Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies.
Immune checkpoint inhibitors (ICIs) block cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) receptors that control antitumor activities of lymphocytes. While highly efficacious, these drugs have been associated with several immune-related adverse events (irAEs) due to the disruption of self-tolerance. Immune-mediated hepatitis (IMH) usually presents as mild elevations of liver enzymes though it can rarely be associated with life-threatening hepatic injury. Areas covered: A comprehensive review was performed to define the clinicopathologic forms of liver injury associated with ICIs, comparing the various ICI classes as well as comparing this form of IMH with idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. Liver biopsy has proven very useful in selected patients. A specific form of fibrin ring granulomatous hepatitis appears to be associated with IMH. The current societal treatment algorithms and emerging data were reviewed to determine when to utilize corticosteroids. Expert opinion: Monitoring for severe ICI-IMH is recommended although acute liver failure remains rare. Most patients with grade 3-4 hepatotoxicity respond to corticosteroids, but a subset of patients with mild hepatitis on liver biopsy resolve without steroids and need to be carefully selected in concert with the consultation of a hepatologist.


Effect of mizoribine on pulmonary lesions in MRL/lpr/lpr mice.
The present study was made to investigate the effect of mizoribine (MZR), an imidazole nucleoside immunosuppressant, on pulmonary lesions and immunological mode of action of MRL/lpr/lpr mice. Four-week-old female MRL/lpr/lpr mice were injected subcutaneously with 20 mg/kg body weight of MZR every other day. For control, mice were given phosphate-buffered saline (PBS) every other day. MZR caused the delay in the histological development of peribronchial and perivascular lymphocytic infiltrations in the lungs of MRL/lpr/lpr (MRL/lpr) mice. And then, MZR suppressed the number of immunoglobulin (Ig) (IgG and IgM) secreting B cells and anti-DNA-secreting B cells in the spleen of MRL/lpr/lpr mice. The above data indicate that MZR could be useful for the treatment of pulmonary lesions associated with autoimmune disorders such as systemic lupus erythematosus (SLE).


Vancomycin administration: mistakes made by nursing staff.
To identify the number and types of errors made by assistant and technical nurses when administering intravenous (IV) vancomycin. Preparation and IV administration of 143 doses of vancomycin by 55 assistant and technical nurses were observed in four acute wards (three adult and one paediatric) in a public university hospital in Brazil. Non-participant observers completed a structured checklist for each dose. A total of 27 (19%) doses were administered correctly and 116 (81%) incorrectly. There were 268 errors of four types: (i) incorrect dose; (ii) improper preparation of a dose; (iii) inadequate administration technique; and (iv) infusion at an incorrect rate. For 13 of 143 (9%) doses, errors occurred in all four aspects of administration. Errors were observed on all four wards. The high incidence of suboptimal administration of vancomycin observed is a cause for concern. Focused education and safety measures have been introduced and their impact is being evaluated.


The complete mitochondrial genome sequence of Ancherythroculter nigrocauda (Cypriniformes:Cyprinidae).
Ancherythroculter nigrocauda is a fish endemic to the upper reaches of the Yangtze River in China. In this study, we determined and analyzed the complete mitochondrial DNA (mtDNA) sequence of this species. The mitogenome is 16,623 bp in length. It consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non-coding regions: origin of light-strand replication (O(L)) and control region (D-loop). This mitogenome sequence data can contribute to elucidate the evolutionary mechanisms, molecular systematics, and biogeography of Ancherythroculter and is useful to conservation genetics and stock evaluation for A. nigrocauda.


Inflammatory loops in the epithelial-immune microenvironment of the skin and skin appendages in chronic inflammatory diseases.
The epithelial-immune microenvironment (EIME) of epithelial tissues has five common elements: (1) microbial flora, (2) barrier, (3) epithelial cells, (4) immune cells, and (5) peripheral nerve endings. EIME provides both constant defense and situation-specific protective responses through three-layered mechanisms comprising barriers, innate immunity, and acquired immunity. The skin is one of the largest organs in the host defense system. The interactions between the five EIME elements of the skin protect against external dangers from the environment. This dysregulation can result in the generation of inflammatory loops in chronic inflammatory skin diseases. Here, we propose an understanding of EIME in chronic skin diseases, such as atopic dermatitis, psoriasis, systemic lupus erythematosus, alopecia areata, and acne vulgaris. We discuss the current treatment strategies targeting their inflammatory loops and propose possible therapeutic targets in the future.


Desiderata for sharable computable biomedical knowledge for learning health systems.
In this commentary, we work out the specific desired functions required for sharing knowledge objects (based on statistical models) presumably to be used for clinical decision support derived from a learning health system, and, in so doing, discuss the implications for novel knowledge architectures. We will demonstrate how decision models, implemented as influence diagrams, satisfy the desiderata. The desiderata include locally validate discrimination, locally validate calibration, locally recalculate thresholds by incorporating local preferences, provide explanation, enable monitoring, enable debiasing, account for generalizability, account for semantic uncertainty, shall be findable, and others as necessary and proper. We demonstrate how formal decision models, especially when implemented as influence diagrams based on Bayesian networks, support both the knowledge artifact itself (the "primary decision") and the "meta-decision" of whether to deploy the knowledge artifact. We close with a research and development agenda to put this framework into place.


Down-regulation of CK2α correlates with decreased expression levels of DNA replication minichromosome maintenance protein complex (MCM) genes.
Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α') and two regulatory subunits (CK2β). It is implicated in every stage of the cell cycle and in the regulation of various intracellular pathways associated with health and disease states. The catalytic subunits have similar biochemical activity, however, their functions may differ significantly in cells and in vivo. In this regard, homozygous deletion of CK2α leads to embryonic lethality in mid-gestation potentially due to severely impaired cell proliferation. To determine the CK2α-dependent molecular mechanisms that control cell proliferation, we established a myoblast-derived cell line with inducible silencing of CK2α and carried out a comprehensive RNA-Seq analysis of gene expression. We report evidence that CK2α depletion causes delayed cell cycle progression through the S-phase and defective response to replication stress. Differential gene expression analysis revealed that the down-regulated genes were enriched in pathways implicated in cell cycle regulation, DNA replication and DNA damage repair. Interestingly, the genes coding for the minichromosome maintenance proteins (MCMs), which constitute the core of the replication origin recognition complex, were among the most significantly down-regulated genes. These findings were validated in cells and whole mouse embryos. Taken together, our study provides new evidence for a critical role of protein kinase CK2 in controlling DNA replication initiation and the expression levels of replicative DNA helicases, which ensure maintenance of proliferative potential and genome integrity in eukaryotic cells.


Carotid, not aortic, chemoreceptors mediate the fetal cardiovascular response to acute hypoxemia in lambs.
The fetal cardiovascular response to acute hypoxemia consists of a decrease in heart rate, a variable change in mean arterial pressure, and an increase in peripheral vascular resistance. This response is mediated by the arterial chemoreceptors. To determine whether chemoreceptors in the carotid artery or in the aorta mediate the fetal cardiovascular response to acute hypoxemia, we studied the response to acute hypoxemia in fetal lambs at 125 to 130 d of gestation after selective carotid (six fetuses) or aortic (five fetuses) denervation. One to 3 d after insertion of catheters, hypoxemia was induced by inflating a balloon occluder around the ewe's hypogastric artery or by giving the ewe 95% N2 and 5% O2 to breathe. The chemoreflex response was measured as decrease in heart rate per decrease in Hb O2 saturation. To validate our results, we also studied the response to chemical stimulation of the chemoreceptors by injection of sodium cyanide into the inferior vena cava. We found that carotid denervation abolished the heart rate and peripheral vascular resistance responses to hypoxemia but that aortic denervation did not. Responses after injection of sodium cyanide were similar to those seen during acute hypoxemia. We conclude that the carotid chemoreceptors, and not the aortic chemoreceptors, mediate the fetal cardiovascular response to acute hypoxemia.


Physical activity for women with breast cancer after adjuvant therapy.
Women with a diagnosis of breast cancer may experience short- and long-term disease and treatment-related adverse physiological and psychosocial outcomes. These outcomes can negatively impact prognosis, health-related quality of life (HRQoL), and psychosocial and physical function. Physical activity may help to improve prognosis and may alleviate the adverse effects of adjuvant therapy. To assess effects of physical activity interventions after adjuvant therapy for women with breast cancer. We searched the Cochrane Breast Cancer Group (CBCG) Specialised Registry, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Physiotherapy Evidence Database (PEDro), SPORTDiscus, PsycINFO, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform, on 18 September 2015. We also searched OpenGrey and Healthcare Management Information Consortium databases. We searched for randomised and quasi-randomised trials comparing physical activity interventions versus control (e.g. usual or standard care, no physical activity, no exercise, attention control, placebo) after adjuvant therapy (i.e. after completion of chemotherapy and/or radiation therapy, but not hormone therapy) in women with breast cancer. Two review authors independently selected studies, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when needed. We calculated an overall effect size with 95% confidence intervals (CIs) for each outcome and used GRADE to assess the quality of evidence for the most important outcomes. We included 63 trials that randomised 5761 women to a physical activity intervention (n = 3239) or to a control (n = 2524). The duration of interventions ranged from 4 to 24 months, with most lasting 8 or 12 weeks (37 studies). Twenty-eight studies included aerobic exercise only, 21 involved aerobic exercise and resistance training, and seven used resistance training only. Thirty studies described the comparison group as usual or standard care, no intervention, or control. One-fifth of studies reported at least 20% intervention attrition and the average physical activity adherence was approximately 77%.No data were available on effects of physical activity on breast cancer-related and all-cause mortality, or on breast cancer recurrence. Analysis of immediately postintervention follow-up values and change from baseline to end of intervention scores revealed that physical activity interventions resulted in significant small-to-moderate improvements in HRQoL (standardised mean difference (SMD) 0.39, 95% CI 0.21 to 0.57, 22 studies, 1996 women; SMD 0.78, 95% CI 0.39 to 1.17, 14 studies, 1459 women, respectively; low-quality evidence), emotional function (SMD 0.21, 95% CI 0.10 to 0.32, 26 studies, 2102 women, moderate-quality evidence; SMD 0.31, 95% CI 0.09 to 0.53, 15 studies, 1579 women, respectively; low-quality evidence), perceived physical function (SMD 0.33, 95% CI 0.18 to 0.49, 25 studies, 2129 women; SMD 0.60, 95% CI 0.23 to 0.97, 13 studies, 1433 women, respectively; moderate-quality evidence), anxiety (SMD -0.57, 95% CI -0.95 to -0.19, 7 studies, 326 women; SMD -0.37, 95% CI -0.63 to -0.12, 4 studies, 235 women, respectively; low-quality evidence), and cardiorespiratory fitness (SMD 0.44, 95% CI 0.30 to 0.58, 23 studies, 1265 women, moderate-quality evidence; SMD 0.83, 95% CI 0.40 to 1.27, 9 studies, 863 women, respectively; very low-quality evidence).Investigators reported few minor adverse events.Small improvements in physical activity interventions were sustained for three months or longer postintervention in fatigue (SMD -0.43, 95% CI -0.60 to -0.26; SMD -0.47, 95% CI -0.84 to -0.11, respectively), cardiorespiratory fitness (SMD 0.36, 95% CI 0.03 to 0.69; SMD 0.42, 95% CI 0.05 to 0.79, respectively), and self-reported physical activity (SMD 0.44, 95% CI 0.17 to 0.72; SMD 0.51, 95% CI 0.08 to 0.93, respectively) for both follow-up values and change from baseline scores.However, evidence of heterogeneity across trials was due to variation in intervention components (i.e. mode, frequency, intensity, duration of intervention and sessions) and measures used to assess outcomes. All trials reviewed were at high risk of performance bias, and most were also at high risk of detection, attrition, and selection bias. In light of the aforementioned issues, we determined that the evidence was of very low, low, or moderate quality. No conclusions regarding breast cancer-related and all-cause mortality or breast cancer recurrence were possible. However, physical activity interventions may have small-to-moderate beneficial effects on HRQoL, and on emotional or perceived physical and social function, anxiety, cardiorespiratory fitness, and self-reported and objectively measured physical activity. The positive results reported in the current review must be interpreted cautiously owing to very low-to-moderate quality of evidence, heterogeneity of interventions and outcome measures, imprecision of some estimates, and risk of bias in many trials. Future studies with low risk of bias are required to determine the optimal combination of physical activity modes, frequencies, intensities, and durations needed to improve specific outcomes among women who have undergone adjuvant therapy.


Do graphemes attract spatial attention in grapheme-color synesthesia?
Grapheme-color synesthetes perceive concurrent colors for some objectively achromatic graphemes (inducers). Using oscillatory responses in the electroencephalogram, we tested the hypothesis that inducers automatically attract spatial attention and, thus, favor a conscious experience of color. Achromatic inducers and real-colored non-inducers were presented to the left or to the right visual hemifield and orientation judgments were required for subsequently presented Gabor patches. The graphemes were irrelevant for the task so that the related brain response was purely stimulus-driven. Synesthetes (n =12), but not an equal number of controls, showed an early theta power increase for inducers presented to the right compared to the left hemifield, with sources in left fusiform gyrus. Alpha power asymmetries indicative of shifts of spatial attention were not observed. Together, synesthetes showed an increased responsiveness to inducers in grapheme processing areas. However, contrary to our hypothesis, inducers did not attract spatial attention in synesthetes.


Oxygen reactivity of both respiratory oxidases in Campylobacter jejuni: the cydAB genes encode a cyanide-resistant, low-affinity oxidase that is not of the cytochrome bd type.
The microaerophilic bacterium Campylobacter jejuni is a significant food-borne pathogen and is predicted to possess two terminal respiratory oxidases with unknown properties. Inspection of the genome reveals an operon (cydAB) apparently encoding a cytochrome bd-like oxidase homologous to oxidases in Escherichia coli and Azotobacter vinelandii. However, C. jejuni cells lacked all spectral signals characteristic of the high-spin hemes b and d of these oxidases. Mutation of the cydAB operon of C. jejuni did not have a significant effect on growth, but the mutation reduced formate respiration and the viability of cells cultured in 5% oxygen. Since cyanide resistance of respiration was diminished in the mutant, we propose that C. jejuni CydAB be renamed CioAB (cyanide-insensitive oxidase), as in Pseudomonas aeruginosa. We measured the oxygen affinity of each oxidase, using a highly sensitive assay that exploits globin deoxygenation during respiration-catalyzed oxygen uptake. The CioAB-type oxidase exhibited a relatively low affinity for oxygen (K(m) = 0.8 microM) and a V(max) of >20 nmol/mg/s. Expression of cioAB was elevated fivefold in cells grown at higher rates of oxygen provision. The alternative, ccoNOQP-encoded cyanide-sensitive oxidase, expected to encode a cytochrome cb'-type enzyme, plays a major role in the microaerobic respiration of C. jejuni, since it appeared to be essential for viability and exhibited a much higher oxygen affinity, with a K(m) value of 40 nM and a V(max) of 6 to 9 nmol/mg/s. Low-temperature photodissociation spectrophotometry revealed that neither oxidase has ligand-binding activity typical of the heme-copper oxidase family. These data are consistent with cytochrome oxidation during photolysis at low temperatures.


Wideband tunable optoelectronic oscillator based on a phase modulator and a tunable optical filter.
A widely tunable optoelectronic oscillator (OEO) based on a broadband phase modulator and a tunable optical bandpass filter is proposed and experimentally demonstrated. A tunable range from 4.74 to 38.38 GHz is realized by directly tuning the bandwidth of the optical bandpass filter. To the best of our knowledge, this is the widest fundamental frequency tunable range ever achieved by an OEO. The phase noise performance of the generated signal is also investigated. The single-sideband phase noise is below -120 dBc/Hz at an offset of 10 KHz within the whole tunable range.


Use of Nasal Bubble CPAP in Children with Hypoxemic Clinical Pneumonia-Report from a Resource Limited Set-Up.
Nasal bubble continuous positive airway pressure (bCPAP) is preferred in developing economies for easy applicability and low cost. Because its use in older children is unexplored, we sought to evaluate its utility in hypoxemic clinical pneumonia. Of 330 children (1 month-12 years) with clinical pneumonia enrolled prospectively over 1 year, those with increased work of breathing and/or SpO2 <92% received bCPAP delivered via an underwater 'T' tube through nasal prongs. Proportion requiring intubation despite bCPAP constituted primary outcome. Incidence of complications, duration of bCPAP and emergency stay were secondary outcomes. Oxygen was initiated by nasal prongs (NPO2) in 204 (61.8%), and by bCPAP in 110 (33.3%). Sixteen (4.8%) were intubated at the outset. Fifty-three (25.9%) on NPO2 were shifted to bCPAP for worsening distress and hypoxemia. Only three (1.8%) from bCPAP group required intubation, of which one died. Failure rate and complications were negligent. The median emergency stay was 4 days. Nasal bCPAP was safe and effective in children with hypoxemic clinical pneumonia.


Myeloid surface antigen expression in adult acute lymphoblastic leukemia.
The expression of myeloid surface markers was investigated in 41 cases of untreated adult acute lymphoblastic leukemia (ALL). Nineteen cases (46%) reacted with at least one myeloid monoclonal antibody (CD15 in 16 cases, CD13 in 10 cases, CD14 in five cases, and CD33 in four cases). Double-staining confirmed the coexpression of myeloid and lymphoid markers. In addition, 35 samples were tested for CD34 expression. Fourteen of the 17 myeloid-positive cases tested were positive for CD34 vs. eight of 18 negative cases (p less than 0.05). A t(9;22) translocation was found in eight cases, and a t(4;11) translocation in two cases, all expressing CD34 and myeloid antigens. These findings confirm the high frequency of myeloid markers on the surface of adult ALL blasts, and suggest that these leukemias may originate in a poorly differentiated precursor cell with mixed differentiation capacities.


Radiation-induced micro-RNA modulation in glioblastoma cells differing in DNA-repair pathways.
Human glioblastomas often develop resistance to radiation therapy. The molecular details of this phenomenon are not completely understood. Recent studies have suggested that deficiency in DNA repair pathways may alter the resistance to ionizing radiation in gliobastomas. The human glioma cell line M059J is deficient in DNA-dependent protein kinase (DNA-PK), whereas cell line M059K, isolated from the same malignant tumor, has normal DNA-PK activity. DNA-PK plays a central role in the repair of ionizing-radiation-induced double-strand break repair, and its deficiency has been correlated with ionizing radiation sensitivity in these glioblastoma cells. We argued that other cellular pathways could also play a role in the resistance to radiation therapy in gliomas. We hypothesized that micro-RNAs (miRNAs) are differentially modulated in M059J and M059K cells exposed to ionizing radiation and that the miRNA modulation contributes to the resistance to ionizing radiation. miRNAs are small nonprotein coding single-stranded RNA molecules, which are crucial posttranscriptional regulators of gene expression. Numerous studies have documented the participation of miRNAs in a wide range of biological processes. The contribution of miRNAs in mediating resistance of glioblastoma cell to ionizing radiation treatment has not been elucidated. To test this hypothesis, we examined the expression patterns of a number of miRNAs involved in carcinogenesis in irradiated M059J and M059K cells. The relative expression level as determined by real-time quantitative PCR for miRNAs belonging to the let-7 family indicated an upregulation in irradiated M059K cells. On the contrary, the analysis of irradiated M059J cells for the modulation of let-7 family of miRNAs revealed an overall downregulation. The miR-17-3p, miR-17-5p, miR-19a, miR-19b, miR-142-3p, and miR-142-5p were upregulated in both M059K and M059J cells. The miR-15a, miR-16, miR-143, miR-155, and miR-21 were upregulated in M059K, and the modulation of these miRNAs fluctuated in M059J cells in a time-dependent manner. These results indicate the involvement of miRNAs in the differential response of glioblastoma cells to ionizing radiation treatment.


The orientation of the semicircular canals in the guinea pig.
In 10 adult guinea pigs the stereotaxic coordinates of a series of points along each osseous semicircular canal were analysed to yield an equation of that canal plane in stereotaxic space. Angular relationships among the canal planes and between the canal planes and the major stereotaxic planes are presented together with the optimal positions of the head for physiological stimulation of each canal or pair of synergistic canals. The planes of the semicircular canals in each labyrinth are not perpendicular to one another and the planes of contralateral synergistic canals depart from parallelism by about 30 degrees.


[Mechanical ventilation in pediatrics (III). Weaning, complications and other types of ventilation. High-frequency ventilation].
In the era of lung-protective ventilation strategies, high frequency oscillatory ventilation (HFOV) has attracted renewed interest and its use has dramatically increased in neonatal and pediatric intensive care units. HFOV is able to reduce ventilator-induced lung injury by limiting the incidence of volutrauma, atelectrauma, barotrauma and biotrauma. During HFOV, adequate oxygenation and ventilation is achieved by using low tidal volumes and small pressure swings at supraphysiologic frequencies. Unlike other high-frequency ventilation modes, HFOV has an active expiration phase. HFOV constitutes a safe and successful ventilation mode for managing pediatric patients with respiratory insufficiency refractory to optimized conventional mechanical ventilation and provides better results when initiated early. However, the elective use of HFOV requires further studies to identify its benefits over conventional modes of mechanical ventilation and to support its routine use as a first line therapy. In the present article, the Respiratory Working Group of the Spanish Society Pediatric Critical Care reviews the main issues in the pediatric application of HFOV. In addition, a general practical protocol and specific management strategies, as well as the monitoring, patient care and other special features of the use of HFOV in the pediatric setting, are discussed.


P. micra and F. necrophorum: Hepatic Abscesses in a Healthy Soldier.
Parvimonas micra (P. micra) and Fusobacterium necrophorum (F. necrophorum) are two pathogens known to cause odontogenic and oropharyngeal infections. It is exceedingly rare for these bacteria to cause coinfection and even systemic infection. There is limited literature on liver abscesses and bacteremia involving P. micra. Most cases are found in elderly patients with associated gastrointestinal malignancy (24%) or laryngeal pharynx malignancy (28%). However, a substantial portion of described cases were unable to identify a source (36%). A 36-year-old, otherwise healthy male presented for fevers and chills for 2 weeks. After testing negative for initial infectious workup, including COVID-19 multiple times, he was found to have multiple liver abscesses which grew P. micra and F. necrophorum. This case highlights a rare coinfection of hepatic abscesses in an otherwise healthy young immunocompetent adult with a solitary dental caries, resulting in septic shock.


CCR3 and CXCR3 as drug targets for allergy: principles and potential.
Atopic disorders include a range of conditions such as allergic asthma, -rhinitis, -conjunctivitis, -dermatitis, food and drug allergies and anaphylaxis. Induction of T helper (Th)-2 immune response with consequent IgE dependent eosinophil, basophil and mast cell mediated tissue damage is the characteristic feature of allergies. The mechanism underlying this unique and long appreciated feature of allergy is being elucidated at the molecular level with advances in our knowledge of the chemokine system. Thus, chemokines that target CCR3 in concert with Th2 cytokines appear to play a pathogenic role in allergy. In contrast, chemokines that target CXCR3 in concert with Th1 cytokine appear to play a beneficial role. Accordingly, inhibiting CCR3/Th2 pathway using CCR3 antagonists is viewed as a potentially useful strategy for anti-allergy drug development. In contrast, the idea of using CXCR3 agonists to inhibiting allergic response by promoting CXCR3/Th1 pathway faces serious concerns of their potential pro-inflammatory activities in vivo. In this article we have critically evaluated the literature examining the principle and potential of this anti-allergy drug development strategy including a summary of various compounds that are under investigation.


Gaucher disease among Chinese patients: review on genotype/phenotype correlation from 29 patients and identification of novel and rare alleles.
Gaucher disease, the most prevalent lysosomal storage disease, results from an inherited deficiency in the enzyme glucocerebrosidase. Three clinical forms of Gaucher disease have been described: Type 1 non-neuronopathic, Type 2 acute neuronopathic, and Type 3 subacute neuronopathic. Although Gaucher disease is panethnic, its presentation reveals some ethnic-specific characteristics. The Type 1 form is most common among Caucasian patients. In contrast, the majority of Chinese Gaucher disease patients have early age of onset, severe hematological and skeletal complications, and often neurological involvement, resulting in early childhood death. In this report, we review 29 cases of Gaucher disease from 23 unrelated patients and 6 patients from 3 non-consanguineous families. Among these patients, 13 were diagnosed as Type 1, 10 as Type 2, and 6 as Type 3. A novel mutation, del 205-209ACCTT, was identified in the heterozygous form with mutation R353W (c.1174C>T) by DNA sequence analysis in 2 Type 1 patients who are sibs. Mutation R353W was also found in the heterozygous form in 3 other Type 1 patients, with mutation L444P in 2 sibs and a second unknown Gaucher allele in the third patient. The Gaucher genotypes of the remaining Type 1 patients were F37V/L444P, G46E/L444P, R48W/R120W, N188S/L444P, Y205C/L444P, N370S/L444P, and L444P/unknown. It was noted that mutation N370S in the patient was linked to the pv1.1(-)(1) haplotype present in Jewish patients. Among the Type 2 patients, L444P was present in the heterozygous form with mutation F213I, L385P, or the complex allele (RecNci) in 5 patients. The second most common mutation, F213I, was found in the heterozygous form in 6 patients with mutations N382K, L383R, or L444P. The other mutations found in the Type 2 patients were P122L, V375L, Y363C, M416V, and 383-400del. The genotypes of the 6 Type 3 patients identified were D409H/D409H, D409H/G202R, G46E/N188S, N188S/unknown, and L444P/L444P. While D409H has been reported as being associated with cardiovascular/ocular involvements in Gaucher disease, there have been no such complications in these patients. As noted, the majority of the Gaucher mutations we identified in the Chinese patients were either rare or absent in other populations. With the exception of N370S and R353W found only in the Type 1 form, the majority of these mutations are severe ones that result in poor prognosis and often Types 2 and 3 Gaucher disease.


[Urinary alanine aminopeptidase excretion in children: reference values and effect of nephrotropic contrast media].
The catalytic activity of alanine aminopeptidase (EC 184.108.40.206) in urine shows a clear cut difference between boys (1530 mU/d X m2) and girls (1143 mU/d X m2). Nineteen children (preterms to 14 years) received contrast media (loxaglate (Hexabrix) (N = 15) or lotalamate (Conray 70) (N = 4] according to the diagnostic indication. The alanine aminopeptidase activity increases to 10-fold of the initial value in the loxaglate and 19-fold of the initial value in the lotalamate group. These results demonstrate a much higher response of the kidney to contrast medium in children than in adults.


Newborn genetic screening: ethical and social considerations for the nineties.
As we head into the next decade, the impact of the use of genetic screening programs for immunological surveillance purposes (such as for HIV) and for possible DNA typing should not be underestimated. The authors present ten principles which seek to reaffirm the basic tenents of neonatal screening programs -- the benefit of newborns. These principles are both protective and yet open to the complex ethical and social considerations raised by such new uses of newborn genetic screening programs.


Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.
Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.


Animal Models for Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS): Achievements and Future Perspectives.
Since 2012, Associated Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has been standing in the limelight of modern liver surgery and numerous questions have been raised regarding this novel approach. On the one hand, ALPPS has proved to be a valuable method in the treatment of hepatic tumors, while on the other hand, there are many controversies, such as high mortality and morbidity rates. Further surgical research is essential for a better understanding of underlying mechanisms and for enhancing patient safety. Until recently, only 8 animal models have been created with the purpose to mimic ALPPS-induced liver regeneration. From these 7 are rodent (6 rat and 1 mouse) models, while only 1 is a large animal model, which uses pigs. In case of rodent models, portal flow deprivation of 75-90% is achieved via portal vein ligation leaving only the right (20-25%) or left median (10-15%) lobes portally perfused, while liver splitting in general is carried out positioned according to the falciform ligament. As for the swine model, the left lateral and medial lobes (70-75% of total liver volume) are portally ligated, and the right lateral lobe (accounting for 20-24% of the parenchyma) is partially resected in order to reach critical liver volume. Each model is capable of reproducing the accelerated liver regeneration seen in human cases. However, all species have significantly different liver anatomy compared with the human anatomic situation, making clinical translation somewhat difficult. Key Messages: Unfortunately, there are no perfect animal models available for ALPPS research. Small animal models are inexpensive and well suited for basic research, but may only provide limited translational potential to humans. Clinically large animal models may provide more relevant data, but currently no suitable one exists.


Age-specific neural strategies to maintain motor performance after an acute social stress bout.
Stress due to cognitive demands and fatigue have shown to impair motor performance in older adults; however, the effect of social stress and its influence on prefrontal cortex (PFC) functioning in older adults during upper extremity motor performance tasks is not known. The present study explored the after-effects of an acute social stress bout on neural strategies, measured using PFC and hand/arm muscle activation, and adopted by younger and older adults to maintain handgrip force control. Nine older [74.1 (6.5) years; three men, six women] and ten younger [24.2 (5.0) years, four men, six women] adults performed handgrip force control trials at 30% maximum voluntary contractions before and after the Trier Social Stress Test (TSST). PFC activity was measured using functional near infrared spectroscopy and muscle activity from the flexor and extensor carpi radialis (FCR/ECR) was measured using electromyography. In general, aging was associated with decreased force steadiness and force complexity with a concomitant increase in bilateral PFC activity. While motor performance remained comparable before and after the TSST stress session in both age groups, the associated neural strategies differed between groups. While the stress condition was associated with lower FCR and ECR activity in younger adults despite no change in the PFC activation, stress was associated with increases in FCR activity in older adults. This stress-related compensatory neural strategy of increasing hand/arm muscle activation, potentially via the additional recruitment of the stress-motor neural circuitry, may have played a role in maintaining motor performance in older adults.


Residual risk of hepatocellular carcinoma development for chronic hepatitis C patients treated by all oral direct-acting antivirals with sustained virological response.
The treatment of chronic hepatitis C (CHC) infection underwent a significant transformation with the introduction of all-oral direct-acting anti-virals (DAAs). These medications offered a high success rate in treatment, shorter duration, good tolerability, and expanded treatment options. However, a residual risk of hepatocellular carcinoma (HCC) development remained for a few patients even after achieving sustained virological response (SVR). To date, there is a lack of real-world data on evaluating risk factors associated with de novo HCC in CHC patients post-SVR, particularly in Taiwan. Between January 2017 and December 2019, a total of 671 consecutive CHC patients who achieved SVR after receiving DAAs were included for analysis. Patients with a history of HCC or liver transplantation prior to DAAs, a short follow-up period (<1 year), or treatment failure with DAAs were excluded. The primary outcome was the development of HCC following the initiation of DAAs. Variables associated with the primary outcome were assessed using multivariate Cox proportional hazards models. The mean age of the enrolled patients was 65.1 ± 12.8 years, with 39.6% of them being male. Among the patients, 30.6% had advanced (F3-4) fibrosis, and the median follow-up period was 2.90 years. The cumulative incidence of HCC in CHC patients post-SVR12 was 1.6% at 1 year, 4.4% at 2 years, 4.8% at 3 years, 5.3% at 4 years, and 6.1% at 4.8 years, respectively. Variables independently associated with de novo HCC were advanced liver fibrosis (hazard ratio [HR] = 6.745; 95% CI = 1.960-23.218; p = 0.002), end-of-treatment 12 weeks (EOT 12 ) alpha-fetoprotein (AFP) >7 ng/mL (HR = 3.059; 95% CI = 1.215-7.669; p = 0.018), EOT 12 albumin-bilirubin (ALBI) grade ≥ 2 (HR = 2.664; 95% CI = 1.158-6.128; p = 0.021), and body mass index (BMI) ≥ 25 kg/m 2 (HR = 2.214; 95% CI = 1.011-4.852; p = 0.047). Despite achieving viral clearance with DAAs, CHC patients still face a residual risk of de novo HCC. Establishing a risk stratification model based on independent variables could facilitate the prediction of future HCC development and enhance screening strategies.


Size prediction of recombinant human growth hormone nanoparticles produced by supercritical fluid precipitation.
Solution-enhanced dispersion by supercritical fluids (SEDS) was applied to produce nano-sized recombinant human growth hormone (hGH) particles. Ethanol was used to help the supercritical carbon dioxide to extract water from the aqueous protein solution. Various sizes of hGH nanoparticles were successfully prepared with a narrow particle size distribution from aqueous ethanol solution without using any additive. The theoretical particle sizes were deduced from the calculated droplet sizes based on a modified Jasuja's equation. The calculated mean particle sizes and the experimentally obtained ones were compared and the results showed an excellent correlation coefficient (R (2)) of 0.995.


Effectiveness of Dry Needling in Improving Pain and Function in Comparison with Other Techniques in Patients with Chronic Neck Pain: A Systematic Review and Meta-Analysis.
The purpose of this systematic review and meta-analysis was to assess the short-, mid-, and long-term effectiveness of dry needling in improving pain and functional capacity of patients with chronic neck pain. Search strategy was performed on PubMed, Web of Science, Scopus, PEDro, and Cochrane Library Plus biomedical databases. The risk of bias was assessed using the RoB2 tool. Randomised controlled clinical trials in which at least 1 of the groups received dry needling were included. 662 studies were found; 14 clinical trials were selected for qualitative analysis and 13 for quantitative analysis. The quality of most of the studies included was "high." All the studies reported improvements in cervical pain and/or disability, regardless of the protocol followed and the muscles targeted. No serious adverse effects were reported. Dry needling showed to be more effective when compared with other therapies in both women and men, without differences by sex. When the analysis was carried out by age, patients over 40 years old benefitted more than those below 40 years old. Our meta-analysis supports the use of dry needling to improve pain and functional capacity in patients with chronic neck pain at short- and mid-term intervals.


Piriformospora indica mycorrhization increases grain yield by accelerating early development of barley plants.
Root colonization by the basidiomycete fungus Piriformospora indica induces host plant tolerance against abiotic and biotic stress, and enhances growth and yield. As P. indica has a broad host range, it has been established as a model system to study beneficial plant-microbe interactions. Moreover, its properties led to the assumption that P. indica shows potential for application in crop plant production. Therefore, possible mechanisms of P. indica improving host plant yield were tested in outdoor experiments: Induction of higher grain yield in barley was independent of elevated pathogen levels and independent of different phosphate fertilization levels. In contrast to the arbuscular mycorrhiza fungus Glomus mosseae total phosphate contents of host plant roots and shoots were not significantly affected by P. indica. Analysis of plant development and yield parameters indicated that positive effects of P. indica on grain yield are due to accelerated growth of barley plants early in development.


Pharmacological Activity, Pharmacokinetics, and Toxicity of Timosaponin AIII, a Natural Product Isolated From Anemarrhena asphodeloides Bunge: A Review.
Anemarrhena asphodeloides Bunge is a famous Chinese Materia Medica and has been used in traditional Chinese medicine for more than two thousand years. Steroidal saponins are important active components isolated from A. asphodeloides Bunge. Among which, the accumulation of numerous experimental studies involved in Timosaponin AIII (Timo AIII) draws our attention in the recent decades. In this review, we searched all the scientific literatures using the key word "timosaponin AIII" in the PubMed database update to March 2020. We comprehensively summarized the pharmacological activity, pharmacokinetics, and toxicity of Timo AIII. We found that Timo AIII presents multiple-pharmacological activities, such as anti-cancer, anti-neuronal disorders, anti-inflammation, anti-coagulant, and so on. And the anti-cancer effect of Timo AIII in various cancers, especially hepatocellular cancer and breast cancer, is supposed as its most potential activity. The anti-inflammatory activity of Timo AIII is also beneficial to many diseases. Moreover, VEGFR, X-linked inhibitor of apoptosis protein (XIAP), B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1), thromboxane (Tx) A2 receptor, mTOR, NF-κB, COX-2, MMPs, acetylcholinesterase (AChE), and so on are identified as the crucial pharmacological targets of Timo AIII. Furthermore, the hepatotoxicity of Timo AIII was most concerned, and the pharmacokinetics and toxicity of Timo AIII need further studies in diverse animal models. In conclusion, Timo AIII is potent as a compound or leading compound for further drug development while still needs in-depth studies.


Retinoic Acid Increases Cellular Cholesterol in Leishmania donovani-Infected Macrophages in an mTOR-Independent Manner.
Infection with Leishmania donovani reduces cellular cholesterol and thus deprives the host cells by inhibiting its synthesis and uptake. Changes in cholesterol levels increase the chance of attachment and internalization of L. donovani in macrophages (Mϕ). Retinoic acid (RA), an important micronutrient, restores the lysosomal uptake of cholesterol in L. donovani-infected Mϕ. Importantly, mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) increases the cellular cholesterol level by increasing expression of sterol regulatory element-binding protein 2 (SREBP2). Whether the efficacy of RA in L. donovani-infected Mϕ is mediated by mTOR is not yet established. Moreover, there are contradicting reports suggesting potential activation and inhibition of mTOR in L. donovani-infected Mϕ. Intrigued by this, we attempted to understand the RA-mediated restoration of cholesterol as well as the possible roles of mTORC1, if any. Our findings suggest that L. donovani infection impairs the synthesis of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), uptake of low-density lipoprotein receptor (LDLR), and secretion of ATP-binding cassette transporter (ABCA1) in Mϕ. L. donovani infection possibly impairs mTORC1 formation, as it inhibits the expression of regulatory-associated protein of mammalian target of rapamycin (RAPTOR). Importantly, all these are restored upon RA supplementation. RA also restores the levels of SREBP2 in L. donovani-infected Mϕ, resulting in increased cellular cholesterol and thus reducing the parasite burden. When mTORC1 was inhibited, RA exerted a similar response in L. donovani-infected Mϕ; i.e., it restored cholesterol levels and reduced the parasite burden. In summary, RA restores cholesterol levels in L. donovani-infected Mϕ and reduces the parasite burden in an mTOR-independent manner. IMPORTANCE People who reside in regions where leishmaniasis is endemic and who lack proteins, iron, zinc, and vitamin A in their diet are more prone to develop visceral leishmaniasis (VL) as a full-blown disease. Vitamin A deficiency favors the development of a parasitic infection in the human host, and the WHO recommends administering 200,000-IU doses to VL patients on admission. Additionally, Leishmania entry and its survival inside the host are achieved by utilizing host cholesterol, as all trypanosomatids lack de novo synthesis of sterol. We have already shown that RA regulates cellular cholesterol levels associated with an efficient immune response. A deficiency of retinoic acid (RA) favors the parasite in Leishmania donovani-infected macrophages by downregulating the immune response. In the present work, we observed that RA restores cellular cholesterol levels in Leishmania donovani-infected macrophages. This study proposes using RA as an immune potentiator along with standard therapy.


Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping.
Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions. The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction. The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests. Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (approximately 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (approximately 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (approximately 1% of the variance). These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.


Recent genome-wide replication promoted expansion and functional differentiation of the JAZs in soybeans.
Jasmonate Zim-domain (JAZ) protein is an inhibitor of the jasmonate (JA) signal transduction pathway, and plays an important role in regulating plant growth, development, and defense. However, there have been few studies on its function under environmental stress in soybeans. In this study, a total of 275 JAZs protein-coding genes were identified in 29 soybean genomes. SoyC13 contained the least JAZ family members (26 JAZs), which was twice as high as AtJAZs. The genes are mainly generated by recent genome-wide replication (WGD), which replicated during the Late Cenozoic Ice Age. In addition, transcriptome analysis showed that the differences in gene expression patterns in the roots, stems, and leaves of the 29 cultivars at the V1 stage were not significant, but there was a significant difference among the three seed development stages. Finally, qRT-PCR results showed that GmJAZs responded the most strongly to heat stress, followed by drought and cold stress. This is consistent with the reason for their expansion and promoter analysis results. Therefore, we explored the significant role of conserved, duplicated, and neofunctionalized JAZs in the evolution of soybeans, which will contribute to the functional characterization of GmJAZ and the improvement of crops.


Building of Pressure-Assisted Ultra-High Temperature System and Its Inactivation of Bacterial Spores.
The pressure-assisted ultra-high temperature (PAUHT) system was built by using soybean oil as pressure-transmitting medium, and the multiple regression equation of soybean oil temperature change (ΔTP ) during pressurization as a function of initial temperature (Ti ) and set pressure (P) was developed: ΔTP = -13.45 + 0.46 Ti + 0.0799 P - 0.0037 T i 2 - 2.83 × 10-5 P2. The fitted model indicated that the temperature of the system would achieve ≥121°C at 600 MPa when the initial temperature of soybean oil was ≥84°C. The PAUHT system could effectively inactivate spores of Bacillus subtilis 168 and Clostridium sporogenes PA3679 (less than 1 min). Treatment of 600 MPa and 121°C with no holding time resulted in a 6.75 log reductions of B. subtilis 168 spores, while treatment of 700 MPa and 121°C with pressure holding time of 20 s achieved more than 5 log reductions of C. sporogenes PA3679 spores. By comparing the PAUHT treatment with high pressure or thermal treatment alone, and also studying the effect of compression on spore inactivation during PAUHT treatment, the inactivation mechanism was further discussed and could be concluded as follows: both B. subtilis 168 and C. sporogenes PA3679 spores were triggered to germinate firstly by high pressure, which was enhanced by increased temperature, then the germinated spores were inactivated by heat.


Nucleation versus spinodal decomposition in confined binary solutions.
Basic features of spinodal decomposition, on one side, and nucleation, on the other side, and the transition between both mechanisms are analyzed within the framework of a generalized thermodynamic cluster model based on the generalized Gibbs approach. Hereby the clusters, representing the density or composition variations in the system, may change with time both in size and in their intensive state parameters (density and composition, for example). In the first part of the analysis, we consider phase separation processes in dependence on the initial state of the system for the case when changes of the state parameters of the ambient system due to the evolution of the clusters can be neglected as this is the case for cluster formation in an infinite system. As a next step, the effect of changes of the state parameters on cluster evolution is analyzed. Such depletion effects are of importance both for the analysis of phase formation in confined systems and for the understanding of the evolution of ensembles of clusters in large (in the limit infinite) systems. The results of the thermodynamic analysis are employed in both cases to exhibit the effect of thermodynamic constraints on the dynamics of phase separation processes.


Clinical usefulness of MLCs in robotic radiosurgery systems for prostate SBRT.
Stereotactic body radiation therapy (SBRT) using recently introduced multileaf collimators (MLC) is preferred over circular collimators in the treatment of localized prostate cancer. The objective of this study was to assess the clinical usefulness of MLCs in prostate SBRT by comparing the effectiveness of treatment plans using fixed collimators, variable collimators, and MLCs and by ensuring delivery quality assurance (DQA) for each. For each patient who underwent conventional radiation therapy for localized prostate cancer, mock SBRT plans were created using a fixed collimator, a variable collimator, and an MLC. The total MUs, treatment times, and dose-volume histograms of the planning target volumes and organs at risk for each treatment plan were compared. For DQA, a phantom with a radiochromic film or an ionization chamber was irradiated in each plan. We performed gamma-index analysis to evaluate the consistency between the measured and calculated doses. The MLC-based plans had an ~27% lower average total MU than the plans involving other collimators. Moreover, the average estimated treatment time for the MLC plan was 31% and 20% shorter than that for the fixed and variable collimator plans respectively. The gamma-index passing rate in the DQA using film measurements was slightly lower for the MLC than for the other collimators. The DQA results acquired using the ionization chamber showed that the discrepancies between the measured and calculated doses were within 3% in all cases. The results reinforce the usefulness of MLCs in robotic radiosurgery for prostrate SBRT treatment planning; most notably, the total MU and treatment time were both reduced compared to the cases using other types of collimators. Moreover, although the DQA results based on film dosimetry yielded a slightly lower gamma-index passing rate for the MLC than for the other collimators, the MLC accuracy was determined to be sufficient for clinical use.


Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-).
Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain (18)F for use in positron-emission tomography (PET) imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, attack of a nucleophile at a carbon atom bearing a 'leaving group' leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant (18)F-deoxyfluorination reaction of phenols, which can be used to synthesize (18)F-PET probes. Selective (18)F introduction, without the need for the common, but cumbersome, azeotropic drying of (18)F, can now be accomplished from phenols as starting materials, and provides access to (18)F-labelled compounds not accessible through conventional chemistry.


Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations.
The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and +1q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly.


Nitric oxide-induced Cl- secretion in isolated rat colon is mediated by the release of thromboxane A2.
We have shown previously that thromboxane A2 (TXA2), which may be released by the anti-tumour drug irinotecan and by platelet-activating factor (PAF), causes Cl- secretion in the isolated rat colon. In the present study, the involvement of TXA2 in nitric oxide-induced Cl- secretion in isolated rat colon was investigated. In colonic mucosa set between Ussing chambers, the NO donor sodium nitroprusside (SNP; 100 microM) caused Cl- secretion, an effect that was almost completely inhibited by the NO scavenger carboxy-PTIO at 200 microM. The SNP-induced Cl- secretion was inhibited in a concentration-dependent manner by the TXA2 receptor antagonist ONO-3708 (IC50 = 2 microM) and the TX synthase inhibitor Y-20811 (IC50 = 0.4 microM). SNP significantly increased the release of TXA2 (measured as TXB2 release) from the mucosa. The SNP-induced increases in Cl- secretion and TXA2 release were blocked by a NO-sensitive guanylate cyclase inhibitor (ODQ). Dibutyryl cGMP (500 microM) also induced Cl- secretion, which was sensitive to ONO-3708 (10 microM) and Y-20811 (1 microM), and increased the release of TXA2 from the mucosa. PAF-induced (10 microM) Cl- secretion was inhibited by carboxy-PTIO (200 microM) and ODQ (10 microM), whereas irinotecan-induced (500 microM) Cl- secretion was not significantly inhibited by these drugs. A stable TXA2 analogue (STA2) but not SNP (100 microM) changed the membrane potential of epithelial cells in isolated colonic crypts under the whole-cell current-clamp condition. These results indicate that PAF elicits the NO-cGMP pathway and then stimulates the release of TXA2, which is a stimulant of colonic Cl- secretion. In contrast, the NO-cGMP pathway is not involved in the TXA2-mediated Cl- secretion induced by irinotecan.


Polysaccharides from Paecilomyces hepiali Prevent Acute Colitis in Association with Modulating Gut Microbiota and Treg/Th17 Immune Balance in Mice.
Cordyceps exopolysaccharide (CEP) has shown emerging potential in adjustment of gut microbiota and immune cell function. In this study, a water-soluble CEP with a molecular weight of 58.14 kDa was extracted from the fermentation broth of Paecilomyces hepiali, an endophytic fungus of Cordyceps sinensis. Our results indicated that Paecilomyces hepiali polysaccharide (PHP) showed significantly preventive potential on dextran sulfate sodium (DSS)-induced colitis in mice, which can prevent colon shortening, reduce intestinal epithelial cell (IEC) destruction, suppress inflammatory cell infiltration, and regulate the balance between regulatory T (Treg) cells and T helper type 17 (Th17) cells. Meanwhile, the disturbed gut microbiota was partially restored after PHP treatment. Further Pearson correlation coefficient analyses exhibited that the alteration of the gut microbiota was significantly related to adjustment of the IEC barrier and Treg/Th17 balance. In conclusion, all findings proposed that purified PHP has the potential to develop into a promising agent for colitis prevention and adjuvant therapy via maintaining intestinal homeostasis of gut microbiota and immune system.


Trends of partial and radical nephrectomy in managing small renal masses.
Use of partial nephrectomy (PN) for renal tumors appears to have relatively lower incidence rates in Jordan. We sought to characterize its trend at King Hussein Cancer Center for the last 10 years. A retrospective review of our renal cell cancer data was performed. We identified 169 patients who had undergone surgery for renal tumors measuring ≤7 cm between 2005 and 2015. We characterized tumor size, pathology, type of surgery and clinical outcomes. Factors associated with the use of PN were evaluated using univariable and multivariable logistic regression models. Of the 169 patients, 34 (20%) and 135 (80%) had undergone partial and radical nephrectomy (RN) respectively for tumors ≤7 cm in diameter. Total number of 48 patients with tumors of ≤4 cm in diameter had undergone either PN (n=19; 40%) or RN (n=29; 60%). The frequency of PN procedures steadily increased over the years from 6% in 2005-2008, to 32% in 2013-2015, contrary to RN which was less frequently applied 94% in 2005-2008, and 68% in 2013-2015. In multivariable analysis, delayed surgery (p=0.01) and smaller tumor size (p=0.0005) were significant independent predictors of PN. During follow-up period, incidence of metastasis was lower in PN versus RN (13% and 32%, respectively, p=0.043). Local recurrence rates were not significantly different between PN (6.9%) and RN (7.2%) (p=0.99). The mean tumor sizes for patients who had undergone PN and RN were 4.1 and 5.5 cm respectively, (p<0.0001). The mean follow-up period for PN was 20 months, and for RN 33 months, (p=0.0225). Partial nephrectomy for small renal tumors is relatively less frequently applied in Jordan, however an increase in its use has been observed over the years. Our data showed lower rates of distant metastasis and similar rates of local recurrence in favor of PN.


Landscape of Health Systems in the United States.
Despite the prevalence of vertical integration, data and research focused on identifying and describing health systems are sparse. Until recently, we lacked an enumeration of health systems and an understanding of how systems vary by key structural attributes. To fill this gap, the Agency for Healthcare Research and Quality developed the Compendium of U.S. Health Systems, a data resource to support research on comparative health system performance. In this article, we describe the methods used to create the Compendium and present a picture of vertical integration in the United States. We identified 626 health systems in 2016, which accounted for 70% of nonfederal general acute care hospitals. These systems varied by key structural attributes, including size, ownership, and geographic presence. The Compendium can be used to study the characteristics of the U.S. health care system and address policy issues related to provider organizations.


Effect of knee position on ultrasound Doppler findings in patients with patellar tendon hyperaemia (jumper's knee).
The purpose of this study is to see if changes in patient positioning result in significant changes in Doppler findings. 30 consecutive patients with jumper's knee in the proximal portion of the patellar tendon formed the study group. The patellar tendon was scanned in the longitudinal plane with colour and spectral Doppler with the knee fully extended as well as, flexed at 15 degrees and 20 degrees . All subjects were randomised to either extension or 20 degrees flexion as the initial position. The amount of colour Doppler activity inside the tendon was expressed with the colour fraction (colour pixels/total pixels) in the proximal portion of the tendon. With spectral Doppler, the resistive index was measured ((peak systolic velocity--end-diastolic velocity)/ peak systolic velocity). The mean (+/- SE) colour fraction in the fully extended position and 20 degrees flexion was 36.7 +/- 3.4% and 13.3 +/- 3.4%, respectively (p<0.0001). The mean resistive index was 0.607 +/- 0.036 with full extension and 0.914 +/- 0.036 with 20 degrees flexion (p<0.0001). On an individual patient basis, a decrease in colour fraction was observed in all 30 patients (100%), whereas an increase in resistive index was observed in 29 patients (97%). Maximum perfusion was seen in all positions when flexion was the initial position. We advocate that for the examination of the patellar tendon by Doppler sonography, the patients should have fully extended and relaxed knees. Otherwise, the colour Doppler findings will underestimate the flow, and the spectral Doppler will overestimate peripheral vascular resistance.


[Isolation and cultivation of mouse bone marrow mesenchymal stem cells].
To establish the best condition of isolation and cultivation of mouse bone marrow mesenchymal stem cells (BMSCs) in vitro, we isolated BMSCs from BALB/C mouse using density gradient centrifugation and adherent selecting. The effects of different centrifuge power, adherent time, serum concentration and cell density on the isolation and cultivation of BMSCs were investigated. The best isolating condition is: 500g x 30min, 24 hours adhering. The best cell density is 12-20 x 10(5)/ml of primary cells and 6.4-25.6 x 10(4)/ml of secondary cells. The best serum concentration is 10%. More than 90% of subcultured cells were adhesive in 8 hours. Thus we have established a cell biological method of isolation and cultivation of BMSCs.


Pharmacological studies on EB-382, a new non-steroidal antiinflammatory agents: mode of action of the analgesic effects.
The analgesic mechanism of (+/-)-2-[p-[(2-methylallyl)amino]phenyl]propionic acid (EB-382), a new non-steroidal antiinflammatory agent, was studied. EB-382 exerted a potent analgesic effect on yeast-induced hyperalgesia in rats and bradykinin-induced writhing in mice, and its potency was superior to that of ibuprofen. EB-382 had a comparatively weak inhibitory effect on the prostaglandin E2 production from arachidonic acid in sheep seminal vesicle microsomal fraction in vitro. EB-382 exhibited a dose-dependent inhibitory effect on the phospholipase A2 activity in 3T3 mouse fibroblast cells with a different mechanism from steroidal agents, although indomethacin and ibuprofen did not reveal any significant inhibition. EB-382 did not affect the bradykinin-induced contraction of isolated rat uterus. Intracisternal injection of EB-382 did not affect the acetic acid-induced writhing response in mice. From these results, it is suggested that the analgesic effect of EB-382 in inflammation is exerted through its direct peripheral action, and inhibition of prostaglandin biosynthesis via phospholipase A2, rather than cyclooxygenase.


[The application of cell cultures, body fluids and tissues in oncoproteomics].
Mass spectrometry (MS)-based proteomics is a rapidly developing technology for the large scale analysis of proteins, their interactions and subcellular localization. In recent years proteomics has attracted much attention in medicine. Since a single biomarker might not have sufficient sensitivity and specificity in clinical practice, the identification of biomarker panels that comprise several proteins would improve the detection and clinical management of cancer patients. Additionally, the characteristics of protein profiles of most severe human malignancies certainly contribute to the understanding of the biology of cancer and fill the gap in our knowledge of carcinogenesis. This knowledge also is likely to result in the discovery of novel potential cancer markers and targets for molecular therapeutics. It is believed that the novel biomarkers will help in the development of personalized therapy tailored to the individual patient and will thereby reduce the mortality rate from cancer. In this review, the use of different types of human clinical samples (cell cultures, tissues and body fluids) in oncoproteomics is explained and the latest advances in mass spectrometry-based proteomics biomarker discovery are discussed.


Evaluation of the Early In Vivo Response of a Functionally Graded Macroporous Scaffold in an Osteochondral Defect in a Rabbit Model.
Cartilage tissue engineering is a multifactorial problem requiring a wide range of material property requirements from provision of biological cues to facilitation of mechanical support in load-bearing diarthrodial joints. The study aim was to design, fabricate and characterize a template to promote endogenous cell recruitment for enhanced cartilage repair. A polylactic acid poly-ε-caprolactone (PLCL) support structure was fabricated using laser micromachining technology and thermal crimping to create a functionally-graded open pore network scaffold with a compressive modulus of 9.98 ± 1.41 MPa and a compressive stress at 50% strain of 8.59 ± 1.35 MPa. In parallel, rabbit mesenchymal stem cells were isolated and their growth characteristics, morphology and multipotency confirmed. Sterilization had no effect on construct chemical structure and cellular compatibility was confirmed. After four weeks implantation in an osteochondral defect in a rabbit model to assess biocompatibility, there was no evidence of inflammation or giant cells. Moreover, acellular constructs performed better than cell-seeded constructs with endogenous progenitor cells homing through microtunnels, differentiating to form neo-cartilage and strengthening integration with native tissue. These results suggest, albeit at an early stage of repair, that by modulating the architecture of a macroporous scaffold, pre-seeding with MSCs is not necessary for hyaline cartilage repair.


A human judgment approach to epidemiological forecasting.
Infectious diseases impose considerable burden on society, despite significant advances in technology and medicine over the past century. Advanced warning can be helpful in mitigating and preparing for an impending or ongoing epidemic. Historically, such a capability has lagged for many reasons, including in particular the uncertainty in the current state of the system and in the understanding of the processes that drive epidemic trajectories. Presently we have access to data, models, and computational resources that enable the development of epidemiological forecasting systems. Indeed, several recent challenges hosted by the U.S. government have fostered an open and collaborative environment for the development of these technologies. The primary focus of these challenges has been to develop statistical and computational methods for epidemiological forecasting, but here we consider a serious alternative based on collective human judgment. We created the web-based "Epicast" forecasting system which collects and aggregates epidemic predictions made in real-time by human participants, and with these forecasts we ask two questions: how accurate is human judgment, and how do these forecasts compare to their more computational, data-driven alternatives? To address the former, we assess by a variety of metrics how accurately humans are able to predict influenza and chikungunya trajectories. As for the latter, we show that real-time, combined human predictions of the 2014-2015 and 2015-2016 U.S. flu seasons are often more accurate than the same predictions made by several statistical systems, especially for short-term targets. We conclude that there is valuable predictive power in collective human judgment, and we discuss the benefits and drawbacks of this approach.


Erosion caused by gastroesophageal reflux: diagnostic considerations.
Dental erosion occurs with a high prevalence in the general population, but its impact on prosthodontic care is often unrecognized. The etiology of dental erosion is difficult to establish because it may result from a variety of causes and may have different presentations. Our purpose was to review the literature relevant to dental erosion and to report a patient presentation in which an unusual pattern of severe erosion was the dental manifestation of asymptomatic gastroesophageal reflux disease.


The Relationship Between the Customer Relationship Management and Patients' Loyalty to Hospitals.
Customer Relationship Management (CRM) with its various components has been considered as a tool causing customers' loyalty. The present study aims to investigate the relationship between the various components of customer relationship management and patients' loyalty to the place of their treatment. This cross sectional and descriptive-analytical study was conducted among nurses and hospitalized patients in inpatient wards in selected hospitals in 2014. Using the stratified random sampling method, 224 valid and reliable researcher-drafted questionnaires were completed for CRM by nurses and 359 questionnaires were completed by patients for patients' loyalty in the studied wards. Data were analyzed using the SPSS(20) software. There was no statistically significant relationship between the level of patients' loyalty and organizational indicators, information technology and knowledge management (P Value>0.05). However, there was a statistically significant relationship between loyalty and the dimensions of the service process (P Value=0.04), human resources (P Value=0.002) and CRM (P Value=0.038). The strength of these relationships were 34, 40 and 36 percent, respectively all of which were positive. Customer Relationship Management is a tool for improving influencing factors on patients' satisfaction and loyalty. Therefore, attempts to implement customer relationship management as a process for improving hospitals performance and improving communication between service providers in hospitals and customers leading to enhance patients' loyalty should be taken into account by managers and policy makers in the health sectors.


Foetal echoencephalography and Doppler ultrasonography of the middle cerebral artery in canine foetuses.
This study aimed to evaluate the characteristics of the brain and vascular indices of the middle cerebral artery of canine foetuses. Twenty-five bitches were selected. Tissue development, echogenicity, echotexture and brain echobiometric data were studied, and the major structures were identified between the 5th and 8th gestational weeks. The area and volume of the brain mass (BMA and BMV), cranial area and volume (AC and VC), brain mass index (BMI) and brain volume index (BVI) were determined. A single ultrasound examination was performed during each studied week (6th, 7th and 8th). Doppler ultrasonography was performed to assess the maximum and minimum velocity, resistance and pulsatility index of middle cerebral artery of the foetuses. Echoencephalography was performed to evaluate the morphological characteristics of the central nervous system. Cerebral echobiometry indicated an increase in area and volume of the hemispheres and cranium (P<0·001) but no changes in BMI or BVI over the gestational period studied. Doppler ultrasonography identified increases in peak systolic velocity (P=0·0188) and end diastolic velocity (P=0·0274) and decreases in resistance index (P=0·0002) and pulsatility index (P<0·001). Echoencephalography and spectral Doppler ultrasonography of the middle cerebral artery in canine foetuses might be a useful technique for prenatal care.


Conversion locked-in syndrome after implantation of a spinal cord stimulator.
The locked-in syndrome is defined as quadriplegia and anarthria (loss of articulate speech) with the preservation of consciousness. It is typically caused by a lesion to the ventral pons. Conversion disorder is the deficit of voluntary motor or sensory function requiring an extensive work-up to exclude any organic cause. After surgery for an implantation of a spinal cord stimulator, a 42-year-old woman presented with quadriplegia and lower facial diplegia, but was able to open and blink her eyes. We found no organic causes to explain her condition after appropriate radiological studies looking for intracranial or intraspinal causes, and reversal drugs were administered with no immediate effect. Over the course of several hours, the patient gradually recovered and was discharged the following day. A psychology consultation was obtained during her stay and she was found to meet the criteria for a conversion disorder to explain her condition. Before considering a psychological cause, all organic factors should be excluded with proper tests and consultations, as conversion disorder is a diagnosis of exclusion. We report a patient who, after implantation of a spinal cord stimulator, manifested locked-in syndrome resulting from a conversion disorder.


Priapism pathophysiology: clues to prevention.
Priapism, in which penile erection persists in the absence of sexual excitation, is an enigmatic yet devastating erectile disorder. Current endeavors to manage the disorder suffer from a poor fundamental knowledge of the etiology and pathogenesis of priapism. These endeavors have remained essentially reactive, which commonly fail to avert its pathological consequences of erectile tissue damage and erectile disability, not to mention its psychological toll. The role of preventative management seems paramount with respect to priapism. As a prerequisite to formulating prevention strategies, gaining understanding of its pathogenic features and likely pathophysiologic mechanisms is viewed to be quite important. This review combined an analysis of clinicopathologic reports as well as a summary of clinical and basic science investigations on the subject to date. These assessments support the basic classification of priapism into low-flow (ischemic) and high-flow (nonischemic) hemodynamic categories, resulting from venous outflow occlusion and unregulated arterial overflow of the penis, respectively. In addition, consistent with the hypothesis that dysregulative physiology of penile erection accounts for some presentations of priapism, several plausible molecular mechanisms influencing the functional state of the erectile tissue are discussed. Current progress in the field suggests prevention possibilities using androgenic suppressive therapy, adrenergic agonist therapies, and effectors of the nitric oxide-dependent erection regulatory pathway in the penis. New ideas for prevention may emerge from targeting molecular mechanisms involved in regulating erectile tissue function.


Sensing Passive Eye Response to Impact Induced Head Acceleration Using MEMS IMUs.
The eye may act as a surrogate for the brain in response to head acceleration during an impact. Passive eye movements in a dynamic system are sensed by microelectromechanical systems (MEMS) inertial measurement units (IMU) in this paper. The technique is validated using a three-dimensional printed scaled human skull model and on human volunteers by performing drop-and-impact experiments with ribbon-style flexible printed circuit board IMUs inserted in the eyes and reference IMUs on the heads. Data are captured by a microcontroller unit and processed using data fusion. Displacements are thus estimated and match the measured parameters. Relative accelerations and displacements of the eye to the head are computed indicating the influence of the concussion causing impacts.


RMOD: a tool for regulatory motif detection in signaling network.
Regulatory motifs are patterns of activation and inhibition that appear repeatedly in various signaling networks and that show specific regulatory properties. However, the network structures of regulatory motifs are highly diverse and complex, rendering their identification difficult. Here, we present a RMOD, a web-based system for the identification of regulatory motifs and their properties in signaling networks. RMOD finds various network structures of regulatory motifs by compressing the signaling network and detecting the compressed forms of regulatory motifs. To apply it into a large-scale signaling network, it adopts a new subgraph search algorithm using a novel data structure called path-tree, which is a tree structure composed of isomorphic graphs of query regulatory motifs. This algorithm was evaluated using various sizes of signaling networks generated from the integration of various human signaling pathways and it showed that the speed and scalability of this algorithm outperforms those of other algorithms. RMOD includes interactive analysis and auxiliary tools that make it possible to manipulate the whole processes from building signaling network and query regulatory motifs to analyzing regulatory motifs with graphical illustration and summarized descriptions. As a result, RMOD provides an integrated view of the regulatory motifs and mechanism underlying their regulatory motif activities within the signaling network. RMOD is freely accessible online at the following URL: http://pks.kaist.ac.kr/rmod.


[Early detection in prostate cancer and shared decision making].
Screening of prostate cancer with PSA is a challenge for the aid to decision. Beside the rather mediocre characteristics of the screening test, there the additional problem of the peculiar biology of this cancer, with its late development and its ability to remain latent for a prolonged period. On the other hand, the treatment (surgery, irradiation) is associated with important side-effects: impotence and urinary leakage. Several studies, which appear to be a form of aid to information than aid to shared decision, have been carried out to analyse the effect of various modes of information on the behaviour of potential candidates to screening of prostate cancer, with the following results: better knowledge of the problem, lower rate of acceptance of PSA testing and trend towards watchful waiting rather than surgery in case of discovery of cancer.


A novel device to apply controlled flexion and extension to the rat knee following anterior cruciate ligament reconstruction.
We designed and validated a novel device for applying flexion-extension cycles to a rat knee in an in vivo model of anterior cruciate ligament reconstruction (ACL-R). Our device is intended to simulate rehabilitation motion and exercise post ACL-R to optimize physical rehabilitation treatments for the improved healing of tendon graft ligament reconstructions. The device was validated for repeatability of the knee kinematic motion by measuring the force versus angular rotation response from repeated trials using cadaver rats. The average maximum force required for rotating an ACL reconstructed rat knee through 100 degrees of flexion-extension was 0.4 N with 95% variability for all trials within ±0.1 N.


Propofol in ICU Settings: Understanding and Managing Anti-Arrhythmic, Pro-Arrhythmic Effects, and Propofol Infusion Syndrome.
Propofol has revolutionized anesthesia and intensive care medicine owing to its favorable pharmacokinetic characteristics, fast onset, and short duration of action. This drug has been shown to be remarkably effective in numerous clinical scenarios. In addition, propofol has maintained an overwhelmingly favorable safety profile; however, it has been associated with both antiarrhythmic and proarrhythmic effects. This review concisely summarizes the dual arrhythmic cardiovascular effects of propofol and a rare but serious complication, propofol infusion syndrome (PRIS). We also discuss the need for careful patient evaluation, compliance with recommended infusion rates, and vigilant monitoring.


Host modulation therapy for improving the osseointegration of dental implants under bone healing-suppressed conditions: a preclinical rodent-model experiment.
Placing dental implants in areas with low bone density or in conditions where bone healing is suppressed is challenging for clinicians. An experiment using a rodent model was performed with the aim of determining the efficacy of host modulation by increasing the systemic level of cholesterol sulfate (CS) using Irosustat in the context of the bone healing process around dental implants. In 16 ovariectomised female Sprague-Dawley rats, 2 implant fixtures were placed in the tibial bones (1 fixture on each side). At 1 week after surgery, the high-CS group (n=8) received Irosustat-mixed feed, while the control group (n=8) was fed conventionally. Block specimens were obtained at 5 weeks post-surgery for histologic analysis and the data were evaluated statistically (P<0.05). Unlike the high-CS group, half of the specimens in the control group demonstrated severe bone resorption along with a periosteal reaction in the cortex. The mean percentages of bone-to-implant contact (21.5%) and bone density (28.1%) near the implant surface were significantly higher in the high-CS group than in the control group (P<0.05), as was the number of Haversian canals (by 5.3). Host modulation by increasing the CS level may enhance the osseointegration of dental implants placed under conditions of impaired bone healing.


Oxyphil cell neoplasms of the thyroid gland.
Despite several extensive reviews of the literature within the past decade, the treatment of oxyphil cell tumors of the thyroid gland remains controversial. The foremost questions today concern the acceptable criteria for diagnosis of oxyphil malignancies and the appropriate surgical treatment of these neoplasms. This review provides a forum for debate on the treatment of oxyphil neoplasms, with emphasis on their unique histopathologic features and unpredictable clinical behavior.


Effect of losartan on the blood-brain barrier permeability in diabetic hypertensive rats.
Our previous publication has stressed the benefits of losartan, an angiotensin II receptor blocker, on the permeability of blood-brain barrier (BBB) and blood pressure during L-NAME-induced hypertension. This study reports the impacts of anti-hypertensive treatment by losartan on the brain endothelial barrier function and the arterial blood pressure, during acute hypertension episode, in experimentally diabetic hypertensive rats. Systolic blood pressure measurements were taken with tail cuff method before and during administration of L-NAME (0.5 mg/ml). We induced diabetes by using alloxan (50 mg/kg, i.p). Losartan (3 mg/kg, i.v) was given to rats following the L-NAME treatment. Acute hypertensive vascular injury was induced by epinephrine (40 microg/kg). The BBB disruption was quantified according to the extravasation of the Evans blue (EB) dye. L-NAME induced a significant increase in arterial blood pressure on day 14 in normoglycemic and hyperglycemic rats (p < 0.05). Losartan significantly reduced the increased blood pressure in hypertensive and diabetic hypertensive rats (p < 0.01). Epinephrine-induced acute hypertension in diabetic hypertensive rats increased the content of EB dye dramatically in cerebellum and diencephalon (p < 0.01) and slightly in both cerebral cortex (p < 0.05). Losartan treatment reduced the increased BBB permeability to EB dye in the brain regions of diabetic hypertensive rats treated with epinephrine (p < 0.05). This study indicates that, in diabetic hypertensive rats, epinephrine administration leads to an increase in microvascular-EB-albumin efflux to brain, however losartan treatment significantly attenuates this protein's transport to brain tissue.


Changes of Shoulder, Elbow, and Wrist Stiffness Matrix Post Stroke.
Stroke affects multiple joints in the arm with stereotypical patterns of arm deformity involving the shoulder, elbow, wrist, and hand and with disrupted coordination of multiple joints in active movements. However, there is a lack of systematic methods to evaluate multi-joints and multi-degree of freedoms (DOF) neuro-mechanical changes, especially for complex systems with three or more joints/DOFs involved. This paper used a novel systematic method to characterize dynamics and control of the shoulder, elbow, and wrist of the human arm individually and simultaneously, including the couplings across the multiple joints during controlled movements. A novel method was developed to decompose the complex system into manageable single-joint level for more reliable characterizations. The method was used in clinical studies to characterize the multi-joint changes associated with spastic impaired arm of 11 patients post stroke and 12 healthy controls. It was found that stroke survivors showed not only increased stiffness at the individual joints locally but also significantly higher couplings across the joints. The relative increases in couplings are often higher than that of the local joint stiffness. The multi-joint characterization provided a tool to characterize impairment of individual patients, which would allow more focused impairment-specific treatment. In general, the decomposition method can be used for even more complex systems, making characterization of intractable system dynamics of three or more joints/DOFs manageable.


The Effect of Foam Rolling on Recovery Between two Eight Hundred Metre Runs.
With the increased popularity of foam rolling as a means of recovery, it is important to establish the exact manner in which the practice is useful. The purpose of this study was to examine the impact of foam rolling on recovery between two 800 m runs. Sixteen trained males (mean ± sd; age, 20.5 ± .5 yr; average 800 m treadmill run time, 145.2 ± 1.8 s) participated in the study, using a randomized, crossover design. The subjects completed two 800 m runs on a treadmill, separated by a 30 min rest, during which time a foam rolling protocol or passive rest period was performed. The speed of each run was as fast as possible. Subjects had access to speed controls, but were blinded to the actual speed. Blood lactate concentration and [Formula: see text]CO2 were measured prior to and following each run. Stride length, 800 m run time, and hip extension were measured during each run. [Formula: see text]CO2, stride length, 800 m run time, and hip extension were not significantly different between conditions (p > .05). For blood lactate, no statistical interaction was found between condition and time (p > .05). Foam rolling between two 800 m runs separated by 30 min performed by trained male runners does not alter performance.


Regional ventricular wall thickening reflects changes in cardiac fiber and sheet structure during contraction: quantification with diffusion tensor MRI.
Dynamic changes of myocardial fiber and sheet structure are key determinants of regional ventricular function. However, quantitative characterization of the contraction-related changes in fiber and sheet structure has not been reported. The objective of this study was to quantify cardiac fiber and sheet structure at selected phases of the cardiac cycle. Diffusion tensor MRI was performed on isolated, perfused Sprague-Dawley rat hearts arrested or fixed in three states as follows: 1) potassium arrested (PA), which represents end diastole; 2) barium-induced contracture with volume (BV+), which represents isovolumic contraction or early systole; and 3) barium-induced contracture without volume (BV-), which represents end systole. Myocardial fiber orientations at the base, midventricle, and apex were determined from the primary eigenvectors of the diffusion tensor. Sheet structure was determined from the secondary and tertiary eigenvectors at the same locations. We observed that the transmural distribution of the myofiber helix angle remained unchanged as contraction proceeded from PA to BV+, but endocardial and epicardial fibers became more longitudinally orientated in the BV- group. Although sheet structure exhibited significant regional variations, changes in sheet structure during myocardial contraction were relatively uniform across regions. The magnitude of the sheet angle, which is an index of local sheet slope, decreased by 23 and 44% in BV+ and BV- groups, respectively, which suggests more radial orientation of the sheet. In summary, we have shown for the first time that geometric changes in both sheet and fiber orientation provide a substantial mechanism for radial wall thickening independent of active components due to myofiber shortening. Our results provide direct evidence that sheet reorientation is a primary determinant of myocardial wall thickening.


The functional meaning of "prey size" in water snakes (Nerodia fasciata, Colubridae).
The evolutionary success of macrostomatan (enlarged-gape) snakes has been attributed to their ability to consume large prey, in turn made possible by their highly kinetic skulls. However, prey can be "large" in several ways, and we have little insight into which aspects of prey size and shape affect skull function during feeding. We used X-ray videos of broad-banded water snakes (Nerodia fasciata) feeding on both frogs and fish to quantify movements of the jaw elements during prey transport, and of the anterior vertebral column during post-cranial swallowing. In a sample of additional individuals feeding on both frogs and fish, we measured the time and the number of jaw protractions needed to transport prey through the buccal cavity. Prey type (fish vs. frog) did not influence transport kinematics, but did influence transport performance. Furthermore, wider and taller prey induced greater movements of most cranial elements, but wider prey were transported with significantly less anterior vertebral bending. In the performance trials, heavier, shorter, and wider prey took significantly more time and a greater number of jaw protractions to ingest. Thus, the functional challenges involved in prey transport depend not only upon prey mass, but also prey type (fish vs. frog) and prey shape (relative height, width and length), suggesting that from the perspective of a gape-limited predator, the difficulty of prey ingestion depends upon multiple aspects of prey size.


Phase 2 study of high dose etoposide (VP16-213) in hepatocellular carcinoma.
A phase II study of etoposide (VP16-213) in hepatocellular carcinoma was conducted among 18 Chinese patients. There was no observable tumour response but the treatment was relatively well tolerated with an overall median survival interval of 74 days.


Wnt11/beta-catenin signaling in both oocytes and early embryos acts through LRP6-mediated regulation of axin.
Current models of canonical Wnt signaling assume that a pathway is active if beta-catenin becomes nuclearly localized and Wnt target genes are transcribed. We show that, in Xenopus, maternal LRP6 is essential in such a pathway, playing a pivotal role in causing expression of the organizer genes siamois and Xnr3, and in establishing the dorsal axis. We provide evidence that LRP6 acts by degrading axin protein during the early cleavage stage of development. In the full-grown oocyte, before maturation, we find that axin levels are also regulated by Wnt11 and LRP6. In the oocyte, Wnt11 and/or LRP6 regulates axin to maintain beta-catenin at a low level, while in the embryo, asymmetrical Wnt11/LRP6 signaling stabilizes beta-catenin and enriches it on the dorsal side. This suggests that canonical Wnt signaling may not exist in simple off or on states, but may also include a third, steady-state, modality.


In-Gel Direct Laser Writing for 3D-Designed Hydrogel Composites That Undergo Complex Self-Shaping.
Self-shaping and actuating materials inspired by biological system have enormous potential for biosensor, microrobotics, and optics. However, the control of 3D-complex microactuation is still challenging due to the difficulty in design of nonuniform internal stress of micro/nanostructures. Here, we develop in-gel direct laser writing (in-gel DLW) procedure offering a high resolution inscription whereby the two materials, resin and hydrogel, are interpenetrated on a scale smaller than the wavelength of the light. The 3D position and mechanical properties of the inscribed structures could be tailored to a resolution better than 100 nm over a wide density range. These provide an unparalleled means of inscribing a freely suspended microstructures of a second material like a skeleton into the hydrogel body and also to direct isotropic volume changes to bending and distortion motions. In the combination with a thermosensitive hydrogel rather small temperature variations could actuate large amplitude motions. This generates complex modes of motion through the rational engineering of the stresses present in the multicomponent material. More sophisticated folding design would realize a multiple, programmable actuation of soft materials. This method inspired by biological system may offer the possibility for functional soft materials capable of biomimetic actuation and photonic crystal application.