Effect of Angiotensin-converting enzyme inhibition on one-year mortality and frequency of repeat acute myocardial infarction in patients with acute myocardial infarction.
Controversy exists regarding whether all patients with acute myocardial infarction (AMI) benefit from angiotensin-converting enzyme inhibitors (ACEIs). We examined the association between ACEI treatment and mortality in a large, unselected population of patients with AMI. The present study included 105,224 patients with AMI who were not treated with ACEIs on admission. A logistic regression analysis, including 33 variables, calculated a propensity score for each patient to estimate the probability of receiving ACEIs at discharge, given the background. The association between ACEI treatment at discharge and the 1-year outcome was evaluated in prespecified subgroups using the Cox regression analyses, adjusting for the propensity score and medications at discharge. A total of 38,395 patients (36.5%) received ACEIs at discharge. After adjustment, ACEI treatment was associated with a 24% reduction in mortality (relative risk 0.76, 95% confidence interval 0.73 to 0.80). The benefit was largest in patients with a history or present signs of heart failure. In patients without heart failure, a significant benefit of ACEI treatment was seen only in patients with renal dysfunction (relative risk 0.69, 95% confidence interval 0.54 to 0.88). In the whole group, the risk of AMI decreased by 7% (relative risk 0.93, 95% confidence interval 0.90 to 0.96), with a larger effect seen in patients with ST-segment elevation AMI or systolic left ventricular dysfunction. In conclusion, in unselected patients with AMI, ACEI treatment was associated with a reduction in 1-year mortality, mainly in patients with heart failure or renal dysfunction, and a small reduction in the risk of reinfarction, mainly in patients with ST-segment elevation AMI or systolic left ventricular dysfunction.


An invasive whitefly feeding on a virus-infected plant increased its egg production and realized fecundity.
Plant-pathogenic begomoviruses have a complex association with their insect vectors. The interactions of begomoviruses and reproduction of their vectors are poorly understood. Bemisia tabaci is known to transmit many begomoviruses, and the spread of B. tabaci, especially the B and Q 'biotypes', has been accompanied by the epidemics of begomoviruses. One of these identified disease-causing agents was Tomato yellow leaf curl China virus (TYLCCNV). In this study, we compared the egg production and realized fecundity of two 'biotypes' or putative species of the whitefly B. tabaci, including the alien invasive B and the indigenous ZHJ1 from Zhejiang, China, feeding on either healthy or TYLCCNV-infected tobacco plants. The ovary of the whitefly was composed of 12-22 telotrophic ovarioles. According to the morphology of the oocytes and level of yolk content, oocytes in ovarioles were divided into four developmental phases (I-IV). Significantly higher proportion of immature oocytes (phase II, III) and mature oocytes (phase IV) was observed in ovary of females that fed on TYLCCNV-infected tobacco compared to that on healthy plants. Moreover, there was significant increase of eggs laid of B whitefly that fed on TYLCCNV-infected tobacco plants during the early developmental stages. In contrast, the proportion of oocytes of different developmental phases and eggs laid had no significant differences between ZHJ1 whiteflies feeding on TYLCCNV-infected and non-infected host plants. The invasive B whitefly benefits from feeding on a begomovirus-infected plant through increased egg production and realized fecundity.


Subtypes of medulloblastoma have distinct developmental origins.
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.


Rehabilitative ultrasound imaging of the levator scapula muscle at rest and during contraction: Technical description and reliability.
Altered scapular muscle activity is associated with abnormal scapular motions and shoulder pain. Hence, quantification of these activities is a challenging issue. The purposes of this study were to establish the reliability of measuring levator scapula muscle thickness and to examine how thickness of this muscle changes with contraction. Twenty-one asymptomatic individuals (mean age 22.29 ± 2.17 years) participated in this study. Three separate ultrasound images of the levator scapula muscle were captured at the neck-shoulder junction at rest and during a loaded isometric contraction. The procedures were repeated twice, four to seven days apart to establish intra-rater test-retest reliability. Interclass correlation coefficients (ICC) and standard error of measurement (SEM) were used to determine the reliability, and a paired t-test was performed to examine the difference in muscle thickness between two conditions. The results demonstrated that intra-examiner reliability was good at rest (ICC = 0.88, SEM = 1.16 mm) and excellent during loaded isometric contraction (ICC = 0.95, SEM = 0.91 mm). Furthermore, the thickness of levator scapula muscle significantly increased from rest to the loaded isometric contraction (Effect size = 1.99, P < 0.001). This study demonstrates that the thickness of the levator scapula muscle can be measured reliably at the neck-shoulder junction. Furthermore, ultrasound measures can reliably detect changes in muscle thickness from rest to a contracted state. Therefore, if the need exists to evaluate muscle morphology before and after any treatment strategy, thickness measurement of levator scapula can be determined reliably using ultrasound.


Induction of selective biological responses to chemoattractants in a human monocyte-like cell line.
The availability of monocyte cell lines that can be induced to differentiate in a predictable fashion can provide important tools for the study of the biochemical mechanisms of specific cellular responses. The U937 human monocyte cell line was previously shown to differentiate into chemotactically responsive cells when incubated with supernatants of lectin-stimulated lymphocytes (conditioned medium). Considering the heterogeneous nature of stimulated lymphocyte supernatants, attempts were made to identify well-defined agents that could reproducibly induce U937 cell differentiation. Both dimethyl sulfoxide and dibutyryl cAMP induced expression of receptors for the N-formylated oligopeptide chemoattractants in U937 cells. Unstimulated U937 cells contained no detectable receptors. After cells were exposed to 1 mM dibutyryl cAMP, 1.3% dimethyl sulfoxide, or 5% conditioned medium for 72 h, the average number of oligopeptide chemoattractant receptors per U937 cell was 33,000, 4,000, and 3,400, respectively. Specific binding proteins for the chemoattractants were identified by covalent affinity labeling on the differentiated U937 cells as well as on normal human monocytes. Cells exposed to conditioned medium responded chemotactically, secreted lysosomal enzymes, and formed superoxide anion when incubated with the chemoattractant. Treatment of U937 cells with dibutyryl cAMP resulted in the most reproducible and rapid increase in the number of chemoattractant receptors as well as in chemotactic responsiveness. The receptors on dibutyryl cAMP-treated cells and on dimethyl sulfoxide-treated cells initiated chemotaxis and lysosomal enzyme secretion in response to chemoattractants, but not the formation of superoxide anion. These findings demonstrate that development of the chemotactic and respiratory burst functions during the differentiation of a monocyte-like cell line can occur independently.


[Effect of sodium succinate on several carbohydrate metabolism indices of ischemic myocardium].
The influence of sodium succinate on the content of lactic, pyruvic acids and glucose in the venous blood flowing from the ischemic zone of the myocardium was studied in dogs with ligated coronary artery. The intracoronary injection of the preparation in doses of 2 and 10 mg/kg diminished the content of blood lactic acid flowing from the ischemic zone; a dose of 10 mg/kg decreased the consumption of glucose by the ischemic myocardium. Sodium succinate (100 mg/kg) intravenously reduced the content of the lactic acid significantly and inhibited the glucose consumption by the ischemic myocardium, with its increase in the arterial blood. A fall of lactacidemia can be connected with the activation of Krebs cycle and an increase of oxygen utilization by the ischemic myocardium.


Transcriptional activation of c-fos protooncogene by 17beta-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition.
17Beta-estradiol (E2) induced c-fos protooncogene mRNA levels in MCF-7 human breast cancer cells, and maximal induction was observed within 1 h after treatment. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibited the E2-induced response within 2 h. The molecular mechanism of this response was further investigated using pFC2-CAT, a construct containing a -1400 to +41 sequence from the human c-fos protooncogene linked to a bacterial chloramphenicol acetyltransferase (CAT) reporter gene. In MCF-7 cells transiently transfected with pFC2-CAT, 10 nM E2 induced an 8.5-fold increase of CAT activity, and cotreatment with 10 nM TCDD decreased this response by more than 45%. Alpha-Naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist, blocked the inhibitory effects of TCDD; moreover, the inhibitory response was not observed in variant Ah-nonresponsive MCF-7 cells, suggesting that the AhR complex was required for estrogen receptor cross-talk. The E2-responsive sequence (-1220 to -1155) in the c-fos gene promoter contains two putative core pentanucleotide dioxin-responsive elements (DREs) at -1206 to -1202 and -1163 to -1159. In transient transfection assays using wild-type and core DRE mutant constructs, the downstream core DRE (at -1163 to -1159) was identified as a functional inhibitory DRE. The results of photo-induced cross-linking, gel mobility shift, and in vitro DNA footprinting assays showed that the AhR complex interacted with the core DRE that also overlapped the E2-responsive GC-rich site (-1168 to -1161), suggesting that the mechanism for AhR-mediated inhibitory effects may be due to quenching or masking at the Sp1-binding site.


Molecular analysis of bacterial contamination on stethoscopes in an intensive care unit.
Culture-based studies, which focus on individual organisms, have implicated stethoscopes as potential vectors of nosocomial bacterial transmission. However, the full bacterial communities that contaminate in-use stethoscopes have not been investigated. We used bacterial 16S rRNA gene deep-sequencing, analysis, and quantification to profile entire bacterial populations on stethoscopes in use in an intensive care unit (ICU), including practitioner stethoscopes, individual-use patient-room stethoscopes, and clean unused individual-use stethoscopes. Two additional sets of practitioner stethoscopes were sampled before and after cleaning using standardized or practitioner-preferred methods. Bacterial contamination levels were highest on practitioner stethoscopes, followed by patient-room stethoscopes, whereas clean stethoscopes were indistinguishable from background controls. Bacterial communities on stethoscopes were complex, and community analysis by weighted UniFrac showed that physician and patient-room stethoscopes were indistinguishable and significantly different from clean stethoscopes and background controls. Genera relevant to healthcare-associated infections (HAIs) were common on practitioner stethoscopes, among which Staphylococcus was ubiquitous and had the highest relative abundance (6.8%-14% of contaminating bacterial sequences). Other HAI-related genera were also widespread although lower in abundance. Cleaning of practitioner stethoscopes resulted in a significant reduction in bacterial contamination levels, but these levels reached those of clean stethoscopes in only a few cases with either standardized or practitioner-preferred methods, and bacterial community composition did not significantly change. Stethoscopes used in an ICU carry bacterial DNA reflecting complex microbial communities that include nosocomially important taxa. Commonly used cleaning practices reduce contamination but are only partially successful at modifying or eliminating these communities.


The interferon gamma receptor 1 (IFNGR1) -56C/T gene polymorphism is associated with increased risk of early gastric carcinoma.
It has been demonstrated that polymorphisms within inflammation-related genes are associated with the risk of gastric carcinoma (GC) in people infected with Helicobacter pylori. Recently, polymorphisms in the gene encoding the interferon gamma receptor 1 (IFNGR1) were found to be associated with increased susceptibility to H pylori infection. We aimed to determine the association between polymorphisms in the IFNGR1 gene and development of chronic gastritis and GC. In a case-control study including 733 controls, 213 patients with chronic gastritis and 393 patients with GC, the IFNGR1 -611*G/*A, -56*C/*T, +1004*A/*C and +1400*T/*C polymorphisms were genotyped. A second independent case-control study including 100 controls and 65 patients with GC was used for confirmation of the original results. The effect of the -56*C/*T promoter polymorphism in the level of expression of the IFNGR1 gene was evaluated by an IFNGR1 -56*C/*T allele specific luciferase reporter assay. In patients with early onset GC (defined as being less than 40 years of age at the time of diagnosis) we found a significant over-representation of the IFNGR1 -56*T/*T homozygous genotype with an odds ratio (OR) of 4.1 (95% confidence interval (CI) 1.6 to 10.6). This result was confirmed in a second independent case-control study. In the luciferase reporter assay we observed a 10-fold increase (p<0.001) in luciferase expression associated with the IFNGR1-56*T allele. Our results indicate that the IFNGR1 -56C/T polymorphism is a relevant host susceptibility factor for GC development. Our data also indicate that this genetic polymorphism is functionally relevant and may be related to the early development of GC.


Influence of acid-pepsin secretion on gastric emptying of solids in humans: studies with cimetidine.
The commonly accepted model for gastric emptying suggests that the 'antral mill' is responsible for the triturition and subsequent emptying of solid food from the stomach. Little is known about the contribution to solid emptying made by other digestive mechanisms such as acid-pepsin secretion. We have investigated the effect of inhibiting gastic secretion on the rate at which a solid test meal emptied from the stomach. Using a radiolabelled beefburger, we performed paired gammacamera studies on consecutive days in 10 fasted, healthy volunteers to compare gastric emptying of the test meal with and without oral cimetidine (400 mg 1 hour before the test, 800 mg at the start of the meal). Inhibition of acid-pepsin secretion by cimetidine was associated with an appreciable delay in the rate of emptying of the burger from the stomach (T50 cimetidine 187 (16) min (mean (SEM); T50 no cimetidine 146 (15) min; p less than 0.01, paired t test). This delay was related to a change in the slope of the emptying profile and was not associated with a prolonged lag phase. These results may be explained by the relative achlorhydria and reduced pepsin activity induced by cimetidine impairing the breakdown of solid food into particles small enough to leave the stomach.


Clinician attitudes toward CDC interim pre-exposure prophylaxis (PrEP) guidance and operationalizing PrEP for adolescents.
Prior to issuing formal HIV pre-exposure prophylaxis (PrEP) clinical practice guidelines in 2014, the US Centers for Disease Control and Prevention (CDC) had released interim guidance for oral PrEP use among adults. Because oral PrEP may be used off-label for youth and may soon be indicated for minor adolescents, we examined the potential adoption of the interim guidance among clinicians who care for HIV-infected and at-risk youth. Individual, semi-structured interviews were conducted with 15 US clinicians who were recruited through an adolescent HIV research network. The theory-driven interview guide, consisting primarily of open-ended questions, assessed demographics, familiarity with the guidance, attitudes toward the guidance, and attitudes toward the use of the guidance for adult and adolescent patients. Transcripts were analyzed using framework analysis. Most clinicians (11/15) reported that the guidance was compatible with their practice, although several reported that some aspects, particularly frequency of follow-up visits, needed to be tailored to meet their patients' needs. We found variability in clinician reported characteristics of appropriate PrEP candidates (e.g., youth with substance use and mental health issues were noted to be both suitable and unsuitable PrEP candidates) and PrEP use in serodiscordant couples (e.g., whether PrEP would be recommended to a patient whose HIV-infected partner is virally suppressed). Clinician reported steps for initiation, monitoring, and discontinuing PrEP were largely consistent with the guidance. The observed variability in clinician practice with regard to oral PrEP may be reduced through interventions to educate clinicians about the content and rationale for guideline recommendations.


Diet-induced atherosclerosis in the domestic cat.
The domestic cat has not been used in studies of atherosclerosis, with the exception of a single study published in 1970. We have further evaluated the susceptibility of the domestic cat to diet-induced atherosclerosis, the ultimate intent being to discern the atherogenic risk due to lipoprotein lipase deficiency in an affected feline kindred with a phenotype very similar to that of the human form of this condition. We subjected a group of normal domestic cats to a moderately high-fat, cholesterol-enriched diet (30% fat and 3% cholesterol) for a period of 2 to 8 months. Plasma lipid levels were monitored monthly. At the time of killing, all organs and the entire vascular tree were removed, sectioned, processed, and stained with hematoxylin and eosin. The entire vascular tree was also stained with Movat's pentachrome and oil red O (ORO) and assessed semiquantitatively (0 to 5+/5+) and quantitatively (mean intimal area and ORO positivity, mm2). Both blood lipid measurements (total cholesterol, high-density lipoprotein-cholesterol, triglycerides, and low-density lipoprotein-cholesterol) and vessel wall lesion assessment (intimal area, mm2) were statistically elevated (p < 0.05) in the cholesterol-fed cats as compared to those on a normal diet. The highest correlations obtained between blood lipid components and vessel wall measures were the percent increase in triglyceride from base line versus the ORO measurement or foam cell grade (r = 0.86), and percent increase in triglycerides versus the intimal area in the lower abdominal aorta (r = 0.91). Similar relationships were found when the intimal area in the brachiocephalic/subclavian vessels was correlated with the absolute triglyceride values (r = 0.85) or with the percent increase in triglycerides (r = 0.83). Thus, we produced atherosclerotic lesions in the cat within 2 to 4 months on a cholesterol-enriched diet; blood lipid levels were highly correlated with lesional measurements in the vessel wall. This study will provide the basis for evaluation of the susceptibility of New Zealand lipoprotein lipase-deficient cats to diet-induced atherosclerosis.


Where do features come from?
It is possible to learn multiple layers of non-linear features by backpropagating error derivatives through a feedforward neural network. This is a very effective learning procedure when there is a huge amount of labeled training data, but for many learning tasks very few labeled examples are available. In an effort to overcome the need for labeled data, several different generative models were developed that learned interesting features by modeling the higher order statistical structure of a set of input vectors. One of these generative models, the restricted Boltzmann machine (RBM), has no connections between its hidden units and this makes perceptual inference and learning much simpler. More significantly, after a layer of hidden features has been learned, the activities of these features can be used as training data for another RBM. By applying this idea recursively, it is possible to learn a deep hierarchy of progressively more complicated features without requiring any labeled data. This deep hierarchy can then be treated as a feedforward neural network which can be discriminatively fine-tuned using backpropagation. Using a stack of RBMs to initialize the weights of a feedforward neural network allows backpropagation to work effectively in much deeper networks and it leads to much better generalization. A stack of RBMs can also be used to initialize a deep Boltzmann machine that has many hidden layers. Combining this initialization method with a new method for fine-tuning the weights finally leads to the first efficient way of training Boltzmann machines with many hidden layers and millions of weights.


Ever-increasing diversity of drug-induced pancreatitis.
With over 100000 hospital admissions per annum, acute pancreatitis remains the leading gastrointestinal cause of hospitalization in the United States and has far-reaching impact well beyond. It has become increasingly recognized that drug-induced pancreatitis (DIP), despite accounting for less than 3% of all cases, represents an important and growing though often inconspicuous cause of acute pancreatitis. Nevertheless, knowledge of DIP is often curtailed by the limited availability of evidence needed to implicate given agents, especially for non-prescription medications. Indeed, the majority of available data is derived from case reports, case series, or case control studies. Furthermore, the mechanism of injury and causality for many of these drugs remain elusive as a definitive correlation is generally not established (< 10% of cases). Several classification systems have been proposed, but no single system has been widely adopted, and periodic updates are required in light of ongoing pharmacologic expansion. Moreover, infrequently prescribed medications or those available over-the-counter (including herbal and other alternative remedies) are often overlooked as a potential culprit of acute pancreatitis. Herein, we review the ever-increasing diversity of DIP and the potential mechanisms of injury with the goal of raising awareness regarding the nature and magnitude of this entity. We believe this manuscript will aid in increasing both primary and secondary prevention of DIP, thus ultimately facilitating more expedient diagnosis and a decrease in DIP-related morbidity.


Genetic risk score has added value over initial clinical grading stage in predicting disease progression in age-related macular degeneration.
Several prediction models for progression of age-related macular degeneration (AMD) have been developed, but the added value of using genetic information in those models in addition to clinical characteristics is ambiguous. In this prospective cohort study, we explored the added value of genetics using a genetic risk score (GRS) based on 52 AMD-associated variants, in addition to the clinical severity grading at baseline as quantified by validated drusen detection software, to predict disease progression in 177 AMD patients after 6.5 years follow-up. The GRS was strongly associated with the drusen coverage at baseline (P < 0.001) and both the GRS and drusen coverage were associated with disease progression. When the GRS was added as predictor in addition to the drusen coverage, R2 increased from 0.46 to 0.56. This improvement by the GRS was predominantly seen in patients with a drusen coverage <15%. In patients with a larger drusen coverage, the GRS had less added value to predict progression. Thus, genetic information has added value over clinical characteristics in predicting disease progression in AMD, but only in patients with a less severe disease stage. Patients with a high GRS should be made aware of their risk and could be selected for clinical trials for arresting progression.


Metabolic intermediates selectively stimulate transcription factor interaction and modulate phosphate and purine pathways.
Cells use strategic metabolites to sense the metabolome and accordingly modulate gene expression. Here, we show that the purine and phosphate pathways are positively regulated by the metabolic intermediate AICAR (5'-phosphoribosyl-5-amino-4-imidazole carboxamide). The transcription factor Pho2p is required for up-regulation of all AICAR-responsive genes. Accordingly, the binding of Pho2p to purine and phosphate pathway gene promoters is enhanced upon AICAR accumulation. In vitro, AICAR binds both Pho2p and Pho4p transcription factors and stimulates the interaction between Pho2p and either Bas1p or Pho4p in vivo. In contrast, SAICAR (succinyl-AICAR) only affects Pho2p-Bas1p interaction and specifically up-regulates purine regulon genes. Together, our data show that Bas1p and Pho4p compete for Pho2p binding, hence leading to the concerted regulation of cellular nucleotide synthesis and phosphate consumption.


The examination of peer review and publication in neurology.
Despite remarkable growth in the clinical neurology literature, there is little research on peer review and biomedical publication in neurology. Biomedical publication research encompasses every step of the research process, from the methodology to the publication of research findings. Some general medical journals have served as leaders in improving scientific publication. Many medical fields have taken it upon themselves to characterize journals and peer reviewers within their own fields. Not all of these data can be applied to the clinical neurology literature; research methodologies, article types, and the journals themselves are unique to every medical field. This article reviews current publication research in the neurology literature and concludes that, to sustain and improve upon the integrity of clinical neurology research, further study is needed of the journals and the peer review process in neurology. Otherwise, the value of clinical research findings and patient care guidelines will be diminished.


Effect of mash maceration on the polyphenolic content and visual quality attributes of cloudy apple juice.
The effects of enzymatic mash treatments on yield, turbidity, color, and polyphenolic content of cloudy apple juice were studied. Using HPLC-ESI-MS, cryptochlorogenic acid was identified in cv. Brettacher cloudy apple juice for the first time. Commercial pectolytic enzyme preparations with different levels of secondary protease activity were tested under both oxidative and nonoxidative conditions. Without the addition of ascorbic acid, oxidation substantially decreased chlorogenic acid, epicatechin, and procyanidin B2 contents due to enzymatic browning. The content of chlorogenic acid as the major polyphenolic compound was also influenced by the composition of pectolytic enzyme preparations because the presence of secondary protease activity resulted in a rise of chlorogenic acid. The latter effect was probably due to the inhibited protein-polyphenol interactions, which prevented binding of polyphenolic compounds to the matrix, thus increasing their antioxidative potential. The results obtained clearly demonstrate the advantage of the nonoxidative mash maceration for the production of cloud-stable apple juice with a high polyphenolic content, particularly in a premature processing campaign.


Multiresolution histograms and their use for recognition.
The histogram of image intensities is used extensively for recognition and for retrieval of images and video from visual databases. A single image histogram, however, suffers from the inability to encode spatial image variation. An obvious way to extend this feature is to compute the histograms of multiple resolutions of an image to form a multiresolution histogram. The multiresolution histogram shares many desirable properties with the plain histogram including that they are both fast to compute, space efficient, invariant to rigid motions, and robust to noise. In addition, the multiresolution histogram directly encodes spatial information. We describe a simple yet novel matching algorithm based on the multiresolution histogram that uses the differences between histograms of consecutive image resolutions. We evaluate it against five widely used image features. We show that with our simple feature we achieve or exceed the performance obtained with more complicated features. Further, we show our algorithm to be the most efficient and robust.


Congenital primary hypoparathyroidism presented with extensive cutaneous and subcutaneous calcifications.
Congenital primary hypoparathyroidism is very rare in infancy. It may be isolated or associated with other developmental defects, arising from the third and fourth pharyngeal pouches such as DiGeorge syndrome. Initial symptom of isolated primary hypoparathyroidism in an infant is usually generalized convulsion due to hypocalcemia. However, the clinical spectrum of DiGeorge's anomaly is highly variable. We report a two-hour-old neonate with congenital hypoparathyroidism presenting with extensive cutaneous and subcutaneous calcifications. To our knowledge, extensive calcification of the skin and subcutaneous tissue as a presenting feature of congenital primary hypoparathyroidism in an infant is reported for the first time.


Phase errors due to speckles in laser fringe projection.
When measuring a three-dimensional shape with triangulation and projected interference fringes it is of interest to reduce speckle contrast without destroying the coherence of the projected light. A moving aperture is used to suppress the speckles and thereby reduce the phase error in the fringe image. It is shown that the phase error depends linearly on the ratio between the speckle contrast and the modulation of the fringes. In this investigation the spatial carrier method was used to extract the phase, where the phase error also depends on filtering the Fourier spectrum. An analytical expression for the phase error is derived. Both the speckle reduction and the theoretical expressions for the phase error are verified by simulations and experiments. It was concluded that a movement of the aperture by three aperture diameters during exposure of the image reduces the speckle contrast and hence the phase error by 60%. In the experiments, a phase error of 0.2 rad was obtained.


Lung flute improves symptoms and health status in COPD with chronic bronchitis: A 26 week randomized controlled trial.
Chronic obstructive pulmonary disease (COPD) is characterized by mucus hypersecretion that contributes to disease related morbidity and is associated with increased mortality. The Lung Flute® is a new respiratory device that produces a low frequency acoustic wave with moderately vigorous exhalation to increase mucus clearance. We hypothesized that the Lung Flute, used on a twice daily basis will provide clinical benefit to patients with COPD with chronic bronchitis. We performed a 26 week randomized, non-intervention controlled, single center, open label trial in 69 patients with COPD and Chronic Bronchitis. The primary endpoint was change in respiratory symptoms measured with the Chronic COPD Questionnaire (CCQ). Secondary endpoints included health status, assessed by the St. George Respiratory questionnaire (SGRQ), BODE (Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity) index score and exacerbation frequency. While the control patients did not demonstrate any significant changes in the primary endpoint (CCQ change at 26 weeks of +0.01, p = 0.8), a trend (p = 0.08) to decrease (improvement) in the CCQ (-0.23 at 26 weeks) was seen with the Lung Flute. Furthermore, a significant improvement in the symptom domain of the CCQ was seen only with the lung flute (-0.42, p = 0.004). Health status (SGRQ) improvement, was also only seen with the Lung Flute (-3.23, p = 0.03). The BODE score increased in the control group (3.31 at baseline, 4.14 at 26 weeks), however it remained stable in the Lung Flute arm (3.16 at baseline and 26 weeks), with the changes from baseline being significantly different between the 2 arms (p = 0.01). There was a trend for less exacerbations in the Lung Flute group (p = 0.07). Adverse effects were minor, with only 1 patient discontinuing treatment because of lack of efficacy. Serious adverse effects seen were all determined to be unrelated to the device use. The Lung Flute is a safe and effective treatment in COPD with chronic bronchitis, providing a wide array of benefits. NCT01186822.


Identification and Experimental Validation of Immune-Associate lncRNAs for Predicting Prognosis in Cervical Cancer.
Cervical cancer (CC) is a major risk for health of modern women. Immune-related long non-coding RNAs (lncRNAs) can also serve as prognostic markers of overall survival (OS) in patients with CC. This study aimed to identify an immune-related lncRNA signature for the prospective assessment of prognosis in CC patients. We first calculated immune scores of CC patients in the Cancer Genome Atlas (TCGA) database. Univariate Cox, Lasso Cox and multivariate Cox regression analyses were perfumed to establish an immune-relative lncRNA signature. In addition, we processed pathway enrichment analysis and immune infiltration analysis between patients with higher or lower risk. Finally, T-cell Chemotaxis assays were processed to verify the function of 2 key lncRNAs. Our results suggested that patients with higher immune scores had longer survival time and some lncRNAs expressed differentially between two groups. Eight lncRNAs (LINC02802, LINC01877, RBAKDN, LINC02480, WWC2-AS2, LINC01281, ZBTB20-AS1, IFNG-AS1) were identified as prognostic signatures for CC. The immune-related lncRNA signature was correlated with disease progression and worse prognosis. Immune infiltration analysis indicated that the expression of 8-lncRNA signatures were corrected with infiltration level of immune cell subtypes. In addition, T-cell Chemotaxis assay validated that 2 key lncRNAs (ZBTB20-AS1 and LINC01281) could significantly promote the migration ability of T cells to CC cells. Our finding demonstrated the value of lncRNAs in evaluating the immune infiltrate of the tumor. The 8-lncRNA signature could predict the prognosis of CC and contribute to decisions regarding the immunotherapeutic strategy.


A new time-domain narrowband velocity estimation technique for Doppler ultrasound flow imaging. I. Theory.
A significant improvement in blood velocity estimation accuracy can be achieved by simultaneously processing both temporal and spatial information obtained from a sample volume. Use of the spatial information becomes especially important when the temporal resolution is limited. By using a two-dimensional sequence of spatially sampled Doppler signal "snapshots" an improved estimate of the Doppler correlation matrix can be formed. Processing Doppler data in this fashion addresses the range-velocity spread nature of the distributed red blood cell target, leading to a significant reduction in spectral speckle. Principal component spectral analysis of the "snapshot" correlation matrix is shown to lead to a new and robust Doppler mode frequency estimator. By processing only the dominant subspace of the Doppler correlation matrix, the Cramer-Rao bounds on the estimation error of target velocity is significantly reduced in comparison to traditional narrowband blood velocity estimation methods and achieves almost the same local accuracy as a wideband estimator. A time-domain solution is given for the velocity estimate using the root-MUSIC algorithm, which makes the new estimator attractive for real-time implementation.


A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1.
The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., HMGB1) pro-inflammatory cytokines. Our recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We previously reported that green tea brewed from the leaves of the plant Camellia sinensis is effective in inhibiting endotoxin-induced HMGB1 release. Here we demonstrate that its major component, (-)-epigallocatechin-3-gallate (EGCG), but not catechin or ethyl gallate, dose-dependently abrogated HMGB1 release in macrophage/monocyte cultures, even when given 2-6 hours post LPS stimulation. Intraperitoneal administration of EGCG protected mice against lethal endotoxemia, and rescued mice from lethal sepsis even when the first dose was given 24 hours after cecal ligation and puncture. The therapeutic effects were partly attributable to: 1) attenuation of systemic accumulation of proinflammatory mediator (e.g., HMGB1) and surrogate marker (e.g., IL-6 and KC) of lethal sepsis; and 2) suppression of HMGB1-mediated inflammatory responses by preventing clustering of exogenous HMGB1 on macrophage cell surface. Taken together, these data suggest a novel mechanism by which the major green tea component, EGCG, protects against lethal endotoxemia and sepsis.


Sounding the alarm: Defining thresholds to trigger a public health response to monkeypox.
Endemic to the Democratic Republic of the Congo (DRC), monkeypox is a zoonotic disease that causes smallpox-like illness in humans. Observed fluctuations in reported cases over time raises questions about when it is appropriate to mount a public health response, and what specific actions should be taken. We evaluated three different thresholds to differentiate between baseline and heightened disease incidence, and propose a novel, tiered algorithm for public health action. Monkeypox surveillance data from Tshuapa Province, 2011-2013, were used to calculate three different statistical thresholds: Cullen, c-sum, and a World Health Organization (WHO) method based on monthly incidence. When the observed cases exceeded the threshold for a given month, that month was considered to be 'aberrant'. For each approach, the number of aberrant months detected was summed by year-each method produced vastly different results. The Cullen approach generated a number of aberrant signals over the period of consideration (9/36 months). The c-sum method was the most sensitive (30/36 months), followed by the WHO method (12/24 months). We conclude that triggering public health action based on signals detected by a single method may be inefficient and overly simplistic for monkeypox. We propose instead a response algorithm that integrates an objective threshold (WHO method) with contextual information about epidemiological and spatiotemporal links between suspected cases to determine whether a response should be operating under i) routine surveillance ii) alert status, or iii) outbreak status. This framework could be modified and adopted by national and zone level health workers in monkeypox-endemic countries. Lastly, we discuss considerations for selecting thresholds for monkeypox outbreaks across gradients of endemicity and public health resources.


Enzyme Kinetic Assay to Measure the Activity of Tumor M2 Pyruvate Kinase in Breast Cancer Patients.
M2 type Pyruvate kinase (PKM2) is the key rate-limiting enzyme of glycolysis, and it mainly exists as a dimer in tumor cells. This study aims to establish an enzyme kinetic assay for serum tumor M2 pyruvate kinase (TuM2-PK), and to evaluate its diagnostic value in breast cancer. The catalytic kinetics of Pyruvate Kinase (PK) was examined. Its allosteric regulation property and Michaelis constant were then measured. Next, the levels of TuM2-PK in serum were detected and compared with results from an enzyme-linked immunosorbent assay (ELISA). Finally, the levels of TuM2-PK among breast cancer patients, post-mastectomy patients, patients with benign breast diseases, and healthy controls were compared. A PK kinetic assay was established in this study. The assay reaction time is 108 seconds, and the optimum pH level is 8.0. In the presence of the allosteric activator fructose 1, 6-bisphosphate (FBP), the Km of PK for phosphoenolpyruvate (PEP) is 0.15 mmol/L and the Vmax is 330 μmol/min. The levels of TuM2-PK in serum obtained by enzyme kinetics are comparable to the ELISA results. Both assays showed that TuM2-PK in breast cancer patients was increased from stage I to IV. Importantly, TuM2-PK levels were significantly different between early and late-stage breast cancer patients (stage I and stage II vs. stage III and IV), as well as between late-stage and non-malignant patients (p<0.05). No statistical difference was found between benign breast disease patients and healthy controls. An enzyme kinetic assay of serum TuM2-PK was successfully established and may be useful for breast cancer diagnosis.


Evaluation of a new automated homogeneous PCR assay, GenomEra C. difficile, for rapid detection of Toxigenic Clostridium difficile in fecal specimens.
We evaluated a new automated homogeneous PCR assay to detect toxigenic Clostridium difficile, the GenomEra C. difficile assay (Abacus Diagnostica, Finland), with 310 diarrheal stool specimens and with a collection of 33 known clostridial and nonclostridial isolates. Results were compared with toxigenic culture results, with discrepancies being resolved by the GeneXpert C. difficile PCR assay (Cepheid). Among the 80 toxigenic culture-positive or GeneXpert C. difficile assay-positive fecal specimens, 79 were also positive with the GenomEra C. difficile assay. Additionally, one specimen was positive with the GenomEra assay but negative with the confirmatory methods. Thus, the sensitivity and specificity were 98.8% and 99.6%, respectively. With the culture collection, no false-positive or -negative results were observed. The analytical sensitivity of the GenomEra C. difficile assay was approximately 5 CFU per PCR test. The short hands-on (<5 min for 1 to 4 samples) and total turnaround (<1 h) times, together with the high positive and negative predictive values (98.8% and 99.6%, respectively), make the GenomEra C. difficile assay an excellent option for toxigenic C. difficile detection in fecal specimens.


Reduction of Cav1.3 channels in dorsal hippocampus impairs the development of dentate gyrus newborn neurons and hippocampal-dependent memory tasks.
Cav1.3 has been suggested to mediate hippocampal neurogenesis of adult mice and contribute to hippocampal-dependent learning and memory processes. However, the mechanism of Cav1.3 contribution in these processes is unclear. Here, roles of Cav1.3 of mouse dorsal hippocampus during newborn cell development were examined. We find that knock-out (KO) of Cav1.3 resulted in the reduction of survival of newborn neurons at 28 days old after mitosis. The retroviral eGFP expression showed that both dendritic complexity and the number and length of mossy fiber bouton (MFB) filopodia of newborn neurons at ≥ 14 days old were significantly reduced in KO mice. Both contextual fear conditioning (CFC) and object-location recognition tasks were impaired in recent (1 day) memory test while passive avoidance task was impaired only in remote (≥ 20 days) memory in KO mice. Results using adeno-associated virus (AAV)-mediated Cav1.3 knock-down (KD) or retrovirus-mediated KD in dorsal hippocampal DG area showed that the recent memory of CFC was impaired in both KD mice but the remote memory was impaired only in AAV KD mice, suggesting that Cav1.3 of mature neurons play important roles in both recent and remote CFC memory while Cav1.3 in newborn neurons is selectively involved in the recent CFC memory process. Meanwhile, AAV KD of Cav1.3 in ventral hippocampal area has no effect on the recent CFC memory. In conclusion, the results suggest that Cav1.3 in newborn neurons of dorsal hippocampus is involved in the survival of newborn neurons while mediating developments of dendritic and axonal processes of newborn cells and plays a role in the memory process differentially depending on the stage of maturation and the type of learning task.


Characterization of exposure to low levels of viable Penicillium chrysogenum conidia and allergic sensitization induced by a protease allergen extract from viable P. Chrysogenum conidia in mice.
Previous evidence by our laboratory has shown that mice inoculated with viable Penicillium Chrysogenum conidia or spores at levels comparable to those found in contaminated buildings induced spore antigen-specific allergic responses. We proposed that mice exposed to low levels of viable P. Chrysogenum conidia would not develop allergic symptoms. We also hypothesized that the symptoms induced by high numbers of conidia were the result of sensitization to allergens released by the conidia. C57BL/6 and BALB/c mice were exposed to 1 x 10(2) viable P. Chrysogenum conidia by intranasal instillation weekly for a period of 11 weeks. C57BL/6 mice were also sensitized to a viable P. Chrysogenum conidia protease extract by intraperitoneal injections for a period of 6 weeks followed by intranasal challenge with protease extract, viable, or nonviable P. Chrysogenum conidia for 2 weeks. C57BL/6 mice inoculated with low numbers of conidia developed no significant lung inflammation or increased serum immunoglobulins. Mice sensitized to the protease extract and challenged with both protease extract and viable conidia produced significant increases in serum IgE and IgG1. Mice sensitized to and challenged with the protease extract developed significant eosinophilia and mucus hyperproduction as determined by bronchoalveolar lavage and histopathological examination of lung tissue. Mice did not develop allergic symptoms in response to challenge with low levels of P. Chrysogenum conidia. Protease allergens from viable conidia induced specific allergic responses in mice, indicating the importance of P. Chrysogenum conidia in allergic sensitization to the organism.


α(2)-Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells.
We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by α(2)-adrenoceptor (α(2)-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect. α(2)-AR expression was assessed by immunocytochemistry and immunohistochemistry, cell proliferation by [(3)H]-Thymidine incorporation and tumor growth by measuring with caliper. All tested mouse and human fibroblasts expressed at least two α(2)-AR subtypes and α(2)-adrenergic agonists enhanced fibroblast proliferation. In vivo, the α(2)-adrenergic agonist clonidine significantly enhanced tumor growth. The α(2)-adrenergic antagonist rauwolscine reversed this effect, but when administered alone, significantly inhibited tumor growth. Clonidine significantly stimulated cell proliferation in the epithelial-enriched fraction, the cancer associated fibroblast-enriched fraction and the co-culture of both fractions in primary cultures from both tumors (IBH-4 and IBH-6). Rauwolscine reversed clonidine stimulation in every fraction. However, when incubated alone, the inhibitory effect was observed in fractions from IBH-4 tumors but not from IBH-6 tumors. These experiments show that fibroblasts from tumor stroma are also influenced by α(2)-adrenergic compounds through the α(2)-ARs expressed in these cells. Moreover, the α(2)-adrenergic antagonist rauwolscine could eventually block in both epithelial and stromal cells, the mitogenic effect of catecholamines released during stress, providing a potential additional treatment for breast cancer patients. Chemists synthesizing adrenergic compounds should consider their action in breast cancer patients.


Melbourne Mobile Stroke Unit and Reperfusion Therapy: Greater Clinical Impact of Thrombectomy Than Thrombolysis.
Background and Purpose- Mobile stroke units (MSUs) are increasingly used worldwide to provide prehospital triage and treatment. The benefits of MSUs in giving earlier thrombolysis have been well established, but the impacts of MSUs on endovascular thrombectomy (EVT) and effect on disability avoidance are largely unknown. We aimed to determine the clinical impact and disability reduction for reperfusion therapies in the first operational year of the Melbourne MSU. Methods- Treatment time metrics for MSU patients receiving reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment modeled using quantile regression analysis. Time savings were subsequently converted to disability-adjusted life years avoided using published estimates. Results- In the first 365-day operation of the Melbourne MSU, prehospital thrombolysis was administered to 100 patients (mean age, 73.8 years; 62% men). The median time savings per MSU patient, compared with the control cohort, was 26 minutes (P<0.001) for dispatch to hospital arrival and 15 minutes (P<0.001) for hospital arrival to thrombolysis. The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes (95% CI, 36.0-49.0). In the same period, 41 MSU patients received EVT (mean age, 76 years; 61% men) with median dispatch-to-treatment time saving of 51 minutes ([95% CI, 30.1-71.9], P<0.001). This included a median time saving of 17 minutes ([95% CI, 7.6-26.4], P=0.001) for EVT hospital arrival to arterial puncture for MSU patients. Estimated median disability-adjusted life years saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT. Conclusions- The Melbourne MSU substantially reduced time to reperfusion therapies, with the greatest estimated disability avoidance driven by the more powerful impact of earlier EVT. These findings highlight the benefits of prehospital notification and direct triage to EVT centers with facilitated workflow on arrival by the MSU.


A randomized control trial investigating the effect of presurgical orthopedics on feeding in infants with cleft lip and/or palate.
To investigate the controversial assertion that presurgical orthopedics (PSO) facilitate feeding in infants with cleft lip and palate. Randomized control trial of 34 infants with nonsyndromic complete unilateral cleft lip and palate and 16 with cleft of the soft and at least two thirds of the hard palate. Allocation to receive presurgical orthopedics or not used minimization for parity and gender. Other aspects of care were standardized. The North Thames Regional Cleft Centre. Measurements were made at 3 months of age (presurgery) and at 12 months of age (postsurgery). Primary outcomes were anthropometry and oral motor skills. Objective measures of sucking also were collected at 3 months using the Great Ormond Street Measure of Infant Feeding. Twenty-one infants also had videofluoroscopic assessment. At 1 year, all infants had normal oral motor skills and no clear pattern of anthropometric differences emerged. For both cleft groups, infants randomized to presurgical orthopedics were, on average, shorter. The presurgical orthopedics infants were, on average, lighter in the unilateral cleft and lip palate group, but heavier in the isolated cleft palate group. Infants with complete unilateral cleft and lip palate randomized to presurgical orthopedics had lower average body mass index (mean difference PSO-No PSO: -0.45 (95% confidence interval [-1.78, 0.88]), this trend was reversed among infants with isolated cleft palates (mean difference PSO-No PSO: 1.98 [-0.95, 4.91]). None of the differences were statistically significant at either age. Presurgical orthopedics did not improve feeding efficiency or general body growth within the first year in either group of infants.


Requirement for endocytosis of poly(rI).poly(rC) to generate toxicity on interferon-treated LM cells.
Poly(rI).poly(rC) induces a lytic reaction in interferon-treated mouse LM cells. We have attempted to determine whether the intracellular penetration of poly(rI).poly(rC) is a prerequisite for cell lysis and to gain some insight into the pathway followed. We found that poly(rI).poly(rC) coupled to Sepharose beads was unable to generate lysis of interferon-treated cells whereas the cells underwent lysis after microinjection of poly(rI).poly(rC). Some inhibitors of endocytosis were found to inhibit the development of the lytic reaction. Lysosomotropic amines or a low temperature (19 degrees C) blocked endocytosis of poly(rI).poly(rC) but did not prevent its uptake. The internalization of poly(rI).poly(rC) was energy-dependent and was blocked when sodium azide and 2-deoxyglucose were added simultaneously. We conclude that poly(rI).poly(rC) is internalized and reaches an acidic compartment before triggering the lytic reaction in the cell.


Using decision trees to manage hospital readmission risk for acute myocardial infarction, heart failure, and pneumonia.
To improve healthcare quality and reduce costs, the Affordable Care Act places hospitals at financial risk for excessive readmissions associated with acute myocardial infarction (AMI), heart failure (HF), and pneumonia (PN). Although predictive analytics is increasingly looked to as a means for measuring, comparing, and managing this risk, many modeling tools require data inputs that are not readily available and/or additional resources to yield actionable information. This article demonstrates how hospitals and clinicians can use their own structured discharge data to create decision trees that produce highly transparent, clinically relevant decision rules for better managing readmission risk associated with AMI, HF, and PN. For illustrative purposes, basic decision trees are trained and tested using publically available data from the California State Inpatient Databases and an open-source statistical package. As expected, these simple models perform less well than other more sophisticated tools, with areas under the receiver operating characteristic (ROC) curve (or AUC) of 0.612, 0.583, and 0.650, respectively, but achieve a lift of at least 1.5 or greater for higher-risk patients with any of the three conditions. More importantly, they are shown to offer substantial advantages in terms of transparency and interpretability, comprehensiveness, and adaptability. By enabling hospitals and clinicians to identify important factors associated with readmissions, target subgroups of patients at both high and low risk, and design and implement interventions that are appropriate to the risk levels observed, decision trees serve as an ideal application for addressing the challenge of reducing hospital readmissions.


Long-term prognosis and incidence of acute myocardial infarction in patients on chronic hemodialysis. The Okinawa Dialysis Study Group.
Mortality from cardiovascular disease is high in chronic dialysis patients. We observed the occurrence of acute myocardial infarction (AMI) in the chronic dialysis population in Okinawa, Japan. A total of 3,741 chronic dialysis patients (2,073 men, 1,668 women) were followed up for 10 years from April 1, 1988, to March 31, 1998. Only definite cases of AMI were registered. Data were compared with AMI registry data obtained from the general population of the same district. The total duration of observation was 15,748.8 patient-years. During the study period, 61 patients (40 men, 21 women) had AMI. The incidence of AMI was 3.9/1,000 patient-years (men, 4.4/1,000 patient-years; women, 3.1/1,000 patient-years). Twenty-four percent of the AMI cases occurred at 12 months after starting dialysis therapy. Mean age at onset of AMI was 60.9 +/- 11. 4 (SD) years; 58.9 +/- 11.4 years in men and 64.7 +/- 10.7 years in women. Survival rates after AMI were 50.8% at 1 month, 45.0% at 6 months, 36.5% at 12 months, and 13.0% at 44 months. Patients with diabetes mellitus (DM) had a greater incidence of AMI and a worse prognosis than patients without DM. The long-term prognosis of AMI was poor in chronic dialysis patients.


Congenital amegakaryocytic thrombocytopenia with severe neurological findings.
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive disorder characterized by thrombocytopenia from failure of megakaryopoiesis. The genetic background of CAMT is mutations in the myeloproliferative ligand gene encoding the thrombopoietin receptor. In our patient with CAMT, we identified homozygous missense mutations [c.407C>T (p.P136L)]. The association of CAMT and central nervous system (CNS) abnormalities is uncommon. Here we present a case in which CAMT appears linked to CNS abnormalities (encephalomalacia, global atrophy) and developmental delay related with intrauterine intracranial hemorrhage.


Next-Generation Cancer Immunotherapy Targeting Glypican-3.
Glypican-3 (GPC3), a 65 kD protein consisting of 580 amino acids, is a heparan sulfate proteoglycan bound to the cell membrane by glycosylphosphatidylinositol. This protein is expressed in the liver and the kidney of healthy fetuses but is hardly expressed in adults, except in the placenta. Contrarily, GPC3 is specifically expressed in hepatocellular carcinoma (HCC), ovarian clear cell carcinoma, melanoma, squamous cell carcinoma of the lung, hepatoblastoma, nephroblastoma (Wilms tumor), yolk sac tumor, and some pediatric cancers. Although the precise function of GPC3 remains unclear, it has been strongly suggested that it is related to the malignant transformation of HCC. We identified GPC3 as a promising target for cancer immunotherapy and have been working on the development of cancer immunotherapeutic agents targeting it through clinical trials. In some trials, it was revealed that the GPC3 peptide vaccines we developed using human leukocyte antigen-A24- and A2-restricted GPC3-derived peptides could induce GPC3-specific cytotoxic T cells in most vaccinated patients and thereby improve their prognosis. To further improve the clinical efficacy of cancer immunotherapy targeting GPC3, we are also developing next-generation therapeutic strategies using T cells engineered to express antigen-specific T-cell receptor or chimeric antigen receptor. In addition, we have successfully monitored the levels of serum full-length GPC3 protein, which is somehow secreted in the blood. The utility of GPC3 as a biomarker for predicting tumor recurrence and treatment efficacy is now being considered. In this review article, we summarize the results of clinical trials carried out by our team and describe the novel agent targeting the cancer-specific shared antigen, GPC3.


Identification and characterization of bovine herpesvirus-1 glycoproteins E and I.
To identify the products of the bovine herpesvirus-1 (BHV-1) gE and gI genes, we constructed baculovirus recombinants containing the putative gE or gI genes. These recombinant viruses synthesized BHV-1 gE and gI with apparent molecular masses of 84 and 41 kDa, respectively. Polyclonal antibodies against these recombinant gE or gI proteins were produced and by using these antibodies, we showed the presence of gE and gI with apparent molecular masses of 94 and 45 kDa, respectively, in purified BHV-1 virions. We also demonstrated that like their herpes simplex virus-1 and pseudorabies virus counterparts BHV-1 gE and gI form a complex. A gI- BHV-1 mutant failed to express gI but gE was found in the virions. On the other hand, neither gE nor gI was found in the virions of a gE- BHV-1 mutant. In the gE- BHV-1 mutant, gI was produced but released into the medium without being integrated in the virions.


Bronchial anthracofibrosis and tuberculosis presenting as a middle lobe syndrome.
Bronchial anthracofibrosis, a clinical entity described less than a decade ago, is characterised by anthracotic pigmentation of the bronchial mucosa with multifocal bronchial lumen narrowing. The right middle lobe is predominantly involved and is frequently associated with tuberculosis. The condition is generally seen in non-smoking elderly ladies with a longstanding history of wood smoke exposure. A 65 year-old lady presented to us with a one-month history of dry cough. The chest radiograph revealed a middle lobe syndrome which was confirmed on computed tomography (CT) scanning. In addition, narrowing of the right middle lobe bronchus was seen. This raised the suspicion of a malignancy. Fibreoptic bronchoscopy revealed anthracotic pigmentation, and bronchial aspirate showed acid fast bacilli. Culture of the aspirate grew Mycobacterium tuberculosis. The patient responded to standard antituberculous treatment.


Severity-related changes of bronchial microbiome in chronic obstructive pulmonary disease.
Bronchial colonization by potentially pathogenic microorganisms (PPMs) is often demonstrated in chronic obstructive pulmonary disease (COPD), but culture-based techniques identify only a portion of the bacteria in mucosal surfaces. The aim of the study was to determine changes in the bronchial microbiome of COPD associated with the severity of the disease. The bronchial microbiome of COPD patients was analyzed by 16S rRNA gene amplification and pyrosequencing in sputum samples obtained during stable disease. Seventeen COPD patients were studied (forced expiratory volume in the first second expressed as a percentage of the forced vital capacity [FEV1%] median, 35.0%; interquartile range [IQR], 31.5 to 52.0), providing a mean of 4,493 (standard deviation [SD], 2,598) sequences corresponding to 47 operational taxonomic units (OTUs) (SD, 17) at a 97% identity level. Patients were dichotomized according to their lung function as moderate to severe when their FEV1% values were over the median and as advanced when FEV1% values were lower. The most prevalent phyla in sputum were Proteobacteria (44%) and Firmicutes (16%), followed by Actinobacteria (13%). A greater microbial diversity was found in patients with moderate-to-severe disease, and alpha diversity showed a statistically significant decrease in patients with advanced disease when assessed by Shannon (ρ = 0.528; P = 0.029, Spearman correlation coefficient) and Chao1 (ρ = 0.53; P = 0.028, Spearman correlation coefficient) alpha-diversity indexes. The higher severity that characterizes advanced COPD is paralleled by a decrease in the diversity of the bronchial microbiome, with a loss of part of the resident flora that is replaced by a more restricted microbiota that includes PPMs.


Inoculum standardization for antifungal susceptibility testing of filamentous fungi pathogenic for humans.
Two methods of inoculum preparation for filamentous fungi were compared: counting with a hematocytometer and spectrophotometric adjustment. One hundred eighty-two filamentous fungi pathogenic for humans were used. Colony counts were done for all inoculum preparations. The agreement between the hematocytometer counts and the colony counts (CFU per milliliter) was 97.2%. The reproducibility between the hematocytometer counts and the colony counts by means of an intraclass correlation coefficient was 0.70. Pearson's correlation index for hematocytometer counts versus colony counts was 0.56, whereas that for optical density versus colony counts was 0.008. Both methods can be used for inoculum size adjustment. However, the use of the spectrophotometric method requires that each species be standardized separately.


[Real-world study of an online platform for the prescription of physical exercise to obese patients - Effect on anthropometric, biochemical parameters and quality of life].
Introduction: one of the risk factors related to obesity is a sedentary lifestyle. Physical exercise produces metabolic benefits. Its prescription through online tools has been poorly evaluated, though. Objective: the objective of our study was to assess the effect of the prescription of physical exercise through an online platform on anthropometric parameters, cardiovascular risk factors, and quality of life in sedentary obese patients. Material and methods: in a total of 35 obese patients, anthropometric data, muscle mass by ultrasound at the quadriceps level, laboratory parameters, blood pressure, and quality of life using the SF36 tool were collected at baseline and at 12 weeks. For 12 weeks, a structured physical exercise program was prescribed through an online platform - www.vibraup.com. Results: after the physical exercise program with the online platform, there was a significant improvement in body mass index (-1.51 ± 0.1 kg/m2; p = 0.01), weight (-3.7 ± 0.6 kg; p = 0.01), waist circumference (-6.9 ± 0.3 cm; p = 0.01), fat mass (-3.9 ± 0.2 kg ; p = 0.01), muscle mass (5.5 ± 1.6 kg; p = 0.01), diastolic blood pressure (-4.5 ± 0.4 mm Hg; p = 0.01), insulin (-2.8 ± 0.1 IU/L; p = 0.04), and insulin resistance (HOMA-IR) (-0.9 ± 0.1 units; p = 0.03). The ultrasound parameters of the anterior rectus muscle also improved significantly. The prevalence of metabolic syndrome decreased from 27.3 % to 12.1 % (p = 0.03). The SF36 quality of life test showed a significant improvement in general health (20.9 ± 4.1 points; p = 0.001), physical role (6.9 ± 0.9 points; p = 0 .01), and mental health (14.0 ± 1.3 points; p = 0.01). Conclusion: the prescription of physical exercise with an online platform to obese patients improves weight, decreases body fat mass and increases muscle mass, with a decrease in insulin resistance and an improvement in quality of life.


Laser therapy in 100 tracheobronchial tumours.
One hundred patients with tracheobronchial tumours were treated with the neodymium YAG (yttrium-aluminium-garnet) or argon laser for symptoms of airways obstruction caused by tumour (59 cases), complete collapse of a lung (17 cases), or recurrent haemoptysis (24 cases). Seventy four of them had relapsed or failed to respond to radiotherapy or chemotherapy and all were inoperable. Objective improvement in results of lung function tests or haemoptysis diary charts was seen in 37 patients with airways obstruction (63%), five (29%) with collapsed lung, and 14 (58%) with haemoptysis. Overall, 68 patients had symptomatic benefit and there was objective improvement in 56. Two deaths occurred in 288 treatment sessions both occurring as a result of asphyxia from minor haemorrhage in patients with advanced cylindromas and critical narrowing of the trachea or single remaining bronchus. In suitable patients with intraluminal tumour laser phototherapy is a valuable addition to conventional treatment.


Physical activity in the management of patients with coronary artery disease: a review.
Cardiovascular diseases remain the leading cause of death in the Western world despite advances in therapeutics and interventions. The prescription of physical activity is a key component of cardiac rehabilitation following myocardial infarction. This review aims to outline the impact of physical activity in particular patient cohorts with coronary artery disease. The current understanding of the mechanisms involved in atherosclerosis, plaque rupture and thrombosis, and how these can be modified by physical activity, are also discussed. There is the potential for future research to investigate the clinical and mechanistic effects of different exercise types, intensities, duration, and frequencies in patients hospitalized for coronary artery disease.


A case of enchondromatosis concomitant with cerebral hamartomas: radiologic findings.
Enchondromatosis is a congenital nonhereditary condition characterized by multiple symmetrically distributed intraosseous cartillaginous masses in the metaphyses and diaphyses of bones. We report a case of bilateral multiple enchondromas and cerebral hamartomas in an 11-year-old boy in whom x-rays displayed distortion and expansion of bilateral long tubuler bones, hands and feet, scapulas, pelvis, and occipital regions of the calvarium. In addition to osseous abnormalities, bilateral cerebral hamartomas were observed on cranial magnetic resonance imaging (MRI). To the best of our knowledge, this is the first case in the literature with enchondromatosis and cerebral hamartomas.


Impacts of perianal disease and faecal incontinence on quality of life and employment in 1092 patients with inflammatory bowel disease.
Patient reported outcomes regarding perianal disease and faecal incontinence in the community-based inflammatory bowel disease population are poorly described. To determine the impacts of perianal disease and faecal incontinence on quality of life and employment in inflammatory bowel disease patients. For this cross-sectional study, a comprehensive survey was sent out to members of the Dutch National Crohn's and Colitis patient organisation. Validated questionnaires regarding faecal incontinence and active perianal disease were used to estimate its prevalence's. The effect on the quality of life (36-Item Short Form Survey) and on employment status (multivariate binary regression analysis) was assessed in this inflammatory bowel disease population. A total number of 1092 returned questionnaires (58% responders) were used for analysis; 750 respondents (69%) were female; mean age was 47 years (IQR 35-59). In 621 patients (57%) Crohn's disease, in 422 (39%) ulcerative colitis and in 49 (4%) patients unclassifiable inflammatory bowel disease was self-reported. The 114 patients (10%) with a stoma were excluded for continence related analyses. Faecal incontinence was reported in 555 patients (57%), was comparable between the different inflammatory bowel disease diagnoses and affected all 36-Item Short Form Survey subscales adversely (incontinence vs continence: Physical functioning 75 vs 84, P < 0.0001; Limitations due to physical health 49 vs 63, P < 0.0001; Limitations due to emotional problems 49 vs 64, P < 0.0001; Energy/fatigue 47 vs 53, P < 0.0001; Emotional well-being 71 vs 74, P = 0.005; Social functioning 63 vs 73, P < 0.0001; Pain 66 vs 75, P < 0.0001; General health 41 vs 48, P < 0.0001). Active perianal disease was reported in 39% Crohn's disease, 16% ulcerative colitis (84% fissures) and 20% unclassifiable inflammatory bowel disease patients. Faecal incontinence was more common in patients with perianal disease (67% vs 53%, P = 0.003). When correcting for age, disease duration, inflammatory bowel disease-related surgery and faecal incontinence, active perianal disease was independently affecting employment (OR 0.67; 95% CI 0.50-0.91; P = 0.01). Faecal incontinence and perianal disease are quality of life determining factors. Faecal incontinence needs more attention among clinicians, and development of new (drug) therapies needs to be focussed on perianal disease.


[Neonatal Doppler velocimetry in full term small-for-gestational age newborns].
This study aimed to evaluate the cerebral blood flow of full term small-for-gestational age newborns, using cranial ultrasound Doppler at birth. This study was performed at CAISM/UNICAMP (Tertiary Health Center for Women). Sixty term newborns were selected and divided in two groups: appropriate-for-gestational age (AGA) (36 neonates) and small-for-gestational age (SGA) (24 neonates). Cranial ultrasound Doppler evaluation was performed on both groups, between 24 and 48 hours after birth. Cerebral blood flow velocity (CBFV) was lower in the small-for-gestational age group, in the anterior cerebral artery (ACA). Doppler measurements were different statistically between the groups only for values related to peak systolic flow velocity (PSFV) and mean flow velocity (MFV) in the ACA. There was no significant difference for any evaluated parameters of flow velocity in the middle cerebral artery (MCA). It was concluded that SGA newborns showed PSFV and MFV significantly reduced only in the ACA. Weight/gestational age, neonatal polycythemia and mean arterial blood pressure values were statistically related to MFV in the ACA. In presence of fetal suffering, mean arterial blood pressure values and smoking in the pregnancy were statistically related to MFV in the MCA.


Determinants of patient satisfaction in postmastectomy breast reconstruction.
In today's increasingly competitive health care marketplace, consumer satisfaction has become an important measure of quality. Furthermore, measures of satisfaction with treatment inteerventions are influential factors in determining patients' and payers' choices of health care. This study sought to evaluate satisfaction with postmastectomy breast reconstruction and to assess the effects of procedure type and timing on patient satisfaction. As part of the Michigan Breast Reconstruction Outcome Study, patients undergoing first-time mastectomy reconstruction were prospectively evaluated, including cohorts of women choosing expander/implant, pedicle TRFAM flap, and free TRAM flap procedures. Preoperatively and 1 year postoperatively, participants completed a questionnaire that collected a variety of health status information. The postoperative questionnaire had an additional seven items assessing both general satisfaction with reconstruction (five items) and aesthetic satisfaction (two items) as separate subscales. Patients were asked to respond to each item using a five-point Likert scale. Item responses ranged from 1, indicating high satisfaction, to 5, reflecting low satisfaction. In the data analysis, only patients responding with a 1 or 2 for all of the items within a subscale were classified as "satisfied" for the subscale. To assess the effects of procedure type (implant, pedicle TRAM flap, and free TRAM flap) and timing (immediate versus delayed) on satisfaction and to control for possible confounding effects from other independent variables, multiple logistic regression was employed. In our analysis, odds ratios and associated 95 percent confidence intervals were calculated for each independent variable in the regression. Statistical significance was designated at the p < or = 0.05 level. A total of 212 patients were followed during the period of 1994 to 1997, including 141 immediate and 71 delayed reconstructions. The study population consisted of 49 expander/implant, 102 pedicle TRAM flap, and 61 free TRAM flap reconstruction patients. The analysis showed a significant association between procedure type and patient satisfaction. TRAM flap patients (both free and pedicle) appeared to have significantly greater general and aesthetic satisfaction compared with expander/implant patients (p = 0.03 and 0.001, respectively). Furthermore, pedicle TRAM flap patients were more aesthetically satisfied than those with free TRAM flaps (p = 0.072). The other independent variables of age and procedure timing did not appear to significantly affect either general or aesthetic satisfaction. However, preoperative physical activity was positively correlated with general satisfaction at the p = 0.034 level. The choice of procedure seems to have a significant effect on both aesthetic and general patient satisfaction with breast reconstruction. In this study, autogenous tissue reconstructions produced higher levels of patient aesthetic and general satisfaction compared with implant techniques. Pedicle and free TRAM flap patients do not seem to differ significantly in general satisfaction. However, women receiving pedicle TRAM flaps reported greater aesthetic satisfaction compared with patients undergoing free TRAM flaps. Furthermore, patient age and procedure timing may not have an effect on patient satisfaction with breast reconstruction.


Analysis of melanoma onset: assessing familial aggregation by using estimating equations and fitting variance components via Bayesian random effects models.
We investigate whether relative contributions of genetic and shared environmental factors are associated with an increased risk in melanoma. Data from the Queensland Familial Melanoma Project comprising 15,907 subjects arising from 1912 families were analyzed to estimate the additive genetic, common and unique environmental contributions to variation in the age at onset of melanoma. Two complementary approaches for analyzing correlated time-to-onset family data were considered: the generalized estimating equations (GEE) method in which one can estimate relationship-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modeled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov Chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the free ware package BUGS. In addition, we also used a Bayesian model to investigate the relative contribution of genetic and environmental effects on the expression of naevi and freckles, which are known risk factors for melanoma.


[Inveterate dislocation fracture of the sternoclavicular joint].
We present the case report of a 21-year-old man with a late diagnosis of retrosternal dislocation of the sternoclavicular joint with a fractured sternal end of the clavicle. The first symptom leading to the diagnosis was dysphagia associated with physical activity. The diagnosis was based on computed tomography examination. In the first place, the fragment of the medial clavicular end was fixed with two screws. During surgery the sternoclavicular joint was wrongly identified; this fact was revealed by the following radiographic examination. On revision surgery, the sternoclaviculr ligament was reconstructed using a semitendinosus tendon graft. The reconstructed ligament was augmented with two Orthocord sutures running between the clavicle and the first rib. At 2 years after surgery the functional outcome and sternoclavicular joint stability were excellent.


Assessment of the Cape Cod phylogeographic break using the bamboo worm Clymenella torquata reveals the role of regional water masses in dispersal.
Previous genetic studies suggest Cape Cod, MA, as a phylogenetic break for benthic marine invertebrates; however, diffuse sampling in this area has hindered fine-scale determination of the break's location and underlying causes. Furthermore, some species exhibit breaks in different places, and others exhibit no breaks in this region. We analyze the phylogeographic patterns of 2 mitochondrial genes from 10 populations of the bamboo worm Clymenella torquata (Annelida: Maldanidae) focused around Cape Cod but extending from the Bay of Fundy, Canada, to New Jersey. A common invertebrate along the US coast, C. torquata, possesses life-history characteristics that should make it sensitive to factors such as dispersal barriers, bottlenecks, and founder events. As an inhabitant of soft sediments, C. torquata offers a unique contrast to existing research dominated by organisms dwelling on hard substrates. Our genetic data show a clear phylogenetic break and a cline of haplotype frequencies from north to south. Fine-scale sampling of populations on Cape Cod, combined with other sampled populations, confirm that this distinct break is not on the Cape Cod peninsula itself but to the south near a boundary of oceanic water masses. Low levels of gene flow occur in these populations, in an asymmetric manner congruent with coastal current patterns. No significant effect of Pleistocene glaciation was seen in the pattern of genetic diversity over the sampled range.


Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions.
Increased urinary albumin excretion rate is widely accepted as the first clinical sign of diabetic nephropathy. However, it is possible that some diabetic patients could first manifest reduced glomerular filtration rate (GFR) or hypertension. Relatively advanced diabetic renal lesions can be present in some diabetic patients with long-standing normoalbuminuria, and this might indicate increased risk of progression to microalbuminuria and then to overt diabetic nephropathy. The aim of this study was to identify a group of normoalbuminuric type 1 diabetic patients with low GFR and compare them with normoalbuminuric patients with normal GFR. Altogether, 105 normoalbuminuric type 1 diabetic patients with at least 10 years of diabetes duration that had a renal biopsy performed for research purposes were studied. Patients were divided according to GFR into groups with normal (>/=90 ml x min(-1) x 1.73 m(-2)) or reduced (<90 ml x min(-1) x 1.73 m(-2)) GFR. Clinical and renal structural parameters were compared between these two groups. Glomerular structural parameters were estimated by electron microscopic morphometry. The 23 patients with reduced GFR had more advanced diabetic glomerular lesions. The finding of reduced GFR was much more common among female patients, particularly if retinopathy and/or hypertension were also present. This report confirms that reduced GFR occurs among long-standing normoalbuminuric type 1 diabetic patients and is associated with more advanced diabetic glomerular lesions and, probably, with increased risk of progression. For these reasons, we suggest that regular measurements of GFR be performed in long-standing normoalbuminuric type 1 diabetic female diabetic patients, especially in those with retinopathy or hypertension.


mini spindles: A gene encoding a conserved microtubule-associated protein required for the integrity of the mitotic spindle in Drosophila.
We describe a new Drosophila gene, mini spindles (msps) identified in a cytological screen for mitotic mutant. Mutation in msps disrupts the structural integrity of the mitotic spindle, resulting in the formation of one or more small additional spindles in diploid cells. Nucleation of microtubules from centrosomes, metaphase alignment of chromosomes, or the focusing of spindle poles appears much less affected. The msps gene encodes a 227-kD protein with high similarity to the vertebrate microtubule-associated proteins (MAPs), human TOGp and Xenopus XMAP215, and with limited similarity to the Dis1 and STU2 proteins from fission yeast and budding yeast. Consistent with their sequence similarity, Msps protein also associates with microtubules in vitro. In the embryonic division cycles, Msps protein localizes to centrosomal regions at all mitotic stages, and spreads over the spindles during metaphase and anaphase. The absence of centrosomal staining in interphase of the cellularized embryos suggests that the interactions between Msps protein and microtubules or centrosomes may be regulated during the cell cycle.


Regioselective chromatic orthogonality with light-activated metathesis catalysts.
The ability to selectively guide consecutive chemical processes towards a preferred pathway by using light of different frequencies is an appealing concept. Herein we describe the coupling of two photochemical reactions, one the photoisomerization and consequent activation of a sulfur-chelated latent olefin-metathesis catalyst at 350 nm, and the other the photocleavage of a silyl protecting group at 254 nm. Depending on the steric stress exerted by a photoremovable neighboring chemical substituent, we demonstrate the selective formation of either five- or six-membered-ring frameworks by light-triggered ring-closing metathesis. The orthogonality of these light-induced reactions allows the initiation of these processes independently and in interchangeable order, according to the wavelength of light used to promote them.


DNA looping between the origin of replication of Epstein-Barr virus and its enhancer site: stabilization of an origin complex with Epstein-Barr nuclear antigen 1.
Epstein-Barr nuclear antigen 1 (EBNA-1) is the only viral protein required to support replication of Epstein-Barr virus during the latent phase of its life cycle. The DNA segment required for latent replication, oriP, contains two essential binding regions for EBNA-1, termed FR and DS, that are separated by 1 kilobase pair. The FR site appears to function as a replicational enhancer providing for the start of replication at the DS site. We have used electron microscopy to visualize the interaction of EBNA-1 with its binding sites and to study the mechanism for communication between the FR and DS sites. We have found that DNA-bound EBNA-1 forms a DNA loop between the FR and DS sites. From these results, we suggest that EBNA-1 bound to the replicational enhancer acts by a DNA-looping mechanism to facilitate the initiation of DNA replication. Occupancy of the DS site alone is highly sensitive to competition with nonspecific DNA. In contrast, occupancy of the DS site by looping from FR is largely resistant to the competitor DNA. These experiments support the concept that enhancers act in cis from nearby sites to provide a high local concentration of regulatory proteins at their target sites and to stabilize regulatory interactions.


Nasal mucous transport and our ambient air.
The nose usually serves to conduct air in and out of the lungs; but it also defends the body against airborne noxious materials and modifies the physical condition of inspired air prior to its arrival in the lungs. A major factor in these physiological functions is mucociliary clearance which depends on the secretion of airway secretions and ciliary activity. This function is impaired by certain air pollutants, but not by relative humidity or temperature of the ambient air.


Arylation with unsymmetrical diaryliodonium salts: a chemoselectivity study.
Phenols, anilines, and malonates have been arylated under metal-free conditions with twelve aryl(phenyl)iodonium salts in a systematic chemoselectivity study. A new "anti-ortho effect" has been identified in the arylation of malonates. Several "dummy groups" have been found that give complete chemoselectivity in the transfer of the phenyl moiety, irrespective of the nucleophile. An aryl exchange in the diaryliodonium salts has been observed under certain arylation conditions. DFT calculations have been performed to investigate the reaction mechanism and to elucidate the origins of the observed selectivities. These results are expected to facilitate the design of chiral diaryliodonium salts and the development of catalytic arylation reactions that are based on these sustainable and metal-free reagents.


[Elements of NOT (Scientific Organization of Labor) in a clinical diagnostic laboratory].
The suggested graphic variants of laboratory forms permit a rapid and accurate assessment of laboratory data, help detect organ abnormalities and relationships between shifts in laboratory characteristics of various systems of the body. These forms are convenient for dynamic assessment of changes in laboratory parameters, they permit a further mathematical processing of the data. Use of such forms will help reduce the number of laboratory analyses at the expense of purposeful laboratory tests, much more rapidly interpreted, thus saving the clinician's time.


Induced non-enzymatic browning of soybean meal. I. Effects of factors controlling non-enzymatic browning on in vitro ammonia release.
Non-enzymatic browning was tested as a means of suppressing degradation of soybean meal (SBM) by ruminal microbes in five trials with in vitro ammonia release as the response criterion. Treatments imposed on SBM included reducing sugar source (xylose, glucose, fructose and lactose), reducing sugar level (1, 3 and 5 mol/mol SBM-lysine), pH (6.5, 8.5 and 10.0), dry matter (DM) content (65, 70, 75, 80, 85 and 90%) and varying lengths of heating time (0 to 90 min) at 150 C. Samples heated under conditions that promoted non-enzymatic browning gave greater (P less than .01) ammonia release suppression that when SBM was heated without these treatments. Xylose was the most reactive sugar, but extended heating of SBM containing glucose, fructose or lactose resulted in ammonia release similar to xylose. Increasing sugar level from 1 to 5 mol/mol SBM-lysine caused linear decreases (P less than .01) in ammonia release for xylose, glucose and fructose, but not lactose. Ammonia release was higher (P less than .01) at pH 6.5 than pH 8.5 and 10.0, and higher (P less than .01) at pH 9.5 than pH 10.0. Rate of non-enzymatic browning decreased when samples containing greater than 80% DM were heated. These results are interpreted to show that controlled non-enzymatic browning may be effective for reducing ruminal degradation of SBM.


Assessing COVID-19-related health literacy and associated factors among school teachers in Hong Kong, China.
The coronavirus disease 2019 (COVID-19) pandemic developed rapidly, with changing guidelines, misinformation, inaccurate health information and rumors. This situation has highlighted the importance of health literacy, especially among educators. The aims of this study were (i) to assess COVID-19-specific health literacy among school teachers in Hong Kong and (ii) to examine its association with demographic factors, self-endangering work behaviors (i.e., work intensification, work extensification and work quality reduction), secondary burnout symptoms (i.e., exhaustion related to work and psychosomatic complaints), the level of knowledge of COVID-19- or pandemic-related information and the level of confusion about COVID-19-related information. A self-report survey was administered to 366 Hong Kong school teachers from April 2021 to February 2022. COVID-19-specific health literacy was measured using the HLS-COVID-Q22 instrument. Other instruments, including self-endangering work behavior scales (i.e., extensification of work, intensification of work and work quality reduction) and two dimensions of the Burnout Assessment Tool (i.e., psychosomatic complaints and exhaustion) were also used for assessment. Data were analyzed using an independent samples Student's t-test, analysis of variance, correlation analysis and adjusted multilinear regression models. The results showed that 50.8% of school teachers had sufficient health literacy, 38.3% had problematic health literacy and 10.9% had inadequate health literacy. The HLS-COVID score did not vary by sex, but varied according to the type of school, the number of working hours per week and the number of students attending the school. Teachers with sufficient health literacy scored significantly lower for two types of self-endangering work behavior-intensification of work (p = 0.003) and work quality reduction (p = 0.007)-than those with insufficient health literacy. After excluding those who had already been vaccinated, respondents with sufficient health literacy felt more positive about COVID-19 vaccination than those with insufficient health literacy (t[180] = 4.168, p < 0.001). In addition, teachers with sufficient health literacy felt more informed (p < 0.001) and less confused (p < 0.001) about COVID-19-related information than those with insufficient health literacy. Multiple linear regression analysis revealed that age (β = 0.14, p = 0.011) and the number of teaching hours per week (β = -0.206, p < 0.001) were significant predictors of the HLS-COVID score. The findings of this study may serve as a guide for addressing health literacy gaps among school teachers.


Interactions of NBU1 IntN1 and Orf2x proteins with attachment site DNA.
NBU1 is a mobilizable transposon found in Bacteroides spp. Mobilizable transposons require gene products from coresident conjugative transposons for excision and transfer to recipient cells. The integration of NBU1 requires IntN1, which has been identified as a tyrosine recombinase, as well as Bacteroides host factor BHFa. Excision of NBU1 is a more complicated process, involving five element-encoded proteins (IntN1, Orf2, Orf2x, Orf3, and PrmN1) as well as a Bacteroides host factor and a cis-acting DNA sequence. Little has been known about what role the proteins play in excision, although IntN1 and Orf2x have been shown to be the only proteins absolutely required for detectable excision. To determine where IntN1 and Orf2x bind during the excision of NBU1, both proteins were partially purified and tested in DNase I footprinting experiments with the excisive attachment sites attL and attR. The results demonstrate that IntN1 binds to four core-type sites that flank the region of cleavage and strand exchange, as well as six arm-type sites. A unique feature of the system is the location of DR2a and DR2b arm-type sites immediately downstream of the attL core. The DR1a, DR1b, DR3a, and DR3b arm-type sites were shown to be required for in vitro integration of NBU1. In addition, we have identified one Orf2x binding site (O1) on attL as well as a dA+dT-rich upstream element that is required for Orf2x interactions with O1.


The oncoprotein HBXIP upregulates Lin28B via activating TF II D to promote proliferation of breast cancer cells.
Hepatitis B X-interacting protein (HBXIP) is a novel oncoprotein and plays a key role in the development of breast cancer. However, its mechanisms of action are poorly understood. Lin28B functions as an oncogene in a variety of human cancers. In our study, we report that HBXIP acts with its partner Lin28B to contribute to carcinogenesis. Our data showed that the expression levels of HBXIP were significantly positively correlated with those of Lin28B in clinical breast cancer tissues. Then, we found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. Chromatin immunoprecipitation assay (ChIP) and electrophoretic mobility shift assay (EMSA) revealed that HBXIP occupied the promoter region (-1199/-1073 nt) of Lin28B. Importantly, co-immunoprecipitation (Co-IP) and GST pull-down assay validated that HBXIP directly bound to the TATA-binding protein (TBP), a basal subunit of transcription factor TF II D complex. In addition, we discovered that Lin28B could block the downregulation of HBXIP via suppressing miR-520b which directly targeted HBXIP mRNA in the cells. In function, we demonstrated that HBXIP enhanced the proliferation of breast cancer cells through Lin28B in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. Therapeutically, HBXIP may serve as a target of breast cancer.


Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome.
A mouse model for the autosomal form of Alport syndrome was produced. These mice develop a progressive glomerulonephritis with microhematuria and proteinuria, consistent with the human disease. End-stage renal disease develops at approximately 14 weeks of age. TEM analysis of the glomerular basement membranes (GBM) during development of renal pathology revealed focal multilaminated thickening and thinning beginning in the external capillary loops at 4 weeks and spreading throughout the GBM by 8 weeks. By 14 weeks, half of the glomeruli were fibrotic with collapsed capillaries. Immunofluorescence analysis of the GBM showed the absence of type IV collagen alpha-3, alpha-4, and alpha-5 chains and a persistence of alpha-1 and alpha-2 chains (these chains normally localize to the mesangial matrix). Northern blot analysis using probes specific for the collagen chains illustrate the absence of COL4A3 in the knockout, whereas mRNAs for the remaining chains are unchanged. An accumulation of fibronectin, heparan sulfate proteoglycan, laminin-1, and entactin was observed in the GBM of the affected animals. The temporal and spatial pattern of accumulation was consistent with that for thickening of the GBM as observed by TEM. Thus, expression of these basement membrane-associated proteins may be involved in the progression of Alport renal disease pathogenesis. The levels of mRNAs encoding the basement membrane-associated proteins at 7 weeks were unchanged.