the newborn.
Except for the hyperinsulinism associated with the infant of a diabetic mother (accounting for about 5 percent of NICU admissions annually), pancreatic disorders of the newborn are rare. Congenital anomalies (such as annular pancreas) and endocrine disorders (such as hyperinsulinism of nesidioblastosis or hyperglycemia of neonatal diabetes mellitus) present many challenges to the personnel caring for these infants and their families. The potential mortality and morbidity of these disorders make it imperative for nurses and nurse practitioners working with infants to recognize and understand pancreatic dysfunction so that appropriate and timely intervention can prevent complications of brain injury and developmental delay. The home care needs of these infants and the extensive teaching needs of their parents require skilled nursing care to ensure a safe discharge.


Rupture process of the 2021 M7.4 Maduo earthquake and implication for deformation mode of the Songpan-Ganzi terrane in Tibetan Plateau.
The deformation mode of the Tibetan Plateau is of crucial importance for understanding its construction and extrusion processes, as well as for the assessment of regional earthquake potential. Block motion and viscous flow models have been proposed to describe the deformation field but are not fully supported by modern geophysical observations. The 2021 Mw 7.4 Maduo earthquake, which occurred inside the Songpan-Ganzi terrane (SGT) in central-east Tibet, provides a chance to evaluate the associated deformation mode of the region. We conduct a joint inversion for this earthquake and resolve a bilateral rupture process, which is characterized by super- and subshear rupture velocities, respectively. We interpret this distinct rupture behavior to be the result of the respective slip concentration depths of the two ruptured segments. We analyze geological, seismic, and geodetic evidence and find that the SGT upper crust shows distributed shear deformation and distinct transverse anisotropy, which are associated with folded structures originating from compression of the paleo-Tethys ocean accretional prism realigned by following shear deformation. The SGT receives lateral shear loading from its NS boundary and accommodates a right-step sinistral motion across the terrane boundary faults. The unique tectonic setting of the SGT defines locations and behaviors of internal faulting and strong earthquakes such as the 2021 Maduo earthquake, with the latter occurring on slow-moving faults at intervals of several thousands of years.


The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases.
Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARΓ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4(+) T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.


MaGuS: a tool for quality assessment and scaffolding of genome assemblies with Whole Genome Profiling™ Data.
Scaffolding is an essential step in the genome assembly process. Current methods based on large fragment paired-end reads or long reads allow an increase in contiguity but often lack consistency in repetitive regions, resulting in fragmented assemblies. Here, we describe a novel tool to link assemblies to a genome map to aid complex genome reconstruction by detecting assembly errors and allowing scaffold ordering and anchoring. We present MaGuS (map-guided scaffolding), a modular tool that uses a draft genome assembly, a Whole Genome Profiling™ (WGP) map, and high-throughput paired-end sequencing data to estimate the quality and to enhance the contiguity of an assembly. We generated several assemblies of the Arabidopsis genome using different scaffolding programs and applied MaGuS to select the best assembly using quality metrics. Then, we used MaGuS to perform map-guided scaffolding to increase contiguity by creating new scaffold links in low-covered and highly repetitive regions where other commonly used scaffolding methods lack consistency. MaGuS is a powerful reference-free evaluator of assembly quality and a WGP map-guided scaffolder that is freely available at https://github.com/institut-de-genomique/MaGuS. Its use can be extended to other high-throughput sequencing data (e.g., long-read data) and also to other map data (e.g., genetic maps) to improve the quality and the contiguity of large and complex genome assemblies.


Oxic-anoxic regime shifts mediated by feedbacks between biogeochemical processes and microbial community dynamics.
Although regime shifts are known from various ecosystems, the involvement of microbial communities is poorly understood. Here we show that gradual environmental changes induced by, for example, eutrophication or global warming can induce major oxic-anoxic regime shifts. We first investigate a mathematical model describing interactions between microbial communities and biogeochemical oxidation-reduction reactions. In response to gradual changes in oxygen influx, this model abruptly transitions between an oxic state dominated by cyanobacteria and an anoxic state with sulfate-reducing bacteria and phototrophic sulfur bacteria. The model predictions are consistent with observations from a seasonally stratified lake, which shows hysteresis in the transition between oxic and anoxic states with similar changes in microbial community composition. Our results suggest that hysteresis loops and tipping points are a common feature of oxic-anoxic transitions, causing rapid drops in oxygen levels that are not easily reversed, at scales ranging from small ponds to global oceanic anoxic events.The role of microbial communities in regime shifts is poorly understood. Here, the authors use a mathematical model and field data from a seasonally stratified lake to show that gradual environmental changes can induce oxic-anoxic regime shifts mediated by microbial community dynamics and redox processes.


Towards the optimization of passive undulatory locomotion on land: mathematical and physical models.
The current study investigates the body-environment interaction and exploits the passive viscoelastic properties of the body to perform undulatory locomotion. The investigations are carried out using a mathematical model based on a dry frictional environment, and the results are compared with the performance obtained using a physical model. The physical robot is a wheel-based modular system with flexible joints moving on different substrates. The influence of the spatial distribution of body stiffness on speed performance is also investigated. Our results suggest that the environment affects the performance of undulatory locomotion based on the distribution of body stiffness. While stiffness may vary with the environment, we have established a qualitative constitutive law that holds across environments. Specifically, we expect the stiffness distribution to exhibit either an ascending-descending or an ascending-plateau pattern along the length of the object, from head to tail. Furthermore, undulatory locomotion showed sensitivity to contact mechanics: solid-solid or solid-viscoelastic contact produced different locomotion kinematics. Our results elucidate how terrestrial limbless animals achieve undulatory locomotion performance by exploiting the passive properties of the environment and the body. Application of the results obtained may lead to better performing long-segmented robots that exploit the suitability of passive body dynamics and the properties of the environment in which they need to move.


Genetic instability in cancer: theory and experiment.
Epidemiologic data and molecular biology have combined to demonstrate that multiple genetic changes may be required in carcinogenesis. Mutator mutations, defined as genetic changes which increase the rate of genetic change, including both single base changes and chromosomal instability, may accelerate this process. Key questions remain in defining the role of mutator mutations in carcinogenesis as well as in cancer therapy. Theoretical approaches, including deterministic and stochastic models, have played a significant role in hypothesis generation, experimental design, and refinement of conclusions in this field, and are expected to continue to do so in the future.


Relationship between personality traits and pharmacist performance in a pharmacy practice research trial.
Pharmacy practice research is one avenue through which new pharmacy services can be integrated into daily pharmacy practice. However, pharmacists' participation in this research has not been well characterized. Drawing from the literature on work performance and personality traits, 4 hypotheses were developed to gain insight into pharmacists' performance in a pharmacy practice research trial. This study was an observational, cross-sectional survey of pharmacists participating in a research trial. All pharmacists were asked to complete the Big Five Inventory (BFI), a validated, reliable instrument of personality traits. These results were then compared with measures of pharmacists' performance in the trial. Thirty pharmacists expressed interest in participating in the trial; 23 completed the BFI and 14 actively participated in the pharmacy practice research trial. No statistically significant differences were identified in the examination of the predetermined hypotheses. Exploratory analyses revealed significant relationships between the BFI trait of extroversion and pharmacists' participation in the study, obtaining prescribing authority for the study and the number of patients lost to follow-up. In addition to identifying a number of personality traits that have been shared by other samples of pharmacists, this work suggests the possibility of an interaction between pharmacists' personality traits and their performance in a pharmacy practice research trial. Future research should better characterize the relationship between pharmacists' personality traits and participation in pharmacy practice research trials to gain insight into the context of pharmacy practice and how pharmacists are integrating this research into their practices.


Axial interactions in the mixed-valent CuA active site and role of the axial methionine in electron transfer.
Within Cu-containing electron transfer active sites, the role of the axial ligand in type 1 sites is well defined, yet its role in the binuclear mixed-valent CuA sites is less clear. Recently, the mutation of the axial Met to Leu in a CuA site engineered into azurin (CuA Az) was found to have a limited effect on E(0) relative to this mutation in blue copper (BC). Detailed low-temperature absorption and magnetic circular dichroism, resonance Raman, and electron paramagnetic resonance studies on CuA Az (WT) and its M123X (X = Q, L, H) axial ligand variants indicated stronger axial ligation in M123L/H. Spectroscopically validated density functional theory calculations show that the smaller ΔE(0) is attributed to H2O coordination to the Cu center in the M123L mutant in CuA but not in the equivalent BC variant. The comparable stabilization energy of the oxidized over the reduced state in CuA and BC (CuA ∼ 180 mV; BC ∼ 250 mV) indicates that the S(Met) influences E(0) similarly in both. Electron delocalization over two Cu centers in CuA was found to minimize the Jahn-Teller distortion induced by the axial Met ligand and lower the inner-sphere reorganization energy. The Cu-S(Met) bond in oxidized CuA is weak (5.2 kcal/mol) but energetically similar to that of BC, which demonstrates that the protein matrix also serves an entatic role in keeping the Met bound to the active site to tune down E(0) while maintaining a low reorganization energy required for rapid electron transfer under physiological conditions.


Evaluation of the Efficiency of TIMP-2 as a Biomarker for Acute Kidney Injury in Sepsis.
The aim of this study was to evaluate the biomarker potential of TIMP-2 in septic-induced acute kidney injury (AKI). Healthy male rats (n=56, age 8-10 weeks, body weight 250-300 g) were randomized into 3 groups: controls (intact rats, n=6), sham-operated (SO, n=24), and sepsis model (cecum ligation and perforation, CLP, n=24). Thirty minutes before and 6, 12, 24, and 48 h after surgery, blood samples were collected to measure serum creatinine, blood urea nitrogen (BUN), and TIMP-2 and the kidneys were isolated for histopathological analysis and Western blotting. The key sepsis-related genes were screened through bioinformatics analysis. In 24 and 48 h after surgery, 2 rats in the SO group reached the diagnostic criteria of AKI (increased levels of serum creatinine and BUN). In the CLP group, serum creatinine in 6 h after the surgery was slightly higher than 30 min before the surgery, but this change did not meet the diagnostic criteria for AKI. In the CLP group, BUN was normal 6 h after the surgery, but increased after 12 h. In more than 50% rats of the CLP group, serum creatinine and BUN significantly increased 12 h after operation, so this can be diagnosed as AKI. In rats of the CLP group, plasma TIMP-2 was elevated 6 h after surgery and increased with time, suggesting that plasma TIMP-2 can be used as an early marker of AKI. Histological examination of the kidneys in this group revealed destruction of the renal tubular structure, swelling of renal tubular epithelium, the disappearance of brush edge and collapse of necrotic epithelial cells, etc., and the degree of damage increased with time. Immunohistochemistry showed that TIMP-2 was expressed in rats of the CLP group at all terms of the experiment. The expression of TIMP-2 and pyroptosis-related proteins (NLRP3, IL-1β, caspase-1, and GSDMD) in the CLP group was higher than in the SO group (p<0.05) and increased with time, suggesting that pyroptosis is involved in AKI. Thus, plasma TIMP-2 is sensitive indicator for the early detection of kidney injury and can be used as an early biomarker of AKI.


Long-term outcomes of image-guided ablation and laparoscopic partial nephrectomy for T1 renal cell carcinoma.
To compare long-term outcomes and peri-operative outcomes of image-guided ablation (IGA) and laparoscopic partial nephrectomy (LPN). This is a retrospective cohort study of localised RCC (T1a/bN0M0) patients undergoing cryoablation (CRYO), radio-frequency ablation (RFA), or LPN at our institution from 2003 to 2016. Oncological outcomes were compared using Cox regression and log-rank analysis. eGFR changes were compared using Kruskal-Wallis and Wilcoxon-rank tests. A total of 296 (238 T1a, 58 T1b) consecutive patients were identified; 103, 100, and 93 patients underwent CRYO, RFA, and LPN, respectively. Median follow-up time was 75, 98, and 71 months, respectively. On univariate analysis, all oncological outcomes were comparable amongst CRYO, RFA, and LPN (p > 0.05). On multivariate analysis, T1a patients undergoing RFA had improved local recurrence-free survival (LRFS) (HR 0.002, 95% CI 0.00-0.11, p = 0.003) and metastasis-free survival (HR 0.002, 95% CI 0.00-0.52, p = 0.029) compared to LPN. In T1a and T1b patients combined, both CRYO (HR 0.07, 95% CI 0.01-0.73, p = 0.026) and RFA (HR 0.04, 95% CI 0.03-0.48, p = 0.011) had improved LRFS rates. Patients undergoing CRYO and RFA had a significantly smaller median decrease in eGFR post-operatively compared to LPN (T1a: p < 0.001; T1b: p = 0.047). Limitations include retrospective design and limited statistical power. IGA is potentially as good as LPN in oncological durability. IGA preserves kidney function significantly better than LPN. More studies with larger sample size should be performed to establish IGA as a first-line treatment alongside LPN. • Ablative therapies are alternatives to partial nephrectomy for managing small renal cell carcinomas. • This study reports long-term outcomes of image-guided ablation versus partial nephrectomy. • Ablative therapies have comparable oncological durability and better renal function preservation compared to partial nephrectomy.


A rapid and sensitive chemiluminescence enzyme-linked immunosorbent assay for the determination of fumonisin B1 in food samples.
An enzyme-linked immunosorbent assay (ELISA) based on polyclonal antibody with enhanced chemiluminescent (ECL) detection of fumonisin B1 (FB1) in food samples has been developed. Assay conditions, including concentrations of antibody and enzyme conjugate, competition time and so on, were optimized. The effects of pH and two different organic solvents were investigated. The optimized ECL-ELISA system allowed FB1 determination in a linear working range of 0.14-0.9 microg L(-1) with IC50 value of 0.32 microg L(-1) and a limit of detection of 0.09 microg L(-1). The ECL-ELISA was about 10 times more sensitive and about 30% time less than that of colorimetric ELISA using the same antibody and HRP-conjugate. Good recoveries with spiked food samples were obtained, and the results correlated well with those obtained using conventional direct competition ELISA assay and HPLC method, which indicated that ECL-ELISA was capable of being applied for the specific detection and routine monitoring of FB1 in food samples.


Modelling the present and future distribution of Biomphalaria species along the watershed of the Middle Paranapanema region, São Paulo, Brazil.
The Middle Paranapanema region in the state of São Paulo, Brazil, is an area with high diversity for Biomphalaria species, with municipalities historically marked by cases of schistosomiasis transmission. The objectives of the study were to evaluate the current distribuition and predict the future distribution of habitats of Biomphalaria species at a high spatial resolution along 114 freshwater sites in the Middle Paranapanema watershed. The modelling encompassed 55 municipalities of the Middle Paranapanema region, which were analyzed through the maximum entropy algorithm. All geographic coordinates of the Biomphalaria species collected from 2015-2018 and environmental data were obtained through WorldClim, HydroSHEDS, TOPODATA and Secretaria do Meio Ambiente for the 1970-2017 period. For the 2041-2060 period we used the HadGEM2-ES climate model. Due to climate change, MaxEnt showed that there was a high probability for the maintenance of B. glabrata habitats near Ourinhos and Assis, an expansion of scattered spots, and a 50% probability that the species will spread throughout new suitable areas. The results showed that the geographical range of B. straminea will most likely expand in the future along the Middle Paranapanema hydrographic basin, especially in the municipalities near Ourinhos. For B. glabrata and B. straminea, the geographic expansion was related to the predicted increase in the annual temperature range. The habitats suitable for B. tenagophila and B. peregrina seemed to slightly expand around the west border of the Middle Paranapanema region. Biomphalaria occidentalis may have a small reduction in its distribution due to climate change. The variables that contributed the most to the future modelling for these three species were precipitation and temperature. Identifying the sites with intermediate hosts for schistosomiasis may guide public health measures to avoid or reduce future transmissions in this region.


Exercise training in childhood cancer: A systematic review and meta-analysis of randomized controlled trials.
Physical capacity and quality of life (QoL) are typically impaired in children/adolescents with cancer. Our primary objective was to examine the effects of exercise training performed after diagnosis of any type of pediatric cancer on physical capacity-related endpoints, survival, disease relapse and adverse effects. (a) Search and selection criteria: Systematic review in Pubmed and Web of Science (until August 2018) of randomized controlled trials (RCTs) of exercise interventions in children with cancer during treatment or within one year after its end. (b) Data collection: Two authors independently identified studies meeting inclusion criteria, extracted data, and assessed risk of bias using standardized forms. When needed, we contacted authors to request clarifications or additional data. (c) Statistical Analysis: The pooled standardized mean differences (SMD) were calculated for those endpoints for which a minimum of three RCTs used the same assessment method. We also calculated the pooled odds ratio (OR) of dying or having a tumor relapse. Eight RCTs (n = 283 patients) were included in the systematic review. Of these, five studies (n = 173) could be meta-analyzed. Exercise training during pediatric cancer treatment significantly improves patients' functional mobility, as assessed with the timed up and down stairs test (SMD: -0.73, p < 0.001) and does not affect mortality (OR: 0.85, p = 0.76) or relapse risk (OR: 0.96, p = 0.94). Exercise training in children with cancer improves functional mobility. More RCTs analyzing the effects of supervised exercise interventions are needed, as well as the development of a core-set of outcomes in pediatric oncology exercise research.


Novel sequence-responding fluorescent oligoDNA probe bearing a silylated pyrene molecule.
A novel fluorescent phosphoramidite derivative of dimethylsilylated pyrene was prepared and incorporated into oligoDNA. The fluorescent oligoDNA exhibited marked fluorescent signal upon binding to the fully matched complementary DNA strand, however, the signal was strongly quenched in the single-stranded form as well as in the duplex having mismatched base pair at the terminus of the duplex-forming region.


Interpreting machine for ambiguous figures.
Quantum theory presents a unique scenario pertaining to collapse processes. A device that measures variables incompatible with those being detected collapses randomly into one of the states defined by the measuring device. The distinction that a collapsed output is not an accurate description of reality but rather a random selection from a set of values derived from the measuring device allows us to utilize the collapse process to propose a scheme wherein a machine becomes capable of performing interpreting processes. We present herein a basic schematic of a machine that demonstrates the principle of interpretation relying on the polarization phenomenon of photons. The operation of the device is demonstrated using an ambiguous figure. We believe that building an interpreting device can contribute to the field of AI.


Water-soluble cyclodiphosphazanes: synthesis, gold(I) metal complexes and their in vitro antitumor studies.
The newly synthesized water-soluble cyclodiphosphazane ligands and their gold(I) complexes inhibit HeLa cell proliferation by activating p53 protein and inducing apoptosis.


Functional network dynamics and decreased conscientiousness in multiple sclerosis.
Conscientiousness is a personality trait that declines in people with multiple sclerosis (PwMS) and its decline predicts worse clinical outcomes. This study aims to investigate the neural underpinnings of lower Conscientiousness in PwMS by examining MRI anomalies in functional network dynamics. 70 PwMS and 50 healthy controls underwent personality assessment and resting-state MRI. Associations with dynamic functional network properties (i.e., eigenvector centrality) were evaluated, using a dynamic sliding-window approach. In PwMS, lower Conscientiousness was associated with increased variability of centrality in the left insula (tmax = 4.21) and right inferior parietal lobule (tmax = 3.79); a relationship also observed in regressions accounting for handedness, disease duration, disability, and tract disruption in relevant structural networks (ΔR2 = 0.071, p = 0.003; ΔR2 = 0.094, p = 0.004). Centrality dynamics of the observed regions were not associated with Neuroticism (R2 < 0.001, p = 0.956; R2 < 0.001, p = 0.945). As well, higher Conscientiousness was associated with greater variability in connectivity for the left insula with the default-mode network (F = 3.92, p = 0.023) and limbic network (F = 5.66, p = 0.005). Lower Conscientiousness in PwMS was associated with increased variability in network centrality, most prominently for the left insula and right inferior parietal cortex. This effect, specific to Conscientiousness and significant after accounting for disability and structural network damage, could indicate that overall stable network centrality is lost in patients with low Conscientiousness, especially for the insula and right parietal cortex. The positive relationship between Conscientiousness and variability of connectivity between left insula and default-mode network potentially affirms that dynamics between the salience and default-mode networks is related to the regulation of behavior.


Nano-sized Soluplus® polymeric micelles enhance the induction of tetanus toxin neutralising antibody response following transcutaneous immunisation with tetanus toxoid.
The use of Soluplus® polymeric micelles as a novel adjuvant for tetanus toxoid (TTxd) in transcutaneous immunisation was evaluated. TTxd was added to Soluplus® polymeric micelles to form TTxd-Soluplus® nano-aggregates with a size of 68nm. Non-adjuvanted TTxd commonly induces very poor antibody response by the transcutaneous route. However, in this study, the use of TTxd-Soluplus® resulted in a significant increase in the antibody response to TTxd, which was similar to that induced in the presence of CPG-oligodeoxynucleotides (CPG-ODNs) adjuvant. The toxin neutralising potency of the immune sera induced by TTxd-Soluplus® was also much stronger than that from TTxd alone, in a passive transfer experiment in mice. Soluplus® also enhanced the immunogenicity of the toxoid when TTxd-Soluplus® was stored at 4°C for 4weeks, but not at higher temperatures. Confocal microscopy imaging showed a much higher uptake of TTxd in the epidermis and dermis layers of the skin when it was associated with Soluplus®, suggesting that the mechanism for Soluplus® adjuvanticity is through enhanced uptake of the TTxd through the skin. Overall, our findings demonstrated that Soluplus® is an effective novel adjuvant for transcutaneous immunisation.


Advances in genetic mechanisms of hypothalamic dysfunction in Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a rare congenital developmental disorder mainly due to the absent expression of genes on the paternally inherited chromosome 15q11-q13 region. Most of the clinical symptoms of PWS are related to hypothalamic dysfunction, including hyperphagia, morbid obesity, mental retardation, and hypogonadism. However, the molecular genetic mechanism of PWS is not fully understood, especially the relationship between genotype and phenotype. In this review, we focus on the genetic mechanisms behind the hypothalamus dysfunction, summarizing the latest research progress of the roles of PWS candidate genes in chromosome 15q11-q13 region (NIPA1, NIPA2, TUBGCP5, CYFIP1, MAGEL2, NDN, MKRN3 and SNORD116) in hypothalamic disorders such as hyperphagia and obesity, hypogonadism, sleep-disordered breathing, growth retardation in PWS patients, to deepen the understanding of PWS syndrome and explore potential new drug targets.


Mutagenic effect on L5178Y mouse lymphoma cells by growth in ethylene oxide-sterilized polycarbonate flasks.
The mutation frequency of L5178Y mouse lymphoma cells to resistance to 5'-bromo-2'-deoxyuridine increased 6- to 14-fold after growth in ethylene oxide-sterilized polycarbonate culture flasks compared to growth in glass flasks. No comparable increase was observed when L5178Y cells were grown in identical polycarbonate culture flasks sterilized by autoclaving.


Author Correction: Large-scale variation in density of an aquatic ecosystem indicator species.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


First detailed records of water mite larvae (Hydrachnidia: Hydrovolzidae, Hydryphantidae) parasitizing empidid flies (Diptera: Empididae: Clinocerinae).
Five species of the subfamily Clinocerinae from the Tatra Mountains (S Poland) were observed to be parasitized by larval water mites. Two of them: Kowarzia plectrum Mik, 1880 and Clinocera storchi Mik, 1880 are recorded from this massif for the first time. In addition, C. storchi, is new for Polish fauna. The most infected species was Clinocera appendiculata Zetterstedt, 1838, following by Wiedemannia mikiana (Bezzi, 1899), Clinocera storchi Mik, 1880, Kowarzia plectrum Mik, 1880 and Wiedemannia jazdzewski Niesiołowski, 1987. The highest number of hosts occurred in the case of Panisopsis curvifrons (Walter, 1907) with five host species, following by both Hydrovolzia placophora (Monti, 1905) and Protzia eximia (Protz, 1896) with one species each. In the case of Clinocera appendiculata more parasites were recorded on males than on females and in C. storchi more parasites were recorded on females. The abdomen of the hosts was the most often chosen by water mites larvae.


Immunoglobulin M (IgM) multiple myeloma versus Waldenström macroglobulinemia: diagnostic challenges and therapeutic options: two case reports.
Immunoglobulin M multiple myeloma and Waldenström macroglobulinemia are two different hematological diseases with the common finding of an immunoglobulin M monoclonal gammopathy of unknown significance. However, clinical characteristics of the two entities can overlap. In this report, we describe two cases of immunoglobulin M neoplasm with the same histological bone marrow presentation but with different clinical behavior, cytogenetics, and biological assessment. On the basis of comprehensive diagnostic workup, these patients were considered to have different diseases and treated accordingly with different approaches. Patient 1 (Caucasian man) presented with increased serum protein and immunoglobulin M (7665 mg/L) with an M-spike electrophoresis of 4600 mg/L. His bone marrow biopsy revealed a small-cell immunoglobulin M multiple myeloma. The result of testing for the MYD88 L265P mutation was negative, while fluorescence in situ hybridization analysis showed translocation t(11,14). A diagnosis of immunoglobulin M-κ multiple myeloma was made. Patient 1 was a candidate for bortezomib plus thalidomide and dexamethasone, followed by autologous stem cell transplant consolidation. Patient 2 (Caucasian man) showed an M-spike by protein electrophoresis (300 mg/L, 4.9%), with serum immunoglobulin M level of 327 mg/L. His bone marrow biopsy revealed immunoglobulin M-κ multiple myeloma. Computed tomography showed many enlarged lymph nodes and splenomegaly. Patient 2's clinical features were suggestive of Waldenström macroglobulinemia, in contrast to the bone marrow biopsy results. The result of testing for the MYD88 L265P mutation was positive. Patient 2 was diagnosed with Waldenström macroglobulinemia and received rituximab, cyclophosphamide, and dexamethasone. A correct differential diagnosis between immunoglobulin M multiple myeloma and Waldenström macroglobulinemia is a critical point in the setting of a new immunoglobulin M monoclonal gammopathy onset. These patients should undergo a complete diagnostic workup with pathological, radiological, and serological examinations to establish the diagnosis and plan the most appropriate treatment in order to improve the prognosis.


The inheritance of sinking-pre-beta lipoprotein and its relation to the Lp(a) antigen.
We have investigated the genetics of plasma sinking-pre-beta lipoprotein (sp beta) as determined by the method of Breckenridge and Maguire, using several approaches: (i) a population study, (ii) a twin study and (iii) the use of family data. In addition, by the use of split samples, the sp beta level as determined by us was correlated with Lp(a) typing carried out in Oslo by Dr. Kåre Berg. Although the sp beta level is a continuous character, the results clearly showed it to be to a considerable extent under the control of the major autosomal gene pair constituted by the alleles Lpa and Lp, which mainly control the production of the Lp(a) antigen, Lpa being dominant. In our data the boundary between the LpLp and LpaLp genotypes appeared to fall between the sp beta 2 and 3 mg% levels, while that between LpaLp and LpaLpa was in the 15 mg% region. These boundaries, which were inferred from both typing and population statistics, received good confirmation from the family data. It appears that some 88% of the variation in sp beta level is directly ascribed to segregation of Lpa and Lp. On the basis of the twin study and other data, we conclude that the residual observed variation in sp beta is almost entirely ascribed to analytical error of determination and polygenic effects, the influence of environment being negligible. The heritability is close to 100%.


Sarcopenia, physical rehabilitation and functional outcomes of patients in a subacute geriatric care unit.
Sarcopenia is the loss of muscle mass and strength, which in the elderly can result in disability and affect functional outcomes after hospitalization. The aim of this study was to evaluate the functional outcomes and mortality during hospitalization and at three months post-discharge, according to the presence of sarcopenia. Prospective study of 99 patients (38.4% men, aged 84.6) admitted in a subacute geriatric care unit who underwent a rehabilitation intervention. Main outcomes were mortality and functional improvement at discharge and at three-month follow-up. Sarcopenia was assessed by handgrip strength (hydraulic dynamometer) and by body composition bioimpedance. Forty-six (46.5%) patients met diagnostic criteria of sarcopenia. Patients with sarcopenia had a worse prior functional status than those without the condition (Barthel Index: 64.2±22.8 vs 73.3±21.8; p=0.04) but both groups had similar functional decline at admission (Barthel Index: 24±15.1 vs 28.5±15.2; p=0.1) and achieved similar functional improvement at discharge (20.4±18.3 vs 27.4±21; p=0.08). Barthel Index at discharge remained comparatively worse in patients with sarcopenia (44.2±26.6 vs 55.9±26.7; p=0.03). After completing a 3-month at-home rehabilitation program, no changes in functional capacity were observed in patients with sarcopenia; their peers improved their Barthel Index scores (45.5±24.8 vs 61.6±26.6; p=0.007). Mortality rates at 3-month follow-up did not differ between groups. In conclusion, patients with sarcopenia had a worse functional status, similar functional improvement during hospitalization and a lack of recovery after returning home. Further studies are needed to establish long-terms effects on mortality.


"If you got a problem, I got a problem too": working toward making academic science more equitable.
I am extraordinarily grateful and humbled to win the ASCB Prize for Excellence in Inclusivity. However, even as I continue to center equity in all aspects of my work as a scientist, educator, and professor, I hope that we can make this award, and awards like it, obsolete. To do that, we need to recognize all the ways that academic science, and our society in general, is structured to limit who gets to fully participate as scientists and scientific leaders, limiting true innovation and advancement of science and technology. This essay is an attempt to illuminate those connections.


Fhl2 deficiency results in osteopenia due to decreased activity of osteoblasts.
Osteoporosis is one of the major health problems today, yet little is known about the loss of bone mass caused by reduced activity of the bone-forming osteoblasts. Here we show that mice deficient for the transcriptional cofactor four and a half LIM domains 2 (Fhl2) exhibit a dramatic decrease of bone mass in both genders. Osteopenia is caused by a reduced bone formation rate that is solely due to the diminished activity of Fhl2-deficient osteoblasts, while their number remains unchanged. The number and activity of the bone-resorbing cells, the osteoclasts, is not altered. Enforced expression of Fhl2 in differentiated osteoblasts boosts mineralization in cell culture and, importantly, enhances bone formation in transgenic animals. Fhl2 increases the transcriptional activity of runt-related transcription factor 2 (Runx2), a key regulator of osteoblast function, and both proteins interact in vitro and in vivo. In summary, we present Fhl2-deficient mice as a unique model for osteopenia due to decreased osteoblast activity. Our data offer a novel concept to fight osteoporosis by modulating the anabolic activity of osteoblasts via Fhl2.


Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer's disease.
To examine in an observational study (1) relationships between cholinesterase inhibitors (ChEI) and memantine use, and functional and cognitive end points and mortality in patients with Alzheimer's disease (AD); (2) relationships between other patient characteristics and these clinical end points; and (3) whether effects of the predictors change across time. The authors conducted a multicenter, natural history study that included three university-based AD centers in the United States. A total of 201 patients diagnosed with probable AD with modified Mini-Mental State Examination (MMSE) scores ≥ 30 at study entry were monitored annually for 6 years. Discrete-time hazard analyses were used to examine relationships between ChEI and memantine use during the previous 6 months reported at each assessment, and time to cognitive (MMSE score ≤ 10) and functional (Blessed Dementia Rating Scale score ≥ 10) end points and mortality. Analyses controlled for clinical characteristics, including baseline cognition, function, and comorbid conditions, and presence of extrapyramidal signs and psychiatric symptoms at each assessment interval. Demographic characteristics included baseline age, sex, education, and living arrangement at each assessment interval. ChEI use was associated with delayed time in reaching the functional end point and death. Memantine use was associated with delayed time to death. Different patient characteristics were associated with different clinical end points. Results suggest long-term beneficial effects of ChEI and memantine use on patient outcomes. As for all observational cohort studies, observed relationships should not be interpreted as causal effects.


How does wrist position affect the length of the distal radioulnar ligament: a three-dimensional image study in vivo?
This study was designed to investigate the length changes of the distal radioulnar ligament at different wrist positions and to determine the effect of hyperextension on the distal radioulnar ligament and to find out the most vulnerable position where the distal radioulnar ligament rupture and foveal avulsion. We obtained computed tomography scans of the wrists for 12 volunteers including two groups: hyperextension group and hyperextension with maximal rotation group. The images were reconstructed to the three-dimensional bone structures with customized software. The four portions of the distal radioulnar ligament were measured and analyzed statistically. No significant differences were noted in the lengths of the each portion of the distal radioulnar ligament among neutral position, wrist hyperextension, and hyper-radial extension. From neutral position to hyperextension with maximal pronation, the lengths of the palmar superficial radioulnar ligament (psRU) and dorsal deep radioulnar ligament (ddRU) decreased significantly, whereas the dorsal superficial radioulnar ligaments (dsRU) and palmar deep radioulnar ligament (pdRU) increased significantly. From neutral position to hyperextension with maximal supination, the lengths of the pdRU and dsRU ligaments decreased significantly, and the lengths of psRU and ddRU ligaments changed little. The factor of hyperextension has little effect on the length of the distal radioulnar ligament and the distal radioulnar ligament may be under great tension at the position of hyperextension with maximal pronation. These findings can provide more information to understand the pathomechanics of the triangular fibrocartilage complex injury caused by a fall on the outstretched hand and can provide information relevant to the distal radioulnar ligament restoration.


Regulation of human placental drug transporters in HCV infection and their influence on direct acting antiviral medications.
The objectives of this study were to determine how HCV infection affects placental drug transporters, and to determine the role of drug transporters on the cellular accumulation of direct-acting antiviral drugs in human trophoblasts. Eighty-four ABC and SLC transporter genes were first screened in normal and HCV infected pregnant women using PCR profiler array. The changes in expression were confirmed by qPCR and Western blot. The impact of selected drug transporters on the cellular accumulation of radiolabeled antiviral drugs sofosbuvir, entecavir, and tenofovir was measured in primary human trophoblasts (PHT) and BeWo b30 cells in the presence or absence of transporter-specific inhibitors. PHT were then treated with CL097, ssRNA40, and imquimod to determine the impact of Toll-like receptor (TLR) 7/8 activation on drug transporter expression. The expression of the ABC efflux transporters ABCB1/P-gp and ABCG2/BCRP was increased in placenta of women with HCV, while the nucleoside transporters SLC29A1/ENT1 and SLC29A2/ENT2 remained unchanged. The accumulation of sofosbuvir and tenofovir was unaffected by inhibition of these transporters in trophoblast cells. Entecavir accumulation was decreased by the inhibition of ENT2. P-gp and BCRP inhibition enhanced entecavir accumulation in BeWo b30, but not PHT. Overall, there was little effect of TLR7/8 activation on these drug transporters, and the accumulation of entecavir in PHT. The data suggest that expression of placental drug transporters and selection of antiviral drug may impact fetal drug exposure in pregnancies complicated by HCV infections.


Effects of conductive hearing loss on auditory nerve activity in gerbil.
The goal of this research was to define the effects of conductive hearing loss (CHL) produced by malleus removal (MR) on auditory nerve activity in the absence of acoustic stimulation. Subjects were gerbils in two age groups: 21 days (P21) and 42 days (P42). Ensemble background activity (EBA) of the auditory nerve was measured by spectral analysis of a signal recorded from the round window. The EBA measure was studied following MR in an acute setting in P42 animals, and in chronic experiments either 5 days (P21 and P42 animals) or 3 weeks (P21 animals) after MR. Findings were: (1) an EBA can be reliably measured in the gerbil, and this measure is highly stable over time; (2) the EBA is eliminated by application of tetrodotoxin, confirming the auditory nerve as the source of this measure; (3) MR results in a statistically significant decrease in the magnitude of the EBA in adult animals; and (4) the EBA measure is age-dependent. The EBA was significantly lower in P21 than in P42 animals, and response to MR varied as a function of age. We conclude that CHL decreases 'spontaneous' activity of the auditory nerve in young adult gerbils.


High-resolution survey in familial Parkinson disease genes reveals multiple independent copy number variation events in PARK2.
A high density comparative genomic hybridization array was designed to evaluate CNVs in the genomic region of six familial PD genes in 181 PD cases and 67 controls. No CNV was found in PARK7, ATP13A2, PINK1, and LRRK2. Intronic-only CNVs were found in SNCA and PARK2 but were not associated with PD risk. A whole-gene duplication of SNCA was found in one case. The allele frequency of PARK2 exonic CNV is significantly higher in cases than in controls (P = 0.02), higher in early-onset (AAO ≤ 40) than in late-onset cases (P = 0.001), and higher in familial than in sporadic cases (P = 0.005). Except for single exon 2 duplications, all PARK2 exonic CNVs have different breakpoints, even when the same exon(s) were involved. In conclusion, except for SNCA and PARK2, CNVs are not a major contributing mechanism for the familial PD genes examined. The majority of PARK2 exonic CNVs are not recurrent.


Antiproliferative, differentiating and apoptotic effects elicited by imidazo[1,2-a]pyrazine derivatives.
1. The activity of two series of imidazo[1,2-a]pyrazine derivatives on cell proliferation and differentiation and on apoptosis was examined in relation to their effects on phosphodiesterase (PDE) activity and on purinoceptors. 2. In the first series SC-18 and SC-51 inhibited mitogen-induced 3H-thymidine incorporation in human lymphocytes. 3. The compounds of the new series PAB13, PAB23 and SCA40 inhibited the proliferation of the HEL cell line. 4. Nine imidazo[1,2-a]pyrazine derivatives of the new series have been studied on the Dami cell proliferation. SCA41 and SCA44 inhibited cell growth, SCA40 and PAB40 were moderately effective, whereas PAB12 and PAB30 were devoid of effect. The antiproliferative effects of these six non-cytotoxic compounds could not be related to their action on PDE or on purinoceptors, but rather to their lipophilicity. Conversely, for PAB13, PAB15, and PAB23, the decrease in cell number was related to their cytotoxic and apoptotic effects through their cAMP-increasing and PDE-inhibitory potency, but unrelated to an effect on purinoceptors. 5. Imidazo[1,2-a]pyrazine derivatives decreased the expression of Glycoprotein (GP)Ib in Dami cells while some of them enhanced that of GPIIb/IIIa. These effects appeared to involve inhibition of both cAMP- and cGMP-PDE. 6. These studies demonstrate the potential interest of imidazo[1,2-a]pyrazine derivatives in the query of novel anticancer drugs.


Gene expression of glutamate receptors GluR1 and NR1 is differentially modulated in striatal neurons in rats after 6-hydroxydopamine lesion.
In the present study, we attempted to address the modulation of the gene expression of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors in the neostriatum of the 6-hydroxydopamine (6-OHDA)-lesioned rat, an animal model of Parkinson's disease. After 2 weeks of lesion, reverse transcriptase-polymerase chain reactions (RT-PCRs) revealed significant reduction in GluR1 mRNA expression but a significant enhancement of NR1 mRNA expression in the striatal tissues of the lesioned side. No modulation in the mRNA expression of GluR2, GluR3, GluR4 and NR2B were found. Immunofluorescence with digital imaging analysis also demonstrated a significant reduction in GluR1 immunoreactivity in the lesioned neostriatum. Interestingly, the reduction in GluR1 immunoreactivity was primarily observed in presumed striatal medium spiny neurons but not in parvalbumin-labeled striatal GABAergic interneurons. Immunoreactivity for GluR2, GluR2/3, GluR4, NR1 and NR2B was unchanged in neurons of the neostriatum of the lesioned side. The present results indicate that there is an opposite trend in modulation in the gene expressions of GluR1 and NR1 in the neostriatum of 6-OHDA-lesioned rats after dopamine denervation. Modulation of GluR1 mRNA and immunoreactivity is likely to be limited in the striatal projection neurons. These findings have implications for the use of NMDA and AMPA receptor antagonists in the treatment of Parkinson's disease.


Mixed chimaerism is common at the time of acute graft-versus-host disease and disease response in patients receiving non-myeloablative conditioning and allogeneic stem cell transplantation.
We report the clinical outcome and results of chimaerism analysis in various cell lineages of 30 patients given non-myeloablative conditioning, followed by allogeneic stem cell transplantation (SCT). The commonest diagnoses were chronic myelogenous leukaemia (n = 11) and solid tumours (n = 11). Twenty-one patients received SCT from human leucocyte antigen (HLA)-identical siblings and nine from matched unrelated donors. Median patient age was 53 (28-77) years. Four non-myeloablative protocols were used, including fludarabine (30 mg/m2 x 3-6), busulphan (4 mg/kg x 2), cyclophosphamide (Cy) (30 mg/kg/day x 2) or total body irradiation (2 Gy), and anti-thymocyte globulin. The patients were analysed by polymerase chain reaction (PCR) analysis of minisatellites on days 14, 21 and 28, then every other week up to 3 months and monthly thereafter. All samples were cell separated for T, B and myeloid cells using immunomagnetic beads. Eighteen patients were alive at a median follow-up of 11 (6-20) months. Acute graft-versus-host disease (GVHD) occurred in 22 patients. Eighteen of the 22 patients with acute GVHD showed mixed chimaerism (MC) in the T-cell fraction at the time of acute GVHD. However, all patients with acute GVHD showed donor chimaerism (DC) in the T-cell fraction median 76 (7-414) days after onset versus three out of eight patients without acute GVHD, P < 0.001]. Disease response was diagnosed in 15 patients, median 100 (37-531) days after SCT. At the time of disease response, six out of 15 patients showed MC in the T-cell fraction. In conclusion, mixed chimaerism in the T-cell fraction is common at the time of acute GVHD and disease response in patients conditioned with non-myeloablative therapy.


[The HELLP syndrome as a severe complication of EPH gestosis].
On the basis of a literature review the extremely severe form of EPH gestosis--the HELLP syndrome is described. In the clinical manifestations of the syndrome a symptom triad predominates: haemolytic anaemia, raised values of hepatic enzymes and thrombocytopenia. The only causative treatment saving the life of the mother and fetus is possibly early termination of pregnancy and adequate supplementation of blood deficiency. The pathophysiology, clinical manifestations, differential diagnosis and treatment of the HELLP syndrome are discussed.


Prostacyclin receptors: Transcriptional regulation and novel signalling mechanisms.
The prostanoid Prostacyclin plays diverse physiologic roles within the vasculature and other systems, and is widely implicated in several cardiovascular, pulmonary and renal diseases. Despite this, knowledge of the factors regulating expression of the I prostanoid receptor (the IP) remained largely unknown. This review details recent advances in understanding the key transcriptional regulators determining expression of the PTGIR gene in the human vasculature and the identification of novel interacting partners of the IP that impact on its function therein. Included in this are the trans-acting factors that regulate expression of the PTGIR under basal- and regulated-conditions, particularly those determining its up-regulation in response to cellular differentiation, estrogen and low serum-cholesterol. Moreover, the functional implications of the interactions between the IP with PDZK1, a multi PDZ-domain containing protein essential for reverse-cholesterol transport and endothelialization, and the IP with IKEPP, the intestinal and kidney enriched PDZ protein, for the role of the prostacyclin-IP axis within the vasculature are reviewed.


ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes.
Adenosine deaminase acting on RNA 1 (ADAR1) is an essential protein for embryonic liver development. ADAR1 loss is embryonically lethal because of severe liver damage. Although ADAR1 is required in adult livers to prevent liver cell death, as demonstrated by liver-specific conditional knockout (Alb-ADAR1(KO)) mice, the mechanism remains elusive. We systematically analyzed Alb-ADAR1(KO) mice for liver damage. Differentiation genes and inflammatory pathways were examined in hepatic tissues from Alb-ADAR1(KO) and littermate controls. Inducible ADAR1 KO mice were used to validate regulatory effects of ADAR1 on inflammatory cytokines. We found that Alb-ADAR1(KO) mice showed dramatic growth retardation and high mortality because of severe structural and functional damage to the liver, which showed overwhelming inflammation, cell death, fibrosis, fatty change, and compensatory regeneration. Simultaneously, Alb-ADAR1(KO) showed altered expression of key differentiation genes and significantly higher levels of hepatic inflammatory cytokines, especially type I interferons, which was also verified by inducible ADAR1 knockdown in primary hepatocyte cultures. We conclude that ADAR1 is an essential molecule for maintaining adult liver homeostasis and, in turn, morphological and functional integrity. It inhibits the production of type I interferons and other inflammatory cytokines. Our findings may provide novel insight in the pathogenesis of liver diseases caused by excessive inflammatory responses, including autoimmune hepatitis.


Phytoaccumulation prospects of cadmium and zinc by mycorrhizal plant species growing in industrially polluted soils.
The natural vegetation growing along a wastewater channel was subjected to analyze the uptake of Cadmium (Cd) and Zinc (Zn) and their subsequent accumulation in aboveground and underground plant parts. Species which were mycorrhizal and growing in soils receiving industrially contaminated wastewater were collected along with their rhizospheric soil samples. The nearby uncontaminated control (reference) area was also subjected to sampling on similar pattern for comparison. Both Cd and Zn concentrations were significantly higher in soils of the study area as compared to the reference site. Five plant species i.e. Desmostachya bipinnata, Dichanthium annulatum, Malvastrum coromandelianum, Saccharum bengalense, and Trifolium alexandrinum were analyzed for metal uptake. The maximum phytoaccumulation of Cd was observed in Desmostachya bipinnata (20.41 microg g(-1)) and Dichanthium annulatum (15.22 microg g(-1)) for shoot and root tissues, respectively. However, Malvastrum coromandelianum revealed maximum Zn accumulation for both the shoot and the root tissues (134 and 140 mug g(-1), respectively). The examination of cleared and stained roots of the plants from both the areas studied revealed that all of them were colonized to a lesser or a greater degree by arbuscular mycorrhizal (AM) fungi. The Cd hyperaccumulating grasses i.e. Desmostachya bipinnata and Dichanthium annulatum, from study area had smaller root:shoot (R/S) ratio as compared to those growing on reference area indicating a negative pressure of soil metal contamination. The lower R/S ratio in the mycorrhizal roots observed was probably due to increased AM infection and its mediatory role in soil plant transfer of heavy metals. Furthermore, comparatively lower soil pH values in the study areas may have played a key role in making the overall phytoavailability of both the metals. Consequently variations in Cd and Zn tissue concentration among species were observed that also indicate the phytoaccumulation potential of the native species.


Chemotactic response of mesenchymal cells, fibroblasts and osteoblast-like cells to bone Gla protein.
Bone gla protein (BGP) and decarboxylated bone gla protein (dBGP) were tested for chemotactic activity against stage 24 chick limb bud mesenchymal cells, chick embryonic muscle-derived fibroblasts, murine Balb/C 3T3 cells, and two lines of rat osteosarcoma cells, ROS-17/2.8 and -25/1. Both BGP and dBGP were potent chemoattractants for all the cell types except 3T3 cells. The dose response curves were bell-shaped, with maximal chemotactic response ranging from 5 pg/ml for ROS 25/1 cells to 10 ng/ml for the stage 24 limb bud cells. dBGP was equally potent a chemoattractant as BGP for all cell types tested indicating that the gamma-carboxylation of the glutamic acid residues is not required for chemotactic activity. Given this chemotactic capability, it is possible that BGP acts in bone remodelling by attracting osteogenic cells to the sites of bone resorption where BGP may be liberated or exposed.


Exploring quality of life in patients with and without heart failure.
The EuroHeart Failure Survey Questionnaire (EHFSQ-1) has 39 questions on symptoms and quality of life (QoL); many items are related. We sought to identify underlying clusters amongst EHFSQ-1 questions, construct an overall "QoL score" and investigate its relationship to a single question asking patients to self-rate QoL. Factor analysis based on the principal component technique was used to identify patterns amongst responses to QoL questions from patients referred with symptoms suggesting heart failure (HF). Of 1031 patients, median age 71 (IQR: 63-77) years, 64% were men and 626 had confirmed HF. For patients with HF, seven symptom-clusters were identified: "breathlessness", "psychological distress", "sleep quality", "frailty", "cognitive/psychomotor function", "cough" and "chest pain". These clusters accounted for 65% of the total variance in QoL score. Cluster pattern was similar in patients with and without HF. A summary factor score was tightly correlated with summary QoL score (correlation coefficient: r=0.96; p<0.0001). Both summary factors and QoL scores were highly correlated with patient self-rating of overall health (r1=0.61 and r2=0.66 respectively, p<0.0001) or overall QoL (r1=0.60 and r2=0.66, p<0.0001). The medians (IQR) of the summary QoL score for patients with HFrEF, HFnEF and no-HF were, respectively, 83 (60-106), 82 (59-104) and 71 (51-94). EHFSQ-1, comprises seven symptom clusters in patients with HF. Either summary factors or QoL scores can be used as a QoL outcome measure. However, if the key question is 'what is this patient's QoL?' rather than the reason why it is impaired, then a single, direct question may suffice.


A spectrophotometric assay for deacetoxycephalosporin C synthase.
A continuous direct spectrophotometric assay for deacetoxycephalosporin C synthase was developed, based on the absorption at 260 nm characteristic of the dihydrothiazine moiety of cephalosporins. Km values of 0.18 mM for penicillin N and 0.16 mM for alpha-ketoglutarate were determined. A coupled assay using succinate thiokinase, pyruvate kinase and lactate dehydrogenase showed that succinate was a product of both deacetoxycephalosporin C synthase and hydroxylase reactions. The expandase reaction exhibited a 1:1.06 stoichiometry for deacetoxycephalosporin C and succinate.


Photo-induced charge transfer. A critical test of the mechanism and range of biological electron transfer processes.
The vibronic coupling theory of electron tunneling between biomolecules requires that all such tunnelings involve vibronic coupling, finds temperature dependence to tunneling at finite temperatures, and predicts relatively short tunneling distances. This theory might be expected to apply to most electron transfers involved in the membrane-bound electron transfer reactions of photosynthesis and oxidative phosphorylation. This paper calculates the properties of a weak charge-transfer optical absorption band, whose predicted characteristics are a direct and simple consequence of the model that describes vibronically coupled tunneling. The new absorption band provides the basis for a critical experimental test of the constructs and parameters of the tunneling theory. If the tunneling theory is valid, the oscillator strength of such bands will be the most reliable measure of the tunneling matrix element and of the distance between the sites exchanging an electron.


Asynchronous brain-computer interface for cognitive assessment in people with cerebral palsy.
Typically, clinical measures of cognition require motor or speech responses. Thus, a significant percentage of people with disabilities are not able to complete standardized assessments. This situation could be resolved by employing a more accessible test administration method, such as a brain-computer interface (BCI). A BCI can circumvent motor and speech requirements by translating brain activity to identify a subject's response. By eliminating the need for motor or speech input, one could use a BCI to assess an individual who previously did not have access to clinical tests. We developed an asynchronous, event-related potential BCI-facilitated administration procedure for the peabody picture vocabulary test (PPVT-IV). We then tested our system in typically developing individuals (N = 11), as well as people with cerebral palsy (N = 19) to compare results to the standardized PPVT-IV format and administration. Standard scores on the BCI-facilitated PPVT-IV, and the standard PPVT-IV were highly correlated (r = 0.95, p < 0.001), with a mean difference of 2.0 ± 6.4 points, which is within the standard error of the PPVT-IV. Thus, our BCI-facilitated PPVT-IV provided comparable results to the standard PPVT-IV, suggesting that populations for whom standardized cognitive tests are not accessible could benefit from our BCI-facilitated approach.


On-line rapid palliation using helical tomotherapy: a prospective feasibility study.
Rapid delivery of radiation therapy is expected to benefit patients requiring palliation. We investigated the feasibility of employing a helical tomotherapy unit to scan, plan, and deliver a radiation treatment in a single radiation therapy appointment. Eleven patients each had an MVCT scan acquired, a plan created, and delivery completed while the patient was on the treatment couch. Timelines for each step of the process were recorded for each patient, and compared with the conventional process for similar patients. Preliminary results show that patients routinely can be treated within a 1 hour appointment for the first fraction.


Highly ductile amorphous oxide at room temperature and high strain rate.
Oxide glasses are an integral part of the modern world, but their usefulness can be limited by their characteristic brittleness at room temperature. We show that amorphous aluminum oxide can permanently deform without fracture at room temperature and high strain rate by a viscous creep mechanism. These thin-films can reach flow stress at room temperature and can flow plastically up to a total elongation of 100%, provided that the material is dense and free of geometrical flaws. Our study demonstrates a much higher ductility for an amorphous oxide at low temperature than previous observations. This discovery may facilitate the realization of damage-tolerant glass materials that contribute in new ways, with the potential to improve the mechanical resistance and reliability of applications such as electronic devices and batteries.


Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa.
This study investigated the hypothalamus-pituitary-adrenal (HPA) axis activity in children with anorexia nervosa (AN) before and after inpatient treatment. Salivary cortisol levels were measured to ascertain whether changes in the HPA axis activity following therapeutic intervention could be applicable as a prognostic predictor. This study comprised 21 females with AN and 22 control subjects. Saliva was collected at 2-hour intervals from 9 a.m. to 7 p.m. before and after inpatient treatment. The concentrations for areas under the curve (AUC) were compared with physical parameters, eating attitude score, profile of mood states (POMS), and prognostic factors. Mean salivary cortisol levels at all points and mean AUC cortisol levels in subjects with AN before therapy were significantly higher than those in controls, but returned to control levels after inpatient treatment. Higher AUC cortisol levels were associated with lower standard deviation for weight in AN. A significant positive correlation between the AUC cortisol level and POMS subscale of "Fatigue" was apparent in the control group, but not in the AN group. The increased change values of AUC cortisol level before and after inpatient treatment correlated with increased body weight gain ratio just after treatment, but not with the ratio after one year. The present study indicated that HPA axis activity could reflect severity of illness, but did not show an accurate neuroendocrine response for mood states. Changes in HPA axis activity following treatment could therefore be used to predict prognosis and particularly in the short term.


Zinc (Zn) and adipose-derived mesenchymal stem cells (AD-MSCs) on MPTP-induced Parkinson's disease model: A comparative evaluation of behavioral and immunohistochemical results.
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and sustained neuroinflammation due to microglial activation. Adipose tissue-derived mesenchymal stem cells (AD-MSCs) secrete neuroprotective factors to prevent neuronal damage. Furthermore, Zn regulates stem cell proliferation and differentiation and has immunomodulatory functions. Our in vivo study aimed to investigate whether Zn affects the activities of AD-MSCs in the MPTP-induced mouse model. Male C57BL/6 mice were randomly divided into six groups (n = 6): Control, Zn, PD, PD+Zn, PD+ (AD-MSC), PD+ (AD-MSC)+Zn. MPTP toxin (20 mg/kg) was dissolved in saline and intraperitoneally injected into experimental groups for two days with 12 h intervals. On the 3rd day, AD-MSCs were given to the right lateral ventricle of the PD+ (AD-MSC) and PD+ (AD-MSC)+Zn groups by stereotaxic surgery. Then, ZnSO4H2O was administered intraperitoneally for 4 days at 2 mg/kg. Seven days post MPTP injection, the motor activities of the mouse were evaluated. Then immunohistochemical analyzes were performed in SNpc. Our results showed that motor activity was lower in Group PD. AD-MSC and Zn administration have improved this impairment. MPTP caused a decrease in TH and BDNF expressions in dopaminergic neurons in Group PD. However, TH and BDNF expressions were more intense in the other groups. MCP-1, TGF-β, and IL-10 expressions increased in administered groups compared to the Group PD. The present study indicates that Zn's individual and combined administration with AD-MSCs reduces neuronal damage in the MPTP-induced mouse model. In addition, anti-inflammatory responses that emerge with Zn and AD-MSCs may have a neuroprotective effect.


The bioavailability and nonlinear pharmacokinetics of MK-679 in humans.
MK-679 (R(-)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3- (dimethylamino)-3-oxo-propyl)thio)methyl)thio)propanoic acid) is a potent and specific LTD4-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration-time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg 14C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.


Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis.
Autoimmune posterior uveitis is a chronic, potentially blinding inflammatory disease of the eye. It is commonly treated with immunosuppressive drugs that have adverse long-term effects. Advances in gene transfer techniques have enabled long-term, stable transduction of retinal cells following subretinal injection with adeno-associated viral (AAV) vectors. Here we report for the first time that subretinal injection of rAAV-2 encoding murine IL-10 into the retina of C57BL/6 mice significantly decreases the median experimental autoimmune uveitis (EAU) disease severity. This protection is shown to be due to a decrease in the number and activation status of infiltrating monocytes during EAU, as determined by costimulatory molecule expression and nitrotyrosine detection. No differences within splenocyte proliferative responses or serum antibody levels were detected, emphasizing the potential of gene therapy strategies in ameliorating autoimmune responses in local microenvironments without unwanted systemic effects.


Multivariate genome-wide associations for immune traits in two maternal pig lines.
Immune traits are considered to serve as potential biomarkers for pig's health. Medium to high heritabilities have been observed for some of the immune traits suggesting genetic variability of these phenotypes. Consideration of previously established genetic correlations between immune traits can be used to identify pleiotropic genetic markers. Therefore, genome-wide association study (GWAS) approaches are required to explore the joint genetic foundation for health biomarkers. Usually, GWAS explores phenotypes in a univariate (uv), trait-by-trait manner. Besides two uv GWAS methods, four multivariate (mv) GWAS approaches were applied on combinations out of 22 immune traits for Landrace (LR) and Large White (LW) pig lines. In total 433 (LR: 351, LW: 82) associations were identified with the uv approach implemented in PLINK and a Bayesian linear regression uv approach (BIMBAM) software. Single Nucleotide Polymorphisms (SNPs) that were identified with both uv approaches (n = 32) were mostly associated with immune traits such as haptoglobin, red blood cell characteristics and cytokines, and were located in protein-coding genes. Mv GWAS approaches detected 647 associations for different mv immune trait combinations which were summarized to 133 Quantitative Trait Loci (QTL). SNPs for different trait combinations (n = 66) were detected with more than one mv method. Most of these SNPs are associated with red blood cell related immune trait combinations. Functional annotation of these QTL revealed 453 immune-relevant protein-coding genes. With uv methods shared markers were not observed between the breeds, whereas mv approaches were able to detect two conjoint SNPs for LR and LW. Due to unmapped positions for these markers, their functional annotation was not clarified. This study evaluated the joint genetic background of immune traits in LR and LW piglets through the application of various uv and mv GWAS approaches. In comparison to uv methods, mv methodologies identified more significant associations, which might reflect the pleiotropic background of the immune system more accurately. In genetic research of complex traits, the SNP effects are generally small. Furthermore, one genetic variant can affect several correlated immune traits at the same time, termed pleiotropy. As mv GWAS methods consider strong dependencies among traits, the power to detect SNPs can be boosted. Both methods revealed immune-relevant potential candidate genes. Our results indicate that one single test is not able to detect all the different types of genetic effects in the most powerful manner and therefore, the methods should be applied complementary.


Venous trauma: successful venous reconstruction remains an interesting challenge.
Ligation of some major veins can produce deleterious effects. Based on clinical and experimental research, there is a recent increased interest in repairing injured veins. Despite remaining limitations, successful venous repair has been possible without complications of thrombophlebitis or pulmonary embolism.


Effect of policosanol on intimal thickening in rabbit cuffed carotid artery.
We studied the effect of policosanol on smooth muscle cell proliferation in the cuffed carotid artery of the rabbit. Policosanol is a mixture of higher aliphatic primary alcohols isolated from sugar cane wax, with cholesterol lowering effects proved in experimental models and patients with type II hypercholesterolemia. It acts by inhibiting cholesterol biosynthesis. The positioning of a nonocclusive silicone collar around the rabbit carotid artery results in the formation of a neointima. We wished to determine whether policosanol orally administered prevented intimal thickening. Collars were placed around the left carotid for 15 days. The contralateral artery was sham operated. We included three experimental groups: a control received vehicle and two others policosanol at 5 and 25 mg Kg until sacrificed. Samples of arteries were examined by light and electron microscopy. To evaluate intimal thickening the cross-sectional area of intima and media were measured. Neointima was significantly reduced in policosanol-treated animals compared with controls. The smooth muscle cell proliferation was studied by the immunohistochemical detection of proliferating cell nuclear antigen and a significant reduction was observed in policosanol treated rabbits. It is concluded that policosanol has a protective effect on the neointima formation in this experimental model.