[Pathological study on abducent paralysis of the vocal cord in a patient having multiple system atrophy with nasogastric intubation].
A 74-year-old man developed instability of gait from age 64, difficulty in writing from age 66 and dysarthria-hypohidrosis from around age 67. These symptoms progressed slowly accompanied with orthostatic hypotension and dysarthria, which decline his ADL. At age 71, he was admitted to our hospital and underwent nasogastric intubation. After admission, he also showed the decrease in his voluntary activities, accidental ingestion and loud snoring during sleep. He died of accidental aspiration pneumonia at age 74. Postmortem examination revealed severe pathological changes as multiple system atrophy (MSA) in the central nervous system. There was a small ulcer in the hypopharyngeal region, and acute inflammation of the ulcer came down to the posterior cricoarytenoid muscle. Combined with severe neurogenic atropy due to MSA, local inflammation of the ulcer associated with nasogastric intubation appeared to have resulted in severe damage of the posterior cricoarytenoid muscle.


Encoding and processing of alphanumeric information by chemical mixtures.
A novel infochemical device that is based on (1)H NMR readout of chemical information is presented. This chemical encoding system utilizes two measurable parameters of homogeneous mixtures, chemical shift and peak integration, for three different applications: 1) a text-encoding device that is based on spectral representation of a sequence of symbols, 2) encoding of 21-digit binary numbers, each represented by an NMR spectrum, and their algebraic manipulations, such as addition and subtraction, and 3) encoding of 21-digit decimal numbers. The first application enables molecular information storage and encryption. The relative concentration of each component, as measured by the relevant peak integration, can represent a symbol. The second application of this system, in addition to its obvious memory capability, enables mathematical operations. The NMR spectrum of a given mixture represents a 21-digit binary number where each of the peaks encodes for a specific digit. In any of the input mixtures (numbers) each compound is either present or absent, representing either 1 or 0, respectively. We used the various binary numbers to carry out addition operations by combining two or more solutions (numbers). Subtraction operations were also preformed by digital processing of the information. The third application is the representation of decimal numbers. As before, each of the peaks encodes for a specific digit. In any of the input mixtures each compound is present in one of 10 different relative concentrations, representing the 10 digits of a decimal number.


Droplet-based microfluidics in biomedical applications.
Droplet-based microfluidic systems have been employed to manipulate discrete fluid volumes with immiscible phases. Creating the fluid droplets at microscale has led to a paradigm shift in mixing, sorting, encapsulation, sensing, and designing high throughput devices for biomedical applications. Droplet microfluidics has opened many opportunities in microparticle synthesis, molecular detection, diagnostics, drug delivery, and cell biology. In the present review, we first introduce standard methods for droplet generation (i.e. passive and active methods) and discuss the latest examples of emulsification and particle synthesis approaches enabled by microfluidic platforms. Then, the applications of droplet-based microfluidics in different biomedical applications are detailed. Finally, a general overview of the latest trends along with the perspectives and future potentials in the field are provided.


Pilot study: evaluation of the use of the convergent interview technique in understanding the perception of surgical design and simulation.
It is important to understand the perceived value of surgical design and simulation (SDS) amongst surgeons, as this will influence its implementation in clinical settings. The purpose of the present study was to examine the application of the convergent interview technique in the field of surgical design and simulation and evaluate whether the technique would uncover new perceptions of virtual surgical planning (VSP) and medical models not discovered by other qualitative case-based techniques. Five surgeons were asked to participate in the study. Each participant was interviewed following the convergent interview technique. After each interview, the interviewer interpreted the information by seeking agreements and disagreements among the interviewees in order to understand the key concepts in the field of SDS. Fifteen important issues were extracted from the convergent interviews. In general, the convergent interview was an effective technique in collecting information about the perception of clinicians. The study identified three areas where the technique could be improved upon for future studies in the SDS field.


Building resilience: a mental health intervention for Tanzanian youth living with HIV.
Despite a growing population of youth living with HIV, few interventions have been developed to address their unique mental health needs and to promote resilience. Based on our prior needs assessment, a mental health intervention, Sauti ya Vijana ( The Voice of Youth), was developed to address identified mental health needs and promote resilience. The intervention emphasized resilience strategies for identifying and coping with stressful events, supporting strong familial and social relationships, and planning for a safe and healthy living environment through stigma reduction, planning for disclosure, and instilling hope for the future. Ten group sessions (two of which were joint youth/caregiver sessions) and two individual sessions were developed around these three resilience domains. Youth living with HIV (average age 17.4 years), who were receiving antiretroviral therapy and attending HIV adolescent clinic in Tanzania were randomized to intervention or treatment as usual. Trained group leaders led the intervention sessions. Near perfect program fidelity by the group leaders and unanimous acceptance of the intervention by the youth was documented. SYV successfully promoted youth resilience as measured by youth-reported utilization of new coping skills, improved peer and caregiver relationships, reduced stigma, and improved confidence to live positively according to their personal values.


Sound transmission and the recognition of temporally degraded sexual advertisement signals in Cope's gray treefrog (Hyla chrysoscelis).
Acoustic communication signals degrade as they propagate between signalers and receivers. While we generally understand the degrading effects of sound propagation on the structure of acoustic signals, we know considerably less about how receivers make behavioral decisions based on the perception of degraded signals in sonically and structurally complex habitats where communication occurs. In this study of acoustic mate recognition in Cope's gray treefrog, Hyla chrysoscelis (Cope 1880), we investigated how the temporal structure of male advertisement calls was compromised by propagation in a natural habitat and how females responded to stimuli mimicking various levels of temporal degradation. In a sound transmission experiment, we quantified changes in the pulsed structure of signals by broadcasting synthetic calls during active choruses from positions where we typically encountered signalers, and re-recording the signals from positions where we typically encountered potential receivers. Our main finding was that the silent gaps between pulses become increasingly 'filled in' by background noise and reverberations as a function of increasing propagation distance. We also conducted female phonotaxis experiments to determine the threshold modulation depth required to elicit recognition of the pulsatile structure of the call. Females were surprisingly tolerant of degraded temporal structure, and there was a tendency for greater permissiveness at lower playback levels. We discuss these results in terms of presumed mechanisms of call recognition in complex environments and the acoustic adaptation hypothesis.


Biomechanical Relationships Between Manual Wheelchair Steering and the Position of the Human Body's Center of Gravity.
The purpose of this investigation was to analyze the impact of differential steering of a wheelchair with a pushrim on changes in the position of the body's center of gravity. The method assumed measuring the wheelchair trajectory and the body's center of gravity and determining the transverse relocation of the measured body's center of gravity in relation to a point on the wheelchair trajectory. Twenty-seven measurement tests which demonstrated various wheelchair trajectories were carried out within the investigation. The trajectories were 10 to 15 m long and involved moving forward (test 2), reversing (test 3), turning left (test 1) and right (test 4). The factor of deviation of the center of gravity of human body from the wheelchair trajectory was determined for selected characteristic turning maneuvers. The measured values ranged from 51 to 192 mm. The impact of the wheelchair trajectory on the position of the body's center of gravity was demonstrated as a result of this investigation. Consequently, a trajectory deviation factor for relocation of the human body weight on one side of the wheelchair has been demonstrated.


Production, recognition and treatment of digitalis intoxication.
Recent studies dealing with absorption, distribution in the body and fate of digitalis, have provided a basis for better understanding the great variability of individual responses to this drug. When given to patients in sinus rhythm as a cardiotonic agent, digitalis action cannot be accurately assessed nor monitored by appropriate tests; consequently, blind administration of the drug on average dosages inevitably produces digitalis intoxication in a proportion of patients. Clinical signs of digitalis toxicity, factors enhancing its development, its recognition and treatment are summarized here. It is emphasized that digitalis should always be administered as a calculated risk, when benefits are clearly defined, as in overt cardiac failure and in atrial fibrillation associated with excessive ventricular rates. Use for other indications, particularly prophylactic, should be considered experimental and is to be discouraged.


Three-dimensional reconstruction of metabolic data from quantitative autoradiography of rat brain.
Quantitative autoradiography is a powerful method for studying brain function by the determination of blood flow, glucose utilization, or transport of essential nutrients. Autoradiographic images contain vast amounts of potentially useful information, but conventional analyses can practically sample the data at only a small number of points arbitrarily chosen by the experimenter to represent discrete brain structures. To use image data more fully, computer methods for its acquisition, storage, quantitative analysis, and display are required. We have developed a system of computer programs that performs these tasks and has the following features: 1) editing and analysis of single images using interactive graphics, 2) an automatic image alignment algorithm that places images in register with one another using only the mathematical properties of the images themselves, 3) the calculation of mean images from equivalent images in different experimental serial image sets, 4) the calculation of difference images (e.g., experiment-minus-control) with the option to display only differences estimated to be statistically significant, and 5) the display of serial image metabolic maps reconstructed in three dimensions using a high-speed computer graphics system.


Can bispectral index monitoring predict recovery of consciousness in patients with severe brain injury?
The probability of recovering consciousness in acute brain-injured patients depends on central nervous system damage and complications acquired during their stay in the intensive care unit. The objective of this study was to establish a relation between the Bispectral Index (BIS) and other variables derived from the analysis of the electroencephalographic signal, with the probability of recovering consciousness in patients in a coma state due to severe cerebral damage. Twenty-five critically ill, unconscious brain-injured patients from whom sedative drugs were withdrawn at least 24 h before BIS recording were prospectively studied. BIS, 95% spectral edge frequency, burst suppression ratio, and frontal electromyography were recorded for 20 min. The neurologic condition of the patients was measured according to the Glasgow Coma Score (GCS). Patients were followed up for assessment of recovery of consciousness for 6 months after the injury. The studied variables were compared between the group of patients who recovered consciousness and those who did not recover. Their predictive ability was evaluated by means of the Pk statistic. Univariate and multivariate logistic regression was used to model the relation between variables and probability of recovery of consciousness. Cross-validation was used to validate the proposed model. There were statistically significant differences between the group of patients who recovered consciousness and those who did not with respect to BISmax, BISmin, BISmean, and BISrange, frontal electromyography, signal quality index values, and GCSBIS. The Pk (SE) values were 0.99 (0.01) for electromyelography, 0.96 (0.05) for BISmax, 0.92 (0.05) for BISmean, 0.92 (0.06) for BISrange, and 0.82 (0.09) for GCSBIS. The odds ratio for BISmax in the logistic regression model was 1.17 (95% confidence interval, 1.1-1.35). Cross-validation results reported a high-accuracy median absolute cross-validation performance error of 3.06% (95% confidence interval, 1-22.15%) and a low-bias median cross-validation performance error of 0.84% (0.56-2.12%). The study BIS and other electrophysiologic and clinical variables has enabled construction and cross-validation of a model relating BIS(max) to the probability of recovery of consciousness in patients in a coma state due to a severe brain injury, after sedation has been withdrawn.


Voltage-gated calcium currents in axotomized adult rat cutaneous afferent neurons.
The effect of sciatic nerve injury on the somatic expression of voltage-gated calcium currents in adult rat cutaneous afferent dorsal root ganglion (DRG) neurons identified via retrograde Fluoro-gold labeling was studied using whole cell patch-clamp techniques. Two weeks after a unilateral ligation and transection of the sciatic nerve, the L(4)-L(5) DRG were dissociated and barium currents were recorded from cells 3-10 h later. Cutaneous afferents (35-50 microm diam) were classified as type 1 (possessing only high-voltage-activated currents; HVA) or type 2 (having both high- and low-voltage-activated currents). Axotomy did not change the percentage of neurons exhibiting a type 2 phenotype or the properties of low-threshold T-type current found in type 2 neurons. However, in type 1 neurons the peak density of HVA current available at a holding potential of -60 mV was reduced in axotomized neurons (83.9 +/- 5.6 pA/pF, n = 53) as compared with control cells (108.7 +/- 6.9 pA/pF, n = 58, P < 0.01, unpaired t-test). A similar reduction was observed at more negative holding potentials, suggesting differences in steady-state inactivation are not responsible for the effect. Separation of the type 1 cells into different size classes indicates that the reduction in voltage-gated barium current occurs selectively in the larger (capacitance >80 pF) cutaneous afferents (control: 112.4 +/- 10.6 pA/pF, n = 30; ligated: 72.6 +/- 5.0 pA/pF, n = 36; P < 0.001); no change was observed in cells with capacitances of 45-80 pF. Isolation of the N- and P¿Q-type components of the HVA current in the large neurons using omega-conotoxin GVIA and omega-agatoxin TK suggests a selective reduction in N-type barium current after nerve injury, as the density of omega-CgTx GVIA-sensitive current decreased from 56.9 +/- 6.6 pA/pF in control cells (n = 13) to 31.3 +/- 4.6 pA/pF in the ligated group (n = 12; P < 0.005). The HVA barium current of large cutaneous afferents also demonstrates a depolarizing shift in the voltage dependence of inactivation after axotomy. Injured type 1 cells exhibited faster inactivation kinetics than control neurons, although the rate of recovery from inactivation was similar in the two groups. The present results indicate that nerve injury leads to a reorganization of the HVA calcium current properties in a subset of cutaneous afferent neurons.


Tectonics and evolution of venus.
The global tectonics of Venus differs significantly from that of Earth, most markedly in that the surface is covered predominately by gently rolling terrain; there apparently are no features like ocean rises; the gravity is positively correlated with topography at all wavelengths; and the few highlands are estimated to be supported or compensated at a depth of approximately 100 kilometers. The surface of Venus appears to be covered mainly by an ancient crust, the high surface temperature making subduction difficult. It seems likely that well over 1 billion years ago water was destabilized at the surface and, soon after, plate tectonics ceased. The highlands appear to be actively supported, presumably as manifestations of long-enduring hot spots.


Photocatalyzed Amination of Alkyl Halides to Access Primary Amines.
We demonstrate that oxime ester derivatives can be used as both a halogen atom transfer (XAT) agent and an imine source under photocatalytic conditions, allowing the radical amination of alkyl halides, resulting in the formation of a broad scope of imines. Hydrolysis of the latter gives direct access to the corresponding primary amines. Mechanistically, the reaction is believed to proceed through the formation of aryl radical intermediates, which are responsible for the activation of alkyl halides via XAT.


Nickel-binding proteins.
Nickel enzymes are a relatively new class of metalloenzymes. The seven known nickel enzymes are urease, hydrogenase, CO-dehydrogenase, methyl-coenzyme M reductase, Ni-superoxide dismutase, glyoxalase I and cis-trans isomerase. The requirement for nickel implies the presence of a nickel-processing system, since free transition metals are harmful to the cell. A nickel-processing system involves the recognition and transport of nickel into the cell and the handling of the nickel once it enters the cell until it is inserted into the nickel enzyme. Several mechanisms for nickel transport have been identified and will be reviewed here. Accessory proteins required for the biosynthesis of the nickel active site have been identified. Accessory proteins bind the nickel when it enters the cell and are proposed to assist with the insertion of nickel into the enzyme. The function of the characterized nickel-processing proteins is described, and models for nickel insertion into the nickel enzymes are presented.


Quality of extracranial carotid evaluation with 256-section CT.
To date, no systematic evaluation of image quality has been performed on the 256-section multidetector CT scanner for extracranial carotid evaluations. We evaluated image quality, patient dose, and examination time and compared these parameters with a 64-section multidetector CT. We reviewed extracranial CTA scans obtained on a 256-detector CT scanner in 50 consecutive patients. Image quality was analyzed for artifacts and vessel contrast opacification from the aortic arch to the skull base, dose to patient, and scan time. Results were compared with a control group of 50 patients imaged on a 64-section CT scanner. A Fisher exact test was used to analyze both groups with respect to vessel contrast opacification and presence of artifacts, and a Student t test was used to assess differences in patient dose between the 2 groups. Quantitative and qualitative evaluations revealed >95% acceptable vessel opacification at all levels measured on the 256-section scanner. Scan time was improved (4 seconds on 256-channel). There were fewer artifacts related to metallic streak on the 256-channel CTA study, and DLP was lower on the 256-channel CTA (113.9 versus 159.8 mGy). The 256-channel CTA imaging protocol for carotid arteries yielded similar vessel contrast opacification compared with the 64-channel CTA but with fewer metallic artifacts, a modest decrease in scan time, similar image quality, and a statistically significant reduction in radiation dose of 10%.


[Serum eosinophil cationic protein (sECP) level after cow's milk challenge test in allergic children].
The eosinophil cationic protein (ECP) level in the sera is higher in allergic diseases. The change of the ECP level in the sera of patients with cow milk allergy was examined during the cow's milk challenge test after a long cow's milk free diet period. The sECP level of 35 milk sensitive patients was determined by a fluoroimmunoassay (Pharmacia CAP System ECP FEIA) before the milk challenge test, as well as 2 and 24 hours after it. The average age of the patients was 16 (6-49) months. The basic sECP level of cow's milk allergic patients was significantly higher (12.2 micrograms/l vs. 7.0 micrograms/l, p < 0.05) than that of the control group (n = 20). The sECP level significantly decreased 2 hours after the milk challenge test (12.2 micrograms/l vs. 9.2 micrograms/l, p = 0.01), 24 hours after the challenge it was again on the basic level (11.2 micrograms/l, p = 0.26). Out of the 35 allergic children ten had positive clinical reactions after the milk challenge test (positive group), while 25 had no reaction after it (negative group). Comparing the sECP level of these two groups, no significant difference was found in the sECP level either before the milk challenge test or after it. The significant decrease of the sECP level 2 hours after the beginning of milk challenge test might be explained by the fact that this toxic protein is secreted into the bowel.


High activity of daily-schedule mitoxantrone in newly diagnosed low-grade non-Hodgkin's lymphomas: a 5-year follow-up.
Twenty-one consecutive previously untreated patients with low-grade non-Hodgkin's lymphoma were entered into a trial of mitoxantrone (5 mg/m2 daily for 3 days repeated every 3 weeks) between 1985 and 1986. After 8 to 11 cycles of treatment not exceeding a cumulative dose of 165 mg/m2, the patients were observed without further treatment. Seven patients had small lymphocytic lymphomas, 10 had follicular small cleaved cell lymphomas, and 4 had follicular mixed small- and large-cell lymphomas. As previously reported, both hematologic and nonhematologic toxicity was modest. Nine patients achieved complete remission (CR) and 12 partial remission (PR) (CR plus PR = 100%). In the subsequent 4- to 5-year observation phase, 1 patient withdrew from the study, 10 patients relapsed, and 10 remain in unmaintained remission (7 CR, 3 stable PR). Three relapsed patients have died of treatment-resistant disease. No long-term side effects have been observed. Follow-up studies of left ventricular ejection fraction using multiple-gated acquisition scintigraphy showed no significant decrease in cardiac function.


Advance Progress on Luminescent Sensing of Nitroaromatics by Crystalline Lanthanide-Organic Complexes.
Water environment pollution is becoming an increasingly serious issue due to industrial pollutants with the rapid development of modern industry. Among many pollutants, the toxic and explosive nitroaromatics are used extensively in the chemical industry, resulting in environmental pollution of soil and groundwater. Therefore, the detection of nitroaromatics is of great significance to environmental monitoring, citizen life and homeland security. Lanthanide-organic complexes with controllable structural features and excellent optical performance have been rationally designed and successfully prepared and used as lanthanide-based sensors for the detection of nitroaromatics. This review will focus on crystalline luminescent lanthanide-organic sensing materials with different dimensional structures, including the 0D discrete structure, 1D and 2D coordination polymers and the 3D framework. Large numbers of studies have shown that several nitroaromatics could be detected by crystalline lanthanide-organic-complex-based sensors, for instance, nitrobenzene (NB), nitrophenol (4-NP or 2-NP), trinitrophenol (TNP) and so on. The various fluorescence detection mechanisms were summarized and sorted out in the review, which might help researchers or readers to comprehensively understand the mechanism of the fluorescence detection of nitroaromatics and provide a theoretical basis for the rational design of new crystalline lanthanide-organic complex-based sensors.


CCT3-LINC00326 axis regulates hepatocarcinogenic lipid metabolism.
To better comprehend transcriptional phenotypes of cancer cells, we globally characterised RNA-binding proteins (RBPs) to identify altered RNAs, including long non-coding RNAs (lncRNAs). To unravel RBP-lncRNA interactions in cancer, we curated a list of ~2300 highly expressed RBPs in human cells, tested effects of RBPs and lncRNAs on patient survival in multiple cohorts, altered expression levels, integrated various sequencing, molecular and cell-based data. High expression of RBPs negatively affected patient survival in 21 cancer types, especially hepatocellular carcinoma (HCC). After knockdown of the top 10 upregulated RBPs and subsequent transcriptome analysis, we identified 88 differentially expressed lncRNAs, including 34 novel transcripts. CRISPRa-mediated overexpression of four lncRNAs had major effects on the HCC cell phenotype and transcriptome. Further investigation of four RBP-lncRNA pairs revealed involvement in distinct regulatory processes. The most noticeable RBP-lncRNA connection affected lipid metabolism, whereby the non-canonical RBP CCT3 regulated LINC00326 in a chaperonin-independent manner. Perturbation of the CCT3-LINC00326 regulatory network led to decreased lipid accumulation and increased lipid degradation in cellulo as well as diminished tumour growth in vivo. We revealed that RBP gene expression is perturbed in HCC and identified that RBPs exerted additional functions beyond their tasks under normal physiological conditions, which can be stimulated or intensified via lncRNAs and affected tumour growth.


Streptococcus pneumoniae, S. pyogenes and S. agalactiae membrane phospholipid remodelling in response to human serum.
Streptococcus pneumoniae, S. pyogenes (Group A Streptococcus; GAS) and S. agalactiae (Group B Streptococcus; GBS) are major aetiological agents of diseases in humans. The cellular membrane, a crucial site in host-pathogen interactions, is poorly characterized in streptococci. Moreover, little is known about whether or how environmental conditions influence their lipid compositions. Using normal phase liquid chromatography coupled with electrospray ionization MS, we characterized the phospholipids and glycolipids of S. pneumoniae, GAS and GBS in routine undefined laboratory medium, streptococcal defined medium and, in order to mimic the host environment, defined medium supplemented with human serum. In human serum-supplemented medium, all three streptococcal species synthesize phosphatidylcholine (PC), a zwitterionic phospholipid commonly found in eukaryotes but relatively rare in bacteria. We previously reported that S. pneumoniae utilizes the glycerophosphocholine (GPC) biosynthetic pathway to synthesize PC. Through substrate tracing experiments, we confirm that GAS and GBS scavenge lysoPC, a major metabolite in human serum, thereby using an abbreviated GPC pathway for PC biosynthesis. Furthermore, we found that plasmanyl-PC is uniquely present in the GBS membrane during growth with human serum, suggesting GBS possesses unusual membrane biochemical or biophysical properties. In summary, we report cellular lipid remodelling by the major pathogenic streptococci in response to metabolites present in human serum.


A novel biodegradable implant for neuronal rescue and regeneration after spinal cord injury.
After spinal cord injury, the severed neuronal pathways fail to regenerate spontaneously. This study describes a biodegradable implant using poly-beta-hydroxybutyrate (PHB) fibers as carrier scaffold for matrix components and cell lines supporting neuronal survival and regeneration after spinal cord injury. After cervical spinal cord injury in adult rats, a graft consisting of PHB fibers coated with alginate hydrogel + fibronectin was implanted in the lesion cavity. In control groups, PHB was omitted and only alginate hydrogel or fibronectin, or their combination, were used for grafting. In addition, comparisons were made with animals treated intrathecally after spinal cord injury with the neurotrophic factors BDNF or NT-3. The neurons of the rubrospinal tract served as experimental model. In untreated animals, 45% of the injured rubrospinal neurons were lost at 8 weeks postoperatively. Implantation of the PHB graft reduced this cell loss by 50%, a rescuing effect similar to that obtained after treatment with BDNF or NT-3. In the absence of PHB support, implants of only alginate hydrogel or fibronectin, or their combination, had no effect on neuronal survival. After addition of neonatal Schwann cells to the PHB graft, regenerating axons were seen to enter the graft from both ends and to extend along its entire length. These results show that implants using PHB as carrier scaffold and containing alginate hydrogel, fibronectin and Schwann cells can support neuronal survival and regeneration after spinal cord injury


Comprehensive bioinformatics analysis of key miRNAs and signaling pathways in the body fluids of human knee osteoarthritis.
Osteoarthritis (OA) is one of the principal causes of chronic joint disease with a series of pathological features. The present study aimed to identify key microRNAs (miRNAs) and signaling pathways in OA biological fluids to explain the potential mechanisms underlying the disease and introduce OA biomarkers using computational analysis. Differentially expressed microRNAs (DEmiRNAs) in the serum, plasma, and synovial fluids of OA patients were identified using the GEO2R, limma, and DESeq2 packages in the R software based on the dataset from GSE151341, GSE105027, and GSE126677. The gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and network construction analyses were performed for overlapping DEmiRNAs. Forty DEmiRNAs overlapped in the plasma, serum, and synovial fluids of OA patients. The expression patterns of the DEmiRNAs in the serum and plasma were almost the same, while they were reversed in the synovial fluid. Differentially expressed hsa-miR-146a-5p and hsa-miR-335-5p miRNAs showed downregulation in all 3 OA sample types. According to enrichment analysis regarding OA pathogenesis, the signaling pathways of TGF-β, Hippo, FoxO, PI3K-Akt, and mTOR were significant, with hsa-miR-146a-5p and hsa-miR-335-5p involved in their regulation. The present informatics study for the first time provides insights into the potential diagnostic targets of OA by analyzing overlapping miRNAs and their relevant signaling pathways in human knee fluids (serum, plasma, and synovial fluids).


Frugivory and seed dispersal of Miconia theaezans (Bonpl.) Cogniaux (Melastomataceae) by birds in a transition palm swamp: gallery forest in Central Brazil.
The objective of this study was to evaluate potential avian dispersers of Miconia theaezans by dietary habits in the Cerrado of Central Brazil. Forty-two hours and 40 minutes of focal tree observation were conducted between 7:00 AM and 5:00 PM. For each bird species that consumed the fruit, we registered: the time they remained on the plant, the total amount of fruit they consumed, foraging tactics and strategies to consume the fruit. Five-hundred and fifty-nine units of fruit were consumed in 47 visits by seven bird species. Thraupidae was the most frequent and representative family and Tangara cayana was the main consumer. The Tachyphonus rufus had the highest rate of intake of the entire fruit, however the rates were not significantly different among the visitors. The most-used foraging tactic by all species was to consume the fruit while "perched" (95.74% of the visits). The most commonly-used consumption strategy was to mandibulate the fruit and swallow all the contents (65.12%). Omnivores were the predominant visitors (71.43%) and made most of the visits (89.36%). All visiting species could act as potential dispersers of M. theaezans, which demonstrates the low selectiveness of this pioneer plant towards its frugivorous.


Regulatory effect of bee venom on methamphetamine-induced cellular activities in prefrontal cortex and nucleus accumbens in mice.
Our previous studies demonstrated that subcutaneous injection of bee venom (BV) into the Zusanli (ST36) acupuncture point, namely BV acupuncture, dose-dependently prevents conditioned place preference (CPP) induced by repeated injection of methamphetamine (METH) in mice. To expand on our observations, the present study was designed to determine the suppressive mechanisms of BV acupuncture in the development of METH-induced CPP by evaluating the changes in expression of ΔFosB, phosphorylated extracellular signal-regulated kinase 1/2 (pERK), and phosphorylated calcium/calmodulin-dependent protein kinase type II (pCaMKII) in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in mice. Pre-emptive treatment with BV at 30 min before repeated METH injection completely suppressed acquisition of CPP at the day 7 test session. METH-induced upregulation of ΔFosB and pERK in PFC and NAc was significantly reduced by BV pretreatment. Expression of pCaMKII was significantly elevated by METH in NAc and reduced in PFC. BV pretreatment reversed the changes of pCaMKII expression in PFC and NAc. These findings suggest that BV acupuncture may exert a suppressive effect on METH-induced addiction via regulation of signaling cascades of ΔFosB, ERK, and CaMKII in PFC and NAc.


Factors related to age at natural menopause: longitudinal analyses from SWAN.
Early age at the natural final menstrual period (FMP) or menopause has been associated with numerous health outcomes and might be a marker of future ill health. However, potentially modifiable factors affecting age at menopause have not been examined longitudinally in large, diverse populations. The Study of Women's Health Across the Nation (SWAN) followed 3,302 initially premenopausal and early perimenopausal women from 7 US sites and 5 racial/ethnic groups, using annual data (1996-2007) and Cox proportional hazards models to assess the relation of time-invariant and time-varying sociodemographic, lifestyle, and health factors to age at natural FMP. Median age at the FMP was 52.54 years (n = 1,483 observed natural FMPs). Controlling for sociodemographic, lifestyle, and health factors, we found that racial/ethnic groups did not differ in age at the FMP. Higher educational level, prior oral contraceptive use, and higher weight at baseline, as well as being employed, not smoking, consuming alcohol, having less physical activity, and having better self-rated health over follow-up, were significantly associated with later age at the FMP. These results suggest that age at the natural FMP reflects a complex interrelation of health and socioeconomic factors, which could partially explain the relation of late age at FMP to reduced morbidity and mortality.


Immunology of chronic hepatitis.
Of the two major types of chronic active hepatitis, that associated with autoimmunity, CAH-Type A, has been the more extensively studied and is better recognised. On the other hand, the type associated with the HBV carrier state, CAH-Type B, is the more prevalent, particularly so in South East Asia, and the time is ripe for the immunology of this type to be clarified. Whilst most encounters between host and HBV will result in an acute hepatitis with lasting immunity, a non-sterilizing outcome with a persisting carrier state may ensue. The reasons for persistent infection with HBV are still not elucidated, but may include: (i) incorporation of viral DNA into the host genome, (ii) a carrier state in which there is full T cell tolerance to the virus and its surface antigen, or (iii) an unstable tolerance marked by a persisting damaging immune response to viral antigens expressed on the liver cell membrane, with associated CAH. Whether an autoimmune-type CAH can be included as one possible outcome of HBV infection is uncertain; whilst the association of an HB viral antigen with a liver cell membrane component is one theoretical way by which an autoimmune response could be generated, most cases of autoimmune hepatitis, at least in Caucasian areas, show no evidence of current or past infection with HBV or indeed with any other virus. Thus, pending further knowledge, CAH-Type A must be regarded as a primary autoimmune disease of the liver, and CAH-type B as resulting from an ineffective host response to a chronic virus infection of the liver.


Functional Neural Correlates of Anosognosia in Mild Cognitive Impairment and Alzheimer's Disease: a Systematic Review.
Functional neuroimaging techniques (i.e. single photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging) have been used to assess the neural correlates of anosognosia in mild cognitive impairment (MCI) and Alzheimer's disease (AD). A systematic review of this literature was performed, following the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement, on PubMed, EMBASE, and PsycINFO databases. Twenty-five articles met all inclusion criteria. Specifically, four brain connectivity and 21 brain perfusion, metabolism, and activation articles. Anosognosia is associated in MCI with frontal lobe and cortical midline regional dysfunction (reduced perfusion and activation), and with reduced parietotemporal metabolism. Reduced within and between network connectivity is observed in the default mode network regions of AD patients with anosognosia compared to AD patients without anosognosia and controls. During initial stages of cognitive decline in anosognosia, reduced indirect neural activity (i.e. perfusion, metabolism, and activation) is associated with the cortical midline regions, followed by the parietotemporal structures in later stages and culminating in frontotemporal dysfunction. Although the current evidence suggests differences in activation between AD or MCI patients with anosognosia and healthy controls, more evidence is needed exploring the differences between MCI and AD patients with and without anosognosia using resting state and task related paradigms.


Supervised Exercise Therapy Using Mobile Health Technology in Patients With Peripheral Arterial Disease: Pilot Randomized Controlled Trial.
Mobile health interventions are intended to support complex health care needs in chronic diseases digitally, but they are mainly targeted at general health improvement and neglect disease-specific requirements. Therefore, we designed TrackPAD, a smartphone app to support supervised exercise training in patients with peripheral arterial disease. This pilot study aimed to evaluate changes in the 6-minute walking distance (meters) as a primary outcome measure. The secondary outcome measures included changes in physical activity and assessing the patients' peripheral arterial disease-related quality of life. This was a pilot two-arm, single-blinded, randomized controlled trial. Patients with symptomatic PAD (Fontaine stage IIa/b) and access to smartphones were eligible. Eligible participants were randomly assigned to the study, with the control group stratified by the distance covered in the 6-minute walking test using the TENALEA software. Participants randomized to the intervention group received usual care and the mobile intervention (TrackPAD) for the follow-up period of 3 months, whereas participants randomized to the control group received routine care only. TrackPAD records the frequency and duration of training sessions and pain levels using manual user input. Clinical outcome data were collected at the baseline and after 3 months via validated tools (the 6-minute walk test and self-reported quality of life). The usability and quality of the app were determined using the Mobile Application Rating Scale user version. The intervention group (n=19) increased their mean 6-minute walking distance (83 meters, SD 72.2), while the control group (n=20) decreased their mean distance after 3 months of follow-up (-38.8 meters, SD 53.7; P=.01). The peripheral arterial disease-related quality of life increased significantly in terms of "symptom perception" and "limitations in physical functioning." Users' feedback showed increased motivation and a changed attitude toward performing supervised exercise training. Besides the rating providing a valuable support tool for the user group, the mobile intervention TrackPAD was linked to a change in prognosis-relevant outcome measures combined with enhanced coping with the disease. The influence of mobile interventions on long-term prognosis must be evaluated in the future. ClinicalTrials.gov NCT04947228; https://clinicaltrials.gov/ct2/show/NCT04947228.


Integrated profiling identifies ITGB3BP as prognostic biomarker for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a highly malignant tumor. In this study, we sought to identify a novel biomarker for HCC by analyzing transcriptome and clinical data. The R software was used to analyze the differentially expressed genes (DEGs) in the datasets GSE74656 and GSE84598 downloaded from the Gene Expression Omnibus database, followed by a functional annotation. A total of 138 shared DEGs were screened from two datasets. They were mainly enriched in the "Metabolic pathways" pathway (Padj = 8.21E-08) and involved in the carboxylic acid metabolic process (Padj = 0.0004). The top 10 hub genes were found by protein-protein interaction analysis and were upregulated in HCC tissues compared to normal tissues in The Cancer Genome Atlas database. Survival analysis distinguished 8 hub genes CENPE, SPDL1, Hyaluronan-mediated motility receptor, Rac GTPase activating protein 1, Thyroid hormone receptor interactor 13, cytoskeleton-associated protein (CKAP) 2, CKAP5, and Integrin subunit beta 3 binding protein (ITGB3BP) were considered as prognostic hub genes. Multivariate cox regression analysis indicated that all the prognostic hub genes were independent prognostic factors for HCC. Furthermore, the receiver operating characteristic curve revealed that the 8-hub genes model had better prediction performance for overall survival compared to the T stage (p = 0.008) and significantly improved the prediction value of the T stage (p = 0.002). The Human Protein Atlas showed that the protein expression of ITGB3BP was upregulated in HCC, so the expression of ITGB3BP was further verified in our cohort. The results showed that ITGB3BP was upregulated in HCC tissues and was significantly associated with lymph node metastasis.


Results of central pathology review of prostatic biopsies in a contemporary series from a phase III, multicenter, randomized controlled trial (SHIP0804).
To investigate contemporary rates of variation in the biopsy Gleason grading in prostate cancer, between local and central pathologists, based on central review of the pathological slides from Seed and Hormone for Intermediate-risk Prostate Cancer (SHIP) 0804, a phase III, multicenter, randomized, controlled study. From April 2008 to May 2011, 18 Japanese institutions participated. All H&E slides were reviewed independently, without clinical information, and a tumor grade was assigned according to the modified Gleason grading system proposed by the International Society of Urological Pathology (ISUP). Prostate biopsy specimens of 642 cases were available for evaluation. An exact concordance rate of Gleason score (GS) between local and central pathologists was determined to be 65.3%; with the under-grading and over-grading of grades to be 14.6% and 20.1%, respectively. The central review resulted in numbers of tumor-bearing cores reassigned in 99 of 616 cases in which such information by the local pathologists was available (16.1%). Discordance in biopsy Gleason grading was still found in one third of the cases in the SHIP0804 study. This information is valuable in extrapolating the diagnostic error range in contemporary clinical studies conducted without central pathological review.


Immunohistochemical detection of epithelialmesenchymal transition associated with stemness phenotype in anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma (ATC) is a highly aggressive neoplasm resistant to radiation and chemotherapy. Epithelial-mesenchymal transition (EMT) generating cells with stem cell characteristics have been reported to be associated with chemoradioresistance in cultured cells. However, EMT and stem cell properties in ATC have not been fully investigated. In this study, we retrieved 2 thyroidectomy specimens of ATC with coexisting well differentiated thyroid carcinomas (DTCs) including one papillary carcinoma (PTC) and one follicular carcinoma (FTC). We used im-munohistochemistry to examine the expression of stem cell markers (nestin, CD133 and CD44) and a marker for EMT (E-cadherin). Intense expressions of nestin, CD133 and CD44, and no expression of E-cadherin were observed in both ATCs. In contrast, the PTC and FTC, and non-neoplastic thyroid tissue in both cases were negative for nestin and positive for E-cadherin. The expressions of CD133 and CD44 were variable in the PTC, FTC, and non-neoplastic thyroid tissue and were at a lower level of expression of these markers in the overall pattern. The results confirmed EMT, demonstrated the stem cell phenotype in ATC, and revealed the difference in expression of these markers between ATC and DTCs/non-neoplastic thyroid tissue. Nestin may be the most specific marker for stemness in ATC by immuno-histochemial staining. The results warrant future studies on a large series of cases in order to gain the understanding of the tumor biology and to provide molecular basis for restoring the sensitivities to clinical therapies.


Association of nicotine metabolism and sex with relapse following varenicline and nicotine replacement therapy.
Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline in women and in nicotine normal metabolizers phenotypically determined by nicotine-metabolite ratio. Our objective was to study the influence of nicotine-metabolite ratio, CYP2A6 genotype and sex on the response to nicotine replacement therapy and varenicline. Data were extracted from a longitudinal study which included smokers participating in a smoking cessation program. Response to treatment was defined by the absence of relapse when a set threshold of reduction in cigarettes per day relative to the week before the study was no more reached. The analysis considered total and partial reduction defined by a diminution of 100% and of 90% in cigarettes per day, respectively. The hazard ratio of relapsing was estimated in multivariate Cox regression models including the sex and the nicotine metabolism determined by the phenotype or by CYP2A6 genotyping (rs1801272 and rs28399433). In the normal metabolizers determined by phenotyping and in women, the hazard ratio for relapsing was significantly lower with varenicline for a partial decrease (HR = 0.33, 95% CI [0.12, 0.89] and HR = 0.20, 95% CI [0.04, 0.91], respectively) and nonsignificantly lower for a total cessation (HR = 0.45, 95% CI [0.20, 1.0] and HR = 0.38, 95% CI [0.14, 1.0]). When compared with the normal metabolizers determined by phenotyping, the hazard ratio for a partial decrease was similar in the normal metabolizers determined by genotyping (HR = 0.42, 95% CI [0.18, 0.94]) while it was significantly lower with varenicline for a total cessation (HR = 0.50, 95% CI [0.26, 0.98]). Women and normal nicotine metabolizers may benefit more from varenicline over nicotine replacement therapy. (PsycINFO Database Record


Cardiovascular Disease After Aromatase Inhibitor Use.
Cardiovascular disease (CVD) is an important cause of death in older patients with breast cancer. However, limited information exists on the long-term effect of aromatase inhibitor (AI) use on CVD risk in breast cancer survivors. To this point, no other population-based studies have been able to adjust for CVD risk factors or cardiovascular medications. To determine the long-term influence of adjuvant endocrine therapies on CVD in a cohort of postmenopausal breast cancer survivors in analyses that accounted for major CVD risk factors, medication use, chemotherapy, and radiotherapy. A retrospective cohort of postmenopausal women with breast cancer diagnosed from January 1, 1991, to December 31, 2010, and followed up through December 31, 2011 (maximum, 21 years [72 886 person-years]), was evaluated using records from a managed care organization with nearly 20 community hospitals in California. A total of 13 273 postmenopausal women with hormone receptor-positive breast cancer without prior CVD were included. Cardiovascular disease incidence was compared across endocrine therapy categories. Information on demographics, comorbidity, medication, use, and CVD risk was captured from electronic health records. Multivariate Cox proportional hazards models using time-dependent endocrine drug use variables and propensity scores were conducted. Data analysis was conducted from September 15, 2014, to February 1, 2016. Women were grouped by endocrine therapy status (tamoxifen citrate only, AI only, both, or neither). Person-year rates of CVD for each therapy group. During 72 886 person-years in 13 273 women (mean [SD] age, 66.8 [8.1] years) with follow-up through 2011, we observed 3711 CVD events. In multivariable analyses (reported as hazard ratio [95% CI]), AI-only users had a similar risk of cardiac ischemia (myocardial infarction and angina) (adjusted, 0.97 [0.78-1.22]) and stroke (adjusted, 0.97 [0.70-1.33]) as tamoxifen-only users (reference). However, we found an increased risk of other CVD (dysrhythmia, valvular dysfunction, and pericarditis) (adjusted, 1.29 [1.11-1.50]) in women who used AIs only or sequentially after tamoxifen (1.26 [1.09-1.45]) vs tamoxifen (reference) as well nonhormone users (1.18 [1.02-1.35]). The risk of the most serious cardiovascular events (cardiac ischemia or stroke) was not elevated in AI-only users compared with tamoxifen users. The finding that other CVD events combined were greater in AI users requires further study.


CREB1 is a strong genetic predictor of the variation in exercise heart rate response to regular exercise: the HERITAGE Family Study.
A genome-wide linkage scan identified a quantitative trait locus for exercise training-induced changes in submaximal exercise (50 W) heart rate (DeltaHR50) on chromosome 2q33.3-q34 in the HERITAGE Family Study (n=472). To fine-map the region, 1450 tag SNPs were genotyped between 205 and 215 Mb on chromosome 2. The strongest evidence of association with DeltaHR50 was observed with 2 single-nucleotide polymorphisms (SNPs) located in the 5' region of the cAMP-responsive element-binding protein 1 (CREB1) gene (rs2253206: P=1.6x10(-5) and rs2360969: P=4.3x10(-5)). The associations remained significant (P=0.01 and P=0.023, respectively) after accounting for multiple testing. Regression modeling of the 39 most significant SNPs in the single-SNP analysis identified 9 SNPs that collectively explained 20% of the DeltaHR50 variance. CREB1 SNP rs2253206 had the strongest effect (5.45% of variance), followed by SNPs in the FASTKD2 (3.1%), MAP2 (2.6%), SPAG16 (2.1%), ERBB4 (3 SNPs approximately 1.4% each), IKZF2 (1.4%), and PARD3B (1.0%) loci. In conditional linkage analysis, 6 SNPs from the final regression model (CREB1, FASTKD2, MAP2, ERBB4, IKZF2, and PARD3B) accounted for the original linkage signal: The log of the odds score dropped from 2.10 to 0.41 after adjusting for all 6 SNPs. Functional studies revealed that the common allele of rs2253206 exhibits significantly (P<0.05) lower promoter activity than the minor allele. Our data suggest that functional DNA sequence variation in the CREB1 locus is strongly associated with DeltaHR50 and explains a considerable proportion of the quantitative trait locus variance. However, at least 5 additional SNPs seem to be required to fully account for the original linkage signal.


18F-FDG-PET Imaging Patterns in Autoimmune Encephalitis: Impact of Image Analysis on the Results.
Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose (FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or assisted image reading is not well established to evaluate hypometabolism/hypermetabolism. We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018. Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard visual reading and assisted by voxel-based analyses, compared to a normal database. For the latter, three different methods were performed: two based on statistical surface projections (Siemens syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative. 18F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis. Medial-temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive and localized larger hypermetabolic areas. As it may lead to comparable and accurate results, visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG.


[Identification of Citrobacter species and their occurrence in raw products and foods].
Fifty-nine strains of bacteria were tested in study that were isolated from raw materials and foods (raw milk, farm milking parlors, sausage meat, raw potatoes, cheese, frozen oven-ready foods, confectionery products, cold dishes), and they were included in the genus Citrobacter using a commercial diagnostic kit ENTEROtest 16 (Lachema a.s., Brno), numeric identification program TNW (Czech Collection of Microorganisms, Faculty of Science of Masaryk University at Brno) and identification key (O'Hara et al., 1995). The results of the ENTEROtest itself, including OXI and ONPtests, did not provide satisfactory discrimination of detected strains to the level of species since 64.4% were identified by the genus by TNW program or designated as intermediary strains. Correct species identification was obtained in 33.9% only (Tab. I). Five next conventional tests (dulcitol, alpha-methyl-glucoside, raffinose, melibiose, arginine dihydrolase) were used and their results successfully specified 94.9% tested strains to the species level (Tab. I). A dichotomic identification key (O'Hara et al., 1995) enabled to classify the strains on the basis of the results of ENTEROtest 16 and two conventional tests (dulcitol, melibiosis) relatively easily, and it can be recommended for routine identification of typical Citrobacters from foods. Only ten strains were classified in a wrong way (16.9%) due to false results in ENTEROtest (Tab. II). Tab. III shows the strains classified wrongly by both identifications systems. The tested set contained Citrobacter braakii in a majority of cases (30 strains), followed by C. freundii (17 strains), C. youngae (6 strains), 2 strains of genomospecies 10 and one strain of C. koseri, C. amalonaticus and C farmeri. Tab. IV shows the presence of Citrobacter species in the particular raw materials and foods. The most frequently present species in raw materials: C. braakii (26 strains, 68.4%), C. freundii (3 strains, 7.9%) and C. youngae (3 strains, 7.9%). Foods contained these three species only: C. freundii (14 strains, 66.7%), C. braakii (4 strains, 19.0%) and C. youngae (3 strains, 14.3%). The percentage of the three most frequently present species in raw materials is substantially different from their percentage in foods (Fig. 1). The higher percentage of C. freundii presence in foods can be ascribed to secondary contamination.


Bone tissue and muscle dystrophin deficiency in mdx mice.
Duchenne muscular dystrophy is a neuromuscular disease caused by the lack of dystrophin that affects skeletal muscles, causing degeneration of muscle fibers and replacing them with fibrous and adipose tissue, events that gradually lead to functional loss. Patients with Duchenne muscular dystrophy have shown that bones become more fragile with age and with advancement of the disease. Muscle weakness and reduced mobility have been suggested to be the factors that promote bone deterioration. However, it seems that this does not occur in mdx mice. It has been identified in mdx mice the existence of a factor related or not to the lack of dystrophin that also participates in the impairment of bone quality. Mdx mice also exhibit muscle degeneration, but unlike human, it is compensated by muscle regeneration. In consequence, there is an increase in the muscle mass, but not necessarily of muscle contractile strength. The accommodation of this increased muscle mass promotes bone formation at specific sites, such as at tendo-osseous junctions. In addition, the inflammatory response to muscle injury may be responsible for the increase in angiogenesis and regeneration observed in mdx mice, inducing the release of cytokines and chemokines that play an important role in the recruitment of leukocytes and macrophages. Then, mdx mice may possess compensatory mechanisms in bone in response to a genetic defect.


[GSTM1 and GSTT1 genes analysis in head and neck cancer patients].
To establish the clinical and demographic profile and identify risk factors among patients with head and neck cancer and relate them to the polymorphism of GSTT1 and GSTM1. One hundred patients with head and neck cancer and 100 control group individuals without history of neoplasm were analyzed. . The molecular analysis were made by multiplex polymerase chain reaction. For statistical analysis, data were tabulated and compared by the Fisher's exact test, the Chi-square test and multiple logistic regression were also used. There was prevalence of smokers (OR = 5.32, CI 95% CI = 2.04-13.86 p = 0.0006), alcohol drinkers (OR = 5.04, CI 95% = 2.19-11.59 p = 0.0001) in head and neck cancer patients . The GSTT1 null genotype was found in 47% of the patient and 41% of the control group (OR = 0.67; CI 95%= 0.34-1.35; p = 0.2648). Likewise , the GSTM1 null genotype was found in 66% of the patient and 75% of the control group (OR = 2.25; CI 95%= 1.05 - 4.84; p = 0.0368). The combined GSTT1 and GSTM1 gene null genotype shown association between GSTM1 0/GSTT1 and occurrence of head and neck carcinoma (OR = 7.64; CI 95%= 1.72-34.04; p = 0.0076). Analysis of clinical-pathological features showed association between GSTT1 null genotype and larynx, the inverse relation between this genotype and pharynx. In our study it was possible to establish association between GSTM1 null genotypes and head and neck cancer.


Formation of Citrazinic Acid Ions and Their Contribution to Optical and Magnetic Features of Carbon Nanodots: A Combined Experimental and Computational Approach.
The molecular model is one of the most appealing to explain the peculiar optical properties of Carbon nanodots (CNDs) and was proven to be successful for the bottom up synthesis, where a few molecules were recognized. Among the others, citrazinic acid is relevant for the synthesis of citric acid-based CNDs. Here we report a combined experimental and computational approach to discuss the formation of different protonated and deprotonated species of citrazinic acid and their contribution to vibrational and magnetic spectra. By computing the free energy formation in water solution, we selected the most favoured species and we retrieved their presence in the experimental surface enhanced Raman spectra. As well, the chemical shifts are discussed in terms of tautomers and rotamers of most favoured species. The expected formation of protonated and de-protonated citrazinic acid ions under extreme pH conditions was proven by evaluating specific interactions with H2SO4 and NaOH molecules. The reported results confirm that the presence of citrazinic acid and its ionic forms should be considered in the interpretation of the spectroscopic features of CNDs.


Serum neopterin levels and the angiographic extent of coronary arterial narrowing in unstable angina pectoris and in non-Q-wave acute myocardial infarction.
Systemic serum markers of inflammation are elevated in diseases due to atherosclerosis, but have not been associated with the extent of atherosclerotic disease. We examined the role of neopterin, a byproduct of activated macrophage metabolism, in patients with unstable angina. Baseline neopterin samples and clinical histories were obtained in 52 patients admitted with unstable angina pectoris. Coronary angiograms of 27 patients were reviewed using Sullivan's method to assess the total atherosclerotic burden in the coronary arteries. Twenty-six of the 52 patients were eventually diagnosed with a non-Q-wave acute myocardial infarction (AMI) and had higher neopterin levels (10.1 +/- 6.7 vs 7.2 +/- 4.0 nmol/L, p = 0.06) than patients with a final diagnosis of unstable angina. Patients with neopterin >8.7 were more likely to be diagnosed with a non-Q-wave AMI (75% vs 39%, p = 0.035) and were more likely to have significantly more severe and extensive angiographically determined atherosclerosis than patients with low neopterin levels. Neopterin levels correlated with the score of atherosclerotic extension (Spearman's rank correlation coefficient 0.4807, p = 0.034). This study demonstrates a correlation between immune cell activation and the extent of angiographically determined atherosclerosis and the degree of myocardial ischemia.


Reflective and reflexive action control in patients with frontal brain lesions.
Two types of action control derived from the model of action phases (H. Heckhausen & P. M. Gollwitzer, 1987) were analyzed in patients with frontal lesions, patients with nonfrontal lesions, and university students. In Study 1, reflective action control in terms of goal selection was assessed, and impaired deliberation was found in patients with frontal lesions. Study 2 assessed reflexive action control in terms of automatic action initiation as a result of forming implementation intentions (P. M. Gollwitzer, 1999). All participants sped up their responses to critical stimuli by forming implementation intentions. Moreover, lesion patients with weak performances on the Tower of Hanoi (TOH) task did worse than patients with strong TOH performances in Study 1 but better than control participants in Study 2. Findings are interpreted as a functional dissociation between conscious reflective action control and automatic reflexive action control.


Structural heterogeneity and functional domains of murine immunoglobulin G Fc receptors.
Binding of antibodies to effector cells by way of receptors to their constant regions (Fc receptors) is central to the pathway that leads to clearance of antigens by the immune system. The structure and function of this important class of receptors on immune cells is addressed through the molecular characterization of Fc receptors (FcR) specific for the murine immunoglobulin G isotype. Structural diversity is encoded by two genes that by alternative splicing result in expression of molecules with highly conserved extracellular domains and different transmembrane and intracytoplasmic domains. The proteins encoded by these genes are members of the immunoglobulin supergene family, most homologous to the major histocompatibility complex molecule E beta. Functional reconstitution of ligand binding by transfection of individual FcR genes demonstrates that the requirements for ligand binding are encoded in a single gene. These studies demonstrate the molecular basis for the functional heterogeneity of FcR's, accounting for the possible transduction of different signals in response to a single ligand.


Postpartum Hemorrhage: Prevention and Treatment.
Postpartum hemorrhage is common and can occur in patients without risk factors for hemorrhage. Active management of the third stage of labor should be used routinely to reduce its incidence. Use of oxytocin after delivery of the anterior shoulder is the most important and effective component of this practice. Oxytocin is more effective than misoprostol for prevention and treatment of uterine atony and has fewer adverse effects. Routine episiotomy should be avoided to decrease blood loss and the risk of anal laceration. Appropriate management of postpartum hemorrhage requires prompt diagnosis and treatment. The Four T's mnemonic can be used to identify and address the four most common causes of postpartum hemorrhage (uterine atony [Tone]; laceration, hematoma, inversion, rupture [Trauma]; retained tissue or invasive placenta [Tissue]; and coagulopathy [Thrombin]). Rapid team-based care minimizes morbidity and mortality associated with postpartum hemorrhage, regardless of cause. Massive transfusion protocols allow for rapid and appropriate response to hemorrhages exceeding 1,500 mL of blood loss. The National Partnership for Maternal Safety has developed an obstetric hemorrhage consensus bundle of 13 patient- and systems-level recommendations to reduce morbidity and mortality from postpartum hemorrhage.


Cloning and expression in Escherichia coli of a protective antigen of Erysipelothrix rhusiopathiae.
Erysipelothrix rhusiopathiae is a primary pathogen of swine and turkeys and sporadic cause of disease in a variety of other hosts, including humans. A genomic library of the highly virulent strain of E. rhusiopathiae E1-6P was constructed in the expression-cloning vector lambda gt11 and screened with serum from a pig convalescent from an E. rhusiopathiae experimental infection. Immunoreactive clones were screened for their ability to protectively immunized mice. Two clones, lambda gt11/ersA and lambda gt11/ersB, were obtained that protected mice against challenge with E. rhusiopathiae E1-6P. Antisera against the recombinant clones reacted with polypeptides of molecular weights 66,000, 64,000, and 43,000 in detergent-solubilized surface antigen preparations and whole-cell lysates of E. rhusiopathiae. These polypeptides were also the major antigens recognized by convalescent pig serum when reacted with the same preparations. Western immunoblot and Southern blot analysis revealed that the cloned genes and gene products were present in all of the E. rhusiopathiae strains tested.


β-Glucosidase Discovery and Design for the Degradation of Oleuropein.
Current lye processing for debittering California black table olives produces large amounts of caustic wastewater and destroys many of the beneficial phenolic compounds in the fruit. Herein, we propose using enzyme treatment in place of lye, potentially reducing the amount and causticity of wastewater produced. By specifically targeting the bitterness-causing compound, oleuropein, retention of other beneficial phenolics may be possible. A β-glucosidase from Streptomyces sp. was identified from a screen of 22 glycosyl hydrolases to completely degrade oleuropein in 24 h. Computational modeling was performed on this enzyme, and mutation C181A was found to improve the rate of catalysis by 3.2-fold. This mutant was tested in the context of the olive fruit and leaf extract. Degradation was observed in the olive leaf extract but not in the fruit matrix, suggesting that enzyme fruit penetration is a limiting factor. This work discovers and begins the refinement process for an enzyme that has the catalytic properties for debittering olives and provides direction for future engineering efforts required to make a product with commercial value.


A simple indentation device for measuring micrometer-scale tissue stiffness.
Mechanical properties of cells and extracellular matrices are critical determinants of function in contexts including oncogenic transformation, neuronal synapse formation, hepatic fibrosis and stem cell differentiation. The size and heterogeneity of biological specimens and the importance of measuring their mechanical properties under conditions that resemble their environments in vivo present a challenge for quantitative measurement. Centimeter-scale tissue samples can be measured by commercial instruments, whereas properties at the subcellular (nm) scale are accessible by atomic force microscopy, optical trapping, or magnetic bead microrheometry; however many tissues are heterogeneous on a length scale between micrometers and millimeters which is not accessible to most current instrumentation. The device described here combines two commercially available technologies, a micronewton resolution force probe and a micromanipulator for probing soft biological samples at sub-millimeter spatial resolution. Several applications of the device are described. These include the first measurement of the stiffness of an intact, isolated mouse glomerulus, quantification of the inner wall stiffness of healthy and diseased mouse aortas, and evaluation of the lateral heterogeneity in the stiffness of mouse mammary glands and rat livers with correlation of this heterogeneity with malignant or fibrotic pathology as evaluated by histology.


Electrolyte imbalances in an unselected population in an emergency department: A retrospective cohort study.
Although electrolyte imbalances (EIs) are common in the emergency department (ED), few studies have examined the occurrence of such conditions in an unselected population. To investigate the frequency of EI among adult patients who present to the ED, with regards to type and severity, and the association with age and sex of the patient, hospital length of stay (LOS), readmission, and mortality. A retrospective cohort study. All patients ≥18 years referred for any reason to the ED between January 1, 2010, and December 31, 2015, who had measured blood electrolytes were included. In total, 62 991 visits involving 31 966 patients were registered. EIs were mostly mild, and the most common EI was hyponatremia (glucose-corrected) (24.6%). Patients with increasing severity of EI had longer LOS compared with patients with normal electrolyte measurements. Among all admitted patients, there were 12928 (20.5%) readmissions within 30 days from discharge during the study period. Hyponatremia (glucose-corrected) was associated with readmission, with an adjusted odds ratio (OR) of 1.25 (95% CI, 1.18-1.32). Hypomagnesemia and hypocalcemia (albumin-corrected) were also associated with readmission, with ORs of 1.25 (95% CI, 1.07-1.45) and 1.22 (95% CI, 1.02-1.46), respectively. Dysnatremia, dyskalemia, hypercalcemia, hypermagnesemia, and hyperphosphatemia were associated with increased in-hospital mortality, whereas all EIs except hypophosphatemia were associated with increased 30-day and 1-year mortality. EIs were common and increasing severity of EIs was associated with longer LOS and increased in-hospital, 30-days and 1-year mortality. EI monitoring is crucial for newly admitted patients, and up-to-date training in EI diagnosis and treatment is essential for ED physicians.


Mango polyphenolics suppressed tumor growth in breast cancer xenografts in mice: role of the PI3K/AKT pathway and associated microRNAs.
The cytotoxic and anti-inflammatory properties of mango polyphenolics including gallic acid and gallotannins have been demonstrated in numerous types of cancers. We hypothesized that the phosphoinositide 3-kinase (PI3K)/AKT pathway and the expression of related miRNAs are involved in the chemotherapeutic activities of mango polyphenolics in a mouse xenograft model for breast cancer. The objectives of this research were to determine the tumor-cytotoxic activities of mango polyphenolics and the underlying molecular mechanisms involving posttranscriptional targets in BT474 breast cancer cells and xenografts in mice. In vitro findings showed cytotoxic effects of mango polyphenolics in BT474 breast cancer cells within a concentration range of 2.5 to 20 mg/L gallic acid equivalents. Mango polyphenolics suppressed the expression of PI3K, AKT, hypoxia inducible factor-1α, and vascular endothelial growth factor (VEGF) mRNA, and pAKT, AKT, pPI3K (p85), VEGF and nuclear factor-kappa B protein levels. The involvement of miR-126 was verified by using antagomiR for miR-126, where mango reversed the effect of the antagomiR of miR-126. In vivo, the intake of mango polyphenolics decreased the tumor volume by 73% in BT474 xenograft-bearing mice compared with the control group. In addition, mango reduced the expression of nuclear factor-kappa B (p65), pAKT, pPI3K, mammalian target of rapamycin, hypoxia inducible factor-1α, and VEGF protein in athymic nude mice. A screening for miRNA expression changes confirmed that mango polyphenolics modulated the expression of cancer-associated miRNAs including miR-126 in the xenografted tumors. In summary, mango polyphenolics have a chemotherapeutic potential against breast cancer that at least in part is mediated through the PI3K/AKT pathway and miR-126.


[The septic state in infancy].
In a retrospective study it was investigated in which a course the septicemia appears during the first year of life and which laborchemical and immunological findings are typical for the specific manifestation and can be used for the diagnosis. 27 sucklings with septicemia were admitted at our hospital during 1976-1982. As the clinical course we found: the acute septicemia with pronounced shocksymptoms (Septic-Toxic-Course, STC), the septicemia with a tardy course and hematogenous dispersion of bacteria in one organsystem, namely in the brain (Meningoencephalitis), in the bone (Osteomyelitis) and in the soft tissue (Phlegmon), the septicemia with a tardy course and forms a septicopyemia with secundary dispersion of bacteria in multiple organsystems. Only STC and septicopyemia show the symptoms which are lead back with the dispersion of bacteria. By the septicemia with a tardy course and hematogenous dispersion of bacteria in one organsystem the clinical symptoms are determined only in the infected organ. As the only course of septicemia the STZ shows laborchemically in the blood a damage to the livercells with a constant elevated levels of plasmaencyms GOT, GPT and LDH; this findings can be used for a diagnostic criterion. By septicopyemia, meningitis and osteomyelitis the findings of sepsis exist in the blood but are rare by phlegmon. By septicemia with a tardy course (2, 3) a humoral and/or cellular immundeficiency exist. This is a point of application for therapy to give biological antibody with a large spectrum.


Identification of ALP+/CD73+ defining markers for enhanced osteogenic potential in human adipose-derived mesenchymal stromal cells by mass cytometry.
The impressive progress in the field of stem cell research in the past decades has provided the ground for the development of cell-based therapy. Mesenchymal stromal cells obtained from adipose tissue (AD-MSCs) represent a viable source for the development of cell-based therapies. However, the heterogeneity and variable differentiation ability of AD-MSCs depend on the cellular composition and represent a strong limitation for their use in therapeutic applications. In order to fully understand the cellular composition of MSC preparations, it would be essential to analyze AD-MSCs at single-cell level. Recent advances in single-cell technologies have opened the way for high-dimensional, high-throughput, and high-resolution measurements of biological systems. We made use of the cytometry by time-of-flight (CyTOF) technology to explore the cellular composition of 17 human AD-MSCs, interrogating 31 markers at single-cell level. Subcellular composition of the AD-MSCs was investigated in their naïve state as well as during osteogenic commitment, via unsupervised dimensionality reduction as well as supervised representation learning approaches. This study showed a high heterogeneity and variability in the subcellular composition of AD-MSCs upon isolation and prolonged culture. Algorithm-guided identification of emerging subpopulations during osteogenic differentiation of AD-MSCs allowed the identification of an ALP+/CD73+ subpopulation of cells with enhanced osteogenic differentiation potential. We could demonstrate in vitro that the sorted ALP+/CD73+ subpopulation exhibited enhanced osteogenic potential and is moreover fundamental for osteogenic lineage commitment. We finally showed that this subpopulation was present in freshly isolated human adipose-derived stromal vascular fractions (SVFs) and that could ultimately be used for cell therapies. The data obtained reveal, at single-cell level, the heterogeneity of AD-MSCs from several donors and highlight how cellular composition impacts the osteogenic differentiation capacity. The marker combination (ALP/CD73) can not only be used to assess the differentiation potential of undifferentiated AD-MSC preparations, but also could be employed to prospectively enrich AD-MSCs from the stromal vascular fraction of human adipose tissue for therapeutic applications.


[Study of viral contamination of Japanese quail and cell cultures from their embryos].
Agents identified as adenovirus CELO were isolated from organ suspensions of 1500 Japanese quails (JQ) in 4 experiments. No contaminating viruses were found in examinations of cell cultures prepared from the kidneys of 80 JQ. Negative results were obtained in examinations of 163 antigens from JQ organs in the COFAL test. Agents identified as mycoplasma were isolated in 16 cases from 736 specimens of the virus-containing fluid used for manufacture of measles virus. According to the results of the CFT, 59 antigens prepared from Japanese quail embryo cell cultures contained no oncornavirus antigens and were negative in the COFAL test. Among 1848 JQ sera examined for the presence of antibody to leukemia-sarcoma complex viruses only 2 sera were found in 1976 to contain antibody to Rous sarcoma virus. No antibody to Marek disease virus in 414 serum samples or to Newcastle disease virus in 554 sera were detected. Among 500 sera tested 30.8% contained antibody to adenovirus CELO.


Successful interventional treatment of postoperative bile duct leakage after Billroth II resection by unusual procedure using double balloon enteroscopy.
Endoscopic treatment of advanced biliary disorders and their complications following surgical procedures is often difficult especially after Billroth II gastric resection. In such cases, endoscopic access to the papilla and neopapilla is often low, and access to the choledocho- or hepaticojejunostomy is often difficult. Thus, percutaneous cholangiodrainage or re-operation is therefore indicated when endoscopic access to the papilla failed. But both of those methods are much more invasive and more likely to be followed by complications than use of a purely endoscopic approach. The present case report describes endoscopic access to the papilla with both push enteroscopy and double-balloon enteroscopy (DBE, push-and-pull enteroscopy) in a female patient after Billroth II resection with bile leakage following cholecystectomy. Successful closure of the bile duct fistula could be achieved via an unusual abdominal-biliary-jejunal cannulation way after several attempts of modern enteroscopy and in this way re-operation was avoided. Modern enteroscopy by experienced investigators using push-and-pull enteroscopes can provide access to the papilla even in complex postoperative anatomic rearrangements. Push-and-pull enteroscopes offer a further option for successful cannulation of the papilla and therapeutic interventions via additional stabilization with balloons and the modern enteroscopic approach by push-and-pull enteroscopy appears to provide more patient comfort, requires less analgo-sedation and examination time and in cases with intra-abdominal drainage this external access may be used as an additional aid for exploration and intervention in complex individual cases with extremely difficult treatable bile duct injuries.


Ready, willing, and able to provide MTM services?: A survey of community pharmacists in the USA.
Changes in US Medicare legislation could benefit pharmacy's attempt to make medication therapy management (MTM) practice more commonplace; however, little is known about pharmacists' capabilities and preferences to do so. The purpose of this study was to explore US pharmacists' perceived preparedness, willingness, and challenges toward providing MTM services. A brief purpose of the survey and its website link were included in the electronic weekly newsletter of the National Community Pharmacists Association (NCPA) in January 2007. The web-based survey consisted of 8 demographic questions, 8 questions examining preparedness and willingness of the respondents regarding MTM, 2 questions regarding reimbursement to pharmacists, and 2 checklists for challenges in establishing MTM services. Most of the 143 respondents indicated that they were aware of MTM, and 92 (65%) reported that they were currently practicing MTM. A majority of the sample agreed that pharmacists should provide MTM and have the ability to do so. Major challenges reported by the sample include the different specification of MTM by each health plan, time, staffing, and reimbursement issues. Respondents selected valid measures of program effectiveness but revealed that they needed help with documentation and billing. Expected reimbursement range was $1-10/minute. Community independent pharmacists reported being ready, willing, and able to provide MTM services, but need assistance in the process, that is, standardized MTM protocols, documentation and billing.


Improved Quantum-Classical Treatment of N2-N2 Inelastic Collisions: Effect of the Potentials and Complete Rate Coefficient Data Sets.
In this study, complete (i.e., including all vibrational quantum numbers in an N2 vibrational ladder) data sets of vibration-to-vibration and vibration-to-translation rate coefficients for N2-N2 collisions are explicitly computed along with transport properties (shear and bulk viscosity, thermal conductivity, and self-diffusion) in the temperature range 100-9000 K. To reach this goal, we improved a mixed quantum-classical (MQC) dynamics approach by lifting the constraint of a Morse treatment of the vibrational wave function and intramolecular potential and permitting the use of more realistic and flexible representations. The new formulation has also allowed us to separately analyze the role of intra- and intermolecular potentials on the calculated rates and properties. Ab initio intramolecular potentials are indispensable for highly excited vibrational states, though the Morse potential still gives reasonable values up to v = 20. An accurate description of the long-range interaction and the van der Waals well is a requisite for the correct reproduction of qualitative and quantitative rate coefficients, particularly at low temperatures, making physically meaningful analytical representations still the best choice compared to currently available ab initio potential energy surfaces. These settings were used to directly compute the MQC rates corresponding to a large number of initial vibrational quantum numbers, and the missing intermediate values were predicted using a machine learning technique (i.e., the Gaussian process regression approach). The obtained values are reliable in the wide temperature range employed and are therefore valuable data for many communities dealing with nonlocal thermal equilibrium conditions in different environments.