Catalytic activity, stability, unfolding, and degradation pathways of engineered and reconstituted myoglobins.
The structural and functional consequences of engineering a positively charged Lys residue and replacing the natural heme with a heme-L-His derivative in the active site of sperm whale myoglobin (Mb) have been investigated. The main structural change caused by the distal T67K mutation appears to be mobilization of the propionate-7 group. Reconstitution of wild-type and T67K Mb with heme-L-His relaxes the protein fragment around the heme because it involves the loss of the interaction of one of the propionate groups which stabilize heme binding to the protein. This modification increases the accessibility of exogenous ligands or substrates to the active site. The catalytic activity of the reconstituted proteins in peroxidase-type reactions is thus significantly increased, particularly with T67K Mb. The T67K mutation slightly reduces the thermodynamic stability and the chemical stability of Mb during catalysis, but somewhat more marked effects are observed by cofactor reconstitution. Hydrogen peroxide, in fact, induces pseudo-peroxidase activity but also promotes oxidative damage of the protein. The mechanism of protein degradation involves two pathways, which depend on the evolution of radical species generated on protein residues by the Mb active species and on the reactivity of phenoxy radicals produced during turnover. Both protein oligomers and heme-protein cross-links have been detected upon inactivation.


The Dowling-Orlando technique in a giant primary cerebral hydatid cyst: a case report.
Hydatid cyst disease is a parasitic illness that is rarely located in the brain. We present a case of a 26-year-old female who complained of headache, nausea, and vomiting. The diagnosis was intracranial hydatid cyst disease and was confirmed with radiological and serological tests. Neurological examination revealed papilloedema and left-sided pyramidal signs. She was operated on using the Dowling-Orlando technique. The cyst was removed without rupture, and therapy was completed with albendazole for a period of four weeks. In this article, we discuss the application of the Dowling-Orlando technique, microsurgery, the Valsalva manoeuvre and the positioning of the patient such that gravity could facilitate surgical removal of a giant cerebral hydatid cyst.


Vascular regulation of type II cell exocytosis.
To determine whether lung capillary pressure regulates surfactant secretion, we viewed alveoli of the constantly inflated, isolated blood-perfused rat lung by fluorescence microscopy. By alveolar micropuncture we infused fura 2 and lamellar body (LB)-localizing dyes for fluorescence detection of, respectively, the alveolar cytosolic Ca(2+) concentration ([Ca(2+)](i)) and type II cell exocytosis. Increasing left atrial pressure (Pla) from 5 to 10 cmH(2)O increased septal capillary diameter by 26% and induced marked alveolar [Ca(2+)](i) oscillations that abated on relief of pressure elevation. The rate of loss of LB fluorescence that reflects the LB exocytosis rate increased fourfold after the pressure elevation and continued at the same rate even after pressure and [Ca(2+)](i) oscillations had returned to baseline. In alveoli pretreated with either 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM, the intracellular Ca(2+) chelator, or heptanol, the gap junctional blocker, the pressure-induced exocytosis was completely inhibited. We conclude that capillary pressure and surfactant secretion are mechanically coupled. The secretion initiates in a Ca(2+)-dependent manner but is sustained by Ca(2+)-independent mechanisms.


Measuring flexibility in autistic adults: Exploring the factor structure of the flexibility scale self report.
Cognitive flexibility differences are common for autistic individuals and have an impact on a range of clinical outcomes. However, there is currently a lack of well validated measurement tools to assess flexibility in adulthood. The Flexibility Scale was originally designed as a parent-report measure of real-world flexibility challenges in youth. The original Flexibility Scale provides a total score and five subscales: Routines and Rituals, Transitions and Change, Special Interests, Social Flexibility, and Generativity. In this study, we evaluate the factorial validity of the Flexibility Scale as a self-report (Flexibility Scale Self Report) measure of cognitive flexibility, adapted from the original Flexibility Scale, for use by autistic adults. This study includes both a primary sample (n = 813; mean age = 40.3; 59% female) and an independently recruited replication sample (n = 120; mean age = 32.8; 74% female) of individuals who completed the Flexibility Scale Self Report. The analysis consisted of an initial confirmatory factor analysis (CFA) of the original Flexibility Scale structure, followed by exploratory factor analysis (EFA) and factor optimization within a structural equation modeling framework to identify the optimal structure for the questionnaire in adults. The identified structure was then replicated through CFA in the replication sample. Our results indicate an alternative optimal scale structure from the original Flexibility Scale, which includes fewer items, and only three (Routines/Rituals, Transitions and Change, Special Interests) of the five subscales contributing to the flexibility total score. Comparisons revealed no structural differences within the scale based on sex assigned at birth. Here the Generativity and Social Flexibility scales are treated as independent but related scales. The implications for measurement of cognitive flexibility in clinical and research settings, as well as theoretical underpinnings are discussed.


Non-aqueous synthetic methodology for TiW(5) polyoxometalates: protonolysis of [(MeO)TiW(5)O(18)](3-) with alcohols, water and phenols.
The tetra-n-butylammonium (TBA) salt of [(MeO)TiW(5)O(18)](3-) 1 was reacted with alcohols ROH to give primary, secondary and tertiary alkoxide derivatives [(RO)TiW(5)O(18)](3-) (R = Et 2, (i)Pr 3 and (t)Bu 4), whilst hydrolysis afforded [(mu-O)(TiW(5)O(18))(2)](6-) 5 rather than the hydroxo derivative (R = H). In reactions with (i)PrOH and (t)BuOH, impurity peaks observed at 1015 and 1020 ppm in the (17)O NMR spectra indicate alkoxide degradation and Ti=O bond formation via reactions analogous to those occurring at the surfaces of solid heteropolyacids. Aryloxides [(ArO)TiW(5)O(18)](3-) were prepared by reacting 1 with phenols ArOH (Ar = C(6)H(5) 6, C(6)H(4)Me-4 7, C(6)H(4)(t)Bu-4 8, C(6)H(4)OH-4 9, C(6)H(4)OH-3 10, C(6)H(3)(OH)(2)-3,5 11 and C(6)H(4)CHO-2 13). TiW(5)O(18) units were linked by reacting 1 with 9 to give [(mu-1,4-OC(6)H(4)O)(TiW(5)O(18))(2)](6-) 12. (17)O and (183)W NMR spectra are reported and X-ray crystal structures were obtained for TBA salts of anions 3-10 and 13, which showed that the titanium is six-coordinate in all cases. Reactions were monitored by (1)H NMR, including a 2D-EXSY study of methoxo exchange, and the slow rates observed are probably associated with the reluctance of titanium in these anions to achieve seven-coordination.


Partial purification and properties of the two common inherited forms of human erythrocyte adenylate kinase.
1. The partial purification of adenylate kinase, types 1 and 2, from human erythrocytes is described. 2. Gel chromatography of both forms of the enzyme gave estimates of the molecular weights in the range 20000-23000. 3. Studies on crude haemolysates at various pH values indicated that the type 2 enzyme was less stable than the type 1. Heat denaturation studies on the partially purified enzymes confirmed these findings. 4. Measurements of rates of inhibition by iodoacetate and iodoacetamide showed that the type 2 enzyme reacts more readily than the type 1 enzyme with both reagents. 5. The effect of temperature on the initial velocity of ADP formation was measured at a single concentration of both AMP and MgATP(2-). The two forms of the enzyme responded differently to increasing temperature.


Sickle cell disease in the emergency department.
Acute painful episodes are the most common reason for emergency department visits among patients with sickle cell disease (SCD). Early and aggressive pain management is a priority. Emergency providers (EPs) must also diagnose other emergent diagnoses in patients with SCD and differentiate them from vaso-occlusive crisis. EPs should be aware of cognitive biases that may misdirect the diagnostic process. Administration of intravenous fluids should be used judiciously. Blood transfusion may be considered. Coordination of care with hematology is an important part of the effective emergency department and long-term management of patients with SCD.


Cross-national measurement invariance of the Purpose in Life Test in seven Latin American countries.
The Purpose in Life Test (PIL) is a measure of purpose in life widely used in many cultures and countries; however, cross-cultural assessments are scarce. The present study aimed to evaluate the cross-cultural measurement invariance of the PIL in the general population of seven Latin American countries (Colombia, Ecuador, El Salvador, Mexico, Paraguay, Argentina, and Uruguay). A total of 4306 people participated, selected by non-probabilistic convenience sampling, where Uruguay has the highest mean age (M = 41.8; SD = 16.6 years); while Ecuador has the lowest mean age (M = 24.6; SD = 7.8 years). Furthermore, in each country, there is a higher proportion of women (>60%) than men (<40%). Using Multi-Group Confirmatory Factor Analysis, the factorial structure does not show evidence of invariance among the included countries. However, based on the Multi-Group Factor Analysis Alignment, there is evidence that a three-dimensional structure of the PIL (Meaning of existence, Freedom to make meaning in daily life and Will to find meaning in the face of future challenges) is the same in the participating countries. Results based on item response theory indicate that most PIL items can significantly differentiate responses according to the level of life purpose. In addition, people with low life purpose will tend to choose the lower response alternatives on the PIL; while people with higher life purpose will choose higher response alternatives. The findings indicate that the PIL has the potential to increase knowledge about how people conceive and experience their purpose in life in different countries.


Four kinds of traditional Chinese exercise therapy in the treatment of type 2 diabetes: a systematic review and network meta-analysis.
To perform an evidence-based evaluation of the clinical efficacy of Taijiquan, Baduanjin, Yijinjing and Wuqinxi in interventions for type 2 diabetes. A systematic review and network meta-analysis. The comprehensive search included Chinese and other language databases such as the MEDLINE (PubMed), Web of Science, Excerpta Medica Database (Embase), The Cochrane Library, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China Scientific Journal Database, VIP and China Biomedical Literature Database (CBM). Clinical randomized controlled trials of four traditional Chinese exercise therapies in the treatment of type 2 diabetes, including Taijiquan, Baduanjin, Yijinjing and Wuqinxi, were retrieved. The search time was conducted from the establishment of the database to 30 October 2022. Two researchers screened the documents that met the inclusion criteria, extracted data according to the preset table and evaluated the methodological quality of the included studies according to the quality evaluation tools recommended by the Cochrane System Reviewer Manual V.5.1. The R language, Stata and ADDIS statistical software programs were used to conduct statistics and analysis of intervention measures. A total of 33 randomized controlled trials with 2609 patients were identified. All patients were from China. The results of the network meta-analysis showed that Taijiquan ranked the best for improving HbA1c, 2-h postprandial blood glucose (2hPG), low-density lipoprotein cholesterol (LDL-C) and insulin sensitivity index indicator levels; Yijinjing reduced fasting plasma glucose (FPG) and total cholesterol (TC) indicator levels for the best probability ranking; Baduanjin improved the triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) probability ranking the most. When the training period was less than 12 weeks, Baduanjin had better effects in improving 2hPG, TC, TG, HDL-C and LDL-C indicator levels. Taijiquan had better effects in reducing FPG levels. When the training period was 12 weeks, the effect of Yijinjing in improving FPG, HbAlc, TC and HDL-C levels was better than that in other traditional Chinese exercise, and Taijiquan had better effects in improving 2hPG, TG and LDL-C indicator levels. When the training period was longer than 12 weeks, Taijiquan had better effects in improving FPG, HbAlc, 2hPG and LDL-C indicator levels, and Baduanjin had better effects in improving TC, TG and HDL-C indicator levels. The four traditional Chinese exercise therapies can improve blood glucose levels, blood lipid levels and insulin-related indicators of type 2 diabetes to varying degrees. Studies have shown that Taijiquan has a better targeted treatment effect on type 2 diabetes. CRD42020214786. We published the protocol article "Network meta-analysis of four kinds of traditional Chinese exercise therapy in the treatment of type 2 diabetes: Protocol for a systematic review" in the BMJ Open magazine 2021, Issue 11, Volume 7.


Crystallization behavior of milk fat obtained from linseed-fed cows.
Milk with an increased content of unsaturated fatty acids was obtained by incorporating 60% of extruded linseed into the concentrate of cows. Two groups of Holstein cows (3 animals/group) were fed a concentrate (control or linseed enriched) together with the same roughage diet (ad libitum). After an adaptation period of 3 wk, evening and morning milk samples were collected every 7 d for 3 wk. Milk was decreamed and anhydrous milk fat (AMF) was isolated from the fat fraction by using the Bureau of Dairy Industries method. The objective of this study was to investigate if the crystallization mechanism of milk fat changed when the content of unsaturated fatty acids was increased. Therefore, the crystallization behavior of a milk fat enriched with unsaturated fatty acids was compared with that of a control milk fat. Nonisothermal crystallization was investigated with differential scanning calorimetry, and 1-step and 2-step isothermal crystallization behaviors were investigated using pulsed nuclear magnetic resonance, differential scanning calorimetry, and x-ray diffraction. A higher content of unsaturated fatty acids in AMF resulted in an increased proportion of low melting triglycerides. These triglycerides lowered the solid fat content profile, particularly at refrigerator temperatures. Furthermore, they induced some changes in the crystallization and melting behaviors of milk fat compared with a control AMF, although no fundamental changes in the crystallization mechanism could be revealed. Even though a lower melting point could be observed for milk fat with a higher content of unsaturated fatty acids, a similar degree of supercooling was needed to initiate crystallization, resulting in a shift in onset temperature of crystallization toward lower temperatures. In addition, slower crystallization kinetics were measured, such as a lower nucleation rate and longer induction times, although crystallization occurred in a similar polymorphic crystal lattice. During melting, a shift in offset temperature toward lower temperatures could be observed for the 3 melting fractions of AMF in addition to a higher proportion of low melting triglycerides. These results demonstrate that a higher content of unsaturated fatty acids has some effect on the crystallization behavior of milk fat. This knowledge could be used to produce dairy products of similar or superior quality compared with conventional products by intervening in the production process of dairy products.


Syntactic and non-syntactic sources of interference by music on language processing.
Music and language are complex hierarchical systems in which individual elements are systematically combined to form larger, syntactic structures. Suggestions that music and language share syntactic processing resources have relied on evidence that syntactic violations in music interfere with syntactic processing in language. However, syntactic violations may affect auditory processing in non-syntactic ways, accounting for reported interference effects. To investigate the factors contributing to interference effects, we assessed recall of visually presented sentences and word-lists when accompanied by background auditory stimuli differing in syntactic structure and auditory distraction: melodies without violations, scrambled melodies, melodies that alternate in timbre, and environmental sounds. In Experiment 1, one-timbre melodies interfered with sentence recall, and increasing both syntactic complexity and distraction by scrambling melodies increased this interference. In contrast, three-timbre melodies reduced interference on sentence recall, presumably because alternating instruments interrupted auditory streaming, reducing pressure on long-distance syntactic structure building. Experiment 2 confirmed that participants were better at discriminating syntactically coherent one-timbre melodies than three-timbre melodies. Together, these results illustrate that syntactic processing and auditory streaming interact to influence sentence recall, providing implications for theories of shared syntactic processing and auditory distraction.


A model of voluntary turnover among hospital CEOs.
This study examines factors contributing to hospital CEOs' voluntary decisions to leave their positions in 1990. Using a longitudinal design, we contrast 49 leavers with 1,362 stayers. We view turnover as influenced by both "push" factors that promote leaving (dissatisfaction with the position) and "hump" factors that need to be overcome (the cost of job change). Push factors giving rise to dissatisfaction include lower compensation, the predecessor's termination, and value incongruity between the CEO and the hospital. Testing the impact of key variables from Fiedler's contingency theory of leadership, we show that task-oriented leaders are relatively less satisfied when compared with relationship-oriented leaders. CEOs also express less satisfaction in low-situational control settings, a measure heavily influenced by perceived inadequate support from medical staff and subordinates. "Hump" factors that deterred leaving included family-related obstacles such as spouse's work or children's school, features mentioned most often by younger CEOs. The study suggests that boards should structure competitively paid positions with opportunities to generate support from the medical staff and subordinates. Recruiters for CEO positions are apprised of the importance of nonwork features in CEOs' willingness to consider new positions.


Wrinkled stripes localized by cracks in metal films deposited on soft substrates.
Homogeneous global wrinkling patterns such as labyrinths, herringbones, ripples and straight stripes can be widely observed in natural and artificial systems, but localized wrinkling patterns (not including buckle-driven delaminations, folds, ridges and creases) are seldom observed in experiments. Here we report on the spontaneous formation of highly ordered wrinkled stripes localized by cracks in metal films deposited on soft substrates. The experiment shows that the metal film is under a large tensile stress during deposition, which is relieved by the formation of networked cracks. After deposition, a compressive stress is stored up in the film and it always focuses near the new formed cracks due to the plastic deformation of the film, resulting in the formation of localized wrinkled stripes composed of a large number of straight wrinkles perpendicular to the cracks. The morphological characteristic, formation mechanism and evolution behaviors of the localized wrinkled stripes have been described and discussed in detail.


Voltage-sensitive potassium channels in Drosophila photoreceptors.
A preparation of dissociated Drosophila ommatidia is described that allows single-channel and whole-cell patch-clamp analysis of currents in identified sensory neurons. Three distinct classes of voltage-sensitive potassium conductances are characterized; all were detected in distal parts of ommatidia from sevenless mutants and hence in one cell class (R1-6 photoreceptors). Rapidly inactivating A-channels (IA), coded by the Shaker gene, were isolated in multichannel patches from adult flies. While showing similar kinetics to muscle A-channels, they differ from previously characterized wild-type Shaker channels in having a much more negative voltage operating range, being half-inactivated at approximately -70 mV. Two delayed rectifier conductances were characterized in whole-cell recordings from pupal photoreceptors. The most commonly encountered class (IKs) is similar to previously reported delayed rectifier conductances in Drosophila. It inactivates slowly (time constant, approximately 500 msec) and is half-inactivated at approximately -40 mV. A more rapidly inactivating delayed rectifier (IKf) was detected in approximately 30% of cells; it is half-inactivated at approximately -80 mV. Both IKs and IKf are blocked by 100 microM quinidine. Neither are greatly affected by 4-aminopyridine, which blocks IA at 1-5 mM. None of the three conductances was calcium dependent, nor were they obviously affected by the eag mutation, which affects K channels in muscle. The developmental profile of the channels is the inverse of that described in muscle. Both IKs and IKf are present at the earliest pupal stages examined (approximately 60 hr), but IA was only first detected at approximately 76 hr.(ABSTRACT TRUNCATED AT 250 WORDS)


The pharmacokinetics and effects of meloxicam, gabapentin, and flunixin in postweaning dairy calves following dehorning with local anesthesia.
Approved analgesic compounds in cattle are not currently available in the United States due to the lack of validated pain assessment methods and marker residue depletion studies. In this study, we compared the pharmacokinetic parameters and effect of preemptive analgesics administered to calves subjected to dehorning with local anesthesia. Holstein steers were randomly assigned to receive one of the following treatments per os (PO) or intravenously (IV) (n = 8/group): meloxicam (1 mg/kg PO), gabapentin (15 mg/kg PO), meloxicam (1 mg/kg), and gabapentin (15 mg/kg) PO, flunixin (2.2 mg/kg IV), or a placebo. Plasma drug, haptoglobin, substance P (SP) concentrations, serum cortisol concentrations, ocular thermography, mechanical nociceptive threshold (MNT), and average daily gain (ADG) were evaluated. Data were analyzed using mixed-effects models and noncompartmental pharmacokinetic analysis. Meloxicam, gabapentin, and meloxicam with gabapentin at the present doses did not reduce cortisol concentrations. Analgesic-treated calves had significantly lower plasma SP concentrations and improved ADG compared with controls. Flunixin calves had reduced circulating cortisol compared with controls. Meloxicam-treated calves showed an increase in MNT at two horn bud sites compared with the other treatments. Analgesics improved ADG and reduced biomarkers of pain, but effects differed by compound and route of administration.


Saffron extract interferes with lipopolysaccharide-induced brain activation of the kynurenine pathway and impairment of monoamine neurotransmission in mice.
Although activation of inflammatory processes is essential to fight infections, its prolonged impact on brain function is well known to contribute to the pathophysiology of many medical conditions, including neuropsychiatric disorders. Therefore, identifying novel strategies to selectively counter the harmful effects of neuroinflammation appears as a major health concern. In that context, this study aimed to test the relevance of a nutritional intervention with saffron, a spice known for centuries for its beneficial effect on health. For this purpose, the impact of an acute oral administration of a standardized saffron extract, which was previously shown to display neuromodulatory properties and reduce depressive-like behavior, was measured in mice challenged with lipopolysaccharide (LPS, 830 μg/kg, ip). Pretreatment with saffron extract (6.5 mg/kg, per os) did not reduce LPS-induced sickness behavior, preserving therefore this adaptive behavioral response essential for host defense. However, it interfered with delayed changes of expression of cytokines, chemokines and markers of microglial activation measured 24 h post-LPS treatment in key brain areas for behavior and mood control (frontal cortex, hippocampus, striatum). Importantly, this pretreatment also counteracted by that time the impact of LPS on several neurobiological processes contributing to inflammation-induced emotional alterations, in particular the activation of the kynurenine pathway, assessed through the expression of its main enzymes, as well as concomitant impairment of serotonergic and dopaminergic neurotransmission. Altogether, this study provides important clues on how saffron extract interferes with brain function in conditions of immune stimulation and supports the relevance of saffron-based nutritional interventions to improve the management of inflammation-related comorbidities.


Antidepressant-Like Effect of the Norepinephrine-Dopamine Reuptake Inhibitor Bupropion in a Mouse Model of Huntington's Disease with Dopaminergic Dysfunction.
The pre-motor stages of Huntington's disease (HD) are commonly associated with psychiatric manifestations including depression. Recent clinical data indicate that dopaminergic dysfunction is common in both symptomatic and pre-manifest HD gene carriers. There is also increasing evidence implicating catecholamine dysfunction in the pathophysiology of depression. In this study, we aimed to functionally investigate the dopaminergic system in the R6/1 mouse model of HD prior to onset of motor symptoms. We assessed the effects of acute administration of bupropion (a dopamine-norepinephrine reuptake inhibitor) on spontaneous locomotor activity and depression-like behaviour (using the forced-swim test). Here we show that the bupropion-induced increased locomotor activity found in wild-type animals was no longer observed in HD mice. We also found that acute administration with bupropion rescued depressive-like behaviours in HD animals, possibly through dopamine D2/D3 receptor mechanisms. Our present data are the first in vivo evidence of an impaired dopamine D1 receptor-dependent function in pre-motor symptomatic R6/1 HD mice. Moreover, our findings suggest clinical potential for bupropion to alleviate depressive symptoms in HD.


Assessment of plaque composition by intravascular ultrasound and near-infrared spectroscopy: from PROSPECT I to PROSPECT II.
Atherosclerosis is the main cause of coronary artery disease (CAD), which is today the leading cause of death worldwide and will continue to be the first in the world in 2030. Vulnerable coronary plaques are usually characterized by a high content of necrotic core, a thin inflamed fibrous cap (intense accumulation of macrophages) and scarce presence of smooth muscle cells. None of these characteristics can be estimated by coronary angiography, which on the contrary underestimates the magnitude of atherosclerotic burden, particularly in earlier stage disease when positive vascular remodeling may allow "normal" lumen caliber despite substantial vascular wall plaque. The recognition of the ubiquity of substantial but non-flow limiting lesions that may be at high risk for subsequent plaque rupture has resulted in a paradigm shift in thinking about the pathophysiology of CAD, with the focus no longer solely on the degree of arterial luminal narrowing. This growing need for more information about coronary atherosclerosis in order to identify patients and lesions at risk for complications during PCI and for future adverse cardiac events has been the primary impetus for the development of novel intracoronary imaging methods able to detect plaque composition, in particular presence of a necrotic core/lipid pool, such as intravascular ultrasound virtual histology and near-infrared spectroscopy. These imaging technologies and their clinical and clinical/research applications are discussed in detail.


Breast Cancer Diagnosis Using Texture and Shape Features in MRI.
Contrast-enhanced magnetic resonance (MR) breast imaging represents a tool with great potential for the detection, evaluation and diagnosis of breast cancer (BC). Due to its high sensitivity and in combination with medical imaging biomarkers, it can overcome setbacks and limitations manifested in other diagnostic modalities such as mammography or ultrasound. In order to aid and assist clinicians in the diagnosis of BC, a methodology based on the extraction of 2D texture and 3D shape features in MR images is proposed. To categorize breast tumor malignancy, we considered its location in the coronal plane, divided into 4 quadrants (UOQ, UIQ, LOQ and LOQ), and the tumor type according to its genetic information (positive HER2 and Luminal B with negative HER2). In this regard, six different studies were conducted: one per feature type (texture and shape), as well as the combination of both features (texture + shape) for each of the two covariables (tumor type and location in the coronal plane). A dataset of 43 BC patients were considered. A radiomics approach was implemented extracting 43 texture and 17 shape features and using to train 5 different predictive models (Linear SVM, Gaussian SVM, Bagged Tree, KNN and Naïve Bayes). The highest precision result for the tumor type study (74.04% in terms of AUC) was obtained with 43 texture features. Whereas for the quadrant localization study, the highest precision result (67.99% AUC) was obtained as a combination of 3 textures and shape features. Both results were achieved with the SVM with Linear Kernel classification model.Clinical Relevance- This work emphasizes the use of quantitative biomarkers as texture and shape features in combination with machine learning techniques to aid in breast tumor malignancy diagnosis on MR imaging. Moreover, considering the location of the tumor in the coronal plane and its type according to its genetic information may improve the selection of appropriate treatments, survival rate, and quality of life for breast cancer patients.


Peptide-MHC cellular microarray with innovative data analysis system for simultaneously detecting multiple CD4 T-cell responses.
Peptide:MHC cellular microarrays have been proposed to simultaneously characterize multiple Ag-specific populations of T cells. The practice of studying immune responses to complicated pathogens with this tool demands extensive knowledge of T cell epitopes and the availability of peptide:MHC complexes for array fabrication as well as a specialized data analysis approach for result interpretation. We co-immobilized peptide:DR0401 complexes, anti-CD28, anti-CD11a and cytokine capture antibodies on the surface of chamber slides to generate a functional array that was able to detect rare Ag-specific T cell populations from previously primed in vitro T cell cultures. A novel statistical methodology was also developed to facilitate batch processing of raw array-like data into standardized endpoint scores, which linearly correlated with total Ag-specific T cell inputs. Applying these methods to analyze Influenza A viral antigen-specific T cell responses, we not only revealed the most prominent viral epitopes, but also demonstrated the heterogeneity of anti-viral cellular responses in healthy individuals. Applying these methods to examine the insulin producing beta-cell autoantigen specific T cell responses, we observed little difference between autoimmune diabetic patients and healthy individuals, suggesting a more subtle association between diabetes status and peripheral autoreactive T cells. The data analysis system is reliable for T cell specificity and functional testing. Peptide:MHC cellular microarrays can be used to obtain multi-parametric results using limited blood samples in a variety of translational settings.


A study to evaluate the action of lipocryolysis.
Since ancient times human beings have been conceiving methods that could help reduce the accumulation of undesired fat tissue in their own bodies. Lipocryolysis has already been recognized as an therapy for localized fat reduction by means of a combination of regulated and controlled vacuum and heat extraction therapy. This study was designed to quantify the claimed reduction of local adiposities. For this purpose, 16 treatments were analysed. The data suggested that lipocryolysis is effective for localized reduction of adiposities and that the reduction obtained are measurable.


Impact of managed waiting for coronary artery bypass graft surgery on patients' perceived quality of life.
Current demand for CABG surgery remains high, often exceeds available resources, and has led to the development of managed waiting lists. This study was designed to determine how being placed on a managed waiting list for > 6 weeks for CABG surgery affected patients' perceived quality of life in a Canadian center. Telephone interviews were carried out in the setting of a large urban hospital in northern Alberta. All participants were identified from 3 waiting lists of adult patients waiting for open heart surgery. A master list of patient statements was compiled to formulate the 47-item Waiting List Impact Questionnaire (WLIQ). A total of 102 patients completed the WLIQ by telephone interview. Patients (87.5%) indicated that their quality of life had deteriorated since being placed on the waiting list. None of the patients perceived an improvement in their quality of life. Frequency data for the WLIQ provided a broad, multidimensional perspective of the experience of waiting for CABG surgery and its impact on perceived quality of life. Negative impact was found in each of 5 main themes: employment and income, physical stress, social support, frustration, and quality of life. This study indicates that patients perceived a negative impact on their quality of life after being placed on a managed waiting list for CABG surgery. In the allocation of healthcare resources, attention should be paid to the impact of waiting on patients' physical well-being as well as on quality of life.


Genomic/proteomic analyses of dexamethasone-treated human trabecular meshwork cells reveal a role for GULP1 and ABR in phagocytosis.
The purpose of this study is to examine the expression profile of genes related to integrin-mediated phagocytosis that are altered by dexamethasone (DEX) and/or αvβ3 integrin signaling to gain a better understanding of the molecular basis of phagocytosis and the pathophysiology of glucocorticoid-induced ocular hypertension. RNA and cell lysates were obtained from human trabecular meshwork (HTM) cells incubated with and without DEX for 4-5 d. The relative level of gene expression was evaluated using the Affymetrix Gene Chip® human gene microarray and quantitative PCR (qPCR). Changes in protein expression were validated using western blots or FACS analyses. The involvement of proteins in phagocytosis was determined using siRNA to knock down the expression of these proteins in an immortalized TM-1 cell line. Changes in the phagocytic activity were measured using pHrodo™-labeled S. aureus bioparticles followed by immunofluorescence microscopy. The effect of αvβ3 integrin expression and activity on GULP1 mRNA levels was measured using qPCR in TM-1 cells overexpressing wild type or constitutively active αvβ3 integrin. Gene microarrays revealed statistically significant differences (>2 fold) in the expression of seven genes known to be involved in phagocytosis. Three genes (CD36, ABR, and GULP1) were downregulated, while four genes (ITGB3, CHN1, PIK3R1, and MFGE8) were upregulated. The genes were either associated with modulating RAC1 activity (ABR and CHN1) or integrin signaling (CD36, GULP1, ITGB3, PIK3R1, and MFGE8). Another gene, SIRPA, was also downregulated (1.6 fold) but only in one cell strain. qPCR and western blot analyses verified that DEX caused a decrease in SIRPA and GULP1 mRNA and their protein levels, while levels of CHN1 mRNA and its protein were upregulated by DEX. qPCR showed that although ABR mRNA was downregulated compared to non-treated controls after 5 d of treatment with DEX, no change at the protein level was detected. qPCR analysis also revealed that DEX caused an increase in MFGE8 mRNA levels. The levels of CD36 mRNA and protein varied between cell strains treated with DEX and were not statistically different compared to controls. The knockdown of GULP1 and ABR using siRNAs decreased phagocytosis by 40%. Interestingly, GULP1 mRNA levels were also decreased by 60% when αvβ3 integrin was overexpressed in TM-1 cells. The DEX-induced inhibition of phagocytosis may be caused by the downregulation of ABR and GULP1 disrupting the αvβ5 integrin/RAC1-mediated engulfment pathway. The downregulation of GULP1 by αvβ3 integrin further suggests that this integrin may be a negative regulator of phagocytosis by transcriptionally downregulating proteins needed for phagocytosis. In summary, these results represent new insights into the effects of glucocorticoids and integrin signaling on the phagocytic process in the TM.


Effect of deletion and insertion on double-strand-break repair in Saccharomyces cerevisiae.
I investigated double-strand-break repair in Saccharomyces cerevisiae cells by measuring the frequencies and types of integration events at the PET56-HIS3-DED1 chromosomal region associated with the introduction of linearized plasmid DNAs containing homologous sequences. In general, the integration frequencies observed in strains containing a wild-type region, a 1-kilobase (kb) deletion, or a 5-kb insertion were similar, provided that the cleavage site in the plasmid DNA was present in the host genome. Cleavage at a plasmid DNA site corresponding to a region deleted in the chromosome caused a 10-fold reduction in the integration frequency even when the site was close to regions of homology. However, although the integration frequency was normal even when cleavage occurred only 25 base pairs (bp) outside the deletion breakpoint, 98% of the events were associated not with the usual heterogenote structure, but instead with a homogenote structure containing two copies of the deletion allele separated by vector sequences. Similarly, when cleavage occurred 80 bp outside the 5-kb substitution breakpoint, 40% of the integration events were associated with homogenote structures. From these observations, I suggest that exonuclease and polymerase activities are not rate-limiting steps in double-strand-break repair, exonuclease activity is coupled to the initiation step, the integration frequency is strongly influenced by the amount of homology near the recombinogenic ends, both ends of a linear DNA molecule might interact with the host chromosome before significant exonuclease or polymerase action, and the average repair tract is about 600 bp.


Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients.
The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk. We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk. Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect. Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.


Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome.
Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). To determine the role of LHCGR in transient, pregnancy-induced CS. We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone-positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R. Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient's adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11-deoxycortisol, cortisol, and androstenedione production. CTNNB1, PRKAR1A, ARMC5, and PRKACA gene mutational analyses were negative. Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus.


Depression partially mediates the relationship between alexithymia and somatization in a sample of healthy children.
A link between alexithymia and somatization has been widely established, yet little is known about different factors that may influence this relationship. Evidence supporting the idea of psychopathology as a mediator has been presented but not widely tested, particularly in children. The present study examined depressive symptoms as a mediator of alexithymia and somatization in a sample of healthy children in order to better understand the alexithymia-somatization link from a developmental perspective. Results indicated that depression significantly partially mediated this relationship, at least for two facets of alexithymia (difficulty identifying and describing feelings). Possible mechanisms, implications, and directions for future research are discussed.


Field-based detection of biological samples for forensic analysis: Established techniques, novel tools, and future innovations.
Field based forensic tests commonly provide information on the presence and identity of biological stains and can also support the identification of species. Such information can support downstream processing of forensic samples and generate rapid intelligence. These approaches have traditionally used chemical and immunological techniques to elicit the result but some are known to suffer from a lack of specificity and sensitivity. The last 10 years has seen the development of field-based genetic profiling systems, with specific focus on moving the mainstay of forensic genetic analysis, namely STR profiling, out of the laboratory and into the hands of the non-laboratory user. In doing so it is now possible for enforcement officers to generate a crime scene DNA profile which can then be matched to a reference or database profile. The introduction of these novel genetic platforms also allows for further development of new molecular assays aimed at answering the more traditional questions relating to body fluid identity and species detection. The current drive for field-based molecular tools is in response to the needs of the criminal justice system and enforcement agencies, and promises a step-change in how forensic evidence is processed. However, the adoption of such systems by the law enforcement community does not represent a new strategy in the way forensic science has integrated previous novel approaches. Nor do they automatically represent a threat to the quality control and assurance practices that are central to the field. This review examines the historical need and subsequent research and developmental breakthroughs in field-based forensic analysis over the past two decades with particular focus on genetic methods Emerging technologies from a range of scientific fields that have potential applications in forensic analysis at the crime scene are identified and associated issues that arise from the shift from laboratory into operational field use are discussed.


[Electron microscopy and immunohistochemical studies of the intraocular pressure lowering effect of prostaglandin F2 alpha].
Topically applied prostaglandin F2 alpha (PGF2 alpha) has been shown to lower intraocular pressure in cynomolgus monkeys. In this study the morphological changes following topical treatment of seven cynomolgus monkeys with 4 micrograms PGF2 alpha isopropylester for 5-8 days were investigated and compared with the eyes of five normal animals. Quantitative light microscopical, ultrastructural and immunhistochemical methods were used. No cellular signs of inflammation were seen in any of the eyes. Slight edema in the most anterior part of the ciliary processes occurred in most eyes, but only in parts of the circumference. The most pronounced change was dilation of the intramuscular spaces within the ciliary muscle. No changes were observed in the extracellular matrix within the muscle bundles, which consist partly of type IV and VI collagen, laminin and fibronectin. In the connective tissue between the muscle bundles, loss of collagen type I and III fibrils was observed. Additionally, macrophages were found with phagolysosomes containing phagocytized collagen fibrils. We suggest that loss of extracellular material leads to a widening of the uveoscleral outflow pathways of ciliary muscle and thereby to a reduction in intraocular pressure.


Elevated ozone effects on potato leaf physiology, growth, and yield: a meta-analysis.
Potato is an important crop worldwide and threatened by various environmental stresses, including elevated ozone (e[O3]). Here, we conducted a meta-analysis to quantify the effect of e[O3] on potato plants and how it varies depending upon different experimental conditions. Regarding plant growth and biomass, e[O3] significantly decreased shoot biomass by 18% and belowground biomass by 35%, while it increased the leaf area index by 19% and total number of injured leaves by 146%. As for yield, e[O3] significantly decreased the total tuber number by 21%. A relatively pronounced effect of e[O3] on the stomatal conductance was observed when exposure lasted 31-60 days, which was significantly greater than that after exposure lasted 96-311 days. The overall quantity of leaves was mainly decreased by higher (100-150 ppb) than lower (30-80 ppb) concentrations of e[O3] compared to ambient O3. The effect of e[O3] on the total tuber number was significant mainly when exposure lasted 31-90 days and was greater in plants grown in growth chambers than those planted in open-top chambers and glasshouses. The effect of e[O3] stress on physiology, growth, and yield varied among cultivars, with some cultivars showing marked tolerance relative to other cultivars. The findings can guide strategies to manage the negative impacts of e[O3] stress on potato production.


Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells.
Hepatocyte Growth Factor (HGF) receptor, encoded by the protooncogene c-met, is overexpressed in many human tumours, including those of thyroid epithelium. The absence in most cases of any primary structural abnormality of the met gene suggests that overexpression is secondary to mutation of other gene(s). To test this hypothesis we investigated the effect on met expression of two activated oncogenes known to play a major role in thyroid oncogenesis, ras and ret. To minimize the possibility of unknown co-operating events, we introduced these genes directly into normal human thyrocytes in primary culture using amphotropic retroviral vectors and assessed met expression as early as possible in the resulting epithelial colonies. Double immunofluorescence revealed expression of met protein, strictly localized to cells expressing the mutant ras and ret vectors, expression in background normal cells being barely detectable. In contrast, colonies induced to proliferate at a comparable rate by a vector expressing SV40 T showed no increase in met expression. To permit quantitation by Western blotting we also extended these findings to a thyroid cell line (R18) containing a zinc-inducible mutant ras gene. Induction of the oncogene led to a fourfold increase in met protein expression. We conclude that overexpression of met is induced by activation of the ras or ret signalling pathway and not simply by deregulation of the cell cycle per se. The data suggest that the proliferative advantage conferred by these oncogenes may be in part due to the resulting sensitization of tumour epithelium to paracrine HGF secreted by stromal cells.


cAMP regulates ADP-induced HSP27 phosphorylation in human platelets.
Elevation of cAMP in platelets is recognized to play a suppressive role in platelet functions. We have previously shown that adenosine diphosphate (ADP)-induced phosphorylation of heat shock protein 27 (HSP27) via p38 mitogen-activated protein (MAP) kinase is correlated with platelet-derived growth factor (PDGF)-AB secretion and soluble CD40 ligand (sCD40L) release. In the present study, we investigated the relationship between cAMP and HSP27 phosphorylation in platelet function. 8-Bromoadenosine-3',5'-cyclic monophosphate (8-bromo-cAMP), a plasma membrane-permeable cAMP analogue, or cilostazol, an inhibitor of cAMP phosphodiesterase, markedly attenuated the ADP-induced phosphorylation levels of p38 MAP kinase. In addition, the ADP-induced HSP27 phosphorylation was suppressed by 8-bromo-cAMP or cilostazol. 8-Bromo-cAMP, forskolin and cilostazol remarkably reduced the ADP-stimulated PDGF-AB secretion and sCD40L release. These results strongly suggest that cAMP regulates ADP-stimulated platelet activation due to inhibition of HSP27 phosphorylation via p38 MAP kinase.


[Combined therapy with amlodipin and lisinopril in arterial hypertension: efficacy of a low-dose combination].
To assess antihypertensive efficacy of a low-dose combination of amlodipin with lisinopril in the treatment of patients with arterial hypertension (AH) of the second degree. A total of 42 patients with the second degree of AH (16 males, 26 females, mean age 55-9 +/- 1.9 years) entered an open, comparative and controlled trial. They were divided into three groups by the treatment. Group 1 (n = 14) received amlodipin (normodipin, Gedeon Richter) monotherapy in a mean dose 8.9 +/- 0.6 mg/day, group 2 (n = 12) - lisinopril (diroton, Gedeon Richter) in a mean dose 17.5 +/- 1.4 mg/day, group 3 (n = 16) was given combined therapy with amlodipin+lisinopril in a dose 6.8 +/- 0.7 and 8.7 +/- 0.6 mg/day, respectively. The drugs were given for 12 weeks. The efficacy of the treatment was assessed by the results of 24-h monitoring of blood pressure, echocardiography, endothelium-related vasodilatation of the brachial artery (ERVD), dopplerographic investigation of circulation in the middle cerebral artery (MCA), heart rate and cost-effect estimation. Combined low-dose treatment with amlodipin and lisinopril for 12 weeks allowed achievement of target blood pressure in more patients and lower systolic and diastolic blood pressure than monotherapy with each of the drugs. There was also a positive effect on E/A index, ERVD, MCA circulation. Low-dose combined treatment with lisinopril and amlodipin is more effective and cost-efficient. Moreover, lisinopril addition to amlodipin corrects side effects of amlodipin on central nervous system.


An Analysis of Tumor- and Surgery-Related Factors that Contribute to Inadvertent Positive Margins Following Soft Tissue Sarcoma Resection.
The risk of local recurrence (LR) after soft tissue sarcoma (STS) resection is higher in the setting of inadvertent positive margins (IPMs). This study assessed whether both tumor- and surgery-related factors contribute to IPMs, and whether tumor- versus surgery-related IPMs differ in LR or overall survival (OS). Retrospective review of a tertiary center database identified patients with IPMs following STS resection between 1989 and 2014. Of 2234 resected STSs, 309 (13%) had positive margins; 89 (4%) were IPMs. Mean follow-up was 52 months, mean tumor size was 9.2 cm, and 55% were high grade. Cases were categorized as surgery-related (67, 75%) or tumor-related (22, 25%). There was a significant difference in positive margin location, with the deep margin commonly involved in surgery-related IPMs (55% vs. 9%; p < 0.001). Tissue type also differed (p = 0.01), with surgery-related IPMs frequently in muscle (33%), while tumor-related IPMs favored subcutaneous tissues (41%). STSs with surgery-related IPMs were larger (p = 0.01). Histologic subtypes differed (p = 0.02), with myxofibrosarcoma and undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma predominating in tumor-related IPMs (82%). The cumulative probability of LR after IPMs, with death as a competing risk, was 28% (95% confidence interval [CI] 18-35) at 5 years and 37% (95% CI 24-45) at 10 years. Mortality was 28% (95% CI 18-38) at 5 years and 38% (26-50) at 10 years. There was no difference in LR (p = 0.91) or OS (p = 0.44) between surgery- and tumor-related IPMS. IPMs after STS resection results in substantial LR risk. While demonstrating distinct surgery- and tumor-related contributions, there was no between-group difference in LR or OS. These results may aid in avoiding IPMs. Therapeutic Level III, retrospective comparative study.


[Ultrasound-guided placement of a median nerve catheter in the forearm. Pain-free mobilisation following arthrolysis and tenolysis].
The use of ultrasound is a fast growing area of regional anesthesia and pain medicine in practice and research. The technique of ultrasound-guided nerve block enables the visualization of peripheral nerves in the forearm and the insertion of a catheter for pain therapy. In a 37-year-old female a pain catheter was placed next to the median nerve. Ultrasound was used to visualize the nerve and to confirm correct catheter positioning and allowed extensive and painless early physiotherapy following arthrolysis and tenolysis of the flexor tendons.


Improving iSC performance through outsourcing - Considerations for using third-party service providers to increase innovation, capacity and efficiency.
Development partners and donors have encouraged and incentivized governments in developing countries to explore ways of working with third-party service suppliers to reduce costs and increase service delivery capacity. The distribution of vaccines and medicines has for a long time shown demand for outsourcing but public health systems have struggled to develop the expertise and capital assets necessary to manage such ventures. Existing transport and logistics capacity within public health systems, in particular, is well documented as being insufficient to support existing, let alone future immunization needs. Today, a number of countries are contracting party logistics providers (3PLs) to supplement the in-house distribution operations of public health systems. This commentary reflects on recent, leading examples of outsourcing initiatives to address critical gaps in transport and logistics.


Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers.
Amyloid beta (Abeta) may play a central role in the pathogenesis of Alzheimer disease. A functional gamma-secretase inhibitor, LY450139, was developed that inhibits Abeta formation in whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine the safety and tolerability of this drug, and the reduction of Abeta in plasma and cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 to 50 mg/day given for 14 days. Plasma and CSF concentrations of LY450139, Abeta(1-40) and Abeta(1-X) ("Abeta(total)") were determined, and safety and tolerability were assessed. The plasma half-life of LY450139 was approximately 2.5 hours. Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations, with a Cmax of 828 +/- 19.2 ng/mL after a 50-mg dose. Plasma Abeta concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration, with a maximum decrease of approximately 40% relative to baseline. After returning to baseline, Abeta concentrations were transiently increased. CSF Abeta concentrations were unchanged. Adverse events reported by subjects taking 5-mg, 20-mg, or 40-mg doses were similar to those reported by subjects taking placebo. Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related. In this phase 1 volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma Abeta was demonstrated, and changes in plasma Abeta concentrations were temporally related to the pharmacokinetic characteristics of LY450139.


Functional analysis of kisspeptin peptides in adult immature chub mackerel (Scomber japonicus) using an intracerebroventricular administration method.
In vertebrates (including teleosts), the pivotal hierarchical factor in the control of gonadotropin secretion is the hypothalamic gonadotropin-releasing hormone (GnRH) decapeptide, which regulates the release of pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Recently, kisspeptins encoded by the Kiss1 gene have been shown to act as upstream endogenous regulators of GnRH neurons in mammals. The chub mackerel (Scomber japonicus) brain expresses two kiss genes (kiss1 and kiss2) that show sexually dimorphic expression profiles during the seasonal gonadal cycle. In the present study, we evaluated the biological potency of kisspeptin peptides to induce transcriptional changes in gnrh1 (hypophysiotropic GnRH form in this species), fshβ and lhβ during the immature stage of adult chub mackerel (2+ years old). Synthetic Kiss1 pentadecapeptide (Kiss1-15) or Kiss2 dodecapeptide (Kiss2-12) at a dose of 100 ng were administered into the intracerebroventricular (ICV) region, and brains were sampled at 6 and 12 h post-injection. In female fish, gnrh1 levels decreased in the presence of both kisspeptin peptides at 12 h post-injection. No significant variation was observed in male fish. In contrast, ICV administration of Kiss2-12 (but not Kiss1-15) significantly increased fshβ and lhβ mRNAs at 12 h post-injection compared to a saline injected control in both sexes. These results suggested that synthetic Kiss2-12 could induce transcriptional changes in gnrh1 and gths.


[Effects of prolonged gamma irradiation and hypoxia on bioelectrical activity of myocardial cells].
It was established that prolonged gamma-irradiation of rats leads to the decrease of amplitude and duration of action potentials of right atrial cells, attenuation of the dependence of these electrophysiological characteristics upon the stimulation frequency, depression of the interval of cardiomyocytes reaction on the hypoxia. The revealed post-radiation changes determine the reduction of function resistance of heart cells bioelectrical activity and promote the initiation of arrhythmias.


Remobilization of Tol2 transposons in Xenopus tropicalis.
The Class II DNA transposons are mobile genetic elements that move DNA sequence from one position in the genome to another. We have previously demonstrated that the naturally occurring Tol2 element from Oryzias latipes efficiently integrates its corresponding non-autonomous transposable element into the genome of the diploid frog, Xenopus tropicalis. Tol2 transposons are stable in the frog genome and are transmitted to the offspring at the expected Mendelian frequency. To test whether Tol2 transposons integrated in the Xenopus tropicalis genome are substrates for remobilization, we injected in vitro transcribed Tol2 mRNA into one-cell embryos harbouring a single copy of a Tol2 transposon. Integration site analysis of injected embryos from two founder lines showed at least one somatic remobilization event per embryo. We also demonstrate that the remobilized transposons are transmitted through the germline and re-integration can result in the generation of novel GFP expression patterns in the developing tadpole. Although the parental line contained a single Tol2 transposon, the resulting remobilized tadpoles frequently inherit multiple copies of the transposon. This is likely to be due to the Tol2 transposase acting in discrete blastomeres of the developing injected embryo during the cell cycle after DNA synthesis but prior to mitosis. In this study, we demonstrate that single copy Tol2 transposons integrated into the Xenopus tropicalis genome are effective substrates for excision and random re-integration and that the remobilized transposons are transmitted through the germline. This is an important step in the development of 'transposon hopping' strategies for insertional mutagenesis, gene trap and enhancer trap screens in this highly tractable developmental model organism.


Ovulation inhibition with 17 beta-estradiol cyclo-octyl acetate and desogestrel.
Ovulation inhibition and bleeding control with a combination of 0.5 mg 17 beta-estradiol cyclo-octyl acetate (E2COA) and 0.15 mg desogestrel was investigated in 10 regularly menstruating women for 21 days. In half the group the treatment was extended for 7 days (days 22-28) with 0.03 mg desogestrel in order to evaluate any posttreatment influence on the gonadotropin levels. E2COA, beeing a long-chain fatty ester dissolved in oil, was expected to be resorbed from the intestinal wall via the lymphatic system. By incorporating it in the chylomicrons, E2COA would thereby avoid the unfavourable first liver pass. The serum levels of progesterone were suppressed during treatment. No increase in 17 beta-estradiol (E2) concentration was found; levels remained low and even during medication. No peak values of gonadotropins were seen. Thus follicular hormonal activity and ovulation was inhibited by this combination. Bleeding control was, however unacceptable in all volunteers. The addition of desogestrel during the fourth investigation week apparently did not induce any hormonal differences. The estrogenic activity is shown by the low, even S-E2 levels, but the dosage of E2COA seems to be too low in relation to progestogen dosage. Further studies will have to be performed in order to find the ideal combination.


The Emergence of AI-Based Wearable Sensors for Digital Health Technology: A Review.
Disease diagnosis and monitoring using conventional healthcare services is typically expensive and has limited accuracy. Wearable health technology based on flexible electronics has gained tremendous attention in recent years for monitoring patient health owing to attractive features, such as lower medical costs, quick access to patient health data, ability to operate and transmit data in harsh environments, storage at room temperature, non-invasive implementation, mass scaling, etc. This technology provides an opportunity for disease pre-diagnosis and immediate therapy. Wearable sensors have opened a new area of personalized health monitoring by accurately measuring physical states and biochemical signals. Despite the progress to date in the development of wearable sensors, there are still several limitations in the accuracy of the data collected, precise disease diagnosis, and early treatment. This necessitates advances in applied materials and structures and using artificial intelligence (AI)-enabled wearable sensors to extract target signals for accurate clinical decision-making and efficient medical care. In this paper, we review two significant aspects of smart wearable sensors. First, we offer an overview of the most recent progress in improving wearable sensor performance for physical, chemical, and biosensors, focusing on materials, structural configurations, and transduction mechanisms. Next, we review the use of AI technology in combination with wearable technology for big data processing, self-learning, power-efficiency, real-time data acquisition and processing, and personalized health for an intelligent sensing platform. Finally, we present the challenges and future opportunities associated with smart wearable sensors.


A flux extraction device to measure the magnetic moment of large samples; application to bulk superconductors.
We report the design and construction of a flux extraction device to measure the DC magnetic moment of large samples (i.e., several cm(3)) at cryogenic temperature. The signal is constructed by integrating the electromotive force generated by two coils wound in series-opposition that move around the sample. We show that an octupole expansion of the magnetic vector potential can be used conveniently to treat near-field effects for this geometrical configuration. The resulting expansion is tested for the case of a large, permanently magnetized, type-II superconducting sample. The dimensions of the sensing coils are determined in such a way that the measurement is influenced by the dipole magnetic moment of the sample and not by moments of higher order, within user-determined upper bounds. The device, which is able to measure magnetic moments in excess of 1 A m(2) (1000 emu), is validated by (i) a direct calibration experiment using a small coil driven by a known current and (ii) by comparison with the results of numerical calculations obtained previously using a flux measurement technique. The sensitivity of the device is demonstrated by the measurement of flux-creep relaxation of the magnetization in a large bulk superconductor sample at liquid nitrogen temperature (77 K).


Platelet-bound C4d, low C3 and lupus anticoagulant associate with thrombosis in SLE.
Low C3 and lupus anticoagulant (LAC) are known risk factors for thrombosis in SLE. We evaluated the association between C4d products deposited on platelets (PC4d) and thrombosis in SLE. Antiphosphatidyl serine/prothrombin (PS/PT) complex antibody was also evaluated as an alternative to LAC. This was a cross-sectional analysis of 149 consented patients with SLE (mean age: 47±1 years, 86% female) classified with (n=16) or without (n=133) thrombotic events in the past 5 years. Abnormal PC4d (≥20 units) was measured using flow cytometry. LAC and C3 were measured using dilute Russell's viper venom time (>37 s) and immunoturbidimetry, respectively. Anti-PS/PT antibody status (IgG) was measured by immunoassay. Statistical analysis consisted of logistic regression and calculation of OR estimates with 95% CI. Abnormal PC4d (OR=8.4, 95% CI 2.8 to 24.8), low C3 (OR=9.5, 95% CI 3.0 to 30.3), LAC (OR=5.4, 95% CI 1.3 to 22.3) and anti-PS/PT IgG (OR=3.4, 95% CI 1.2 to 9.7) status associated with thrombosis (p<0.05). Cumulatively, the presence of PC4d, low C3 and LAC abnormalities as a composite risk score was higher in the presence of thrombosis (1.93±0.25) than in its absence (0.81±0.06) (p<0.01). Each unit of this composite risk score yielded an OR of 5.2 (95% CI 2.5 to 10.7) to have thrombosis (p<0.01). The composite risk score with anti-PS/PT antibody status instead of LAC also associated with thrombosis (p<0.01). A composite risk score including PC4d, low C3 and LAC was associated with recent thrombosis and acknowledges the multifactorial nature of thrombosis in SLE.


Cystic meningioma simulating arachnoid cyst: report of an unusual case.
The purpose of this paper is to show an unusual case of meningioma simulating arachnoid cyst on CT scan and MRI, diagnosed in a 63-year-old woman evaluated for headache and vision disorders. The meningioma shown is predominantly cystic with a small mural nodule enhancing after gadolinium and exhibiting diffusion restriction. Cystic portion of the tumor is hypodense on CT, and evidences fluid signal intensity on T1- and T2-weighted MR imaging.


Assessment of residual-limb volume change using bioimpedence.
We investigated electrical bioimpedance as a potential measurement modality to assess residual-limb volume change in lower-limb amputees. Four strip electrodes were positioned across the anterior lateral to posterior lateral aspects of the proximal lower leg or residual limb such that the outer pair applied current and the inner pair sensed voltage. A commercial bioimpedance analyzer supplied current at 50 fre quencies between 5 kHz and 1 MHz and then used a well-validated model to determine fluid resistance. From these data, extracellular fluid volume (V(ECF)) could be estimated. Bench test evaluation showed the instrument to have a root-mean-square error of less than 0.014% over a 1 h interval. Tests of subjects who had been transtibial amputees for at least 2 yr showed V(ECF) changes from postural adjustments well outside the instrument error and normal minute-to-minute biological variability. The rate of V(ECF) change while standing with the prosthesis donned was greater for diabetic subjects than for nondiabetic subjects. Bioimpedance analysis may have use in prosthetics research, where comparing residual-limb volume at different time points or under different treatment conditions is of interest.


Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies.
Glucagon-like peptide (GLP)-1 is a potent glucose-dependent insulinotropic gut hormone released from intestinal L cells. Our previous studies showed that berberine increased GLP-1 secretion in streptozotocin-induced diabetic rats. The aim of this study was to investigate whether berberine affected GLP-1 release in normal rats and in NCI-H716 cells. Proglucagon and prohormone convertase 3 genes regulating GLP-1 biosynthesis were analyzed by RT-PCR. Effects of pharmacological inhibitors on berberine-mediated GLP-1 release were studied. In vivo, 5-week treatment of berberine enhanced GLP-1 secretion induced by glucose load and promoted proglucagon mRNA expression as well as L cell proliferation in intestine. In vitro, berberine concentration-dependently stimulated GLP-1 release in NCI-H716 cells. Berberine also promoted both prohormone convertase 3 and proglucagon mRNA expression. Chelerythrine (inhibitor of PKC) concentration-dependently suppressed berberine-mediated GLP-1 secretion. Compound C (inhibitor of AMPK) also inhibited berberine-mediated GLP-1 secretion. But only low concentrations of H89 (inhibitor of PKA) showed inhibitory effects on berberine-mediated GLP-1 release. The present results demonstrated that berberine showed its modulation on GLP-1 via promoting GLP-1 secretion and GLP-1 biosynthesis. Some signal pathways including PKC-dependent pathway were involved in this process. Elucidation of mechanisms controlling berberine-mediated GLP-1 secretion may facilitate the understanding of berberine's antidiabetic effects.


Structural changes after transmitter release at the frog neuromuscular junction.
The sequence of structural changes that occur during synaptic vesicle exocytosis was studied by quick-freezing muscles at different intervals after stimulating their nerves, in the presence of 4-aminopyridine to increase the number of transmitter quanta released by each stimulus. Vesicle openings began to appear at the active zones of the intramuscular nerves within 3-4 ms after a single stimulus. The concentration of these openings peaked at 5-6 ms, and then declined to zero 50-100 ms late. At the later times, vesicle openings tended to be larger. Left behind at the active zones, after the vesicle openings disappeared, were clusters of large intramembrane particles. The larger particles in these clusters were the same size as intramembrane particles in undischarged vesicles, and were slightly larger than the particles which form the rows delineating active zones. Because previous tracer work had shown that new vesicles do not pinch off from the plasma membrane at these early times, we concluded that the particle clusters originate from membranes of discharged vesicles which collapse into the plasmalemma after exocytosis. The rate of vesicle collapse appeared to be variable because different stages occurred simultaneously at most times after stimulation; this asynchrony was taken to indicate that the collapse of each exocytotic vesicle is slowed by previous nearby collapses. The ultimate fate of synaptic vesicle membrane after collapse appeared to be coalescence with the plasma membrane, as the clusters of particles gradually dispersed into surrounding areas during the first second after a stimulus. The membrane retrieval and recycling that reverse this exocytotic sequence have a slower onset, as has been described in previous reports.


Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids.
Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. Two hundred twenty-four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. High serum periostin levels (≥ 95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS.


Sentinel node navigation in gastric cancer: new horizons for personalized minimally invasive surgical oncology?
Complete (R0) resection and regional lymph nodes (LNs) dissection represent undoubtedly the basic surgical tools for patients with gastric cancer. It is reported that the LN metastasis rate in patients with early gastric cancer (EGC) is approximately 15-20%. Therefore, the innovative clinical application of sentinel node navigation surgery (SNNS) for EGC might be able to prevent unnecessary LN dissection as well as to reduce significantly the volume of gastric resection. Recent evidence suggests that double tracer methods appear superior compared to single tracer techniques. However, the researchers' interest is now focused on the identification of new LN detection methods utilizing sophisticated technology such as infrared ray endoscopy, fluorescence imaging and near-infrared technology. Despite its notable limitations, hematoxylin-eosin is still considered the mainstay staining for assessing the metastatic status of LNs. In this review, we summarize the current evidences and we provide the latest scientific information assessing safety, efficacy and potential limitations of the innovative sentinel node (SN) navigation technique for gastric cancer. We try also to provide a "view" towards a future potential application of personalized minimally invasive surgery in gastric cancer field.


Theodore von karman and applied mathematics in america.
The emergence of applied mathematics as a discipline in the United States is traditionally associated with World War II. Hungarian-born Theodore von Kármán was among those who had waged a long and vigorous campaign well before the war to make applied mathematics respectable to engineers and mathematicians. While advocating the use of mathematics and physics to solve applied problems, he challenged the prevailing philosophy of engineering programs, locked horns with recalcitrant journal editors, and generally encountered the obstacles to building a discipline that cuts across conventional boundaries.


Follicular and Hürthle cell thyroid neoplasms. Is frozen-section evaluation worthwhile?
To determine whether (1) frozen-section (FS) evaluation of follicular and Hürthle cell thyroid neoplasms (FHCNs) is accurate, (2) FS aids in intraoperative decision-making, and (3) FS is cost-effective. Retrospective review of patient histories and FS and paraffin-embedded slides. Permanent histologic sections were considered the standard criterion. Follow-up was achieved in 92% of patients with a mean follow-up of 5.7 years. Tertiary care referral center. All patients undergoing thyroidectomy for a suspected FHCN between January 1, 1985, and December 31, 1994. Patients included were those whose condition was diagnosed as FHCN, either on FS, permanent histologic sections, or both. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FS analysts were determined. Total adjusted hospital charges were compared for those undergoing 1 vs 2 cancer operations. Multivariate analyses were carried out to determine the optimal predictive model for follicular cancer. The study group included 1023 patients (737 women and 286 men), of whom 83 (8.1%) were diagnosed as having a malignant FHCN on permanent section. The diagnosis of malignant neoplasm was correctly established in 65 (78%) of the 83 patients on FS, thereby permitting definitive surgical management at the first operation. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for FS diagnosis of malignant FHCN were 78%, 99%, 90%, 98%, and 98%, respectively. In a multivariate analysis, FS was the most significant variable predictive of malignant neoplasm. Approximately $400,000 was saved in hospital charges by the use of FS as a result of the elimination of many 2-stage operations. Frozen-section evaluation of FHCN can be performed with a high degree of accuracy, permitting considerable cost savings.


Cowpox: reservoir hosts and geographic range.
It is generally accepted that the reservoir hosts of cowpox virus are wild rodents, although direct evidence for this is lacking for much of the virus's geographic range. Here, through a combination of serology and PCR, we demonstrate conclusively that the main hosts in Great Britain are bank voles, wood mice and short-tailed field voles. However, we also suggest that wood mice may not be able to maintain infection alone, explaining the absence of cowpox from Ireland where voles are generally not found. Infection in wild rodents varies seasonally, and this variation probably underlies the marked seasonal incidence of infection in accidental hosts such as humans and domestic cats.


The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation.
The possibility that μ opioid agonists can influence cancer recurrence is a subject of recent interest. Epidemiologic studies suggested that there were differences in cancer recurrence in breast and prostate cancer contingent on anesthetic regimens. In this study, we identify a possible mechanism for these epidemiologic findings on the basis of μ opioid receptor (MOR) regulation of Lewis lung carcinoma (LLC) tumorigenicity in cell and animal models. We used human lung tissue and human non-small cell lung cancer (NSCLC) cell lines and evaluated MOR expression using immunoblot and immunohistochemical analysis. LLC cells were treated with the peripheral opioid antagonist methylnaltrexone (MNTX) or MOR shRNA and evaluated for proliferation, invasion, and soft agar colony formation in vitro and primary tumor growth and lung metastasis in C57BL/6 and MOR knockout mice using VisEn fluorescence mediated tomography imaging and immunohistochemical analysis. We provide several lines of evidence that the MOR may be a potential target for lung cancer, a disease with high mortality and few treatment options. We first observed that there is ∼5- to 10-fold increase in MOR expression in lung samples from patients with NSCLC and in several human NSCLC cell lines. The MOR agonists morphine and [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) increased in vitro LLC cell growth. Treatment with MNTX or silencing MOR expression inhibited LLC invasion and anchorage-independent growth by 50%-80%. Injection of MOR silenced LLC lead to a ∼65% reduction in mouse lung metastasis. In addition, MOR knockout mice do not develop significant tumors when injected with LLC in comparison with wild-type controls. Finally, continuous infusion of the peripheral opioid antagonist MNTX attenuates primary LLC tumor growth and reduces lung metastasis. Taken together, our data suggest a possible direct effect of opiates on lung cancer progression, and provide a plausible explanation for the epidemiologic findings. Our observations further suggest a possible therapeutic role for opioid antagonists.


Current Insight into Novel Delivery Approaches of Resveratrol for Improving Therapeutic Efficacy and Bioavailability with its Clinical Updates.
Resveratrol (RSV) is a polyphenolic phytoalexin, and belongs to the stilbene family. RSV has several therapeutic activities such as cardioprotective, anticancer, and antioxidant. Apart from its therapeutic benefits, its pharmacological uses are limited due to low solubility, poor bioavailability, and short biological halflife. A researcher continuously focuses on overcoming the limitations of RSV through nanotechnology platforms to get the optimum health benefits. In this context, nanocarriers are pioneering to overcome these drawbacks. Nanocarriers possess high drug loading capacity, thermal stability, low production cost, longer shelflife, etc. Fortunately, scientists were proficient in delivering resveratrol-based nanocarriers in the present scenario. Nanocarriers can deliver drugs to the target sites without compromising the bioavailability. Thus, this review highlights how the latest nanocarrier systems overcome the shortcomings of RSV, which will be good for improving therapeutic efficacy and bioavailability. Moreover, recent updates on resveratrol-based novel formulations and their clinical trials have been addressed to manage several health-related problems.


Mountain gorilla genomes reveal the impact of long-term population decline and inbreeding.
Mountain gorillas are an endangered great ape subspecies and a prominent focus for conservation, yet we know little about their genomic diversity and evolutionary past. We sequenced whole genomes from multiple wild individuals and compared the genomes of all four Gorilla subspecies. We found that the two eastern subspecies have experienced a prolonged population decline over the past 100,000 years, resulting in very low genetic diversity and an increased overall burden of deleterious variation. A further recent decline in the mountain gorilla population has led to extensive inbreeding, such that individuals are typically homozygous at 34% of their sequence, leading to the purging of severely deleterious recessive mutations from the population. We discuss the causes of their decline and the consequences for their future survival.


Patients With Multiple Myeloma Have More Complications After Surgical Treatment of Hip Fracture.
Bone lesions from multiple myeloma may lead to pathological fracture of the proximal femur, requiring either fixation or arthroplasty. Little is known about the impact of multiple myeloma on hip fracture care. We investigated whether the patients with multiple myeloma undergoing surgical treatment of hip fractures would be at increased risk for adverse outcomes versus patients who sustain a hip fracture without multiple myeloma. Using discharge records from the Nationwide Inpatient Sample (2002-2011), we identified 2 440 513 patients older than 50 years of age with surgically treated hip fractures. Of which, 4011 (0.2%) were found to have multiple myeloma. We compared perioperative outcomes between the patients with multiple myeloma and the nonmultiple myeloma patients using multivariable logistic regression modeling. Patients with multiple myeloma were more likely to have several postoperative complications, such as in-hospital pneumonia (odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.14-1.51), sepsis (OR: 1.72, 95% CI: 1.32-2.25), surgical site infection (OR: 1.66, 95% CI: 1.38-2.00), and acute renal failure (OR: 1.28, 95% CI: 1.14-1.43). We found that myeloma was not associated with increased inpatient mortality, myocardial infarction, respiratory failure, thromboembolic events, or pulmonary embolism. Patients with multiple myeloma are at increased risk for immediate postoperative complications following surgical treatment of hip fractures including in-hospital pneumonia, surgical site infection, and acute renal failure but not hospital mortality, when compared to hip fracture patients without multiple myeloma. Perioperative management of hip fractures in patients with myeloma may be optimized by increased awareness of these risks in this subset of patients.


Plasticity in the oculomotor system.
The oculomotor system, responsible for the control of eye movement, is capable of a number of kinds of plasticity. The demonstration of such plasticity has been aided by several factors, including the present delineation of the system's major subsystems and their purposes; the relatively simple relationships between the system and the mechanical apparatus on which it acts, the eyeball and its muscles; and the development of techniques for studying central nervous system (CNS) activity in awake, behaving animals. Plasticity has been demonstrated by using noninvasive techniques to disturb the normal relationship between vision and eye movements, thereby creating a need for adjustment by the oculomotor system. Current studies are concerned with the location and identity of the responsible modifiable synapses. The cerebellum and the olivocerebellar pathways are definitely involved in several forms of oculomotor plasticity. However, it remains to be determined whether the responsible changes reside within these structures or are located elsewhere in the CNS.


Integrative bayesian network analysis of genomic data.
Rapid development of genome-wide profiling technologies has made it possible to conduct integrative analysis on genomic data from multiple platforms. In this study, we develop a novel integrative Bayesian network approach to investigate the relationships between genetic and epigenetic alterations as well as how these mutations affect a patient's clinical outcome. We take a Bayesian network approach that admits a convenient decomposition of the joint distribution into local distributions. Exploiting the prior biological knowledge about regulatory mechanisms, we model each local distribution as linear regressions. This allows us to analyze multi-platform genome-wide data in a computationally efficient manner. We illustrate the performance of our approach through simulation studies. Our methods are motivated by and applied to a multi-platform glioblastoma dataset, from which we reveal several biologically relevant relationships that have been validated in the literature as well as new genes that could potentially be novel biomarkers for cancer progression.


Anticonvulsant effect of equilibrative nucleoside transporters 1 inhibitor in a mouse model of Dravet syndrome.
There are limited therapeutic options for patients with Dravet syndrome (DS). The equilibrative nucleoside transporters 1 (ENT1) mediate both the influx and efflux of adenosine across the cell membrane exerted beneficial effects in the treatment of epilepsy. This study aimed to evaluate the anticonvulsant effect of the ENT1 inhibitor in an animal model of DS (Scn1aE1099X/+ mice). J7 (5 mg/kg) treatment was efficacious in elevating seizure threshold in Scn1aE1099X/+ mice after hyperthermia exposure. Moreover, the J7 treatment significantly reduced the frequency of spontaneous excitatory post-synaptic currents (sEPSCs, ~35% reduction) without affecting the amplitude in dentate gyrus (DG) granule cells. Pretreatment with the adenosine A1 receptor (A1R) antagonist, DPCPX, abolished the J7 effects on sEPSCs. These observations suggest that the J7 shows an anticonvulsant effect in hyperthermia-induced seizures in Scn1aE1099X/+ mice. This effect possibly acts on presynaptic A1R-mediated signaling modulation in granule cells.


Thoracoscopy in the evaluation and management of thoracic trauma.
Video-thoracoscopy was used to evaluate and manage patients after thoracic trauma. It was used in 29 patients. Indications included retained hemothorax in 16 patients, empyema in 11, evaluation for the source of thoracic bleeding in 1, and an airleak in 1. The mechanism of injury was blunt trauma in 8 cases, 10 with stab wounds, and 11 with gunshot wounds. In blunt trauma, thoracoscopy was carried out an average of 11.7 days post injury, chest tubes were removed after an average of 7 days post thoracoscopy, and discharge averaged 10.7 days after thoracoscopy. The failure rate was 12.5% with no mortality. In stab wounds, it was carried out an average of 8.8 days post injury, chest tube removal occurred after 6.1 days, and discharge averaged 7.8 days after thoracoscopy. The failure rate was 20% with no mortality. In gunshot wounds, it was carried out an average of 7.5 days after injury, chest tubes were removed after 9.9 days, and discharge averaged 16 days post thoracoscopy. The failure rate was 9% with a mortality of 9%. Overall, the failure rate for thoracoscopy was 13.8% (4/29). The mortality rate was 3.5% (1/29). It was successfully performed up to 30 days post injury. It proved to be effective in the management of empyema, evacuation of clotted hemothorax, and diagnosis of ongoing thoracic bleeding.


Highly efficient Gab2 siRNA delivery to ovarian cancer cells mediated by chitosan-polyethyleneimine nanoparticles.
Malignant bowel obstruction (MBO) is a serious complication which causes high death rate and low quality of life (QOL) for patients diagnosed at an advanced stage of ovarian cancer. RNA interference (RNAi) could be a promising method for the treatment of ovarian cancer and could decrease the morbidity of MBO. Gab2 gene is overexpressed in ovarian cancer compared with normal ovarian tissue, and regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Here, chitosan-polyethyleneimine (PEI, Mw 1800) copolymer nanoparticles were synthesized as nanocarriers to deliver Gab2 siRNA into SKOV3 cells. The silencing effects against the Gab2 gene and the antitumor effects by the chitosan-PEI-Gab2 siRNA nanoparticles (chitosan-PEI-Gab2 NPs) were studied. Results showed that highly efficient silencing effects against Gab2 expression and its downstream effector, AKT protein, at more than 90% deregulation were obtained by chitosan-PEI NP mediated Gab2 siRNA delivery, so as to exhibit obvious antitumor effects against SKOV3 cells with low cytotoxicity, and induce cell apoptosis in early and late stages. The study will provide novel strategies to overcome MBO in ovarian cancer by the efficient knockdown of Gab2 expression.


A door-to-needle time of 30 minutes or less for myocardial infarction thrombolysis is possible in rural emergency departments.
The Canadian Emergency Cardiac Care Coalition, the American Heart Association and similar groups have established a benchmark for the administration of thrombolytics in acute myocardial infarction (AMI) care as a door-to-needle (DTN) time of 30 minutes or less. Previous research suggests that this goal is not being achieved in Canada. The purpose of this study was to determine whether the target DTN time of 30 minutes or less for thrombolysis could be met in 2 rural Ontario emergency departments (EDs). We conducted a retrospective chart review and obtained descriptive data for each case, including demographic information and the Canadian Emergency Department Triage and Acuity Scale (CTAS) score. Visit timeline data were also collected and included the time during which patients saw a physician, had an electrocardiogram (ECG), received thrombolytic therapy and were discharged from the ED. Relevant time intervals, such as the median DTN time, were calculated. A total of 454 charts were reviewed for patients with a diagnosis of AMI who were seen between 1996 and 2007. The final sample consisted of 101 patients who received thrombolytics (63% men) whose median age was 67 years and median CTAS score was Level II (Emergent). The median door-to-ECG time was 6 minutes, door-to-physician time was 8 minutes and DTN time was 27 minutes; 58% of patients received thrombolytics within 30 minutes. A DTN time of 30 minutes or less is achievable in rural EDs.


Artificial intelligence for prenatal chromosome analysis.
This review article delves into the rapidly advancing domain of prenatal diagnostics, with a primary focus on the detection and management of chromosomal abnormalities such as trisomy 13 ("Patau syndrome)", "trisomy 18 (Edwards syndrome)", and "trisomy 21 (Down syndrome)". The objective of the study is to examine the utilization and effectiveness of novel computational methodologies, such as "machine learning (ML)", "deep learning (DL)", and data analysis, in enhancing the detection rates and accuracy of these prenatal conditions. The contribution of the article lies in its comprehensive examination of advancements in "Non-Invasive Prenatal Testing (NIPT)", prenatal screening, genomics, and medical imaging. It highlights the potential of these techniques for prenatal diagnosis and the contributions of ML and DL to these advancements. It highlights the application of ensemble models and transfer learning to improving model performance, especially with limited datasets. This also delves into optimal feature selection and fusion of high-dimensional features, underscoring the need for future research in these areas. The review finds that ML and DL have substantially improved the detection and management of prenatal conditions, despite limitations such as small sample sizes and issues related to model generalizability. It recognizes the promising results achieved through the use of ensemble models and transfer learning in prenatal diagnostics. The review also notes the increased importance of feature selection and high-dimensional feature fusion in the development and training of predictive models. The findings underline the crucial role of AI and machine learning techniques in early detection and improved therapeutic strategies in prenatal diagnostics, highlighting a pressing need for further research in this area.


The effect of very-low-calorie diet on mitochondrial dysfunction in subcutaneous adipose tissue and peripheral monocytes of obese subjects with type 2 diabetes mellitus.
Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low-calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM.