Characterization of transcriptional complexity during berry development in Vitis vinifera using RNA-Seq.
The development of massively parallel sequencing technologies enables the sequencing of total cDNA (RNA-Seq) to derive accurate measure of individual gene expression, differential splicing activity, and to discover novel regions of transcription, dramatically changing the way that the functional complexity of transcriptomes can be studied. Here we report on the first use of RNA-Seq to gain insight into the wide range of transcriptional responses that are associated with berry development in Vitis vinifera 'Corvina'. More than 59 million sequence reads, 36 to 44 bp in length, were generated from three developmental stages: post setting, véraison, and ripening. The sequence reads were aligned onto the 8.4-fold draft sequence of the Pinot Noir 40024 genome and then analyzed to measure gene expression levels, to detect alternative splicing events, and expressed single nucleotide polymorphisms. We detected 17,324 genes expressed during berry development, 6,695 of which were expressed in a stage-specific manner, suggesting differences in expression for genes in numerous functional categories and a significant transcriptional complexity. This exhaustive overview of gene expression dynamics demonstrates the utility of RNA-Seq for identifying single nucleotide polymorphisms and splice variants and for describing how plant transcriptomes change during development.


Ambulatory thyroidectomy: an anesthesiologist's perspective.
Thyroidectomy has been performed on an inpatient basis because of concerns regarding postoperative complications. These include cervical hematoma, bilateral recurrent laryngeal nerve injury and symptomatic hypocalcemia. We have reviewed the current available evidence and aimed to collate published data to generate incidence of the important complications. We performed a literature search of Medline, EMBASE and the Cochrane database of randomized trials. One hundred sixty papers were included. Twenty-one papers fulfilled inclusion criteria. Thirty thousand four hundred fifty-three day-case thyroid procedures were included. Ten papers were prospective and 11 retrospective. The incidences of complications were permanent vocal cord paralysis 7/30259 (0.02%), temporary hypocalcemia 129/4444 (2.9%), permanent hypocalcemia 405/29203 (1.39%), cervical hematoma 145/30288 (0.48%) and readmission rate 105/29609 (0.35%). Analysis of cervical hematoma data demonstrated that in only 3/14 cases the hematoma presented as an inpatient, and in the remaining 11/14, it occurred late, with a range of 2-9 days. There is a paucity of data relating to anesthetic techniques associated with ambulatory thyroidectomy. Cost comparison between outpatient and inpatient thyroidectomy was reported in three papers. Cost difference ranged from $676 to $2474 with a mean saving of $1301 with ambulatory thyroidectomy. There is a body of evidence that suggests that ambulatory thyroidectomy in the hands of experienced operating teams within an appropriate setting can be performed with acceptable risk profile. In most circumstances, this will be limited to hemithyroidectomies to reduce or avoid the potential for additional morbidity. We have found little evidence to support the use of one anesthetic technique over another. The rates of hospital admission and readmission related to anesthetic factors appear to be low and predominantly related to pain and postoperative nausea and vomiting. A balanced anesthetic technique incorporating appropriate analgesic and antiemetic regimens is essential to avoid unnecessary hospital admission/readmission.


Childhood malignant melanoma. Incidence and etiology.
Etiology of malignant melanoma in persons younger than 20 years of age was examined using data from two sources: medical records of 78 patients with this diagnosis at six hospitals, and information on 101 individuals included in 10 U.S. population-based SEER cancer registry areas between 1973-1976. Annual melanoma incidence rate was 3.4 per million in boys, 3.9 per million in girls, and 10-fold greater in white children than in black children. Melanoma was seven times more frequent in the second decade of life than the first. Skin was the primary site of melanoma in approximately 90% of the children in the two study series. The predominant cutaneous sites were head, neck, and trunk among boys, and arms and legs among girls. These variations by age, race, and sex suggest the etiologic role of cumulative skin exposure to sunlight, particularly in two patients with xeroderma pigmentosum. In 14 patients in the hospital series, melanoma was reported to develop within pigmented nevi that were present at birth.


Elevated plasma plasminogen activator inhibitor type-1 is an independent predictor of coronary microvascular dysfunction in hypertension.
Elevated plasma plasminogen activator inhibitor-1 (PAI-1) is related to cardiovascular events, but its role in subclinical coronary microvascular dysfunction remains unknown. Thus, in the present study it was investigated whether elevated plasma PAI-1 activity is associated with coronary microvascular dysfunction in hypertensive patients. Thirty patients with untreated essential hypertension and 10 age-matched healthy controls were studied prospectively. Myocardial blood flow (MBF) was measured by using (15)O-water positron emission tomography. Clinical variables associated with atherosclerosis (low-density lipoprotein-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, homeostasis model assessment (HOMA-IR), and PAI-1 activity) were assessed to determine their involvement in coronary microvascular dysfunction. Adenosine triphosphate (ATP)-induced hyperemic MBF and coronary flow reserve (CFR) were significantly lower in hypertensive patients than in healthy controls (ATP-induced MBF: 2.77+/-0.82 vs 3.49+/-0.71 ml x g(-1) x min(-1); p<0.02 and CFR: 2.95 +/-1.06 vs 4.25+/-0.69; p<0.001). By univariate analysis, CFR was positively correlated with HDL-cholesterol (r=0.46, p<0.02), and inversely with HOMA-IR (r=-0.39, p<0.05) and PAI-1 activity (r=-0.61, p<0.001). By multivariate analysis, elevated PAI-1 activity remained a significant independent determinant of diminished CFR. Elevated plasma PAI-1 activity was independently associated with coronary microvascular dysfunction, which suggests that plasma PAI-1 activity is an important clue linking hypofibrinolysis to the development of atherosclerosis.


MUCUS IN INTESTINAL CONTENTS OF GERMFREE RATS.
The fecal excretion of total nitrogen and of total hexosamines has been determined in germfree and conventional rats. Germfree rats excreted more hexosamines than the conventional rats, while no difference in the nitrogen excretion was found. Infection of the germfree rats with a normal flora resulted in a temporarily increased excretion of hexosamines and nitrogen over a period of 2 to 3 days after which they reached the level of the conventional animals. The contents of the germfree cecum contained 65 to 137 mg of hexosamines and 57 to 127 mg of nitrogen as compared to 1.2 to 5.3 and 7.4 to 23 mg in conventional animals. The high figures for hexosamines were due to an increase in the total amount of contents in the cecum and to a fivefold increase in the concentration of hexosamine-containing material. Studies on the distribution of hexosamine-containing cecal contents between sediment and supernatant after centrifugation at 20,000 g for 2 hours demonstrated that 5 to 10 per cent of the hexosamines occurred in the sediment in the germfree rats, while 75 to 85 per cent was found in this fraction in the conventional rats. The soluble part of the cecal contents in germfree as well as in the conventional rats contained 70 per cent of hexosamines in molecules with a molecular weight above approximatively 100,000 as found by gel filtration experiments on sephadex gels. The higher weight of the germfree cecal wall was reflected in a high total amount of nitrogen and hexosamines. Isolated strains of bacteria capable of reducing the cecal size in vivo did not show any capacity to degrade the mucus in vitro in a test system, where a full intestinal flora was highly active.


Actions of the histrionicotoxins at the ion channel of the nicotinic acetylcholine receptor and at the voltage-sensitive ion channels of muscle membranes.
Various histrionicotoxins tested on frog nerve-muscle preparations showed a qualitative family resemblance to one another. They blocked the nerve-evoked muscle twitch and depressed both the peak amplitudes and the decay time constants of end-plate currents. During repetitive stimulation they progressively decreased the rate of rise and prolonged the falling phase of muscle action potentials, the latter resulting, at least in part, from blockade of voltage-sensitive potassium channels. These results indicated that the histrionicotoxins act at three membrane channels: the channel associated with the acetylcholine receptor, the sodium channel, and the potassium channel. Closer study of perhydrohistrionicotoxin suggested either two topographically distinct sites of action at the acetylcholine receptor-ion channel complex, or one site and two ion channel complex conformations. One site or conformation only alters the kinetics of channel closure. As these sites become saturated, the end-plate current decay time constant asymptotically approaches a limiting value. The other site or conformation prevents the channel from opening altogether. Further analysis indicated that the binding site for perhydrohistrionicotoxin that alters the kinetics of channel closure has an affinity constant of 0.1 microM-1 at -90 mV and that this affinity may be sensitive to the membrane potential. The lipid protein interface is a suggested site of histrionicotoxin action, common to the three channels studied here as well as to other intrinsic membrane proteins affected by histrionicotoxins.


Exploring Working Memory, Self-Criticism, and Rumination as Factors Related to Self-Harm.
The prevalence of self-harm and the relative emotional influences are well understood, but certain cognitive factors such as working memory, rumination, and self-criticism are not fully explored. The aim of the current study is to examine specific aspects of cognition to explore their influence on self-harming behaviors. Participants included 101 undergraduates from a British University. Factors were measured using the Center for Epidemiological Studies Depression Scale, the Depressive Experiences Questionnaire, Ruminative Response Scale, and the Automated Working Memory Assessment. Findings indicated a greater incidence of self-harming behaviors among those who demonstrated higher depressive symptoms, but depression scores were not significantly related to self-harm. Additionally, a binary logistic regression indicated that self-criticism was associated with the presence of self-harming behavior, and a Classification and Regression Trees found that the single strongest predictor of self-harming behavior was a belief that love needs to be continually earned from others. Incorporating treatments that reduce self-criticism, such as improving self-compassion with Compassionate Mind Training, may address underlying mechanisms that trigger self-harm behavior.


[Carbohydrate and lipid metabolism in swine skeletal muscle in the pre- and neonatal periods].
Studies have been made on the activity of hexokinase, phosphofructokinase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, malate dehydrogenase and isocitrate dehydrogenase, as well as on the intensity of in vitro oxidation of [U-14C]-glucose and [U-14C]-palmitate (together with in vivo lipid synthesis from these compounds) in porcine skeletal muscles during pre- and postnatal periods of life. It was shown that active utilization of glucose in oxidative metabolism and lipid synthesis is possible during the transition from prenatal to neonatal period. The increase in the rate of oxidation of fatty acids in skeletal muscles of piglets, in contrast to other animals, does not inhibit carbohydrate utilization.


Properties of beta-adrenergic receptors on porcine corpora lutea and granulosa cells.
The nature of beta-adrenergic binding by swine corpora lutea and granulosa cells was examined with the specific beta-adrenergic radioligand, (+/-)3-[125I]iodocyanopindolol (ICYP). Saturation analyses revealed the presence of high affinity (Kd = 15.2 +/- 2.1 pM; n = 8 experiments) and low capacity (6.7 +/- 0.8 fmol/mg protein) beta-adrenergic receptors on porcine corpora lutea membranes. The properties of beta-adrenergic binding were determined by computer modeling of competition studies with a variety of compounds selective for beta-adrenergic subtypes. These studies disclosed predominantly beta 1-adrenergic receptors on pig luteal membranes. This inference from radioligand binding studies was corroborated functionally by the approximately equipotent biological effects of L-norepinephrine and L-epinephrine on cAMP production by luteal tissue (respective EC50s of 282 +/- 31 and 187 +/- 66 nM; n = 3 experiments). Physiological regulation of specific beta-adrenergic receptor content in the swine ovary was indicated by prominent (up to 9-fold) variations in receptor concentrations among corpora lutea and granulosa cells at various stages of maturity. In addition, there was differential expression of beta-adrenergic receptor subtype. Whereas the beta-adrenergic receptor subtype was predominantly beta 1 in corpora hemorrhagica and corpora lutea, granulosa cells and corpora albicantia contained principally beta 2 receptors. This difference could not be accounted for by blood cell contamination of corpora lutea, since swine blood cells contained predominantly (greater than 98%) beta 2-receptors, which were present at less than 8.6% the concentration of total beta-receptors in luteal tissue. In summary, swine corpora lutea and granulosa cells contain specific high affinity, low capacity beta-adrenergic receptors that are functionally coupled to biological responses. Moreover, total receptor content as well as beta-adrenergic subtype exhibit significant physiological variation in relation to maturational status of ovarian follicular and luteal tissue.


Trial designs likely to meet valid long-term Alzheimer's disease progression effects: learning from the past, preparing for the future.
The International Society for CNS Clinical Trials and Methodology (ISCTM) held its 4th Annual Autumn Conference in Toronto, Ontario, October 6-7, 2008. The purpose of the present report is to provide an overview of one of the sessions at the conference which focused on the designs and methodologies to be applied in clinical trials of new treatments for Alzheimer's disease (AD) with purported "disease-modifying" effects. The session began with a discussion of how neuroimaging has been applied in multiple sclerosis clinical trials (another condition for which disease modification claims have been achieved). The next two lectures provided a pharmaceutical industry perspective on some of the specific challenges and possible solutions for designing trials to measure disease progression and/or modification. The final lecture provided an academic viewpoint and the closing discussion included additional academic and regulatory perspectives on trial designs, methodologies, and statistical issues relevant to the disease modification concept.


Late-life depression, heart failure and frontal white matter hyperintensity: a structural magnetic resonance imaging study.
The relevance of the relationship between cardiac disease and depressive symptoms is well established. White matter hyperintensity, a bright signal area in the brain on T2-weighted magnetic resonance imaging scans, has been separately associated with cardiovascular risk factors, cardiac disease and late-life depression. However, no study has directly investigated the association between heart failure, major depressive symptoms and the presence of hyperintensities. Using a visual assessment scale, we have investigated the frequency and severity of white matter hyperintensities identified by magnetic resonance imaging in eight patients with late-life depression and heart failure, ten patients with heart failure without depression, and fourteen healthy elderly volunteers. Since the frontal lobe has been the proposed site for the preferential location of white matter hyperintensities in patients with late-life depression, we focused our investigation specifically on this brain region. Although there were no significant group differences in white matter hyperintensities in the frontal region, a significant direct correlation emerged between the severity of frontal periventricular white matter hyperintensity and scores on the Hamilton scale for depression in the group with heart failure and depression (P = 0.016, controlled for the confounding influence of age). There were no significant findings in any other areas of the brain. This pattern of results adds support to a relationship between cardiovascular risk factors and depressive symptoms, and provides preliminary evidence that the presence of white matter hyperintensities specifically in frontal regions may contribute to the severity of depressive symptoms in cardiac disease.


Identification of Lycopene epsilon cyclase (LCYE) gene mutants to potentially increase β-carotene content in durum wheat (Triticum turgidum L.ssp. durum) through TILLING.
Increasing β-carotene (a vitamin A precursor) content in Triticum turgidum L. ssp. durum (durum wheat) grains is important to improve pasta nutritional quality. Studies in other species show that altering the expression of LCYE genes increases the flux towards the β-β branch, accumulating higher β-carotene levels. Durum wheat is a tetraploid species that has two LCYE genes (LCYE-A and LCYE-B) associated to the A and B genomes. The objective of this work was to produce durum wheat LCYE mutants through EMS to potentially increase β-carotene content. The LCYE point mutations created with EMS were identified using a Kronos TILLING (Targeting Induced Local Lesion IN Genomes) mutant population. Specific primers that amplified exons 3 through 10 of the LCYE genes were designed and validated. To simplify the TILLING procedure, fragments were digested with CJE (Celery Juice Extract) and visualized on 2% agarose gels. 6X mutant pools were identified, which showed cleavage products and then made into 2X pools to identify mutant individuals. LCYE mutants were then sequenced and evaluated with BLOSUM62, SIFT and PSSM algorithms. Mutants with substitutions W437*, P334L and G368R in LCYE-A and P405L, G352R and T393I in LCYE-B predicted to affect protein function were selected. Substitution W437* increased β-carotene in 75% and overall total carotenoids content in leaves of the mutant 2426 (A1 mutant line), but no significant differences relative to the control were found in grains through HPLC. Finally, the increased levels of β-carotene on leaves have potential applications to improving plant resistance under contaminated environmental conditions.


Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants.
To improve energy intake in sick very low birthweight (VLBW) infants; to decrease growth problems, lessen pulmonary morbidity, shorten hospital stay, and avoid possible feeding related morbidity. Morbidity in VLBW infants thought to be associated with parenteral and enteral feeding includes bronchopulmonary dysplasia, necrotising enterocolitis, septicaemia, cholestasis and osteopenia of prematurity. A prospective randomised controlled trial (RCT) comparing two types of nutritional intervention was performed involving 125 sick VLBW infants in the setting of a regional neonatal intensive care unit. Babies were randomly allocated to either an aggressive nutritional regimen (group A) or a control group (group B). Babies in group B received a conservative nutritional regimen while group A received a package of more aggressive parenteral and enteral nutrition. Statistical analysis was done using Student's t test, the Mann-Whitney U test, the chi 2 test and logistic regression. There was an excess of sicker babies in group A, as measured by initial disease severity (P < 0.01), but mean total energy intakes were significantly higher (P < 0.001) in group A at days 3 to 42 while receiving total or partial parenteral nutrition. Survival and the incidences of bronchopulmonary dysplasia, septicaemia, cholestasis, osteopenia and necrotising enterocolitis were similar in both groups. Growth in early life and at discharge from hospital was significantly better in babies in group A. There were no decreases in pulmonary morbidity or hospital stay. Nutritional intake in sick VLBW infants can be improved without increasing the risk of adverse clinical or metabolic sequelae. Improved nutritional intake resulted in better growth, both in discharge, but did not decrease pulmonary morbidity or shorten hospital stay.


Side Variations of Anterior Cruciate Ligament Coronal Angles: Implications for ACL Reconstruction.
Current literature has shown a biomechanical advantage of recreating the native coronal obliquity of the anterior cruciate ligament (ACL) during grating procedures; however, the majority of studies on ACL morphological variation have been performed unilaterally. This cadaveric study aimed to evaluate sided ACL coronal angle of inclination variation including trend analysis with sex, age, height, and femoral condyle width. The ACLs of 57 embalmed cadaveric specimens were evaluated bilaterally for a total of 114 ACLs. The knees were flexed to 110°. A 0.70-mm wire measured coronal angulation through the lateral tibial plateau and the medial ACL border. An image taken of the wire allowed digital measurement with the ImageJ software. IBM SPSS was utilized for statistical analysis. Bilateral measurements demonstrated a difference in an individual's sided ACL angulation (P < 0.001). Right-sided angulation was greater in 61.4% (35/57). In cadavers with greater right-side angulation, right ACLs averaged 66.2° versus left ACLs averaged 60.9° (P < 0.001). Cadavers with greater left-sided ACL angles demonstrated average left ACLs measuring 65.5° versus right ACLs measuring 60.6° (P < 0.001). Right-sided angles were greater in 69.7% of females. Understanding the anatomy of the ACL's native coronal angle and variations between a patient's knees is imperative during reconstruction surgery to aid in anatomic tunnel placement for improved knee motion and rotational knee kinematics following surgery. A statistically significant difference exists between an individual's right and left ACL coronal angles of inclination. Clin. Anat. 32:1102-1106, 2019. © 2019 Wiley Periodicals, Inc.


Discovery of a Distinct Chemical and Mechanistic Class of Allosteric HIV-1 Integrase Inhibitors with Antiretroviral Activity.
Allosteric integrase inhibitors (ALLINIs) bind to the lens epithelial-derived growth factor (LEDGF) pocket on HIV-1 integrase (IN) and possess potent antiviral effects. Rather than blocking proviral integration, ALLINIs trigger IN conformational changes that have catastrophic effects on viral maturation, rendering the virions assembled in the presence of ALLINIs noninfectious. A high-throughput screen for compounds that disrupt the IN·LEDGF interaction was executed, and extensive triage led to the identification of a t-butylsulfonamide series, as exemplified by 1. The chemical, biochemical, and virological characterization of this series revealed that 1 and its analogs produce an ALLINI-like phenotype through engagement of IN sites distinct from the LEDGF pocket. Key to demonstrating target engagement and differentiating this new series from the existing ALLINIs was the development of a fluorescence polarization probe of IN (FLIPPIN) based on the t-butylsulfonamide series. These findings further solidify the late antiviral mechanism of ALLINIs and point toward opportunities to develop structurally and mechanistically novel antiretroviral agents with unique resistance patterns.


Does the benefit of salvage amputation always outweigh disability in drug-failure mycetoma?: a tale of two cases.
It is popularly believed that eumycetoma cases should be dealt with using surgical amputation for a better chance of cure especially when chemotherapy has failed. However, amputation leads to disability on one hand and on the other it may also fail to be curative. We present two cases with contrasting treatment options and outcome. In the eumycetoma case reported here, a 40-year-old male presented with right foot swelling for 16 years, from which Scedosporium apiospermum was isolated. He responded poorly to antifungal therapy and refused below-knee amputation 12 years ago. With counseling and wound care his condition improved, and Foot and Ankle Ability Measure (FAAM) score remained almost stable at 90% for 16 years, which is much better than the average functional outcome after amputation. Another 46-year-old female underwent below-knee amputation after receiving incomplete courses of antibiotics and antifungals for mycetoma of unknown etiology. She presented to us after recurrence of mycetoma on an amputated stump and was successfully treated by proper courses of antibiotics after detecting the causal agent, Actinomadura madurae. Her post-amputation disability and depression could have been avoided if the hasty decision of amputation had not been taken. In our opinion, living with drug-non-responsive mycetoma, supported by symptomatic management, may be a better option than amputation and its associated morbidities. So before taking the path of salvage amputation, we must consider many aspects, including patient's livelihood, psychological aspects and chances of recurrence even after the procedure.


Robust selection of cancer survival signatures from high-throughput genomic data using two-fold subsampling.
Identifying relevant signatures for clinical patient outcome is a fundamental task in high-throughput studies. Signatures, composed of features such as mRNAs, miRNAs, SNPs or other molecular variables, are often non-overlapping, even though they have been identified from similar experiments considering samples with the same type of disease. The lack of a consensus is mostly due to the fact that sample sizes are far smaller than the numbers of candidate features to be considered, and therefore signature selection suffers from large variation. We propose a robust signature selection method that enhances the selection stability of penalized regression algorithms for predicting survival risk. Our method is based on an aggregation of multiple, possibly unstable, signatures obtained with the preconditioned lasso algorithm applied to random (internal) subsamples of a given cohort data, where the aggregated signature is shrunken by a simple thresholding strategy. The resulting method, RS-PL, is conceptually simple and easy to apply, relying on parameters automatically tuned by cross validation. Robust signature selection using RS-PL operates within an (external) subsampling framework to estimate the selection probabilities of features in multiple trials of RS-PL. These probabilities are used for identifying reliable features to be included in a signature. Our method was evaluated on microarray data sets from neuroblastoma, lung adenocarcinoma, and breast cancer patients, extracting robust and relevant signatures for predicting survival risk. Signatures obtained by our method achieved high prediction performance and robustness, consistently over the three data sets. Genes with high selection probability in our robust signatures have been reported as cancer-relevant. The ordering of predictor coefficients associated with signatures was well-preserved across multiple trials of RS-PL, demonstrating the capability of our method for identifying a transferable consensus signature. The software is available as an R package rsig at CRAN (http://cran.r-project.org).


Effect of wastewater discharge on root anatomy and radial oxygen loss (ROL) patterns of three mangrove species in southern China.
The effects of wastewater discharge on radial oxygen loss (ROL) and root anatomy varied among mangrove species. ROL of Bruguiera gymnorrhiza (L) increased from 22.44 ng cm(-2) min(-1) in the control (just fresh water) to 31.09 ng cm(-2) min(-1) when received normal wastewater (NW) and to 44.22 ng cm(-2) min(-1) when treated with strong wastewater (10NW). However, discharge of both NW and 10NW caused 28% decreases of ROL in the root tip of Excoecaria agallocha L., and the decreases in Acanthus ilicifolius L were even more significant, with 45% when treated by 10NW The changes of ROL were related to the root anatomy. Among three species, A. ilicifolius had the highest proportional cross-sectional area of aerenchyma air spaces, suggesting that the internal oxygen transfer to root tip was the fastest. However, the area of aerenchyma air spaces in the root tip of 10NW treated A. ilicifolius was significantly reduced while area of epidermis and hypodermis (E + H) increased leading to less oxygen supply to root tip. Compared to B. gymnorrhiza and E. agallocha, the (E + H) layer of A. ilicifolius was the thinnest, and the cells without suberized walls were loosely packed in all three treatments. These results suggested that the root anatomy and ROL of B. gymnorrhiza was least affected by wastewater discharge, followed by E. agallocha, and A. ilicifolius was the most susceptible species thus was not suitable for treating strong wastewater.


Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline.
Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure.Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability.Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality.Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.


Red cell distribution width, neutrophil lymphocyte ratio and interleukin 10 are good prognostic markers in multiple myeloma.
Multiple myeloma (MM) is still an incurable disease so we need to continue developing new diagnostic and prognostic options for its management. There are multiple prognostic factors for MM, but most of them are costly and time consuming. Hence comes the urge to identify bed side and low cost prognostic tools, that is why this study was aiming to identify in Egyptian MM patients. The study was carried on 60 newly diagnosed multiple myeloma patients and 20 age and sex matched healthy individuals as controls. Studied subjects were subdivided into two groups: Group I: 60 multiple myeloma patients which were subdivided into three subgroups: Stage I: 10 patients, Stage II: 17 patients, Stage III: 33 patients, Group II: 20 healthy controls. A progressive significant increase in IL-10, RDW, NLR, and beta2 microglobulin (β2M) with disease progression from stage I towards stage III as compared to the control group. However, IL-10, RDW, and NLR have the best prognostic efficiency value regarding to sensitivity, specificity and positive predictive value when compared with β2M. IL-10, RDW, and NLR are simple, easy and bedside tests (in the case of RDW, and NLR). They have high sensitivity and specificity when compared to β2M, which is a well-established prognostic factor that highlights the valuable role they play as prognostic markers in MM.


[Accuracy of imaging techniques and tumor markers in the diagnosis of pancreatic cancer].
The aim of this study was to evaluate the diagnostic accuracy of: a) three imaging techniques: ultrasonography (US), computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP), and b) the serum tumor markers CEA, CA 19-9 and CA 125, in the diagnosis of pancreatic cancer. A total of 137 patients were prospectively evaluated. Pancreatic cancer was diagnosed in 25 patients; chronic pancreatitis in 24; acute pancreatitis in 22; extrapancreatic malignancies in 24, and benign digestive disease in 42. The reference interval for each marker was determined in 36 healthy volunteers. Diagnostic accuracy was determined using receiver operating characteristic (ROC) curves. Each diagnostic test was used in order: a) to diagnose pancreatic cancer when the disease was clinically suspected, and b) to differentiate between pancreatic cancer and chronic pancreatitis. CT (0.976-0.888) and US (0.857) diagnostic accuracy resulted greater than the best serum tumor marker CA 19-9 (0.755-0.786) (p = NS), in both diagnostic conditions. To obtain a diagnostic specificity of 90% in pancreatic cancer, the CA 19-9 cutoff level should increase up to 3 and 7.5 folds being in this case better than CEA and CA 125 (p < 0.05). CT scan offers the greatest accuracy in the diagnosis of PC. Among the tumor markers, CA 19-9 offers the best accuracy in the diagnosis of pancreatic cancer.


Tetraamine-coupled peptides and resulting (99m)Tc-radioligands: an effective route for receptor-targeted diagnostic imaging of human tumors.
The successful application of OctreoScan(®) ([(111)In-DTPA]octreotide) in the diagnosis of sst(2)-expressing neuroendocrine tumors (NETs), on one hand, and the manifestation of peptide receptor targets in a wide range of human cancers, on the other, have synergistically induced a booming emergence of numerous radiolabeled peptide (radiopeptide) probes for tumor diagnosis and therapy in man. Definition of molecular targets and their relation to neoplastic disease has preceded peptide-based radiopharmaceutical design and development. New criteria have been set to safeguard efficient localization of radionuclides on tumor-associated high affinity - low capacity peptide receptor systems. New technical and biological terms, such as specific activity or receptor affinity and internalization, have invaded the Radiopharmacy domain and have irrevocably altered our concept of radiopharmaceutical design. Nonetheless, (99m)Tc remains the gold standard of diagnostic nuclear medicine as a result of ideal nuclear characteristics, cost-effectiveness and wide availability in high purity and high specific activity by means of commercial (99)Mo/(99m)Tc-generators. The evolution of conventional (99m)Tc-perfusion agents into modern state-of-the-art molecular radiopharmaceuticals has been a challenge addressed by several researchers. The present review summarizes recent advances in the development of (99m)Tc-labeled peptides for in vivo targeting of neoplastic disease, and, in particular, those functionalized with acyclic tetraamines. Conclusions on their applicability in non-invasive diagnosis and staging of cancer patients are drawn.


A comparison of patients with spondyloarthropathy seen in specialty clinics with those identified in a communitywide epidemiologic study. Has the classic case misled us?
Undiagnosed cases of seronegative spondyloarthropathy (Spa) are often observed during epidemiologic studies. To determine the extent of and the reasons for the underdiagnosis of Spa. We studied 2 groups of Alaskan native patients with Spa using a standardized protocol that included an interview, physical examination, medical record review, and radiographic and laboratory examinations. One group consisted of patients identified in a communitywide epidemiologic study; the other group consisted of patients from related but geographically separate populations who had been diagnosed by a specialist in the hospital or a specialty clinic. All cases met the current classification criteria for Spa. The clinical and demographic features of the cases in the 2 groups were compared. Fifty-five (72%) of the 76 community cases that we identified in the epidemiologic study had not been diagnosed previously as Spa. Among the undiagnosed patients were 34 (94%) of the 36 women, 11 (65%) of the 17 patients with ankylosing spondylitis, 12 (36%) of the 33 patients with reactive arthritis, and 24 (100%) of those with undifferentiated Spa. The community and specialty clinic patient groups were similar in age of onset of joint and back pain and in overall symptoms. The specialty clinic group had a higher proportion of men, more severe disease, and a higher frequency of iritis. The diagnosis of Spa was missed more often than not in the primary care setting, probably because most of the cases were of mild or moderate severity and did not fit the classic descriptions of spondyloarthropathic disorders. The higher proportion of men among the specialty clinic cases probably reflects provider expectation as well as a slightly milder disease course in women.


Paradigm shift of respiratory viruses causing lower respiratory tract infection in children during COVID-19 pandemic in India.
Acute lower respiratory tract infections (ALRTIs) are the commonest cause of mortality in children mostly attributed to respiratory viruses. During the coronavirus disease 2019 (COVID-19) pandemic, the dynamics and transmission of infections changed worldwide due to widespread public health measures. This study aimed to understand the pattern of respiratory viruses associated with ALRTIs in children pre and during COVID-19 pandemic in India. Respiratory samples were collected from ALRTI patients during pre-pandemic period (October 2019 to February 2020; n = 166), Delta (July 2021 to December 2021; n = 78) and Omicron wave (January 2022 to July 2022; n = 111). Samples were screened for Influenza (Inf) A pdmH1N1, InfA H3N2, InfB, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human bocavirus (hBoV), human rhinovirus (hRV), and parainfluenza virus (PIV-2 and PIV-3) by nucleic acid amplification techniques (NAATs). Significantly higher proportion of children with ALRTIs had virus/es isolated during pre-pandemic period than during mid-pandemic period [78.9% (131/166) vs. 52.9% (100/189); p < 0.001). RSV positivity was significantly higher (51.2%) in pre-pandemic period than 10.3% and 0.9% during the Delta and Omicron waves respectively. No significant difference in positivity rate of Inf A pdmH1N1, Inf A H3N2 and Inf B was seen. The increase in positivity of hRV (39.2% vs 42.3% vs 56.8%) and hBOV (1.2% vs 5.1% vs 9%) was documented in pre-pandemic, delta wave and omicron wave respectively. The COVID-19 pandemic significantly impacted the frequency and pattern of respiratory viruses among hospitalized children with ALRTIs in India.


A clinical ladder for occupational health nurses.
Occupational health nurses must have a growing, expanding knowledge base to remain current in practice. The American Board for Occupational Health Nurses, Inc. encourages advancement with the availability of certification examinations. Health care centers support clinical advancement programs for bedside nurses. Nurses who continue their education either through a degree program or via continuing education or certification advance up the clinical ladder, receiving a higher salary, recognition from their peers, and perhaps even financial assistance to continue climbing, yet occupational health nurses do not have their own clinical advancement ladder. This article examines the steps necessary to develop a clinical ladder and presents a clinical ladder specific to occupational health nursing developed by the author.


Reported practice patterns in the ambulatory care setting for patients with CHD.
In the absence of evidence-based guidelines, paediatric cardiologists monitor patients in the ambulatory care setting largely according to personal, patient, institutional, and/or financial dictates, all of which likely contribute to practice variability. Minimising practice variability may optimise quality of care while incurring lower costs. We sought to describe self-reported practice patterns and physician attitudes about factors influencing their testing strategies using vignettes describing common scenarios in the care of asymptomatic patients with tetralogy of Fallot and d-transposition of the great arteries. We conducted a cross-sectional survey of paediatric cardiologists attending a Continuing Medical Educational conference and at our centre. The survey elicited physician characteristics, self-reported testing strategies, and reactions to factors that might influence their decision to order an echocardiogram. Of 267 eligible paediatric cardiologists, 110 completed the survey. The majority reported performing an annual physical examination (66-82%), electrocardiogram (74-79%), and echocardiogram (56-76%) regardless of patient age or severity of disease. Other tests (i.e. Holter monitors, exercise stress tests or cardiac MRIs) were ordered less frequently and less consistently. We observed within physician consistency in frequency of test ordering. In vignettes of younger children with mild disease, higher frequency testers were younger than lower frequency testers. These results suggest potential practice pattern variability, which needs to be further explored in real-life settings. If clinical outcomes for patients followed by low frequency testers match that of high frequency testers, then room to modify practice patterns and lower costs without compromising quality of care may exist.


Allopregnanolone and Pregnanolone Are Reduced in the Hippocampus of Epileptic Rats, but Only Allopregnanolone Correlates with Seizure Frequency.
Neurosteroids modulate epileptic activity by interacting with the γ-aminobutyric acid type A receptor, but their brain levels are still undetermined. We aimed to establish neurosteroid levels in the neocortex and hippocampus by liquid chromatography/mass spectrometry in epileptic rats. Kainic acid-treated rats were continuously monitored up to 9 weeks to determine seizure frequency by video electrocorticography (n = 23) and compared to age-matched controls monitored in the same manner (n = 11). Decreased allopregnanolone (-50%; p < 0.05, Mann-Whitney test) and pregnanolone levels (-64%; p < 0.01) were found in the hippocampus, whereas pregnenolone sulfate, pregnenolone, progesterone, and 5α-dihydroprogesterone were nonsignificantly reduced. No changes were found in the neocortex. Moreover, allopregnanolone (but not pregnanolone) levels were positively correlated with seizure frequency (r2 = 0.4606, p < 0.01). These findings indicate a selective reduction in hippocampal levels of 3α-reduced neurosteroids. This reduction was partially mitigated by seizures in the case of allopregnanolone.


Vertigo: new approaches to diagnosis and management.
Vertigo may be the presenting symptom in a plethora of pathological conditions. This common complaint can cause significant disability and handicap, which is frequently mismanaged. Nonetheless, a systematic diagnostic strategy allows effective management and rehabilitation in the majority of cases.


Evolving Therapeutic Strategies to Exploit Chromosome Instability in Cancer.
Cancer is a devastating disease that claims over 8 million lives each year. Understanding the molecular etiology of the disease is critical to identify and develop new therapeutic strategies and targets. Chromosome instability (CIN) is an abnormal phenotype, characterized by progressive numerical and/or structural chromosomal changes, which is observed in virtually all cancer types. CIN generates intratumoral heterogeneity, drives cancer development, and promotes metastatic progression, and thus, it is associated with highly aggressive, drug-resistant tumors and poor patient prognosis. As CIN is observed in both primary and metastatic lesions, innovative strategies that exploit CIN may offer therapeutic benefits and better outcomes for cancer patients. Unfortunately, exploiting CIN remains a significant challenge, as the aberrant mechanisms driving CIN and their causative roles in cancer have yet to be fully elucidated. The development and utilization of CIN-exploiting therapies is further complicated by the associated risks for off-target effects and secondary cancers. Accordingly, this review will assess the strengths and limitations of current CIN-exploiting therapies, and discuss emerging strategies designed to overcome these challenges to improve outcomes and survival for patients diagnosed with cancer.


Bilateral Bi-Level Erector Spinae Plane Blocks as a Part of Opioid-Sparing Multimodal Analgesia in Scoliosis Surgery: A Case Series of Six Pediatric Patients.
Background and Aim: Postoperative pain after scoliosis surgery is severe and usually requires long-term intravenous opioid therapy. Local anesthetic options, such as wound infiltration, are limited and include neuraxial analgesia. However, they are rarely used due to side effects and inconsistent efficacy. We report an opioid-sparing multimodal analgesia regimen with bilateral erector spinae plane blocks. This case series evaluated the analgesic effect of the bilateral bi-level erector spinae plane blocks (ESP) in congenital and neurogenic scoliosis surgery. Patients and Methods: Six pediatric patients with congenital or neurogenic scoliosis underwent posterior spinal fusion involving 5 to 12 vertebral levels. Bilateral single-injection ESPB was performed at one or two levels before incision. Preoperatively, patients received intravenous dexamethasone. General anesthesia with endotracheal intubation and volume-controlled ventilation was performed via TIVA with remifentanil and propofol. During and after the procedure, the basic hemodynamic parameters, opioid consumption, pain scores (numerical rating scale/NRS), and possible block complications were monitored. Results: All the patients experienced minimal postoperative pain levels. In addition, on the first day after surgery, they had low opioid requirements with no side effects. Conclusions: ESPB in patients undergoing congenital and neurogenic scoliosis correction surgery seems to be an essential analgesic technique that may reduce both severities of pain and opioid consumption.


Heterozygote detection for maple syrup urine disease in cattle.
The clinical, pathological and biochemical manifestations of maple syrup urine disease (MSUD) are similar in Poll Hereford and Poll Shorthorn x Poll Hereford calves. No significant differences were observed in branched-chain amino acid concentrations in plasma, or of branched-chain keto acid dehydrogenase activity in fibroblasts, between Poll Herefords homozygous normal and heterozygous for the mutation responsible for MSUD. Haemopoietic chimerism resulted in incorrect diagnosis of the MSUD genotype in 30% of non-identical twins when blood DNA was analysed using allele-specific amplification. Hair roots are shown to be a suitable source of target DNA for genotyping Poll Hereford cattle for the MSUD mutation. Twelve of 203 (5.8%) aged Poll Hereford bulls, sampled at saleyards during the last 4 months of 1993, were found to be heterozygous for the mutation. In contrast, the mutant sequence was detected in only 1 of 150 (0.7%) 2- and 3-year-old Poll Hereford bulls offered for sale at 2 stud sales held during 1993, suggesting that the prevalence of the disease may decline over the next few years.


Manipulation of CO adsorption over Me1/CeO2 by heterocation doping: Key roles of single-atom adsorption energy.
The performance of metal atoms chemically bonded to oxide supports cannot be explained solely by the intrinsic properties of the metals such as the d-band center. Herein, we present an in-depth study of the correlation between metal-oxide interactions and the properties of the supported metal using CO adsorption on Me1 (Fe1, Co1, and Ni1) loaded over CeO2 (111) doped with divalent (Ca, Sr, and Ba), trivalent (Al, Ga, Sc, Y, and La), and quadrivalent (Hf and Zr) heterocations. CO adsorption over Me1 is strongly dependent on the binding energies of Me1. Two factors led to this trend. First, the extent of the Me1-surface oxygen (Me1-O) bond relaxation during CO adsorption played a key role. Second, the d-band center shifted drastically because of charge transfer to the oxides. The shift is related to the oxophilicity of metals. Adsorption energies of Me1 over oxides include the contributions of the factors described above. Therefore, we can predict the activities of Me1 using the strength of anchoring by oxide supports. Results show that smaller ionic radii of the doped heterocations were associated with more tightly bound Me1. This finding sheds light on the possibility of heterocation-doping manipulating the reactivity of the Me1 catalyst based on theoretical predictions.


p21 Ras/impedes mitogenic signal propagation regulates cytokine production and migration in CD4 T cells.
The propensity of T cells to generate coordinated cytokine responses is critical for the host to develop resistance to pathogens while maintaining the state of immunotolerance to self-antigens. The exact mechanisms responsible for preventing the overproduction of proinflammatory cytokines including interferon (IFN)-gamma are not fully understood, however. In this study, we examined the role of a recently described Ras GTPase effector and repressor of the Raf/MEK/ERK cascade called impedes mitogenic signal propagation (Imp) in limiting the induction of T-cell cytokines. We found that stimulation of the T cell receptor complex leads to the rapid development of a physical association between Ras and Imp. Consistent with the hypothesis that Imp inhibits signal transduction, we also found that disengagement of this molecule by the Ras(V12G37) effector loop mutant or RNA interference markedly enhances the activation of the NFAT transcription factor and IFN-gamma secretion. A strong output of IFN-gamma is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of Ras(V12G37) caused T cells to accumulate preferentially in the lymph nodes and delayed their escape from the lymphoid tissue, respectively. Together, our results describe a hitherto unrecognized negative regulatory role for Imp in the production of IFN-gamma in T cells and point to Ras-Imp binding as an attractive target for therapeutic interventions in conditions involving the production of this inflammatory cytokine.


Expression of type II toxin-antitoxin systems and ClpP protease of methicillin-resistant Staphylococcus aureus under thermal and oxidative stress conditions.
Staphylococcus aureus is a main human pathogen that causes a variety of chronic to persistent infections. Across the diverse factors of pathogenesis in bacteria, Toxin-Antitoxin (TA) systems can be considered as an anti-bacterial target due to their involvement in cellular physiology counting stress responses. Here, the expression of TA system genes and ClpP protease was investigated under the thermal and oxidative conditions in S. aureus strains. The colony-forming unit (CFU) was used to determine the effects of thermal and oxidative stresses on bacterial survival. Moreover, the expressions of TA system genes in S. aureus strains were evaluated 30 min and 1 h after thermal and oxidative stresses, respectively, by quantitative reverse transcriptase real-time PCR (qRT-PCR). The cell viability was constant across thermal stress while oxidative stress induction showed a significantly decrease in the growth of Methicillin-Resistant S. aureus (MRSA) strain. Based on the qRT-PCR results, the expression of mazF gene increased under both thermal and oxidative stresses in the MRSA strain. A putative TA system (namely immA/irrA) most likely has a role under the stress condition of S. aureus. The MRSA strain responds to stress by shifting the expression level of TA genes that has diverse effects on the survival of the pathogen due to the stress conditions. The TA systems may be introduced as potential targets for antibacterial treatment.


Corporate compliance and voluntary disclosure.
In any event, the decision to institute a corporate compliance program is a relatively simple one. In view of the ambiguity surrounding certain fraud and abuse provisions, and the corporate "death sentence" that may result from program exclusion, a compliance program is always sound corporate policy. To be sure, if the compliance program is administered improperly, it can actually increase the likelihood of whistleblower actions and create a body of potentially hurtful documentation. But these dangers can be minimized by structuring the program to protect the self-evaluative process through relevant privileges. The risks also pale in comparison to the exposure to criminal or exclusionary sanctions when improper conduct goes undetected by an organization.


Dietary and biochemical selenium status of urban 6- to 24-month-old South Island New Zealand children and their postpartum mothers.
A community-based, cross-sectional survey was conducted in the South Island of New Zealand to assess the dietary and biochemical selenium status of children (n = 136) and their mothers (n = 302), and to assess factors influencing selenium status. Serum and plasma samples from children and their mothers were analyzed for selenium using graphite furnace atomic absorption spectrometry. Dietary selenium intakes were analyzed from 3-d weighed diet records, and food sources of selenium were quantified. Mean dietary selenium intakes in infants (6-11.9 mo), toddlers (12-24 mo), and mothers were below recommended levels. Toddlers had higher selenium intakes than infants (13.7 +/- 8.4 and 7.9 +/- 6.2 microg/d, respectively, P = 0.0001) and the selenium density of their diets was also higher [3.2 +/- 1.7 and 2.4 +/- 1.7 microg/(MJ . d), respectively, P = 0.003]. Household smoking was associated with lower serum selenium concentrations in infants and toddlers (P = 0.02). South Island women who were currently pregnant had lower plasma selenium concentrations (0.74 +/- 0.15 micromol/L) than nonpregnant lactating and nonpregnant nonlactating women (0.94 +/- 0.16 and 0.93 +/- 0.16 micromol/L, respectively, P = 0.0001). Clearly, pregnant women, infants and toddlers are at risk of suboptimal selenium status, and further research is warranted to assess potential effects in these groups. The finding of an association between household smoking and lower selenium concentrations in children should be investigated further. Dietary interventions are recommended to improve dietary selenium intakes in South Island children and their mothers.


Chemical profiling and quantification of Dan-Deng-Tong-Nao-capsule using ultra high performance liquid chromatography coupled with high resolution hybrid quadruple-orbitrap mass spectrometry.
Dan-Deng-Tong-Nao capsule (DDTN) was a traditional Chinese medicine (TCM) formula, and has been widely used for the treatment of stroke clinically which caused by blood stasis. However, the bioactive substances and mechanism are unclear because of the complex compositions in DDTN. In this research, An ultra high-performance liquid chromatography (UHPLC) coupled with hybrid quadruple-orbitrap mass spectrometry (Q-Orbitrap MS) method was utilized to identify the chemical constituents of DDTN. In total, 102 compounds including diterpenes, lactones, flavonoids, and phenolic acids were identified by the accurate masses and fragmentation pathways, and 18 of them were unambiguously determined by comparison of reference standards. Besides, 12 representative compounds were simultaneously quantification analyzed and successfully applified for detecting in 9 batches of DDTN samples by UHPLC-Q-Orbitrap MS in parallel reaction monitoring (PRM) mode. The proposed approach was validated to be satisfied in terms of linearity (0.9954-0.9999), LOD (0.771ng/mL), LOQ (2.568ng/mL), intra-day precision ( <2.68%), inter-day precision ( <4.52%), repeatability ( <2.96%), stability ( <3.21%), and recovery (94.6-105.5%). The results indicate that the method of combining UHPLC with Q-Orbitrap MS is practical and efficient for the chemical clarification in DDTN, and has great potential for the integrating quality control of other traditional Chinese medicines.


The Role of the miR-21/SPRY2 Axis in Modulating Proangiogenic Factors, Epithelial Phenotypes, and Wound Healing in Corneal Epithelial Cells.
Subconjunctival injection of antagomir-21 attenuates the progression of corneal neovascularization. We examined the underlying mechanism by investigating the regulation of microRNA (miR)-21 expression and the involvement of miR-21 in the homeostasis of corneal epithelial cells. Corneal epithelial cells were cultured with TGF-β1 and/or under hypoxia conditions. miR-21 expression was measured by quantitative PCR. The direct targets of miR-21 were validated by the 3'-UTR luciferase reporter assay. Alterations of proangiogenic signaling and the epithelial-mesenchymal transition (EMT) phenotype after miR-21/Sprouty2 (SPRY2) knockdown were examined by Western blotting. The effect of conditioned medium on angiogenesis was assessed using the tube formation assay. Wound healing was evaluated by the migration and scratch assays. TGF-β1 or hypoxia upregulated miR-21, and miR-21 silencing abolished TGF-β1/hypoxia-induced hypoxia inducible factor (HIF)-1α and VEGF expression. miR-21 inhibited SPRY2 by directly targeting its 3'-UTR. Simultaneous silencing of miR-21 and SPRY2 significantly upregulated p-ERK, HIF-1α, and VEGF and promoted angiogenesis. Induction of miR-21 or inhibition of SPRY2 reduced the levels of cytokeratin (CK)-3 and CK-12 and promoted EMT. Transwell and wound healing assays indicated that miR-21 promoted cell migration. TGF-β1 or hypoxia induced miR-21 and inhibited SPRY2, thereby enhancing proangiogenic signaling, suppressing the epithelial phenotype, and promoting wound healing in corneal epithelial cells.


[Current topics in the regulation of prostanoids--4. The feedback regulation by PPAR-gamma].
Recently, it has become known that lipophilic hormones such as steroids and thyroid hormones, or fat-soluble vitamins (vitamins A and D) pass through the cellular membrane and bind to the nuclear receptor superfamily to act as transcription factors. The metabolite of prostaglandin (PG) D2, 15-deoxy-D12,14PGJ2, has been identified as the ligand for peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear receptor superfamily. It forms a transcription factor and is responsible not only for the differentiation of fibroblasts to adipocytes, but also for the regulation of activated macrophages. It is now known that thiazolidinediones and non-steroidal anti-inflammatory drugs classified as cyclooxygenase blockers such as indomethacine and ibuprofen also act as PPAR-gamma agonists and inhibit cytokine production from activated macrophages. PPAR-gamma has become recognized as a new therapeutic target for inflammation control.


Surgical versus Nonsurgical Treatments of Acute Primary Patellar Dislocation with Special Emphasis on the MPFL Injury Patterns.
The objective of the present study was to compare the clinical results of the surgical versus nonsurgical treatments of acute primary patellar dislocations with a medial patellofemoral ligament (MPFL) injury in the nonoverlap region with the vastus medialis oblique. In this study, 62 patients with an acute patellar dislocation and a concurrent MPFL injury in the nonoverlap region were randomly divided into two groups based on their birth years (even vs. odd years) and received either surgical or nonsurgical treatment. Of the 62 eligible patients, 30 were in the nonsurgical treatment group (Group 1) and 32 were in the surgical group (Group 2). Patellar stability tests and the Kujala knee questionnaire were performed, and radiographs were evaluated for patellar tilt and the lateral shift ratio by two blinded investigators. An osteochondral injury was noted in six (23.1%) patients from Group 1 and five (16.7%) patients from Group 2, with no statistical difference between the two groups. The mean Kujala score was 80.19 ± 5.07 and 93.57 ± 4.03 (p < 0.001) between the surgical and nonsurgical groups, respectively. The mean patellar tilt was 8.96 ± 1.64 and 6.83 ± 1.44 degrees (p < 0.001) and the lateral shift ratio was 11.08 ± 1.99 and 9.23 ± 1.96 (p = 0.001) between the surgical and nonsurgical groups, respectively. This study showed that the surgical treatment of MPFL injuries in the nonoverlap region achieved better clinical outcomes and improved subjective knee function compared with conservative therapy. Surgery should therefore be considered as the treatment of choice for these specific injuries.


EFFECT OF THE TEMPERATURE OF GROWTH OF ESCHERICHIA COLI ON THE FORMATION OF BETA-GALACTOSIDASE.
Marr, Allen G. (University of California, Davis), John L. Ingraham, and Craig L. Squires. Effect of the temperature of growth of Escherichia coli on the formation of beta-galactosidase. J. Bacteriol. 87:356-362. 1964.-The synthesis of beta-galactosidase was measured during exponential growth of Escherichia coli in a succinate-minimal medium over a temperature range of 10 to 43 C for the following: (i) a constitutive strain, and (ii) an inducible cryptic strain, induced maximally with isopropyl-thio-beta-d-galactopyranoside (IPTG), or induced submaximally with IPTG. The differential rates of synthesis of beta-galactosidase were identical for the constitutive strain and for the fully induced strain; the rates were constant from 20 to 43 C, and decreased progressively with a decrease in temperature below 20 C. Thus, in the absence of specific repression, the ability of E. coli to produce beta-galactosidase decreases at low temperature. The differential rate of the submaximally induced culture was minimal between 20 and 30 C, and increased progressively with temperature both above 30 C and below 20 C. That the repressor concentration is maximal at 20 C was established by measuring the rate of induced synthesis of beta-galactosidase as a function of the concentration of IPTG; the relative concentrations of repressor were 1.00:3.28:0.25 at 40, 20, and 10 C, respectively. After an abrupt change in temperature, the differential rate of a submaximally induced culture changed gradually to the rate of the steady state, which is in agreement with the proposal that the effect of temperature is on the concentration of repressor and not on the equilibrium between repressor and its site of action. The effect of temperature on catabolic repression was determined by comparing the differential rate of synthesis of beta-galactosidase by a constitutive strain grown in succinate-minimal medium with the rate in glucose-minimal medium at various temperatures; the ratio of the rates in the two media decreased progressively and approached 2.0 as the temperature of growth was increased.


Macrognathia of renal osteodystrophy in a dialysis patient. Report of a case.
A case of macrognathia secondary to renal osteodystrophy in a dialysis patient is presented. The case reviewed demonstrates a variety of radiographic and histopathologic features, some of which resemble fibrous dysplasia and others suggestive of Paget's disease of bone. This article contains diagnostic criteria for differentiating renal osteodystrophy from similar fibro-osseous diseases. There is a discussion of the underlying cause and appropriate therapeutic interventions of renal osteodystrophy.


Translational regulation in mouse hepatitis virus infection is not mediated by altered intracellular ion concentrations.
Infection of mouse L-2 fibroblasts with mouse hepatitis virus (MHV) results in strong inhibition of host cell protein synthesis. Since it has been suggested in other virus systems that translational control is modulated by changes in the intracellular ionic environment, we investigated the possible occurrence of similar changes during MHV infection. Membrane permeability to extracellular sodium ions was measured by culturing MHV-infected cells in the presence of 22Na+. Sodium influx into MHV-infected cells rose dramatically from 4 to 6 h post-infection. This influx correlated chronologically with the expression of MHV-mediated cell fusion. Cell fusion was blocked by the addition of a monoclonal antibody against the MHV E2 glycoprotein. This addition also resulted in a reduction in the normal influx of 22Na+, suggesting that E2 expression was responsible, directly or indirectly, for the increased permeability to sodium ions in infected cells. Cultures of MHV-infected cells were labelled with [35S]methionine in the presence of medium supplemented with sodium chloride at final concentrations ranging from 150 mM to 350 mM. Incorporation of radiolabel into proteins decreased with increasing NaCl concentration; however, the ratio of viral to cellular protein synthesis remained relatively constant. Similarly, alteration of intracellular Na+ and K+ levels by treatment of infected cells with ouabain had little effect on the pattern of viral/cellular protein synthesis. Using monoclonal anti-E2 antibody to inhibit Na+ influx, we demonstrated normal inhibition of host cell protein synthesis. We therefore conclude that MHV-induced shut-off of host translation is not mediated by changes in intracellular Na+ concentrations.


Antidiabetic Activities of an LC/MS Fingerprinted Aqueous Extract of Fagonia cretica L. in Preclinical Models.
Diabetes mellitus is a chronic disease and one of the most important public health challenges facing mankind. Fagonia cretica is a medicinal plant used widely in the Punjab in Pakistan. A recent survey has demonstrated that traditional healers and herbalists frequently use this plant to treat diabetes. In the current study, the traditional medicine was prepared as a tea, and the profile of the main metabolites present in the traditional medicine was analysed via LC/MS/MS. The extract was shown to contain a number of phenolic glycosides including quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O-glycoside, kaempferol-3(6'-malonylglucoside), isorhamnetin-3-O-rutinoside, and isorhamnetin 3-(6″-malonylglucoside) in addition to two unidentified sulphonated saponins. The traditional medicine inhibits α-glucosidase in vitro with an IC50 of 4.62 µg/mL. The hypoglycaemic effect of the traditional medicine was evaluated in normoglycaemic and streptozotocin-treated diabetic rats, using glibenclamide as an internal control. The preparation (250 or 500 mg/kg body weight) was administered once a day for 21 consecutive days. The dose of 500 mg/kg was effective in the management of the disease, causing a 45 % decrease in the plasma glucose level at the end of the experimental period. Histological analysis of pancreatic sections confirmed that streptozotocin/nictotinamide treatment caused destruction of pancreatic islet cells, while pancreatic sections from the treatment groups showed that both the extract and glibenclamide partially prevented this deterioration. The mechanism of this protective effect is unclear. However, such a finding suggests that ingestion of the tea could confer additional benefits and should be investigated further.


Endometrial extension of adenosquamous carcinoma of the uterine cervix.
Endometrial in situ extension of cervical cancer is extremely uncommon. Previous reports only present the cases of squamous cell carcinoma or related category. This report presented adenosquamous carcinoma of the uterine cervix that showed a paradoxical extension of each component in a 72-year-old patient. Main tumor in the cervix was revealed to be adenosquamous carcinoma. The glandular component extended to the vagina, while the squamous component grew into the entire uterine cavity and replaced the glandular epithelium. We presented the first case of adenosquamous carcinoma of the uterine cervix with vaginal and endometrial extension. Furthermore, the endometrium was replaced with squamous component, while the vagina was invaded by glandular component. The observed paradoxical extension of the present case was extremely rare.


[Combined evaluation of ovarian tumors with transvaginal B-image and color Doppler ultrasound].
Transvaginal sonomorphologie and colour Doppler measurements were obtained preoperatively in 212 adnexal tumours: 81 premenopausal tumours (13 malignant and 68 benign) and 131 postmenopausal tumours (55 vs 76). Tumours were divided into five different scores according to their sonomorphology [16]. Scores I and II are related to benign tumours. Score V represents typically malignant tumours. Scores III and IV are associated with benign and malignant tumours. If score I and II are considered as benign and score III to V as malignant the sensitivity in pre- and postmenopausal tumours is 90%. However, the specificity is only 56% vs 70% respectively. In order to improve the accuracy, colour Doppler was additionally performed in tumours with sonomorphological score III and IV. The following criteria were tested: minimum resistance index (Rlmin), number of tumour arteries (ART), maximum (Smax) and sum (Ssum) of peak systolic velocities. All criteria showed significant differences between benign and malignant tumours. Tumours of score III and IV were differentiated by colour Doppler with an accuracy between 66% and 81% for premenopausal and 69% to 86% for postmenopausal women. The combination of sonomorphology and colour Doppler increased the accuracy between 84% and 90% with a sensitivity of up to 92% in pre- and 89% in postmenopausal patients. Sequential colour Doppler sonography as a supplement to transvaginal sonography improves tumour differentiation. The limitation of colour Doppler measurements to score III and IV lesions reduced the length of examination time to a reasonable extent.


Intraspinal serotonergic signaling suppresses locomotor activity in larval zebrafish.
Serotonin (5HT) is a modulator of many vital processes in the spinal cord (SC), such as production of locomotion. In the larval zebrafish, intraspinal serotonergic neurons (ISNs) are a source of spinal 5HT that, despite the availability of numerous genetic and optical tools, has not yet been directly shown to affect the spinal locomotor network. In order to better understand the functions of ISNs, we used a combination of strategies to investigate ISN development, morphology, and function. ISNs were optically isolated from one another by photoconverting Kaede fluorescent protein in individual cells, permitting morphometric analysis as they developed in vivo. ISN neurite lengths and projection distances exhibited the greatest amount of change between 3 and 4 days post-fertilization (dpf) and appeared to stabilize by 5 dpf. Overall ISN innervation patterns were similar between cells and between SC regions. ISNs possessed rostrally-extending neurites resembling dendrites and a caudally-extending neurite resembling an axon, which terminated with an enlarged growth cone-like structure. Interestingly, these enlargements remained even after neurite extension had ceased. Functionally, application of exogenous 5HT reduced spinally-produced motor nerve bursting. A selective 5HT reuptake inhibitor and ISN activation with channelrhodopsin-2 each produced similar effects to 5HT, indicating that spinally-intrinsic 5HT originating from the ISNs has an inhibitory effect on the spinal locomotor network. Taken together this suggests that the ISNs are morphologically mature by 5 dpf and supports their involvement in modulating the activity of the spinal locomotor network. © 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018.


Research collaborations can improve the use of organic amendments for plant-parasitic nematode management.
The concept of utilizing organic amendments to manage plant-parasitic nematodes is not new, but the widespread implementation of this management practice has still not been realized. The use of organic amendments for plant-parasitic nematode management is a complex process requiring an understanding of the transformation and generation of active compounds. As a result, research endeavors to understand and maximize the use of this management practice require a multidisciplinary approach which draws upon the expertise of nematologists, microbiologists, natural product chemists and soil scientists. Factors that require analysis and clarification include lethal concentration levels of organic amendments necessary to kill nematodes; chemical composition of incorporation material; fate and exposure potential to nematodes of compounds released into the soil; and the influence of environmental factors (i.e., temperature, microbial community, soil type) on the activity of organic amendments. Examples of research conducted in a collaborative manner with rye (Secale cereale) and a biosolid amendment demonstrate the power of multidisciplinary research. Only through collaborative research can consistent and reliable nematode suppression with organic amendments be achieved.


Prevalence and risk factors of silent cerebral infarction in apparently normal adults.
Cerebrovascular disease is a major cause of death and disability in adults. Silent cerebral infarction (SCI) portends more severe cerebral infarctions or may lead to insidious progressive brain damage resulting in vascular dementia. This study was designed to evaluate the prevalence and risk factors of SCI in an apparently normal adult population. Nine hundred ninety-four consecutive symptom-free adults (mean age 49.0+/-7.7; men:women 830:164) who underwent brain magnetic resonance imaging at the Center for Health Promotion at Samsung Medical Center were assessed. All were neurologically normal in history and physical examination. A total of 121 SCI lesions was observed in 58 subjects. The lesion prevalence adjusted for patient age was 5.1%. There was no gender difference in prevalence. Ninety-nine lesions were <1 cm in diameter, 15 were between 1 and 2 cm, 3 were between 2 and 3 cm, and 4 were >3 cm in diameter. The most frequent site of the SCI lesion was basal ganglia, after which the periventricular white matter, cerebral cortex, and thalamus were the most frequent sites. Old age, hypertension, a history of coronary artery disease, evidence of cardiomegaly in chest radiographs, and high fasting glucose/hemoglobin A1c levels were associated with SCI on univariate analysis. Multivariate analysis demonstrated old age and hypertension to be independent risk factors for SCI, and mild alcohol consumption was revealed as an independent protective factor against SCI.


Levocarnitine Injections Decrease the Need for Erythropoiesis-Stimulating Agents in Hemodialysis Patients with Renal Anemia.
The aim of this study was to evaluate the efficacy of levocarnitine injection for renal anemia in hemodialysis patients. In this randomized controlled clinical trial, we randomly assigned patients on maintenance hemodialysis at our hospital to receive levocarnitine injections (n = 30) or no injection (n = 30) and monitored the patients during 12 months of treatment. In the treatment group, patients received an injection of levocarnitine 1,000 mg 3 times weekly after hemodialysis sessions. All patients received recombinant human erythropoietin as an erythropoiesis-stimulating agent (ESA). Response to ESA therapy was determined by calculating the erythropoietin responsiveness index (ERI; ESA dose·kg-1·g-1· dL-1·week-1). (1) The target levels of hemoglobin and hematocrit were maintained during the study period in both the levocarnitine group and the control group. (2) The dose of ESAs required to maintain these levels decreased gradually in the levocarnitine group and was significantly lower at 6 and 12 months than at study initiation. Furthermore, the dose of ESAs was significantly lower than that in the control group at 12 months. (3) The ERI showed a significant decrease at 6 and 12 months in the levocarnitine group, with a significant difference between the 2 groups at 12 months. Our results suggest that levocarnitine administration can reduce the dose of ESAs required in patients with renal anemia on hemodialysis and improve the response to ESA therapy.


Adaptive Validation Design: A Bayesian Approach to Validation Substudy Design With Prospective Data Collection.
An internal validation substudy compares an imperfect measurement of a variable with a gold-standard measurement in a subset of the study population. Validation data permit calculation of a bias-adjusted estimate, which has the same expected value as the association that would have been observed had the gold-standard measurement been available for the entire study population. Existing guidance on optimal sampling for validation substudies assumes complete enrollment and follow-up of the target cohort. No guidance exists for validation substudy design while cohort data are actively being collected. In this article, we use the framework of Bayesian monitoring methods to develop an adaptive approach to validation study design. This method monitors whether sufficient validation data have been collected to meet predefined criteria for estimation of the positive and negative predictive values. We demonstrate the utility of this method using the Study of Transition, Outcomes and Gender-a cohort study of transgender and gender nonconforming people. We demonstrate the method's ability to determine efficacy (when sufficient validation data have accumulated to obtain estimates of the predictive values that fall above a threshold value) and futility (when sufficient validation data have accumulated to conclude the mismeasured variable is an untenable substitute for the gold-standard measurement). This proposed method can be applied within the context of any parent epidemiologic study design and modified to meet alternative criteria given specific study or validation study objectives. Our method provides a novel approach to effective and efficient estimation of classification parameters as validation data accrue.


Drosophila cell fusion induced by wheat germ agglutinin.
The effects of wheat germ agglutinin on Drosophila embryonic cell lines growing on cover-glasses was examined by scanning electron microscopy. At low concentrations of the lectin (5-10 mug/ml), cells spread against the glass surface and fused to form syncytia. At high concentration, damage to the cell surface was evidenced as extensive membrane shrivelling and loss of surface microfilaments. Fusion also occurred under these conditions. There was some indication that the morphology of cells in division remains undisturbed by wheat germ agglutinin. The coalescence of cells and morphologic disotrtion induced by wheat germ agglutinin were not inhibited by N-acetylglucosamine, the hapten inhibitor of the lectin, under the conditions utilized in this study.


Transported substrate determines exchange rate in the multidrug resistance transporter EmrE.
EmrE, a small multidrug resistance transporter, serves as an ideal model to study coupling between multidrug recognition and protein function. EmrE has a single small binding pocket that must accommodate the full range of diverse substrates recognized by this transporter. We have studied a series of tetrahedral compounds, as well as several planar substrates, to examine multidrug recognition and transport by EmrE. Here we show that even within this limited series, the rate of interconversion between the inward- and outward-facing states of EmrE varies over 3 orders of magnitude. Thus, the identity of the bound substrate controls the rate of this critical step in the transport process. The binding affinity also varies over a similar range and is correlated with substrate hydrophobicity within the tetrahedral substrate series. Substrate identity influences both the ground-state and transition-state energies for the conformational exchange process, highlighting the coupling between substrate binding and transport required for alternating access antiport.


Oral etoposide in gestational trophoblastic disease.
Ten patients with persistent or metastatic trophoblastic disease following molar pregnancy were treated with etoposide orally, administered on an outpatient basis. All patients achieved sustained biochemical remission. The mean duration of treatment was 8 weeks. The side effects were mild. The use of etoposide in patients resistant to conventional chemotherapy is discussed.


Eosinophilic cystitis--diagnosis and treatment in Denmark.
The purpose of this study was to evaluate the incidence, diagnostic criteria and treatment of eosinophilic cystitis (EC) in Denmark during the period 1989-94. A questionnaire was sent to all Danish departments of surgery, urology and pathology. Fifty-six cases of EC were diagnosed in the departments of surgery and urology, and 135 patients were diagnosed in the departments of pathology. The therapy was most often steroid instillation in the bladder or peroral antihistamines. Success rates of treatment were reported to be acceptable. The questionnaire confirmed that EC is a rare disease, which is often confused with other bladder diseases. We recommend strict histological criteria combined with clinical information when making the diagnosis of EC. Therapy is generally symptomatic. A diagnostic code number from the Danish Health Board is needed.


Mechanism of adrenergic stimulation of anion secretion in cultured rat epididymal epithelium.
Primary monolayer cultures of the epithelial cells from the rat cauda epididymidis had a basal transepithelial potential of 1.24 +/- 0.11 mV, apical side negative, a short-circuit current (SCC) of 2.42 +/- 0.17 microA/cm2, and a transepithelial resistance of 503 +/- 29.6 omega/cm2. Epinephrine (0.23 microM) added to the basolateral side caused a rise in the SCC (inward flowing) that was partially reversed by addition of amiloride, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), bumetanide, and acetazolamide to the basolateral side. In the absence of Cl or HCO3, the SCC response to epinephrine was reduced by 65 and 66%, respectively. Removal of K reduced the SCC response by 40%, whereas Na removal completely abolished it. A23187 and phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), stimulated the SCC when added to the apical side. Addition of the Cl channel blockers, anthracene-9-carboxylate and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) to the apical side reduced the SCC in a dose-dependent manner. It is concluded that anion secretion by the epididymis shares common mechanisms with other Cl-secreting epithelia.


Kinetic FRET Assay to Measure Binding-Induced Conformational Changes of Nucleic Acids.
The interaction of small molecules or proteins with RNA or DNA often involves changes in the nucleic acid (NA) folding and structure. A biophysical characterization of these processes helps us to understand the underlying molecular mechanisms. Here, we propose kinFRET (kinetics Förster resonance energy transfer), a real-time ensemble FRET methodology to measure binding and folding kinetics. With kinFRET, the kinetics of conformational changes of NAs (DNA or RNA) upon analyte binding can be directly followed via a FRET signal using a chip-based biosensor. We demonstrate the utility of this approach with two representative examples. First, we monitored the conformational changes of different formats of an aptamer (MN19) upon interaction with small-molecule analytes. Second, we characterized the binding kinetics of RNA recognition by tandem K homology (KH) domains of the human insulin-like growth factor II mRNA-binding protein 3 (IMP3), which reveals distinct kinetic contributions of the two KH domains. Our data demonstrate that kinFRET is well suited to study the kinetics and conformational changes of NA-analyte interactions.


X-ray crystallographic, scanning microprobe X-ray diffraction, and cross-polarized/magic angle spinning 13C NMR studies of the structure of cellulose III(II).
The X-ray crystallographic structure of cellulose III(II) is characterized by disorder; the unit cell (space group P2(1); a = 4.45 A, b = 7.64 A, c = 10.36 A, alpha = beta = 90 degrees, gamma = 106.96 degrees) is occupied by one chain that is the average of statistically disordered antiparallel chains. 13C CP/MAS NMR studies reveal the presence of three distinct molecular conformations that can be interpreted as a mixture of two different crystal forms, one equivalent to cellulose III(I), and another with two independent glucosyl conformations in the asymmetric unit. Both X-ray crystallographic and 13C NMR spectroscopic results are consistent with an aggregated microdomain structure for cellulose III(II). This structure can be generated from a new crystal form (space group P2(1); a = 4.45 A, b = 14.64 A, c = 10.36 A, alpha = beta = 90 degrees, gamma = 90.05 degrees; two crystallographically independent and antiparallel chains; gt hydroxymethyl groups) by multiple dislocation defects. These defects produce microdomains of the new crystal form and cellulose III(I) that scanning microprobe diffraction studies show are distributed consistently through the cellulose III(II) fiber.


Measuring interfraction and intrafraction lung function changes during radiation therapy using four-dimensional cone beam CT ventilation imaging.
Adaptive ventilation guided radiation therapy could minimize the irradiation of healthy lung based on repeat lung ventilation imaging (VI) during treatment. However the efficacy of adaptive ventilation guidance requires that interfraction (e.g., week-to-week), ventilation changes are not washed out by intrafraction (e.g., pre- and postfraction) changes, for example, due to patient breathing variability. The authors hypothesize that patients undergoing lung cancer radiation therapy exhibit larger interfraction ventilation changes compared to intrafraction function changes. To test this, the authors perform the first comparison of interfraction and intrafraction lung VI pairs using four-dimensional cone beam CT ventilation imaging (4D-CBCT VI), a novel technique for functional lung imaging. The authors analyzed a total of 215 4D-CBCT scans acquired for 19 locally advanced non-small cell lung cancer (LA-NSCLC) patients over 4-6 weeks of radiation therapy. This set of 215 scans was sorted into 56 interfraction pairs (including first day scans and each of treatment weeks 2, 4, and 6) and 78 intrafraction pairs (including pre/postfraction scans on the same-day), with some scans appearing in both sets. VIs were obtained from the Jacobian determinant of the transform between the 4D-CBCT end-exhale and end-inhale images after deformable image registration. All VIs were deformably registered to their corresponding planning CT and normalized to account for differences in breathing effort, thus facilitating image comparison in terms of (i) voxelwise Spearman correlations, (ii) mean image differences, and (iii) gamma pass rates for all interfraction and intrafraction VI pairs. For the side of the lung ipsilateral to the tumor, we applied two-sided t-tests to determine whether interfraction VI pairs were more different than intrafraction VI pairs. The (mean ± standard deviation) Spearman correlation for interfraction VI pairs was r̄(Inter)=0.52±0.25, which was significantly lower than for intrafraction pairs (r̄(Intra)=0.67±0.20, p = 0.0002). Conversely, mean absolute ventilation differences were larger for interfraction pairs than for intrafraction pairs, with |ΔV̄(Inter)|=0.42±0.65 and |ΔV̄(Intra)|=0.32±0.53, respectively (p < 10(-15)). Applying a gamma analysis with ventilation/distance tolerance of 25%/10 mm, we observed mean pass rate of (69% ± 20%) for interfraction VIs, which was significantly lower compared to intrafraction pairs (80% ± 15%, with p ∼ 0.0003). Compared to the first day scans, all patients experienced at least one subsequent change in median ipsilateral ventilation ≥10%. Patients experienced both positive and negative ventilation changes throughout treatment, with the maximum change occurring at different weeks for different patients. The authors' data support the hypothesis that interfraction ventilation changes are larger than intrafraction ventilation changes for LA-NSCLC patients over a course of conventional lung cancer radiation therapy. Longitudinal ventilation changes are observed to be highly patient-dependent, supporting a possible role for adaptive ventilation guidance based on repeat 4D-CBCT VIs. We anticipate that future improvement of 4D-CBCT image reconstruction algorithms will improve the capability of 4D-CBCT VI to resolve interfraction ventilation changes.


Occupational differences in US Army suicide rates.
Civilian suicide rates vary by occupation in ways related to occupational stress exposure. Comparable military research finds suicide rates elevated in combat arms occupations. However, no research has evaluated variation in this pattern by deployment history, the indicator of occupation stress widely considered responsible for the recent rise in the military suicide rate. The joint associations of Army occupation and deployment history in predicting suicides were analysed in an administrative dataset for the 729 337 male enlisted Regular Army soldiers in the US Army between 2004 and 2009. There were 496 suicides over the study period (22.4/100 000 person-years). Only two occupational categories, both in combat arms, had significantly elevated suicide rates: infantrymen (37.2/100 000 person-years) and combat engineers (38.2/100 000 person-years). However, the suicide rates in these two categories were significantly lower when currently deployed (30.6/100 000 person-years) than never deployed or previously deployed (41.2-39.1/100 000 person-years), whereas the suicide rate of other soldiers was significantly higher when currently deployed and previously deployed (20.2-22.4/100 000 person-years) than never deployed (14.5/100 000 person-years), resulting in the adjusted suicide rate of infantrymen and combat engineers being most elevated when never deployed [odds ratio (OR) 2.9, 95% confidence interval (CI) 2.1-4.1], less so when previously deployed (OR 1.6, 95% CI 1.1-2.1), and not at all when currently deployed (OR 1.2, 95% CI 0.8-1.8). Adjustment for a differential 'healthy warrior effect' cannot explain this variation in the relative suicide rates of never-deployed infantrymen and combat engineers by deployment status. Efforts are needed to elucidate the causal mechanisms underlying this interaction to guide preventive interventions for soldiers at high suicide risk.


Early Arrival and Climatically-Linked Geographic Expansion of New World Monkeys from Tiny African Ancestors.
New World Monkeys (NWM) (platyrrhines) are one of the most diverse groups of primates, occupying today a wide range of ecosystems in the American tropics and exhibiting large variations in ecology, morphology, and behavior. Although the relationships among the almost 200 living species are relatively well understood, we lack robust estimates of the timing of origin, ancestral morphology, and geographic range evolution of the clade. Herein, we integrate paleontological and molecular evidence to assess the evolutionary dynamics of extinct and extant platyrrhines. We develop novel analytical frameworks to infer the evolution of body mass, changes in latitudinal ranges through time, and species diversification rates using a phylogenetic tree of living and fossil taxa. Our results show that platyrrhines originated 5-10 million years earlier than previously assumed, dating back to the Middle Eocene. The estimated ancestral platyrrhine was small-weighing 0.4 kg-and matched the size of their presumed African ancestors. As the three platyrrhine families diverged, we recover a rapid change in body mass range. During the Miocene Climatic Optimum, fossil diversity peaked and platyrrhines reached their widest latitudinal range, expanding as far South as Patagonia, favored by warm and humid climate and the lower elevation of the Andes. Finally, global cooling and aridification after the middle Miocene triggered a geographic contraction of NWM and increased their extinction rates. These results unveil the full evolutionary trajectory of an iconic and ecologically important radiation of monkeys and showcase the necessity of integrating fossil and molecular data for reliably estimating evolutionary rates and trends.


Investigation of the effect of Interleukin-1 receptor antagonist (IL-1ra) on markers of inflammation in non-ST elevation acute coronary syndromes (The MRC-ILA-HEART Study).
Acute Coronary Syndromes account for 15% of deaths in the UK, and patients remain at significant risk of re-admission for future complications and death. Pathologically the underlying process of atherosclerosis is driven by inflammatory mechanisms, which are activated in ACS patients. Previous studies have investigated the role of inflammatory markers in this process, including interleukin 1 (IL-1) and C Reactive Protein (CRP). Pre-clinical studies indicate that IL-1 may be a primary driver of ACS and that the naturally occurring interleukin-1 receptor antagonist (IL-1ra) may inhibit the atherosclerotic process. This study will investigate the effects of IL-1ra on inflammatory markers in man. Three centres in the UK are planning to recruit 186 Non-ST elevation myocardial infarction patients to receive either interleukin-1 receptor antagonist (Anakinra) or matching placebo. Patients will receive a daily subcutaneous injection of either study drug or placebo over a 14 day period. The primary outcome is area under the curve of high sensitivity C-Reactive Protein (CRP) over the first 7 days. The MRC-ILA-HEART Study is a proof of concept clinical trial investigating the effects of IL-1ra upon markers of inflammation in patients with Non-ST elevation myocardial infarction. It is hoped this will provide new and exciting information in relation to an "anti-inflammatory" strategy for patients with acute coronary syndrome. ISRCTN89369318.


Predicting emotional health indicators from linguistic evidence of psychological distancing.
Psychological distancing, a form of cognitive reappraisal, involves construal of emotionally valenced stimuli in an objective manner, or with perceived spatial and temporal distance. Prior work suggests that in appropriate contexts, reappraisal broadly, and distancing specifically, is related to adaptive mental and physical health outcomes. Additionally, recent research suggests that shifting language to be more distant (i.e., linguistic distancing [LD]) can have adaptive emotion regulatory effects. The present study addressed whether LD is also associated with adaptive health indicators. Participants transcribed their thoughts while viewing negative or neutral stimuli in one of three ways: (a) by implementing objective language, (b) by implementing spatially and/or temporally far away language, or (c) by responding naturally. Across psychological distancing groups, LD was associated with lower negative affectivity (lower perceived stress and depression symptoms), better general well-being (better emotional well-being and energy and vitality), and better emotion regulation (ER; greater reappraisal frequency and fewer difficulties in implementing ER). Participants who used more LD in the objective group had lower negative affectivity, better general well-being, and better ER, and those in the far group had better ER. The results reveal linguistic mechanisms underlying ER and its relationship to health indicators, suggesting future examination of LD interventions.


Unconscious avoidance of eye contact in autism spectrum disorder.
Atypical responses to direct gaze are one of the most characteristic hallmarks of autism spectrum disorder (ASD). The cause and mechanism underlying this phenomenon, however, have remained unknown. Here we investigated whether the atypical responses to eye gaze in autism spectrum disorder is dependent on the conscious perception of others' faces. Face stimuli with direct and averted gaze were rendered invisible by interocular suppression and eye movements were recorded from participants with ASD and an age and sex matched control group. Despite complete unawareness of the stimuli, the two groups differed significantly in their eye movements to the face stimuli. In contrast to the significant positive saccadic index observed in the TD group, indicating an unconscious preference to the face with direct gaze, the ASD group had no such preference towards direct gaze and instead showed a tendency to prefer the face with averted gaze, suggesting an unconscious avoidance of eye contact. These results provide the first evidence that the atypical response to eye contact in ASD is an unconscious and involuntary response. They provide a better understanding of the mechanism of gaze avoidance in autism and might lead to new diagnostic and therapeutic interventions.


Voltage-driven annihilation and creation of magnetic vortices in Ni discs.
Using photoemission electron microscopy (PEEM) to image ferromagnetism in polycrystalline Ni disks, and ferroelectricity in their single-crystal BaTiO3 substrates, we find that voltage-driven 90° ferroelectric domain switching serves to reversibly annihilate each magnetic vortex via uniaxial compressive strain, and that the orientation of the resulting bi-domain reveals the chirality of the annihilated vortex. Micromagnetic simulations reveal that only 60% of this strain is required for annihilation. Voltage control of magnetic vortices is novel, and should be energetically favourable with respect to the use of a magnetic field or an electrical current. In future, stray field from bi-domains could be exploited to read vortex chirality. Given that core polarity can already be read via stray field, our work represents a step towards four-state low-power memory applications.