The effectiveness of joint-protection programs on pain, hand function, and grip strength levels in patients with hand arthritis: A systematic review and meta-analysis.
Systematic review with meta-analysis. Joint protection (JP) has been developed as a self-management intervention to assist people with hand arthritis to improve occupational performance and minimize joint deterioration over time. We examined the effectiveness between JP and usual care/control on pain, hand function, and grip strength levels for people with hand osteoarthritis and rheumatoid arthritis. A search was performed in 5 databases from January 1990 to February 2017. Two independent assessors applied Cochrane's risk of bias tool, and a Grading of Recommendations Assessement, Development and Evaluation (GRADE) approach was adopted. For pain levels at short term, we found similar effects between JP and control standardized mean difference (SMD; -0.00, 95% confidence interval [CI]: -0.42 to 0.42, I2 = 49%), and at midterm and long-term follow-up, JP was favored over usual care SMD (-0.32, 95% CI: -0.53 to -0.11, I2 = 0) and SMD (-0.27, 95% CI: -0.41 to -0.12, I2 = 9%), respectively. For function levels at midterm and long-term follow-up, JP was favored over usual care SMD (-0.49, 95% CI: -0.75 to -0.22, I2 = 34%) and SMD (-0.31, 95% CI: -0.50 to -0.11, I2 = 56%), respectively. For grip strength levels, at long term, JP was inferior over usual care mean difference (0.93, 95% CI: -0.74 to 2.61, I2 = 0%). Evidence of very low to low quality indicates that the effects of JP programs compared with usual care/control on pain and hand function are too small to be clinically important at short-, intermediate-, and long-term follow-ups for people with hand arthritis.


Layer-specific diffusion weighted imaging in human primary visual cortex in vitro.
One of the most prominent characteristics of the human neocortex is its laminated structure. The first person to observe this was Francesco Gennari in the second half the 18th century: in the middle of the depth of primary visual cortex, myelinated fibres are so abundant that he could observe them with bare eyes as a white line. Because of its saliency, the stria of Gennari has a rich history in cyto- and myeloarchitectural research as well as in magnetic resonance (MR) microscopy. In the present paper we show for the first time the layered structure of the human neocortex with ex vivo diffusion weighted imaging (DWI). To achieve the necessary spatial and angular resolution, primary visual cortex samples were scanned on an 11.7 T small-animal MR system to characterize the diffusion properties of the cortical laminae and the stria of Gennari in particular. The results demonstrated that fractional anisotropy varied over cortical depth, showing reduced anisotropy in the stria of Gennari, the inner band of Baillarger and the deepest layer of the cortex. Orientation density functions showed multiple components in the stria of Gennari and deeper layers of the cortex. Potential applications of layer-specific diffusion imaging include characterization of clinical abnormalities, cortical mapping and (intra)cortical tractography. We conclude that future high-resolution in vivo cortical DWI investigations should take into account the layer-specificity of the diffusion properties.


Variations of algal communities cause darkening of a Greenland glacier.
We have assessed the microbial ecology on the surface of Mittivakkat glacier in SE-Greenland during the exceptional high melting season in July 2012 when the so far most extreme melting rate for the Greenland Ice Sheet has been recorded. By employing a complementary and multi-disciplinary field sampling and analytical approach, we quantified the dramatic changes in the different microbial surface habitats (green snow, red snow, biofilms, grey ice, cryoconite holes). The observed clear change in dominant algal community and their rapidly changing cryo-organic adaptation inventory was linked to the high melting rate. The changes in carbon and nutrient fluxes between different microbial pools (from snow to ice, cryoconite holes and glacial forefronts) revealed that snow and ice algae dominate the net primary production at the onset of melting, and that they have the potential to support the cryoconite hole communities as carbon and nutrient sources. A large proportion of algal cells is retained on the glacial surface and temporal and spatial changes in pigmentation contribute to the darkening of the snow and ice surfaces. This implies that the fast, melt-induced algal growth has a high albedo reduction potential, and this may lead to a positive feedback speeding up melting processes.


Iterative design of a holographic beamformer.
A design method is presented for computing the phase functions of an energy efficient system using two holographic elements for converting a Gaussian beam into a uniform beam with rectangular support in the far field of the source. The method is based on a modification of the Gerchberg-Saxton algorithm which includes an x-y separability constraint on the phase of one of the holographic elements. A beamforming system was fabricated using this method, and experimental results were obtained which support the design approach.


Prevalence and pattern of cognitive impairment in systemic lupus erythematosus patients with and without overt neuropsychiatric manifestations.
The prevalence and pattern of cognitive impairment in systemic lupus erythematosus (SLE) patients with (NPSLE) and without (nSLE) overt neuropsychiatric manifestations were investigated. Fifty-two nSLE patients, 23 NPSLE patients and 27 healthy controls were evaluated with a battery of standardized neuropsychological and psychological tests. Disease duration, disease activity index, and current corticosteroid therapy were collected. Cognitive impairment was identified in 14 (26.9%) and in 12 (52.2%) of subjects with nSLE and NPSLE, respectively. Both SLE groups showed a significant impairment compared with controls on tasks assessing verbal and non-verbal long-term memory, and visuoconstructional abilities. In addition, NPSLE patients reported worse performances than both nSLE patients and controls on task evaluating short-term visuospatial memory. NPSLE subjects were significantly more anxious and depressed compared to both nSLE subjects and controls. By multivariate analysis, only depression levels, among clinical variables, significantly predicted cognitive performance. This study shows that cognitive impairment occurs frequently in both nSLE and NPSLE subjects. The higher frequency in NPSLE may be related to coexisting depressive disturbances.


The Saccharomyces cerevisiae CKS1 gene, a homolog of the Schizosaccharomyces pombe suc1+ gene, encodes a subunit of the Cdc28 protein kinase complex.
The Saccharomyces cerevisiae gene CDC28 encodes a protein kinase required for cell cycle initiation. In an attempt to identify genes encoding proteins that interact with the Cdc28 protein kinase, high-copy plasmid suppressors of a temperature-sensitive cdc28 mutation were isolated. One such suppressor, CKS1, was found to encode an 18-kilodalton protein that shared a high degree of homology with the suc1+ protein (p13) of Schizosaccharomyces pombe (67% amino acid sequence identity). Disruption of the chromosomal CKS1 gene conferred a G1 arrest phenotype similar to that of cdc28 mutants. The presence of the 18-kilodalton Cks1 protein in yeast lysates was demonstrated by using Cks-1 specific antiserum. Furthermore, the Cks1 protein was shown to be physically associated with active forms of the Cdc28 protein kinase. These data suggest that Cks1 is an essential component of the Cdc28 protein kinase complex.


Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose.
Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes-induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.


Post-operative complications following adenotonsillectomy in children with severe sleep apnea-hypopnea syndrome. Do they need to be admitted to an intensive care unit?
In recent years, with the rise of sleep-disordered breathing, we have been seeing more articles related to post-operative complications after adenotonsillectomy in children with sleep apnea-hypopnea syndrome (OSAS), especially in those with severe sleep apnea. The objective of this study was to evaluate post-operative complications in children with severe OSAS compared to children who had adenotonsillectomy for a different reason, and establish whether they needed admission to an intensive care unit or not. All children undergoing adenotonsillectomy in our hospital in the last 5 years were initially included in this study. Complications were analysed with a retrospective review. Two hundred and twenty nine children admitted for adenotonsillectomy were finally included. In the whole group, complications occurred in 3.5% of children, 2.2% corresponding to respiratory complications. Children with sleep apnea (3.23% vs 1.47%, P=.39) or severe sleep apnea (3.77% vs 1.70%, P=.32) presented a higher incidence of respiratory complications, which was not statistically significant and was far below those published by other authors. All respiratory complications took place in the immediate post-operative period (operating theatre or anaesthesia recovery), with none in the paediatric ward. In our population, children who undergo adenotonsillectomy, without any other comorbidities, malformation syndrome or neuromuscular disease, are more than 2 years old and have an immediate postoperative period without incidence, do not need to be systematically admitted to an intensive care unit, even if they present with severe OSAS.


Ligand Dictated Photosensitization of Iridium(III) Dithiocarbamate Complexes for Photodynamic Therapy.
Organelle-targeted photosensitizers (PSs) for photodynamic therapy (PDT) are considered as an effective therapeutic strategy for the development of next generation PSs with the least side effects and high therapeutic efficacy. However, multiorganelle targeted PSs eliciting PDT via both type I and type II mechanisms are scarce. Herein, a series of cyclometalated iridium(III) complexes were formulated [Ir(C∧N)2(S∧S)] (C∧N = 2-phenylpyridine (ppy) and 2-(thiophen-2-yl)pyridine (thpy); S∧S = diethyldithiocarbamate (DEDTC), morpholine-N-dithiocarbamate (MORDTC) and methoxycarbonodithioate (MEDTC)) and the newly designed complexes Ir2@DEDTC and Ir1@MEDTC were characterized by single crystal X-ray crystallography. Complexes containing thpy as C∧N ligand exhibit excellent photophysical properties such as red-shifted emission, high singlet oxygen quantum yield (ϕΔ) and longer photoluminescence lifetime when compared with complexes containing ppy ligands. Ir2@DEDTC exhibits the highest ϕΔ and photoluminescence lifetimes among the synthesized complexes. Therefore, Ir2@DEDTC was chosen to evaluate the photosensitizing ability to produce reactive oxygen species (ROS). Upon blue light irradiation (456 nm), it efficiently produces ROS, i.e., hydroxy radical (•OH) and singlet oxygen (1O2), which was confirmed by electron paramagnetic resonance (EPR) spectroscopy. In vitro photocytotoxicity toward HCT116, HeLa, and PC3 cell lines showed that out of all the synthesized complexes, Ir2@DEDTC has the highest photocytotoxic index (PI > 400) value. Ir2@DEDTC is efficiently taken up by the HCT116 cell line and accumulated mainly in the lysosome and mitochondria of the cells, and after PDT treatment, it elicits cell shrinkage, membrane blebbing, and DNA fragmentation. The phototherapeutic efficacy of Ir2@DEDTC has been investigated against 3D spheroids considering its ability to mimic some of the basic features of solid tumors. The morphology was drastically altered in the Ir2@DEDTC treated 3D spheroid after the light irradiation unleashed the potential of the Ir(III) dithiocarbamate complex as a superior PS for PDT. Hence, mitochondria and lysosome targeted photoactive cyclometalated Ir(III) dithiocarbamate complex exerting oxidative stress via both type I and type II PDT can be regarded as a dual-organelle targeted two-pronged approach for enhanced PDT.


Rapid magnetic solid-phase extraction for the selective determination of isoflavones in soymilk using baicalin-functionalized magnetic nanoparticles.
Most protocols of sample preparation for isoflavone determination in soymilk and other liquid soybean products involves tedious freeze-drying and time-consuming extraction procedures. We report a facile and rapid magnetic solid-phase extraction (MSPE) of isoflavones from soymilk for subsequent high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) analysis. The extraction was based on the selective binding of isoflavones to baicalin-functionalized core-shell magnetic nanoparticles (BMNPs). The proposed MSPE-HPLC-MS/MS analytical method had a linear calibration curve in the concentration range from 0.3 to 80 mg/L isoflavones. With the use of calycosin, an isomer of one of the isoflavones targeted as an internal standard, interday (5 days) precisions of the slope and intercept of the calibration curves were found to be in the range between 2.5% and 3.6% (RSD, n = 5). Six isoflavones, that is, daidzein, glycitein, genistein, daidzin, glycitin, and genistin were detected in commercial soymilk samples and quantified by the proposed analytical method. The results indicated that the method was useful for fast determination of isoflavones in soymilk and other liquid soybean products.


Identification of a novel LMX1B nonsense variant associated with congenital talipes equinovarus by prenatal exome sequencing: A case report.
Congenital talipes equinovarus (CTEV) is a rotational foot deformity that affects muscles, bones, connective tissue, and vascular or neurological tissues. The etiology of CTEV is complex and unclear, involving genetic and environmental factors. Nail-patella syndrome is an autosomal dominant disorder caused by variants of the LIM homeobox transcription factor 1 beta gene (LMX1B, OMIM:602575). LMX1B plays a key role in the development of dorsal limb structures, the kidneys, and the eyes, and variants in this gene may manifest as hypoplastic or absent patella, dystrophic nails, and elbow and iliac horn dysplasia; glomerulopathy; and adult-onset glaucoma, respectively. This study aimed to identify pathogenic variants in a fetus with isolated talipes equinovarus diagnosed by ultrasound in the second trimester, whose father exhibited dysplastic nails and congenital absence of bilateral patella. Prenatal whole-exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing. A novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product. Our study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.


The UL4 gene of pseudorabies virus encodes a minor infected-cell protein that is dispensable for virus replication.
Although homologues of the open reading frame (ORF) UL4 of herpes simplex virus 1 (Human herpesvirus 1) have been found in the genomes of all hitherto-analysed alphaherpesviruses, little is known about their function. In a project to analyse systematically, in an isogenic and standardized assay system, the gene products of the alphaherpesvirus pseudorabies virus (PrV; Suid herpesvirus 1), the PrV UL4 gene product was identified using a monospecific rabbit antiserum prepared against a bacterial fusion protein. Western blot and immunofluorescence analyses revealed that the 146 codon UL4 ORF of PrV was translated into a nuclear 15 kDa protein which was detectable from 6 h after infection of rabbit kidney cells, but was not found in purified virus particles. For functional analysis, a UL4-negative virus recombinant (PrV-DeltaUL4F) was generated by mutagenesis of an infectious full-length clone of the PrV genome in E. coli. PrV-DeltaUL4F was replication-competent in rabbit kidney cells, and plaque formation was not affected by the mutation. However, maximum virus titres of PrV-DeltaUL4F were decreased about fivefold compared with wild-type PrV, and electron microscopy of infected cells demonstrated an impairment of release of mature virions. This growth defect of PrV-DeltaUL4F could be corrected completely by propagation in UL4-expressing cells. Correlating with the inconspicuous in vitro phenotype, neurovirulence of PrV-DeltaUL4F was also not affected significantly. Thus, UL4 encodes a non-structural protein of PrV that enhances virion formation but is not essential for PrV replication in vitro or in vivo.


The effectiveness of sit-stand workstations for changing office workers' sitting time: results from the Stand@Work randomized controlled trial pilot.
Prolonged sitting time is detrimental for health. Individuals with desk-based occupations tend to sit a great deal and sit-stand workstations have been identified as a potential strategy to reduce sitting time. Hence, the objective of the current study was to examine the effects of using sit-stand workstations on office workers' sitting time at work and over the whole day. We conducted a randomized controlled trial pilot with crossover design and waiting list control in Sydney, Australia from September 2011 to July 2012 (n = 42; 86% female; mean age 38 ± 11 years). Participants used a sit-stand workstation for four weeks in the intervention condition. In the time-matched control condition, participants received nothing and crossed over to the intervention condition after four weeks. The primary outcomes, sitting, standing and walking time at work, were assessed before and after using the workstations with ActivPALs and self-report questionnaires. Secondary outcomes, domain-specific sitting over the whole day, were assessed by self-report. Linear mixed models estimated changes in outcomes adjusting for measurement time, study grouping and covariates. Intervention participants significantly reduced objectively assessed time spent sitting at work by 73 min/workday (95% CI: -106,-39) and increased standing time at work by 65 min/workday (95% CI: 47, 83); these changes were significant relative to controls (p = 0.004 and p < 0.001, respectively). Total sitting time significantly declined in intervention participants (-80 min/workday; 95% CI: -155, -4). This study shows that introducing sit-stand workstations in the office can reduce desk-based workers' sitting time at work in the short term. Larger scale studies on more representative samples are needed to determine the public health impact of sit-stand workstations. ACTRN12612000072819.


The Effects of the Addiction Programme of Probation on Treatment Motivation, Abstinence and Quality of Life: a Comparative Study with Motivational Interviewing and Individual Intervention.
The aim of this study is to evaluate the effectiveness of Addiction Programme of Probation (APP) created by the Substance Abuse Treatment Commission of Ministry of Health. The sample was consisted of probationers who were referred to Ege University by probation offices in February 2010. Literate probationers aged above 18, who fulfilled the SCID-I criteria for substance dependence, or had positive urine sample for illegal drugs were included. The probationers were allocated respectively to three treatment groups: APP (n=28); Motivational Interviewing (MI; n=30); Individual Intervention (II; n=30). The effectiveness of the treatment modalities was assessed by the State Anxiety Inventory; the WHO Quality of Life-Brief form; the Treatment Motivation Questionnaire. Visual analogue and Likert-type scales were used to assess the sense of the importance and the readiness of quitting drugs also the levels of craving. Urine toxicological analyses were performed fortnightly. The APP increased the readiness of quitting drugs. The MI increased both the sense of importance and readiness of quitting drugs, decreased the frequency and severity of craving. The II improved the mental and physical health, increased the confidence in treatment also readiness of quitting drugs. Additionally, II decreased the level of anxiety, the severity, frequency and duration of craving. There was a significant decrease in positive urine samples of all groups. Because of changing only "the level of being ready to quit substance abuse", APP is considered as an inadequate program compared with MI and II.


[Antimicrobial resistance among species of Salmonella, Shigella, Escherichia, and aeromonas isolated from children with diarrhea in 7 Argentinian centers].
The increasing levels of resistance of enteropathogenic bacteria against antimicrobial agents present geographic variations. We have analysed the antimicrobial susceptibility of isolates obtained from 4,364 children under 5 years of age with acute diarrhea, in 7 cities of Argentina. Diarrheagenic E. coli exhibited 74.5% of resistance against ampicillin, 64.2% against sulfametoxazole-trimethoprim, and Shigella spp., 62% and 75.6% respectively. Salmonella sp. showed 35%, 14%, 41.8%, 65.4%, 14.5%, and 13.6% of resistance against ampicillin, chloranfenicol, sulfametoxazole-trimetoprim, sulfadiazin, gentamycin, and fosfomycin respectively. These values are higher than the ones observed in developed countries. Aeromonas showed significantly lower resistance percentage. Important differences in our country were observed, consequently, local trials should be carried out in order to apply corrective measures.


The nuclear translocation assay for intracellular protein-protein interactions and its application to the Bcr coiled-coil domain.
Protein interactions are critical for normal biological processes and molecular pathogenesis. While it is important to study these interactions, there are limited assays that are performed inside the cell, in the native cell environment, where the majority of protein-protein interactions take place. Here we present a method of studying protein interactions intracellularly using one protein of interest fused to a localization-controllable enhanced GFP (EGFP) construct and the other protein of interest fused to the red fluorescent protein, DsRed. Nuclear translocation of the EGFP construct is induced by addition of a ligand, and the difference in nuclear localization between the induced and noninduced states of the DsRed construct provides an indication of the interaction between the two proteins. This assay, the nuclear translocation assay (NTA), is introduced here as broadly applicable for studying protein interactions in the native environment inside cells and is demonstrated using forms of the coiled-coil domain from the breakpoint cluster region (Bcr) protein.


Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease.
The NH(2)-terminal domains of membrane-bound sterol regulatory element-binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH(2)-terminal cap for a portion of the transmembrane alpha-helix of SREBP, allowing the remainder of the alpha-helix to unwind partially to expose the peptide bond for cleavage by S2P.


Eriodictyol protects H9c2 cardiomyocytes against the injury induced by hypoxia/reoxygenation by improving the dysfunction of mitochondria.
Myocardial infarction is a leading cause of mortality worldwide, while myocardial ischemia and timely reperfusion contribute to myocardial injury. The mitochondria are involved in the injury and mediate the apoptosis of cardiomyocytes. In order to develop novel therapeutic approaches for myocardial infarction, the present study evaluated the myocardial protective effects of eriodictyol and investigated relevant mechanisms in H9c2 cardiomyocytes. As a result, eriodictyol was observed to improve the H9c2 cardiomyocyte viability and block the leakage of cytosolic lactate dehydrogenase under hypoxia/reoxygenation. In addition, the dysfunction of mitochondria induced by hypoxia/reoxygenation was ameliorated by eriodictyol through suppressing the overload of intracellular Ca2+, preventing overproduction of reactive oxygen species, blocking mitochondrial permeability transition pore opening, increasing mitochondrial membrane potential level and decreasing ATP depletion. Finally, the apoptosis of H9c2 cardiomyocyte induced by hypoxia/reoxygenation was prevented by eriodictyol through upregulation of the expression of B-cell lymphoma-2 (Bcl-2) and downregulation of the expression levels of Bcl-2-associated X protein and caspase-3. These results provided evidence for further investigation on myocardial protection and the treatment of myocardial infarction using eriodictyol.


An insulin receptor peptide (1135-1156) stimulates guanosine 5'-[gamma-thio]triphosphate binding to the 67 kDa G-protein associated with the insulin receptor.
Peptides representing two putative G-protein-binding motifs (GPBP1 and GPBP2) derived from insulin-receptor sequences were tested for their ability to stimulate guanosine 5'-[gamma-thio]-triphosphate (GTP[S]; 'GTP gamma S') binding to a preparation containing the 41 and 67 kDa G-proteins that are associated with the insulin receptor [Jo, Cha, Davis and McDonald (1992) Endocrinology (Baltimore) 131, 2855-2861]. GPBP2 (residues 1135-1156) specifically stimulated GTP[S] binding, whereas GPBP1 (1319-1333) did not. Substitution of Arg-1152 with Gln in GPBP2 corresponding to a mutation site in insulin-resistant patients [Cocozza, Porcellini, Riccardi, Monticelli, Condorelli, Ferrera, Pianese, Miele, Capaldo, Beguinot and Varrone (1992) Diabetes 41, 521-526] attenuated the stimulatory potency of GPBP2. Size-exclusion chromatography and studies with purified 67 kDa G-protein revealed that GPBP2 stimulated GTP[S] binding only to the 67 kDa G-protein. These studies provide evidence for a potential regulatory site for G-protein interaction with the insulin receptor in the tyrosine kinase domain.


Outcomes following attempted en bloc resection of cervical chordomas in the C-1 and C-2 region versus the subaxial region: a multiinstitutional experience.
Chordomas involving the mobile spine are ideally managed via en bloc resection with reconstruction to optimize local control and possibly offer cure. In the cervical spine, local anatomy poses unique challenges, limiting the feasibility of aggressive resection. The authors present a multi-institutional series of 16 cases of cervical chordomas removed en bloc. Particular attention was paid to clinical outcome, complications, and recurrence. In addition, outcomes were assessed according to position of tumor at the C1-2 level versus the subaxial (SA) spine (C3-7). The authors reviewed cases involving patients who underwent en bloc resection of cervical chordoma at 4 large spine centers. Patients were included if the lesion epicenter involved the C-1 to C-7 vertebral bodies. Demographic data and details of surgery, follow-up course, exposure to adjuvant therapy, and complications were obtained. Outcome was correlated with presence of tumor in C1-2 versus subaxial spine via a Student t-test. Sixteen patients were identified (mean age at presentation 55 ± 14 years). Seven cases (44%) cases involved C1-2, and 16 involved the subaxial spine. Median survival did not differ significantly different between the C1-2 (72 months) and SA (60 months) groups (p = 0.65). A combined (staged anteroposterior) approach was used in 81% of the cases. Use of the combined approach was significantly more common in treatment of subaxial than C1-2 tumors (100% vs 57%, p = 0.04). En bloc resection was attempted via an anterior approach in 6% of cases (C1-2: 14.3%; SA: 0%; p = 0.17) and a posterior approach in 13% of cases (C1-2: 29%; SA: 0%; p = 0.09). The most commonly reported margin classification was marginal (56% of cases), followed by violated (25%) and wide (19%). En bloc excision of subaxial tumors was significantly more likely to result in marginal margins than excision of C1-2 tumors (C1-2: 29%; SA: 78%; p = 0.03). C1-2 tumors were associated with significantly higher rates of postoperative complications (C1-2: 71%; SA: 22%; p = 0.03). Both local and distant tumor recurrence was greatest for C1-2 tumors (local C1-2: 29%; local SA: 11%; distant C1-2: 14%; distant SA: 0%). Statistical analysis of tumor recurrence based on tumor location was not possible due to the small number of cases. There was no between-groups difference in exposure to postoperative adjuvant radiotherapy. There was no difference in median survival between groups receiving proton beam radiotherapy or intensity-modulated radiotherapy versus no radiation therapy (p = 0.8). Compared with en bloc resection of chordomas involving the subaxial cervical spine, en bloc resection of chordomas involving the upper cervical spine (C1-2) is associated with poorer outcomes, such as less favorable margins, higher rates of complications, and increased tumor recurrence. Data from this cohort do not support a statistically significant difference in survival for patients with C1-2 versus subaxial disease, but larger studies are needed to further study survival differences.


Understanding How Phosphorylation and Redox Modifications Regulate Cardiac Ryanodine Receptor Type 2 Activity to Produce an Arrhythmogenic Phenotype in Advanced Heart Failure.
Heart failure (HF) is a global pandemic with significant mortality and morbidity. Despite current medications, 50% of individuals die within 5 years of diagnosis. Of these deaths, 30-50% will be a result of sudden cardiac death from ventricular arrhythmias. This review discusses two stress-induced mechanisms, phosphorylation from chronic β-adrenoceptor (β-AR) stimulation and thiol modifications from oxidative stress, and how they modulate the cardiac ryanodine receptor type 2 (RyR2) and foster an arrhythmogenic phenotype. Calcium (Ca2+) is the ubiquitous secondary messenger of excitation-contraction coupling and provides a common pathway for contractile dysfunction and arrhythmia genesis. In a healthy heart, Ca2+ is released from the sarcoplasmic reticulum (SR) by RyR2. The open probability of RyR2 is under the dynamic influence of co-proteins, ions, and kinases that are in strict balance to ensure normal physiological functioning. In HF, chronic β-AR activity and production of reactive oxygen species and reactive nitrogen species provide two stress-induced mechanisms uncoupling RyR2 control, resulting in pathological diastolic SR Ca2+ leak. This increased cytosolic [Ca2+] promotes Ca2+ extrusion via the local Na+/Ca2+ exchanger, resulting in net sarcolemmal depolarization, delayed after depolarization and ventricular arrhythmia. Experimental models researching oxidative stress and phosphorylation have aimed to identify how post-translational modifications to the RyR2 macromolecular complex, and the associated Na+/Ca2+ cycling proteins, result in pathological Ca2+ handling and diastolic leak. However, the causative molecular changes remain controversial and undefined. Through understanding the molecular mechanisms that produce an arrhythmic phenotype, novel therapeutic targets to treat HF and prevent its malignant course can be identified.


Effect of the Centers for Medicare & Medicaid Services policy about deep sedation on use of propofol.
On 11 December 2009, the Centers for Medicare & Medicaid Services issued a policy stating that deep sedation can only be administered by an anesthesiologist, a certified registered nurse anesthetist, or a trained medical doctor or a doctor of osteopathy not involved in the performance of a medical procedure. Propofol is a popular sedation agent that is usually administered by anesthesia specialists in a service termed monitored anesthesia care (MAC). Monitored anesthesia care adds substantial new fees to procedural sedation. However, available evidence shows that propofol can be used safely by non-anesthesiologists for procedural sedation. The American Society of Anesthesiologists considers that propofol implies deep sedation and should only be administered by anesthesia specialists. The Centers for Medicare & Medicaid Services policy on deep sedation can be viewed as supporting an ongoing conversion to MAC to deliver propofol for procedural sedation. However, the absence of an evidence base supporting a need for MAC to deliver propofol, combined with its high cost, suggests that alternatives to MAC to deliver propofol deserve fair and balanced evaluation.


Natriuretic peptide pharmacogenetics: membrane metallo-endopeptidase (MME): common gene sequence variation, functional characterization and degradation.
Membrane metallo-endopeptidase (MME), also known as neutral endopeptidase 24.11 (EC 126.96.36.199), is involved in the metabolism of natriuretic peptides that play a key role in modulating cardiac structure and function. Common genetic variation in MME has not been addressed by resequencing the gene using DNA from different ethnic populations. We set out to identify and functionally characterize common genetic variation in MME in three ethnic groups. DNA samples from 96 European-American, 96 African-American, and 96 Han Chinese-American healthy subjects were used to resequence MME. Ninety polymorphisms, 65 novel, were identified, including 8 nonsynonymous single nucleotide polymorphisms (nsSNPs). Expression constructs for the nsSNPs were created and COS-1 cells were transfected with constructs for wild type (WT) and variant allozymes. Recombinant proteins were analyzed by quantitative Western blot analysis and by a one-step fluorometric assay. A significant reduction in enzyme activity (21% of WT) and immunoreactive protein (29% of WT) for the Val73 variant allozyme was observed. Proteasome-mediated degradation and autophagy participated in the degradation of this variant allozyme. The chaperone proteins, BiP and GRP94, were upregulated after transfection with Val73 MME, suggesting protein misfolding, compatible with conclusions based on the MME X-ray crystal structure. Multiple novel polymorphisms of MME were identified in three ethnic groups. The Val73 variant allozyme displayed a significant decrease in MME protein quantity and activity, with degradation mediated by both proteasome and autophagy pathways. This polymorphism could have a significant effect on the metabolism of natriuretic peptides.


Chitiniphilus eburneus sp. nov., a novel chitinolytic bacterium isolated from sludge.
A novel Gram-stain-negative, curved rod-shaped, motile and non-endospore-forming strain, designated HX-2-15T, was isolated from activated sludge of agricultural chemical plant in Nanjing, Jiangsu province, PR China (32° 03' N, 118° 46' E) . Growth was observed at 15-37 °C (optimum between 25 and 30 °C), at pH 6.0-8.0 (optimum at pH 7.0) and with 0-3.0 % (w/v) NaCl (optimum at 0.5 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that the strain showed closest affiliation to Chitiniphilus shinanonensis SAY3T, with a sequence similarity of 99.0 %. The predominant cellular fatty acids were C16:0, C17:0 cyclo and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c). The major quinone was ubiquinone Q-8 . The polar lipid profile was composed of phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, three unidentified phospholipids, one unidentified lipid and one unidentified aminophosphoglycolipid . The genomic DNA G+C content of the strain was 63.6 mol%. The ANI and dDDH values obtained between the genomes of HX-2-15T and C. shinanonensis SAY3T were 85.3 and 29.3 % respectively. On the basis of data from phenotypic, chemotaxonomic and genotypic analysis, strain HX-2-15T represents a novel species of the genus Chitiniphilus, for which the name Chitiniphilus eburneus sp. nov. is proposed. The type strain is HX-2-15T (=KCTC 72286T=CCTCC AB 2019178T).


Chemical reactions on clays.
Layer aluminosilicates catalyze reactions in numerous ways. They stabilize high-energy intermediates. They can store energy in their lattice structures and can release it in the form of chemical energy. They can catalyze redox reactions and can serve as photocatalytic devices. They often exhibit high surface acidity. Organic reactions that are catalyzed by the agency of days are reviewed. The role of clays in prebiotic chemistry is also examined.


[Sensory polyneuropathy and neural conduction block as an initial manifestation of polyarteritis nodosa].
Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis which affects middle calibre arteries and which has a tendency to form aneurysms. It may appear as one of a great variety of clinical forms depending on the vascular territory afflicted. Almost any organ may be involved although the lung is usually unaffected. Neurological manifestations are very frequent in this disease (global incidence being around 80%), especially at the peripheral nervous system level. Multiple mononeuritis is the most usual manifestation classically associated with this type of vasculitis, but it may also appear as distal sensorimotor polyneuropathy, this being its most infrequent form of presentation. The presence of nerve conduction blocks has also been recently described, usually associated with demyelinating processes. However peripheral nerve affectation in vasculitis has its origins in small ischaemic infarcts in the sensorimotor conduction fibres. It may well be that segmentary demyelination and axonal degeneration reflect different levels of ischaemic damage.


TLR3 deficiency exacerbates the loss of epithelial barrier function during genital tract Chlamydia muridarum infection.
Chlamydia trachomatis infections are often associated with acute syndromes including cervicitis, urethritis, and endometritis, which can lead to chronic sequelae such as pelvic inflammatory disease (PID), chronic pelvic pain, ectopic pregnancy, and tubal infertility. As epithelial cells are the primary cell type productively infected during genital tract Chlamydia infections, we investigated whether Chlamydia has any impact on the integrity of the host epithelial barrier as a possible mechanism to facilitate the dissemination of infection, and examined whether TLR3 function modulates its impact. We used wild-type and TLR3-deficient murine oviduct epithelial (OE) cells to ascertain whether C. muridarum infection had any effect on the epithelial barrier integrity of these cells as measured by transepithelial resistance (TER) and cell permeability assays. We next assessed whether infection impacted the transcription and protein function of the cellular tight-junction (TJ) genes for claudins1-4, ZO-1, JAM1 and occludin via quantitative real-time PCR (qPCR) and western blot. qPCR, immunoblotting, transwell permeability assays, and TER studies show that Chlamydia compromises cellular TJ function throughout infection in murine OE cells and that TLR3 deficiency significantly exacerbates this effect. Our data show that TLR3 plays a role in modulating epithelial barrier function during Chlamydia infection of epithelial cells lining the genital tract. These findings propose a role for TLR3 signaling in maintaining the integrity of epithelial barrier function during genital tract Chlamydia infection, a function that we hypothesize is important in helping limit the chlamydial spread and subsequent genital tract pathology.


Monoclonal anti-idiotype antibody 6G6.C4 fused to GM-CSF is capable of breaking tolerance to carcinoembryonic antigen (CEA) in CEA-transgenic mice.
Internal image anti-idiotypic antibodies are capable of mimicking tumor-associated antigens and thus may serve as surrogate for vaccination strategies in cancer patients. The monoclonal antibody (mAb) 6G6.C4 mimics an epitope specific for the human carcinoembryonic antigen (CEA) and generates a CEA-specific response (Ab3) in various experimental animals. In humans, however, 6G6.C4 only yields a very limited humoral anti-CEA reaction presumably due to tolerance against the CEA autoantigen. In this study, we investigated the CEA-specific Ab3 response in mice transgenic for the human CEA and tested whether the antigen tolerance could be overcome by fusing a recombinant single-chain variable fragment of 6G6.C4 (scFv6G6.C4) to the murine granulocyte macrophage colony-stimulating factor (GM-CSF). Like mAb 6G6.C4, the fusion protein (scFv6G6.C4/GM-CSF) retained binding to the CEA-specific idiotype mAb T84.66. Also, scFv6G6.C4/GM-CSF was biologically active as measured by proliferation of the GM-CSF-dependent murine FDC-P1 cells in vitro. After immunization with the scFv6G6.C4/GM-CSF fusion protein, CEA-transgenic animals showed significantly enhanced Ab3 antibody responses to scFv6G6.C4 (P=0.005) and to CEA (P=0.012) compared with the scFV6G6.C4 alone. Sera from mice immunized with the fusion protein specifically recognized CEA in Western blot analyses with no cross-reaction to CEA-related antigens. Finally, the Ab3 antisera detected single CEA-expressing tumor cells in suspension as shown by flow cytometry. Taken together, these data show in a model antigenically related to the human system that vaccination with scFv6G6.C4/GM-CSF improves vaccination against an endogenous tumor-associated antigen resulting in a highly specific humoral Ab3 response in vivo that is capable of bind single circulating CEA-positive tumor cells.


Tomographic image reconstruction from incomplete view data by convex projections and direct fourier inversion.
We consider the problem of reconstructing CAT imagery by the direct Fourier method (DFM) when not all view data are available. To restore the missing information we use the method of projections onto convex sets (POCS). POCS is a recursive image restoration technique that finds a solution consistent with the measured data and a priori known constraints in both the space and Fourier domain. Because DFM reconstruction is a frequency-domain technique it is ideally matched to POCS restoration when, for one reason or another, we are forced to generate an image from a less than complete set of view data. We design and apply an algorithm (PRDF) which interpolates/extrapolates the missing Fourier domain information by POCS and reconstructs an image by DFM. A simulated human thorax cross section is restored and reconstructed. The restorations using POCS are compared with the Gerchberg-Papoulis extrapolation method and shown to be superior. Applications of PRDF to other types of medical imaging modalities are discussed.


Production of protective antibodies against Porphyromonas gingivalis strains by immunization with recombinant gingipain domains.
We studied the effect of antibodies against Porphyromonas gingivalis gingipain domains, preparing them against three recombinant fragments of RgpA (catalytic domain, r-Rgp CAT; hemagglutinin domains, r-Rgp 44 and r-Rgps 15-27) and one fragment of Kgp (catalytic domain, r-Kgp CAT). Enhancement of opsonization and killing by human polymorphonuclear leukocytes were measured in the noninvasive FDC 381 and invasive W50 strains of P. gingivalis. Anti-r-Rgp 44 was the most effective in both strains of P. gingivalis. The present findings lead us to recommend RgpA 44 as a candidate immunogen for vaccines against P. gingivalis.


Assessment of arterial stiffness, a translational medicine biomarker system for evaluation of vascular risk.
Stiffening of the large arteries is a common feature of aging and is exacerbated by a number of disorders such as hypertension, diabetes, and renal disease. Arterial stiffening is recognized as an important and independent risk factor for cardiovascular events. This article will provide a comprehensive review of the recent advance on assessment of arterial stiffness as a translational medicine biomarker for cardiovascular risk. The key topics related to the mechanisms of arterial stiffness, the methodologies commonly used to measure arterial stiffness, and the potential therapeutic strategies are discussed. A number of factors are associated with arterial stiffness and may even contribute to it, including endothelial dysfunction, altered vascular smooth muscle cell (SMC) function, vascular inflammation, and genetic determinants, which overlap in a large degree with atherosclerosis. Arterial stiffness is represented by biomarkers that can be measured noninvasively in large populations. The most commonly used methodologies include pulse wave velocity (PWV), relating change in vessel diameter (or area) to distending pressure, arterial pulse waveform analysis, and ambulatory arterial stiffness index (AASI). The advantages and limitations of these key methodologies for monitoring arterial stiffness are reviewed in this article. In addition, the potential utility of arterial stiffness as a translational medicine surrogate biomarker for evaluation of new potentially vascular protective drugs is evaluated. Assessment of arterial stiffness is a sensitive and useful biomarker of cardiovascular risk because of its underlying pathophysiological mechanisms. PWV is an emerging biomarker useful for reflecting risk stratification of patients and for assessing pharmacodynamic effects and efficacy in clinical studies.


Depression in type 2 diabetes mellitus: prevalence, impact, and treatment.
Clinically significant depression is present in one of every four people with type 2 diabetes mellitus (T2DM). Depression increases the risk of the development of T2DM and the subsequent risks of hyperglycemia, insulin resistance, and micro- and macrovascular complications. Conversely, a diagnosis of T2DM increases the risk of incident depression and can contribute to a more severe course of depression. This linkage reflects a shared etiology consisting of complex bidirectional interactions among multiple variables, a process that may include autonomic and neurohormonal dysregulation, weight gain, inflammation, and hippocampal structural alterations. Two recent meta-analyses of randomized controlled depression treatment trials in patients with T2DM concluded that psychotherapy and antidepressant medication (ADM) were each moderately effective for depression and that cognitive behavior therapy (CBT) had beneficial effects on glycemic control. However, the number of studies (and patients exposed to randomized treatment) included in these analyses is extremely small and limits the certainty of conclusions that can be drawn from the data. Ultimately, there is no escaping the paucity of the evidence base and the need for additional controlled trials that specifically address depression management in T2DM. Future trials should determine both the effects of treatment and the change in depression during treatment on measures of mood, glycemic control, and medical outcome.


Preventive antibiotics in stroke study: rationale and protocol for a randomised trial.
Stroke is a leading cause of death worldwide. Fever after stroke is a strong predictor of a poor outcome. Infections occur in up to 40% of patients with stroke and have also been associated with poor outcomes. Preventive antibiotic therapy lowers the infection rates in patients after stroke, as shown in a recent meta-analysis of randomised studies. Phase III trials evaluating the effect of antibiotic prophylaxis on clinical outcomes in sufficient numbers of patients with stroke have, however, not been performed to date. Ceftriaxone, an off-patent medicine, is an antibiotic with a broad defence against the bacteria that cause the most common infections after stroke. Preventive antibiotic therapy with ceftriaxone may potentially reduce poor outcome after acute stroke and, therefore, a randomised clinical trial is warranted. The aim of the present study is to investigate whether the preventive use of the antibiotic ceftriaxone improves functional outcome in patients with stroke. We will conduct a multicentre prospective, randomised, open-label, blinded end point trial of standard care with preventive ceftriaxone treatment and compare it with standard care without preventive ceftriaxone. Adult patients with stroke (both ischaemic and haemorrhagic) and a score ≥ 1 on the National Institutes of Health Stroke Scale will be included. The 3200 patients will be randomly assigned to two groups of 1600 patients. One group will receive standard care and ceftriaxone at a dose of 2 g, given every 24 h intravenously for four-days, and the other group will receive stroke-unit care without preventive antibiotic treatment. The primary end point will be functional outcome at a three-month follow-up on the modified Rankin Scale, dichotomised as a favourable outcome (0-2) or an unfavourable outcome (3-6). Secondary outcome measures will be death rate at discharge and three-months, infection rate during hospital admission, length of hospital admission, volume of poststroke care, use of antibiotics during the three-month follow-up, functional outcome using the full ordinal scoring range of the modified Rankin Scale, quality-adjusted life years and costs.


Treatment strategies for high resveratrol induction in Vitis vinifera L. cell suspension culture.
Bioprocesses capable of producing large scales of resveratrol at nutraceutical grade are in demand. This study herein investigated treatment strategies to induce the production of resveratrol in Vitis vinifera L. cell suspension cultures. Among seven investigated elicitors, jasmonic acid (JA), salicylic acid, β-glucan (GLU), and chitosan enhanced the production of intracellular resveratrol manyfold. The combined treatment of JA and GLU increased extracellular resveratrol production by up to tenfold. The application of Amberlite XAD-7 resin for in situ removal and artificial storage of secreted resveratrol further increased resveratrol production by up to four orders of magnitude. The level of resveratrol produced in response to the combined treatment with 200 g/L XAD-7, 10 μM JA and 1 mg/mL GLU was approximately 2400 mg/L, allowing the production of resveratrol at an industrial scale. The high yield of resveratrol is due to the involvement of a number of mechanisms working in concert.


A fast spin echo technique with circular sampling.
This paper presents a fast spin echo (FSE) imaging method that employs circular sampling of k-space. The technique has been implemented on a 2 Tesla imaging system and validated on both phantoms and living animals. Experimental studies have shown that circular sampling can produce artifact-free FSE images without the need of phase correction. Although not fully explored, preliminary results also show that circular sampling may have advantages over the conventional rectilinear FSE in signal-to-noise ratio and imaging efficiency. A major disadvantage is the increased sensitivity to off-resonance effects. The authors expect that the FSE technique with circular sampling will find its applications in magnetic resonance microscopy, neuro-functional imaging, and real-time dynamic studies.


The pathological assessment of ovarian neoplasms V: The germ cell tumours.
All neoplasms of the ovary encountered in a 25-yr study period of King George V Memorial Hospital were classified according to the World Health Organisation (WHO) Histological Classification of Ovarian Tumours. Of just fewer than 1700 tumours, 467 fell into the category designated as germ cell tumours: 4 dysgerminomas, one endodermal sinus tumour, one primary choriocarcinoma, 6 immature and 454 mature teratomas and one mixed malignant germ cell tumour. Two additional cases of gonadoblastoma with associated dysgerminoma were encountered and included for discussion. A detailed histological assessment is presented and the major clinical correlates are documented.


Relationship among IgE-binding factors with various molecular weights.
The rat-mouse T cell hybridoma 23B6 forms IgE-binding factors on incubation with IgE. The hybridoma cells incubated with IgE contained intracellular IgE-binding factors of 60K, 30K, 14K, and 10K daltons, and secreted the 60K, 30K, and 14K IgE-binding factors. Both intracellular and extracellular IgE-binding factors of 60K and 14K daltons selectively suppressed the IgE response, whereas the 30K and 10K factors failed to do so. Reduction and alkylation of the extracellular 60K IgE-binding factors yielded fragments of 30K, 14K, and 10K daltons with IgE-binding activity, and the same treatment of the 30K "inactive" IgE-binding factor yielded the 14K and 10K fragments. Among the fragments obtained by reduction and alkylation, only the 14K IgE-binding factors selectively suppressed the IgE response. Monoclonal antibody OX 3, which recognizes an Ia determinant, bound the 60K and 30K IgE-binding factor, and the 30K fragment obtained by reduction and alkylation. None of the 14K and 10K IgE-binding factors and fragments of comparable size obtained by reduction and alkylation contained the antigenic determinant. The results indicate that 30K, 14K, and 10K IgE-binding factors are derived from the 60K precursor molecules. Transfection of COS 7 monkey kidney cells with a single cloned cDNA, 8.3, which encodes rodent IgE-binding factor, resulted in the formation of IgE-binding factors of 60K and 11K daltons. Both species of the factors had affinity for lentil lectin and selectively potentiated the IgE response, but only the 60K IgE-binding factor bound to the monoclonal anti-Ia antibody. Reduction and alkylation of the 60K IgE-binding factors from the cDNA clone yielded an 11K fragment having the same properties as the 11K IgE-binding factor, with respect to the affinity for lentil lectin, and the biologic activities. Because the cDNA clone was constructed from mRNA of 23B6 cells, it appears that the 60K IgE-binding factor molecule from 23B6 cells is composed of a single peptide chain, and that the naturally formed 30K, 14K, and 10K IgE-binding factors are formed by post-translational modification of the 60K peptide.


Environmental controls in the water use patterns of a tropical cloud forest tree species, Drimys brasiliensis (Winteraceae).
Trees from tropical montane cloud forest (TMCF) display very dynamic patterns of water use. They are capable of downwards water transport towards the soil during leaf-wetting events, likely a consequence of foliar water uptake (FWU), as well as high rates of night-time transpiration (Enight) during drier nights. These two processes might represent important sources of water losses and gains to the plant, but little is known about the environmental factors controlling these water fluxes. We evaluated how contrasting atmospheric and soil water conditions control diurnal, nocturnal and seasonal dynamics of sap flow in Drimys brasiliensis (Miers), a common Neotropical cloud forest species. We monitored the seasonal variation of soil water content, micrometeorological conditions and sap flow of D. brasiliensis trees in the field during wet and dry seasons. We also conducted a greenhouse experiment exposing D. brasiliensis saplings under contrasting soil water conditions to deuterium-labelled fog water. We found that during the night D. brasiliensis possesses heightened stomatal sensitivity to soil drought and vapour pressure deficit, which reduces night-time water loss. Leaf-wetting events had a strong suppressive effect on tree transpiration (E). Foliar water uptake increased in magnitude with drier soil and during longer leaf-wetting events. The difference between diurnal and nocturnal stomatal behaviour in D. brasiliensis could be attributed to an optimization of carbon gain when leaves are dry, as well as minimization of nocturnal water loss. The leaf-wetting events on the other hand seem important to D. brasiliensis water balance, especially during soil droughts, both by suppressing tree transpiration (E) and as a small additional water supply through FWU. Our results suggest that decreases in leaf-wetting events in TMCF might increase D. brasiliensis water loss and decrease its water gains, which could compromise its ecophysiological performance and survival during dry periods.


Structural regularized support vector machine: a framework for structural large margin classifier.
Support vector machine (SVM), as one of the most popular classifiers, aims to find a hyperplane that can separate two classes of data with maximal margin. SVM classifiers are focused on achieving more separation between classes than exploiting the structures in the training data within classes. However, the structural information, as an implicit prior knowledge, has recently been found to be vital for designing a good classifier in different real-world problems. Accordingly, using as much prior structural information in data as possible to help improve the generalization ability of a classifier has yielded a class of effective structural large margin classifiers, such as the structured large margin machine (SLMM) and the Laplacian support vector machine (LapSVM). In this paper, we unify these classifiers into a common framework from the concept of "structural granularity" and the formulation for optimization problems. We exploit the quadratic programming (QP) and second-order cone programming (SOCP) methods, and derive a novel large margin classifier, we call the new classifier the structural regularized support vector machine (SRSVM). Unlike both SLMM at the cross of the cluster granularity and SOCP and LapSVM at the cross of the point granularity and QP, SRSVM is located at the cross of the cluster granularity and QP and thus follows the same optimization formulation as LapSVM to overcome large computational complexity and non-sparse solution in SLMM. In addition, it integrates the compactness within classes with the separability between classes simultaneously. Furthermore, it is possible to derive generalization bounds for these algorithms by using eigenvalue analysis of the kernel matrices. Experimental results demonstrate that SRSVM is often superior in classification and generalization performances to the state-of-the-art algorithms in the framework, both with the same and different structural granularities.


Female soldiers' gynecologic healthcare in Operation Iraqi Freedom: a survey of camps with echelon three facilities.
To describe female soldiers' predeployment gynecologic healthcare screening, common symptoms, and availability of gynecologic care during Operation Iraqi Freedom. A questionnaire distributed to U.S. military females presenting to outpatient facilities in level 3 echelon of care between August 2005 and March 2006. Three-hundred ninety seven of 401 surveys (99%) were returned. Ten percent of deployed females (40) had no cervical cytology screening 1 year before deployment and 27% of the 399 required additional treatments for abnormal cervical cytology during deployment. Thirty-five percent reported a gynecologic problem and 44% received care at their base. Irregular bleeding was the most common gynecologic problem. Forty-four percent of women used some form of hormonal contraception; however, 43% changed methods because of unavailability. One-third of soldiers received pre-deployment menses regulation counseling, with 48% of those using continuous oral contraceptive pills for cycle control. Gaps remain in predeployment gynecologic screening and counseling. These critical predeployment medical evaluations must remain a priority for all female soldiers to ensure unit readiness.


Dispersive admicelle solid-phase extraction based on sodium dodecyl sulfate coated Fe3 O4 nanoparticles for the selective adsorption of three alkaloids in Gegen-Qinlian oral liquid before high-performance liquid chromatography.
A novel dispersive admicelle solid-phase extraction method based on sodium dodecyl sulfate-coated Fe3 O4 nanoparticles was developed for the selective adsorption of berberine, coptisine, and palmatine in Gegen-Qinlian oral liquid before high-performance liquid chromatography. Fe3 O4 nanoparticles were synthesized by a chemical coprecipitation method and characterized by using transmission electron microscopy. Under acidic conditions, the surface of Fe3 O4 nanoparticles was coated with sodium dodecyl sulfate to form a nano-sized admicelle magnetic sorbent. Owing to electrostatic interaction, the alkaloids were adsorbed onto the oppositely charged admicelle magnetic nanoparticles. The quick separation of the analyte-adsorbed nanoparticles from the sample solution was performed by using Nd-Fe-B magnet. Best extraction efficiency was achieved under the following conditions: 800 μL Fe3 O4 nanoparticles suspension (20 mg/mL), 150 μL sodium dodecyl sulfate solution (10 mg/mL), pH 2, and vortexing time 2 min for the extraction of alkaloids from 10 mL of diluted sample. Four hundred microliters of methanol was used to desorb the alkaloids by vortexing for 1 min. Satisfactory extraction recoveries were obtained in the range of 85.9-120.3%, relative standard deviations for intra- and interday precisions were less than 6.3 and 10.0%, respectively. Finally, the established method was successfully applied to analyze the alkaloids in two batches of Gegen-Qinlian oral liquids.


Indole diterpenoid natural products as the inspiration for new synthetic methods and strategies.
Indole terpenoids comprise a large class of natural products with diverse structural topologies and a broad range of biological activities. Accordingly, indole terpenoids have and continue to serve as attractive targets for chemical synthesis. Many synthetic efforts over the past few years have focused on a subclass of this family, the indole diterpenoids. This minireview showcases the role indole diterpenoids have played in inspiring the recent development of clever synthetic strategies, and new chemical reactions.


Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia.
Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signaling downstream of a number of receptors. Pharmacologic targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity toward ibrutinib. BTK-targeted RNAi knockdown reduced colony-forming capacity of primary AML blasts and proliferation of AML cell lines. We showed that ibrutinib binds at nanomolar range to BTK. Furthermore, we showed ibrutinib's antiproliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia. These results provide a biological rationale for clinical evaluation of BTK inhibition in AML patients.


Bilateral Vestibular Deficiency: Quality of Life and Economic Implications.
Bilateral vestibular deficiency (BVD) causes chronic imbalance and unsteady vision and greatly increases the risk of falls; however, its effects on quality of life and economic impact are not well defined. To quantify disease-specific and health-related quality of life, health care utilization, and economic impact on individuals with BVD in comparison with those with unilateral vestibular deficiency (UVD). Cross-sectional survey study of patients with BVD or UVD and healthy controls at an academic medical center. Vestibular dysfunction was diagnosed by means of caloric nystagmography. Survey questionnaire. Health status was measured using the Dizziness Handicap Index (DHI) and Health Utility Index Mark 3 (HUI3). Economic burden was estimated using participant responses to questions on disease-specific health care utilization and lost productivity. Fifteen patients with BVD, 22 with UVD, and 23 healthy controls participated. In comparison with patients with UVD and controls, patients with BVD had significantly worse DHI (P < .001) and HUI3 scores. Statistically significant between-group differences were observed for overall HUI3 score (P < .001) and for specific attributes including vision, hearing, ambulation, emotion, and pain (P < .001 for all). Generalized linear model analysis of clinical variables associated with HUI3 scores after adjustment for other variables (including sex, race, education, age, and frequency of dizziness-related outpatient clinic visits) showed that the presence of UVD (P < .001) or BVD (P < .001), increased dizziness-related emergency room visits (P = .002), and increased dizziness-related missed work days (P < .001) were independently associated with worse HUI3 scores. Patients with BVD and UVD incurred estimated mean (range) annual economic burdens of $13,019 ($0-$48,830) and $3531 ($0-$48,442) per patient, respectively. Bilateral vestibular deficiency significantly decreases quality of life and imposes substantial economic burdens on individuals and society. These results underscore the limits of adaptation and compensation in BVD. Furthermore, they quantify the potential benefits of prosthetic restoration of vestibular function both to these individuals and to society.


Association of Body Mass Index, Waist Circumference, and Waist-Stature Ratio With Urine Composition in Patients With Urolithiasis.
This study was aimed to evaluate the correlation of body mass index (BMI), waist circumference (WC), and waist-stature ratio (WSR) with urinary composition in urolithiasis patients. Medical reports of 1410 urolithiasis patients referred to a tertiary in Tehran, from 2010 to 2015, were reviewed. Collected data included WC, BMI, and WSR, 24-hour urine composition, and the first-morning urine pH. Urinary relative supersaturation of calcium oxalate, calcium phosphate, and uric acid were calculated. Linear correlation and logistic regression models were used for study analyses. A total of 511 records were reviewed. In the women, supersaturation of calcium oxalate significantly correlated with BMI, WC, and WSR. Supersaturation of uric acid significantly correlated with WC. Using regression analyses, BMI and WSR were associated with greater supersaturation of calcium oxalate abnormality, which persisted after adjustment for confounding factors (odds ratio, 1.080; 95% confidence interval, 1.001 to 1.166 for BMI; odds ratio, 1.053; 95% confidence interval, 1.001 to 1.108 for WSR). Larger WC accompanied abnormal values for supersaturation of calcium oxalate; however, the model was marginally significant (odds ratio, 1.032; 95% confidence interval, 1.000 to 1.065; P = .05) in multivariable analysis. In the men on the other hand, none of the obesity indexes were associated with the supersaturation measures. Although both obesity and abdominal obesity correlated with supersaturation of calcium oxalate, mostly by changes in urine volume and pH in women, none of those indexes showed significant correlation with urine composition in the men population of our study.


Medical student Dermatology Interest Groups.
The Dermatology Interest Group (DIG) at the University of Texas Medical Branch (UTMB) blog (digutmb.blogspot.com) was created in 2004 with the aims of increasing communication and collaboration among students, faculty, residents, and alumni, promoting educational opportunities, and fostering the missions for which DIG was created. This blog is unique, because its frequent activity is directed toward the educational and professional needs of medical students and residents. We assessed the use of this blog by evaluating the number of blog views and audience members with relationship to the number of posts and post content over time via a tracking system. We found that there has been an increase in blog posts, views, and subscribers, as well as in areas of post content including dermatology resources/news/articles, residency applications, and resident-related information. Usefulness of such posts expands beyond UTMB students, which increases blog views and widens viewer audience. An international viewer population also was evaluated. Recorded blog viewing time was 1 minute, 57 seconds, which is more time than needed to read a post, suggesting use of additional blog information. This review of the DIG at the UTMB blog demonstrates how the use of web-based tools, in addition to the inherent benefits of medical student interests groups, are valuable resources for students, residents, and faculty.


The wearing of hydrophilic contact lenses aboard a commercial jet aircraft: I. Humidity effects on fit.
The increasing use of hydrophilic (soft) lenses in the United States hs prompted interest in the clinical investigation of these lenses under various wearing conditions. Any factor causing lens dehydration during wear may affect lens performance and ultimately cause eye discomfort. The purpose of this study was to evaluate the environmental conditions in the aircraft cabin and to observe any changes in the fit of the hydrophilic lenses that might occur during flight. A "laboratory" for testing was set up aboard a World Airways DC-10 on a scheduled round trip between Oakland, California and Honolulu, Hawaii. A keratometer was used to assess lens fit of seven subjects who were wearing hydrophilic lenses. The efficacy of using a soft lens hydrating solution on the fit of the lens was evaluated, but will also be evaluated in a future paper. Atmospheric pressure, humidity, and temperature measurements were recorded throughout the inflight study. The results showed that a decline in cabin humidity from at least 47% to 11% occurred within 30 min of takeoff. Although previous reports have indicated that there are a number of environmental factors in the aircraft that contribute to eye discomfort for lens wearers, this study indicates that low cabin humidity is possibly the most significant factor.


Academic Nurse-Managed Community Clinics Transitioning to Telehealth: Case Report on the Rapid Response to COVID-19.
In response to the COVID-19 pandemic, many health care organizations have adopted telehealth. The current literature on transitioning to telehealth has mostly been from large health care or specialty care organizations, with limited data from safety net or community clinics. This is a case report on the rapid implementation of a telehealth hub at an academic nurse-managed community clinic in response to the national COVID-19 emergency. We also identify factors of success and challenges associated with the transition to telehealth. This study was conducted at the George Mason University Mason and Partners clinic, which serves the dual mission of caring for community clinic patients and providing health professional education. We interviewed the leadership team of Mason and Partners clinics and summarized our findings. Mason and Partners clinics reacted quickly to the COVID-19 crisis and transitioned to telehealth within 2 weeks of the statewide lockdown. Protocols were developed for a coordination hub, a main patient triage and appointment telephone line, a step-by-step flowchart of clinical procedure, and a team structure with clearly defined work roles and backups. The clinics were able to maintain most of its clinical service and health education functions while adapting to new clinic duties that arose during the pandemic. The experiences learned from the Mason and Partners clinics are transferable to other safety net clinics and academic nurse-led community clinics. The changes arising from the pandemic have resulted in sustainable procedures, and these changes will have a long-term impact on health care delivery and training.


Rapid response to intravenous vitamin K may obviate the need to transfuse prothrombin complex concentrates.
Patients on warfarin who present with bleeding or who require an urgent procedure are commonly treated with intravenous (IV) vitamin K, which is supplemented with repletion of the vitamin K factors using either plasma or a prothrombin complex concentrate (PCC). In some such cases, use of vitamin K alone could be adequate to achieve acceptable hemostasis. An algorithm emphasizing the use of vitamin K alone in patients presenting with non-life-threatening bleeding was encouraged, with repeat testing of the international normalized ratio (INR) within 5 hours. Depending on the INR result, patients received no factor repletion or plasma or PCC, as judged by the physician. Leftover samples from a separate cohort of patients with supratherapeutic INRs (INR > 4.0) were studied for clotting factor evaluation. A total of 46 pre- and postinfusion INRs were evaluable from 41 patients. Median INR decreased from 5.8 to 2.5, with a median dose of 5 mg after a median time of 4.0 hours postinfusion. A total of 27 of 46 (59%) postinfusion samples showed an INR of 2.5 or less. Samples from patients with the highest INR showed the greatest decline in INR. Samples from supratherapeutic INR patients showed very high Factor VIII:C (200%) and a normal activated partial thromboplastin time in 23 of 50 (46%). Use of IV vitamin K as sole therapy for urgent partial reversal of warfarin for non-life-threatening bleeding may provide adequate hemostasis within 5 hours, avoiding the need for clotting factor repletion.


Traumatic reticuloperitonitis combined with embolic pneumonia and hepatitis as unusual symptoms of foreign body syndrome in a Holstein bull.
Traumatic reticuloperitonitis combined with embolic pneumonia and hepatitis is unusual signs of foreign body syndrome in cattle. A 4-year-old Holstein bull presented decreased appetite, dry cough, progressive weight loss, sternal recumbence and reluctance to stand and move. Laboratory tests revealed leucocytosis (18.4 × 103 /μl) accompanied by neutrophilia (10.48 × 103 /μl), and monocytosis (1.28 × 103 /μl), hyperglobulinaemia (6.3 g/dl), hypoalbuminaemia (1.5 g/dl), hyperfibrinogenaemia (10 g/L) and severe increase in gamma-glutamyl transferase activity (1,216 U/L). Reticular ultrasonographical examination showed a large amount of hyperechoic and hypoechoic content between the reticular serosa and the hepatic visceral surface. The main gross findings included fibrin deposition and adhesions between the reticulum, liver and diaphragm surfaces; a 4.0 mm in diameter transmural reticular perforation; a 12.0-cm diameter and scarce small randomly abscesses in the liver's parenchyma. The lungs presented multifocal areas of suppurative embolic foci (pulmonary abscesses), interstitial emphysema and multifocal fibrin deposition on the pleural surface. Ancillary diagnostic tests, such as ultrasonography and laboratory test, associated with clinical evaluation, may increase the accuracy of the correct diagnosis and avoid wasting time and money on untreatable cases.


Caspase-3 and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis as link between inflammation and atherothrombosis.
Macrophages associated with arterial wall lipid deposition contribute to inflammatory processes. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. Intimal cells undergoing apoptosis have been postulated as a source for TF. However, there is only limited knowledge of cell type, plaque component, and conditions associated with TF expression and apoptosis. We examined the hypothesis that macrophages exposed to conditions of lipid-rich plaque undergo apoptosis and express TF. In human carotid (n=15) and coronary (n=6) atherosclerotic plaques, TF and caspase-3 mRNA and protein expression (evaluated by in situ hybridization and immunohistochemistry) were increased significantly in lipid-rich compared with fibrous plaque components (P<0.01) and correlated with high macrophage content (P<0.05). Double-labeling studies demonstrated colocalization of TF and active caspase-3. In hyperlipidemic mice, expression of TF and active caspase-3 was observed simultaneously and colocalized in neointimal macrophages after arterial injury. In neointima of normolipidemic animals, TF and active caspase-3 were absent after arterial injury. In monocytes cultured in the presence of oxidized LDL, strong induction and colocalization of TF and active caspase-3 were found compared with baseline (P<0.05). Both antigens were significantly decreased after cotreatment with a caspase inhibitor (P<0.05) and were absent in untreated control cells. The expression of TF as the primary cell-associated activator of the coagulation pathway proves to be closely related to macrophages undergoing apoptosis in conditions of lipid-rich plaque, pointing to a key role of lipid content and inflammatory cell viability in determining plaque thrombogenicity.


Interstitial cell tumors in a young adult New Zealand white rabbit.
One case of interstitial cell tumors in the testicles of a New Zealand White rabbit was reported. The rabbit was 8-10 months old and had bilateral testicular lesions. There was no enlargement of either testicle and the lesions were first seen on the cut surface. Light and electron microscopy revealed that the cellular morphology resembled the features observed for this tumor in rats, dogs, and a few other domestic animals in which reports are available.


Activation of a mitogen-activated protein kinase pathway is involved in disease resistance in tobacco.
Hypersensitive response (HR), a form of programmed cell death, is frequently associated with plant disease resistance. It has been proposed that mitogen-activated protein kinase (MAPK) cascades regulate HR cell death based on pharmacological studies by using kinase inhibitors. However, direct evidence is lacking. Here, we demonstrate that NtMEK2, a MAPK kinase, is upstream of salicylic acid-induced protein kinase (SIPK) and wounding-induced protein kinase (WIPK), two tobacco MAPKs that are activated by various pathogens or pathogen-derived elicitors. Expression of a constitutively active mutant of NtMEK2 induces HR-like cell death in tobacco, which is preceded by the activation of endogenous SIPK and WIPK. In addition, NtMEK2-SIPK/WIPK cascade appears to control the expression of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) and l-phenylalanine ammonia lyase (PAL), two defense genes encoding key enzymes in the phytoalexin and salicylic acid biosynthesis pathways. These results demonstrate that a plant MAPK cascade controls multiple defense responses against pathogen invasion.


Pulmonary abnormalities in mice with paracoccidioidomycosis: a sequential study comparing high resolution computed tomography and pathologic findings.
Human paracoccidioidomycosis (PCM) is an endemic fungal disease of pulmonary origin. Follow-up of pulmonary lesions by image studies in an experimental model of PCM has not been previously attempted. This study focuses on defining patterns, topography and intensity of lung lesions in experimentally infected PCM mice by means of a comparative analysis between High Resolution Computed Tomography (HRCT) and histopathologic parameters. Male BALB/c mice were intranasally inoculated with 3 x 10(6) Paracoccidioides brasiliensis (Pb) conidia (n = 50) or PBS (n = 50). HRCT was done every four weeks to determine pulmonary lesions, quantify lung density, reconstruct and quantify lung air structure. Lungs were also analyzed by histopathology and histomorphometry. Three different patterns of lesions were evidenced by hrct and histopathology, as follows: nodular-diffuse, confluent and pseudo-tumoral. The lesions were mainly located around the hilus and affected more frequently the left lung. At the 4th week post-challenge HRCT showed that 80% of the Pb-infected mice had peri-bronchial consolidations associated with a significant increase in upper lung density when compared with controls, (-263+/-25 vs. -422+/-10 HU, p<0.001). After the 8th and 12th weeks, consolidation had progressed involving also the middle regions. Histopathology revealed that consolidation as assessed by HRCT was equivalent histologically to a confluent granulomatous reaction, while nodules corresponded to individual compact granulomas. At the 16th week of infection, confluent granulomas formed pseudotumoral masses that obstructed large bronchi. Discrete focal fibrosis was visible gradually around granulomas, but this finding was only evident by histopathology. This study demonstrated that conventional HRCT is a useful tool for evaluation and quantification of pulmonary damage occurring in experimental mouse PCM. The experimental design used decreases the need to sacrifice a large number of animals, and serves to monitor treatment efficacy by means of a more rational approach to the study of human lung disease.


Effects of social manipulations and environmental enrichment on behavior and cell-mediated immune responses in rhesus macaques.
This paper reviews a series of studies that have examined the effects of manipulations to the social and the inanimate environments on the behavior and cell-mediated immune responses of rhesus macaques of various ages living in different settings. In general, enrichment of the inanimate environment with toys, structures, foraging devices, and/or videotapes increased the amount of species-typical behavior expressed by the monkeys, but did not affect their immune responses. Housing monkeys socially, on the other hand, not only resulted in increased time spent in species-typical activities, but also resulted in (1) decreases in time spent in abnormal behavior and (2) changes in a number of immune parameters. Additionally, attempts to directly influence the affiliative interactions of socially housed adult rhesus have resulted in systematic changes in affiliative behavior, although anticipated accompanying systematic alterations to cell-mediated immune responses have yet to be realized. The data suggest that aspects of the physical and social environments influence behavioral and immunological parameters in captive macaques in the absence of other experimental manipulations. As such, these influences need to be appropriately managed and/or controlled in order to minimize potential confounds in experimental designs.


Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity.
Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against β-cell dysfunction, we studied their mechanism(s) of action in β-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic β-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic β-cells. In our current study, we found that both RES (0.1-10 μmol/l) and CUR (1-100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating β-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in β-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic β-cell function.


Melatonin administration in diabetes: regulation of plasma Cr, V, and Mg in young male Zucker diabetic fatty rats.
The use of melatonin, a neurohormone present in plants, represents an exciting approach for the maintenance of optimum health conditions. Melatonin administration ameliorates glucose homeostasis in Zucker diabetic fatty (ZDF) rats. The objective of this study was to investigate the effects of melatonin in diabetes in relation to the levels and regulation of plasma chromium (Cr), vanadium (V), and magnesium (Mg) in Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats. At the age of 6 weeks, ZDF (n = 30) and ZL (n = 30) groups were each subdivided into three groups: control (C) (n = 10), vehicle-treated (V') (n = 10) and melatonin-treated (M) (10 mg kg(-1) per day; n = 10) groups for a 6 week period. After treatment, plasma mineral concentrations were measured by flame (Mg) and electrothermal (Cr and V) atomic absorption spectrometry. No significant differences were found between the C and V' groups (p > 0.05). Plasma Mg levels were significantly lower in C-ZDF vs. C-ZL rats, demonstrating the presence of hypomagnesemia in this diabetes mellitus model. Plasma V and Cr levels were significantly higher in M-ZDF vs. C-ZDF rats. Plasma Mg levels in ZDF rats were not affected by melatonin treatment (p > 0.05). Melatonin administration ameliorates the diabetic status of ZDF rats by enhancing plasma Cr and V concentrations. This appears to be the first report of a beneficial effect of melatonin treatment on plasma Cr and V regulation in ZDF rats.


Involvement of nitric oxide system in experimental muscle crush injury.
Muscle crush injury is often complicated by hemodynamic shock, electrolyte disorders, and myoglobinuric renal failure. In this study, we examined the involvement of the nitric oxide (NO) system in the development of muscle damage in an experimental model of crush injury induced by exertion of standardized mechanical pressure on tibialis muscle of rat. The intact limb served as a control. Four days after injury, the crushed muscle was characterized by extreme capillary vasodilatation as demonstrated by histological morphometric analysis. These changes were accompanied by muscle hyperperfusion as evaluated by measurements of femoral blood flow (ultrasonic flowmetry) and capillary blood flow (laser-doppler flowmetry). Treatment with Nomega-nitro-L-arginine methyl ester, a NO synthase (NOS) inhibitor, largely decreased the hyperperfusion. Furthermore, the expression of the different NOS isoforms, assessed by reverse transcription-PCR and immunoreactive levels, determined by Western blot, revealed a remarkable induction of the inducible NOS in the crushed limb. Similarly, endothelial NOS mRNA increased gradually after the induction of muscle damage. In contrast, the major muscular NOS, i.e., neuronal isoform remained unchanged. In line with the alterations in the mRNA levels, Western blot analysis revealed parallel changes in the immunoreactive levels of the various NOS. These findings indicate that muscle crush is associated with activation of the NO system mainly due to enhancement of iNOS. This may contribute to NO-dependent extreme vasodilatation in the injured muscle and aggravate the hypovolemic shock after crush injury.


Mechanism of vancomycin transport in the kidney: studies in rabbit renal brush border and basolateral membrane vesicles.
The effect of vancomycin, a putatively nephrotoxic amine glycopeptide antibiotic, on the transport of organic cations was examined in rabbit renal basolateral and brush border membrane vesicles. The studies were conducted using a rapid filtration technique and the prototypic organic cation tetraethylammonium. In basolateral membrane vesicles, vancomycin cis-inhibited the electrogenic transport of tetraethylammonium with an IC50 value of 260 microM. In contrast, gentamicin, an aminoglycoside, was without effect. Inhibition by mepiperphenidol, a classical organic cation transport inhibitor, was observed with an IC50 value of 24 microM. Countertransport, that is, trans-stimulation experiments, were initiated in order to determine whether or not vancomycin was capable of traversing the plasma membrane. Vancomycin caused trans-stimulation of tetraethylammonium uptake. The specificity of inhibition was assessed by determining the effect of vancomycin on the transport of p-aminohippurate, an organic anion. Vancomycin did not inhibit transport, whereas probenecid, a classical organic anion inhibitor, did. In the brush border membrane, vancomycin had no effect on the transport of tetraethylammonium. These data are consistent with mediated transport for vancomycin across the basolateral membrane, but not across the brush border membrane. This implies that the nephrotoxicity of vancomycin may be due to entry through the basolateral membrane and the absence of mediated egress at the brush border membrane.


Enteric mechanisms of initiation of migrating myoelectric complexes in dogs.
The enteric mechanisms governing initiation of migrating myoelectric complexes were studied in 6 conscious dogs, each implanted with a set of 12 bipolar electrodes on the small intestine. The small intestine was transected and reanastomosed at three sites to give four isolated segments of equal length. Each segment had three implanted electrodes. All four isolated segments generated migrating myoelectric complexes which were, initially, totally independent of each other in time. The most proximal segment had the longest mean migrating myoelectric complex time period (106.2 +/- 10.1 SEM min) and the second segment had the shortest mean migrating myoelectric complex time period (66.8 +/- 6.7 SEM min). Distal to the second segment, the mean migrating myoelectric complex time period increased progressively (83.1 +/- 11.2 SEM min and 95.8 +/- 7.6 SEM min, respectively). Isolation of the small intestine into segments did not significantly change migrating myoelectric complex propagation characteristics such as velocity and direction of propagation within each segment. The mean duration of phase 3 activity was not affected in the first segment but increased significantly in the distal three segments (p less than 0.05). The propagation of migrating myoelectric complexes across the sites of transection and reanastomosis started recovering 45-60 days after surgery and recovered fully by 98-108 days. The study findings show that enteric mechanisms control the initiation of migrating myoelectric complexes. Each small segment of the small intestine is capable of initiating migrating myoelectric complexes of its own and behaves as a relaxation oscillator. In the intact small intestine, regional migrating myoelectric complex oscillators are coupled by the intrinsic neurons so that the proximal oscillators drive the distal oscillators. Recovery of migrating myoelectric complex propagation across sites of transection and reanastomosis suggest that intrinsic nerves regenerate after transection.


"Money Helps": People who inject drugs and their perceptions of financial compensation and its ethical implications.
This study documents how people who inject drugs (PWID) in rural Puerto Rico perceive payments for participating in HIV epidemiological studies. In-depth interviews were conducted among a subset (n = 40) of active PWID older than 18 years of age who had been previously enrolled in a much larger study (N = 360). Findings suggest that financial compensation was the main motivation for initially enrolling in the parent study. Then, as trust in the researchers developed, participants came to perceive compensation as part of a reciprocal exchange in which they assisted researchers by providing a trustful account of their experiences and researchers reciprocated with financial support.


Operational K9s in the COVID-19 World.
Severe acute respiratory syndrome coronavirus 2 (SARSCov- 2) is hypothesized to have originated from a spillover event from an animal reservoir. This has raised many questions, with an important one being whether the widely disseminated coronavirus disease 2019 (COVID-19) is transmissible to other animal species. SARS-CoV-2 is primarily transmitted person to person. K9-to-human transmission, although theoretically possible via fomites, is considered minimal, if at all, and there have been no reported cases of K9-to-human transmission. Human-to-K9 transmission, although rare, seems more likely; however, in only one case has a K9 been suspected to have displayed symptoms of COVID-19. Preparation, decontamination, hand hygiene, and distancing remain the key factors in reducing transmission of the virus. The information presented is applicable to personnel operating within the military conventional and Special Operation Forces as well as civilian Tactical Emergency Medical Services communities who may have the responsibility of supporting an operational K9.


A Combination of Biochar-Mineral Complexes and Compost Improves Soil Bacterial Processes, Soil Quality, and Plant Properties.
Organic farming avoids the use of synthetic fertilizers and promises food production with minimal environmental impact, however this farming practice does not often result in the same productivity as conventional farming. In recent years, biochar has received increasing attention as an agricultural amendment and by coating it with minerals to form biochar-mineral complex (BMC) carbon retention and nutrient availability can be improved. However, little is known about the potential of BMC in improving organic farming. We therefore investigated here how soil, bacterial and plant properties respond to a combined treatment of BMC and an organic fertilizer, i.e., a compost based on poultry manure. In a pakchoi pot trial, BMC and compost showed synergistic effects on soil properties, and specifically by increasing nitrate content. Soil nitrate has been previously observed to increase leaf size and we correspondingly saw an increase in the surface area of pakchoi leaves under the combined treatment of BMC and composted chicken manure. The increase in soil nitrate was also correlated with an enrichment of bacterial nitrifiers due to BMC. Additionally, we observed that the bacteria present in the compost treatment had a high turnover, which likely facilitated organic matter degradation and a reduction of potential pathogens derived from the manure. Overall our results demonstrate that a combination of BMC and compost can stimulate microbial process in organic farming that result in better vegetable production and improved soil properties for sustainable farming.


Managing breast cancer in younger women: challenges and solutions.
Breast cancer in young women is relatively rare compared to breast cancer occurring in older women. Younger women diagnosed with breast cancer also tend to have a more aggressive biology and consequently a poorer prognosis than older women. In addition, they face unique challenges such as diminished fertility from premature ovarian failure, extended survivorship periods and its attendant problems, and the psychosocial impact of diagnosis, while still raising families. It is therefore imperative to recognize the unique issues that younger women face, and plan management in a multidisciplinary fashion to optimize clinical outcomes. This paper discusses the challenges of breast cancer management for young women, as well as specific issues to consider in diagnosis, treatment, and follow-up of such patients.