Viqualine in resistant depression: a double-blind, placebo-controlled trial.
Viqualine dihydrochloride is a new molecule, which possesses strong serotonin reuptake inhibition properties and, at the same time, diazepam-like actions, such as [3H]-diazepam-binding inhibition and antipunishment effect. The drug was administered double-blindly to 10 patients suffering from major depression resistant to previous treatments with tricyclics. The comparison group (10 patients) received placebo. Lorazepam (10 mg/day) was also given to both groups. Viqualine proved to be significantly superior to placebo in the 4th week of treatment on all the three rating scales which were used. Tolerability of viqualine was good both objectively and on subjective grounds.


Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial.
Skeletal-related events (SREs), common sequelae of metastatic cancer, are reduced by bisphosphonates. In this study, it was postulated that radiopharmaceuticals, added to bisphosphonates, could further decrease the incidence of SREs. NRG Oncology RTOG 0517 randomized patients with breast, lung, and prostate cancer and blastic bone metastases to either zoledronic acid (ZA) alone or ZA plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life (QOL), pain control, overall survival (OS), and toxicity. 261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued between July 2006 and February 2011. The study closed early due to a lower than expected rate of SREs. 52 (42%) patients in the ZA arm and 49 (40%) in the radiopharmaceutical arm experienced an SRE. Median time free of SREs was 29.9 and 27.4 months, respectively (p = 0.84). Median OS in the ZA arm and radiopharmaceutical arms was 32.1 and 26.9 months, respectively (p = 0.37). Cox proportional hazards regression model showed that primary disease site (lung) and number of bone metastases (> 2) had a negative impact on OS (p < 0.0001, p = 0.01, respectively). The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at 1 month based on BPI worst score (p = 0.02). No other group differences were noted for QOL or toxicity. The addition of radiopharmaceuticals to bisphosphonates did not alter time to SREs or OS for patients with breast, lung, prostate cancers and blastic bone metastases, although it was associated with significant pain reduction at 1 month. This protocol (RTOG 0517) is registered with ClinicalTrials.gov (NCT00365105), and may be viewed online at http://www.clinicaltrials.gov/ct2/show/NCT00365105?term=RTOG+0517&rank=1 .


Resolving Strategic Dilemmas in Ambidextrous Organizations: An Integrated Second-Order Factor Model Perspective.
Drawing on relevant literature, this study investigates the process of realizing innovation ambidexterity (IA) by proposing a theoretical model and adopting a specifically integrated mechanism with the aim to resolve strategic dilemmas in ambidextrous organizations (AOs). We analyzed a sample of 136 cross-sectional surveys collected from business managers of 132 medium- and high-tech firms in China by employing a structural equation model combined with moderation analysis to test our hypotheses. Our findings indicate that the second-order theoretical model fits the data well and AO, represented by a higher-order construct, positively affects IA. Instead of structural ambidexterity, balanced contextual ambidexterity and radical performance management can be effectively applied as the factors of the second-order construct; the design comprising balanced contextual ambidexterity and performance management is thus helpful in resolving strategic dilemmas. Our findings demonstrate that Chinese firms, as technology latecomers, are more inclined to conduct near-radical innovation. The risk of exploration crowding out exploitation efforts exists in Chinese high-tech firms. Furthermore, we provides greater insights into the moderating impact of intra-organizational practice on IA based on the fact that performance measurement balance (PMB) did not directly influence the achievement of IA and clarifies the positive role that PMB plays in improving IA.


Reactivated Moraxella osteitis presenting as granulomatous disease.
Granulomatous infections are commonly associated with mycobacteria, brucellosis, actinomycosis, nocardiosis, spirochetes, and fungi. Rarely, granuloma formation is a host response to other bacterial infection. Osteomyelitis and osteitis that reactivate many years after the primary episode is a known phenomenon. A reactivation that presents as a granulomatous disease is rare. We present a case of reactivated osteitis due to Moraxella osloensis with consecutive granuloma formation.


Can human allergy drug fexofenadine, an antagonist of histamine (H1) receptor, be used to treat dog and cat? Homology modeling, docking and molecular dynamic Simulation of three H1 receptors in complex with fexofenadine.
Fexofenadine, a potent antagonist to human histamine 1 (H1) receptor, is a non-sedative third generation antihistamine that is widely used to treat various human allergic conditions such as allergic rhinitis, conjunctivitis and atopic dermatitis. Encouragingly, it's been successfully used to treat canine atopic dermatitis, this supports the notion that it might have a great potential for treating other canine allergic conditions and other mammal pets such as dog. Regrettably, while there is a myriad of studies conducted on the interactions of antihistamines with human H1 receptor, the similar studies on non-human pet H1 are considerably scarce. The published studies using the first and second generation antihistamines drugs have shown that the antihistamine response is varied and unpredictable. Thus, to probe its efficacy on pet, the homology models of dog and cat H1 receptors were built based on the crystal structure of human H1 receptor bound to antagonist doxepin (PDB 3RZE) and fexofenadine was subsequently docked to human, dog and cat H1 receptors. The docked complexes are then subjected to 1000ns molecular dynamics (MD) simulations with explicit membrane. Our calculated MM/GBSA binding energies indicated that fexofenadine binds comparably to the three receptors; and our MD data also showed the binding poses, structural and dynamic features among three receptors are very similar. Therefore, our data supported the application of fexofenadine to the H1 related allergic conditions of dog and cat. Nonetheless, subtle systemic differences among human, dog and cat H1 receptors were also identified. Clearly, there is still a space to develop a more selective, potent and safe antihistamine alternatives such as Fexofenadine for dog or cat based on these differences. Our computation approach might provide a fast and economic way to predict if human antihistamine drugs can also be safely and efficaciously administered to animals.


What is on the horizon for treatment of chronic hepatitis C?
Current guidelines for chronic Hepatitis C recommend peginterferon-alpha and ribavirin combination therapy for 24 or 48 weeks, based on viral factors (genotype, viral load), host factors (stage of liver disease) and virological response during treatment. The main goal of treatment is eradication of Hepatitis C virus (HCV) infection which is defined by HCV RNA negativity 24 weeks after end of treatment (i.e. sustained virological response, SVR). SVR can be achieved in up to 80% of patients. Most patients, however, experience adverse events during therapy which significantly affect drug compliance and treatment outcome. Several strategies have been evaluated in order to optimize outcome of current peginterferon-based therapy, including higher dosing of peginterferon and/or ribavirin, and adjusting therapy duration. Although some patients might benefit from these optimized treatment schedules, viral eradication remains unachievable in a substantial part of patients. In this perspective, there is a clear need for effective alternative or additional agents, especially as the burden of disease is expected to increase over the next decade. Potential novel antiviral targets are now being identified due to improved understanding of the HCV life cycle. Specifically targeted antiviral therapy for Hepatitis C (STAT-C) is in clinical development and has already shown to increase SVR rate. At this moment, however, SVR can only be achieved when combining new molecules with peginterferon therapy. The role of ribavirin has been questioned, but available evidence suggests that ribavirin has significant impact on treatment outcome and should therefore remain part of antiviral therapy. More than a decade of interferon-based therapy and potential new agents will be reviewed.


White matter tract alterations assessed with diffusion tensor imaging and tractography in patients with solid posterior fossa tumors.
This study assesses the tract alterations observed before and after resection of solid posterior fossa tumors (PFTs) using diffusion tensor imaging (DTI) and white matter tractography (WMT). Pre- and post-surgical DTI and WMT data were acquired in eight patients undergoing surgical resections of PFT. A tensor deflection algorithm was used to reconstruct the tracts adjacent to the lesions. The tracts were evaluated regarding their spatial orientation and integrity. A software additionally assessed the luminosity and pixel values from specific regions of interest (ROIs) quantifying the magnitude of tract alterations. The individual neurological condition was additionally evaluated. In eight tumors (metastases (4), neurinomas (2) and meningiomas (2), the preoperative WMT revealed different tract alterations, including deviation (all cases), deformation (7 cases), thinning (8 cases) and apparent tract interruption (4 cases). The ROI histograms from noncompromised tracts showed a tendency for value concentration and peak formation, while affected tracts showed different dispersion patterns. After tumor resection, the compromised white matter tracts showed a resolution (3 cases) or reduction (5 cases) of the deviation. Postoperatively, 7 cases of tract thinning and 3 cases with tract interruptions showed an improvement. The comparison between ROI histograms from preoperative and postoperative compromised tracts mostly revealed a postoperative accentuated reduction of the luminosity with a simultaneous increase of pixels and improved histogram definition (homogeneous values distribution). At this time (5 weeks post-surgery), several neurological functions had improved to different levels. Preoperative and postoperative tract alterations in patients with solid PFT can be accurately assessed with WMT. The magnitude of tract changes can be quantitatively analyzed by assessing color, signal brightness in compromised bundles.


Structural characterization of H-2 antigens purified from mouse liver.
Papain solubilized H-2a histocompatibility antigens (H-2Kk plus H-2Dd) have been purified by a large-scale procedure that can routinely provide 2-3 mg of heavy chain from 1 kg of mouse liver. The heavy chains were homogeneous by sodium dodecyl sulfate electrophoresis. Disc gel electrophoresis resolved two protein bands that were identified as H-2Dd and H-2Kd by immune complex formation and autoradiography. Comparative amino acid composition and NH2-terminal sequence analyses of unfractionated H-2a, H-2Kk, and HLA suggested close structural relationships. However, the following observations suggest that papain cleaves these membrane bound antigens at different positions with respect to the COOH terminus: the molecular weight of the peptide portion of papain solubilized HLA is smaller than that of H-2 (30,000 versus 33,700); the COOH-terminal sequences are different; and, finally, papain-solubilized H-2 contains a free cysteine residue in addition to the two disulfide bridges that are present in both H-2 and HLA.


Study on immunological status of Chinese HIV-infected individuals.
HIV-1 infection is characterized by a gradual decline of immune function, and the immune dysfunction is widely regarded as one of the most important determinants of disease progression. The present study was performed to analyze in more detail the immunological status of HIV-infected people in China. T cell counts, activation of T cells, HIV-1 specific CTL and plasma levels of cytokines were determined with flow cytometry, IFN-gamma Elispot or ELISA techniques. The HIV viral load was negatively correlated with CD4(+), CD8(+) T cell counts (r=-0.654, P<0.001; r=-0.228, P<0.05); the breadth and magnitude of HIV-1 specific CTL responses against HIV-1 Gag peptides was related to disease progression; the activation of CD8(+) T cells was significantly higher than that in HIV-negative controls; the level of plasma IL-12 was much lower and the plasma IFN-gamma, IL-10 and IL-6 were much higher in HIV-infected persons than in HIV-negative controls (P<0.05). Study on immunological status in HIV-infected Chinese is very important in predicting the disease progression and providing information for HAART therapy in China.


N-terminal deletion in the src gene of Rous sarcoma virus results in synthesis of a 45,000-Mr protein with mitogenic activity.
Expression of the v-src gene of Rous sarcoma virus in avian embryo neuroretina cells results in transformation and sustained proliferation of these normally resting cells. Transformed neuroretina cells are also tumorigenic upon inoculation into immunodeficient hosts. We have previously described conditional mutants of Rous sarcoma virus encoding p60v-src proteins which induce proliferation of neuroretina cells in the absence of transformation and tumorigenicity. These results suggest that p60v-src is composed of functionally distinct domains which may interact with multiple cellular targets. In this study, we describe a spontaneous variant of Rous sarcoma virus, subgroup E, which carries a deletion of 278 base pairs in the 5' portion of the v-src gene but which has retained the ability to induce proliferation of quail neuroretina cells. The deleted v-src gene encodes a 45,000-molecular-weight phosphoprotein which contains both phosphoserine and phosphotyrosine, is myristylated, and possesses tyrosine kinase activity indistinguishable from that of wild-type p60v-src. Molecular cloning and sequence analysis of the mutant v-src gene have shown that this deletion extends from amino acid 33 to 126 of the wild-type p60v-src. Therefore, this portion of the v-src protein is dispensable for the mitogenic activity of Rous sarcoma virus in neuroretina cells.


Acute sensory ataxic neuropathy with antibodies to GD1b and GQ1b gangliosides and prompt recovery.
Three patients developed acute pure sensory ataxic neuropathy. Two of the three patients had a recent Campylobacter jejuni infection. Patient 1 had monospecific IgG anti-GD1b. Patients 2 and 3 had cross-reactive IgG anti-GQ1b and anti-GD1b and patient 2 also had IgG anti-GT1a. Motor nerve conduction studies were completely normal. Sensory conductions showed reduced amplitude or absent sensory nerve action potentials with normal or slightly slowed conduction velocities. In patient 2, serial electrophysiological studies showed reappearance and improvement of sensory nerve potential amplitudes in 4 weeks. All patients recovered completely in 2 months and sensory potential amplitudes normalized in 3-5 months. Our findings: (1) confirm the existence of a pure acute sensory ataxic neuropathy with cross-reactive IgG anti-GQ1b and anti-GD1b as a variant of Guillain-Barré syndrome; (2) expand the clinical presentation of Guillain-Barré syndrome after C. jejuni infection and suggest that molecular mimicry is at the basis of acute sensory ataxic neuropathy; and (3) indicate that, in acute sensory ataxic neuropathy with prompt recovery, the site of the lesion is not in the primary sensory neurons and the pathophysiological mechanism may be functional in nature.


D-amino acids do not inhibit Pseudomonas aeruginosa biofilm formation.
Pseudomonas aeruginosa, a known biofilm-forming organism, is an opportunistic pathogen that plays an important role in chronic otitis media, tracheitis, cholesteatoma, chronic wounds, and implant infections. Eradication of biofilm infections has been a challenge because the biofilm phenotype provides bacteria with a protective environment from the immune system and antibiotics; thus, there has been great interest in adjunctive molecules that may inhibit biofilm formation or cause biofilm dispersal. There are reports that D-amino acids may inhibit biofilms. In this study, we test the ability of various D-amino acids to inhibit P. aeruginosa biofilm formation in vitro. We evaluated the effect of D-alanine (10 mM), D-leucine (10 mM), D-methionine (10 mM), D-tryptophan (10 mM), and D-tyrosine (10 uM and 1 mM) on biofilm formation in two commonly studied laboratory strains of P. aeruginosa: PAO1 and PA14. Biofilms were grown in 24-well and 96-well tissue culture plates, documented photographically and stained with 0.1% crystal violet and solubilized in 33% glacial acetic acid for quantification. In strains PAO1 and PA14, the addition of D-amino acids did not result in an inhibitory effect on biofilm growth in 24-well plates. Repeating the study in 96-well plates confirmed our findings that D-amino acids do not inhibit biofilm formation of P. aeruginosa. We conclude that D-amino acids only slow the production of biofilms rather than completely prevent biofilm formation; therefore, D-amino acids represent a poor option for potential clinically therapeutic interventions. N/A.


Preparation of norfloxacin spherical agglomerates using the ammonia diffusion system.
Agglomerated crystals of norfloxacin were prepared by a spherical crystallization technique using the ammonia diffusion system (ADS). This technique makes it possible to agglomerate amphoteric drugs like norfloxacin, which cannot be agglomerated by conventional procedures. When an ammonia-water solution of norfloxacin is poured into an acetone dichloromethane mixture under agitation, a small amount of ammonia is liberated in the system. The ammonia-water solution plays a role both as a good solvent for norfloxacin and as a bridging liquid, allowing the crystals' collection to take place in one step. It has been proven that the agglomeration mechanism follows three steps: first acetone enters into the droplets of ammonia-water (this emulsion is formed because of the system characteristics); dissolved norfloxacin is consequently precipitated while the droplets collect the crystals; simultaneously, a part of the ammonia contained in the agglomerates diffuses to the outer organic solvent phase, thereby forming the norfloxacin spherical agglomerates. The correct selection of solvents has enabled us to obtain a suitable stable crystalline shape.


Chloride channels and cystic fibrosis of the pancreas.
Cystic fibrosis (CF) affects approximately 1 in 2000 people making it one of the commonest fatal, inherited diseases in the Caucasian population. CF is caused by mutations in a cyclic AMP-regulated chloride channel known as CFTR, which is found on the apical plasma membrane of many exocrine epithelial cells. In the CF pancreas, dysfunction of the CFTR reduces the secretory activity of the tubular duct cells, which leads to blockage of the ductal system and eventual fibrosis of the whole gland. One possible approach to treating the disease would be to activate an alternative chloride channel capable of bypassing defective CFTR. A strong candidate for this is a chloride channel regulated by intracellular calcium, which has recently been shown to protect the pancreas in transgenic CF mice. Pharmacological intervention directed at activating this calcium-activated Cl- conductance might provide a possible therapy to treat the problems of pancreatic dysfunction in CF.


Guidelines for medical management of nuclear/radiation emergencies.
Management of victim of radiation injury poses a wide spectrum of challenges to the health care provider starting with the evaluation of the damage, the kind of hospitalization and treatment and the regular monitoring of the patient. Undesirable clinical outcomes are probable if prodromal stage evolves rapidly and is severe. Critical systems like neurovascular, gastrointestinal, haematopoietic and cutaneous are afflicted in Acute Radiation Syndrome. Three main elements which are essential for assessment of prognosis and selection of treatment are vomiting onset time, kinetics of depletion of lymphocyte, and chromosome abnormalities. Larger incidents warrant, a well-structured national response system. Health care institutions must develop protocols to respond to radiation exposure related emergencies in tandem with the local response teams. Multidisciplinary approach between clinical specialists, nursing staff and psychological experts is of critical significance. External decontamination, estimation of dose and fluid and electrolyte replacements form part of support therapy. Reverse isolation, antacids, H2 blockers, use of reverse barrier nursing and prophylactic antimicrobials are part of the treatment plan. Patients with severe bone marrow damage will require blood products support. Increased recovery of neutrophils in radiationaccident victims is the rationale for the use of Colony Stimulating Factors. New directions are under evaluation which includes novel cytokine therapies like interleukin-7, keratinocyte growth factor, and thrombopoietin or its analogues. The final decision regarding allogenic haematopoietic stem cell transplant should be considered after considering the irradiation source, particularity of the situations or circumstances, associated injuries and disease.


A comprehensive autoantigen-ome of autoimmune liver diseases identified from dermatan sulfate affinity enrichment of liver tissue proteins.
Autoimmune diseases result from aberrant immune attacks by the body itself. It is mysterious how autoantigens, a large cohort of seemingly unconnected molecules expressed in different parts of the body, can induce similar autoimmune responses. We have previously found that dermatan sulfate (DS) can form complexes with molecules of apoptotic cells and stimulate autoreactive CD5+ B cells to produce autoantibodies. Hence, autoantigenic molecules share a unique biochemical property in their affinity to DS. This study sought to further test this uniform principle of autoantigenicity. Proteomes were extracted from freshly collected mouse livers. They were loaded onto columns packed with DS-Sepharose resins. Proteins were eluted with step gradients of increasing salt strength. Proteins that bound to DS with weak, moderate, or strong affinity were eluted with 0.4, 0.6, and 1.0 M NaCl, respectively. After desalting, trypsin digestion, and gel electrophoresis, proteins were sequenced by mass spectrometry. To validate whether these proteins have been previously identified as autoantigens, an extensive literature search was conducted using the protein name or its alternative names as keywords. Of the 41 proteins identified from the strong DS-affinity fraction, 33 (80%) were verified autoantigens. Of the 46 proteins with moderate DS-affinity, 27 (59%) were verified autoantigens. Of the 125 proteins with weak DS-affinity, 44 (35%) were known autoantigens. Strikingly, these autoantigens fell into the classical autoantibody categories of autoimmune liver diseases: ANA (anti-nuclear autoantibodies), SMA (anti-smooth muscle autoantibodies), AMA (anti-mitochondrial autoantibodies), and LKM (liver-kidney microsomal autoantigens). This study of DS-affinity enrichment of liver proteins establishes a comprehensive autoantigen-ome for autoimmune liver diseases, yielding 104 verified and 108 potential autoantigens. The liver autoantigen-ome sheds light on the molecular origins of autoimmune liver diseases and further supports the notion of a unifying biochemical principle of autoantigenicity.


Metastatic basal cell carcinoma: report of a case responding to chemotherapy.
Metastases of basal cell carcinoma are very uncommon. Only 10 reported cases have been treated with cytotoxic chemotherapy, and no good responses have been documented. The case is presented of a 54-year-old male who had several basal cell carcinomas (BCCs) removed surgically and who, 12 years after his first presentation, developed respiratory symptoms related to metastatic pulmonary BCCs. These failed to respond to initial chemotherapy with methotrexate, bleomycin, and vincristine, but regressed when treated with cyclophosphamide and cis-diamine dichloroplatinum.


The mitochondrial genome of the glomeromycete Rhizophagus sp. DAOM 213198 reveals an unusual organization consisting of two circular chromosomes.
Mitochondrial (mt) genomes are intensively studied in Ascomycota and Basidiomycota, but they are poorly documented in basal fungal lineages. In this study, we sequenced the complete mtDNA of Rhizophagus sp. DAOM 213198, a close relative to Rhizophagus irregularis, a widespread, ecologically and economical relevant species belonging to Glomeromycota. Unlike all other known taxonomically close relatives harboring a full-length circular chromosome, mtDNA of Rhizophagus sp. reveals an unusual organization with two circular chromosomes of 61,964 and 29,078 bp. The large chromosome contained nine protein-coding genes (atp9, nad5, cob, nad4, nad1, nad4L, cox1, cox2, and atp8), small subunit rRNA gene (rns), and harbored 20 tRNA-coding genes and 10 orfs, while the small chromosome contained five protein-coding genes (atp6, nad2, nad3, nad6, and cox3), large subunit rRNA gene (rnl) in addition to 5 tRNA-coding genes, and 8 plasmid-related DNA polymerases (dpo). Although structural variation of plant mt genomes is well documented, this study is the first report of the presence of two circular mt genomes in arbuscular mycorrhizal fungi. Interestingly, the presence of dpo at the breakage point in intergenes cox1-cox2 and rnl-atp6 for large and small mtDNAs, respectively, could be responsible for the conversion of Rhizophagus sp. mtDNA into two chromosomes. Using quantitative real-time polymerase chain reaction, we found that both mtDNAs have an equal abundance. This study reports a novel mtDNA organization in Glomeromycota and highlights the importance of studying early divergent fungal lineages to describe novel evolutionary pathways in the fungal kingdom.


Infection control in the bronchoscopy suite. A review.
Bronchoscopy can occasionally transmit disease. Infection control in the bronchoscopy suite is especially important because of the risk of transmitting HIV or tuberculosis. Many case reports, patient series, and small studies have been published, but little comprehensive guidance is available for clinicians who wish to learn more about the problem and prevent it. We review the literature and describe three ways in which bronchoscopy can cause disease: by transmitting infections between patients, by transferring microorganisms within a patient, and by triggering coughing that can cause airborne infection of patients or health-care workers. Recommendations for infection control are listed; they include installing powerful air filters, using disposable bronchoscope suction valves, manually cleaning all equipment before disinfection, controlling patient coughing, and in some cases, giving patients prophylactic antibiotics.


What lessons can surgeons learn from sport? The reflections of a retired athlete.
Surgery often looks to other domains of high performance such as the airline industry for ideas on how to improve surgical performance however little is written about what surgeons might learn from high performance sport. In this paper I offer some observations and ideas from my experience as an Olympic swimmer which I feel may be applicable to surgery and some thoughts on how these concepts might be introduced.


Validation of liquid biopsy: plasma cell-free DNA testing in clinical management of advanced non-small cell lung cancer.
Plasma cell-free tumor DNA, or circulating tumor DNA (ctDNA), from liquid biopsy is a potential source of tumor genetic material, in the absence of tissue biopsy, for EGFR testing. Our validation study reiterates the clinical utility of ctDNA next generation sequencing (NGS) for EGFR mutation testing in non-small cell lung cancer (NSCLC). A total of 163 NSCLC cases were included in the validation, of which 132 patients had paired tissue biopsy and ctDNA. We chose to validate ctDNA using deep sequencing with custom designed bioinformatics methods that could detect somatic mutations at allele frequencies as low as 0.01%. Benchmarking allele specific real time PCR as one of the standard methods for tissue-based EGFR mutation testing, the ctDNA NGS test was validated on all the plasma derived cell-free DNA samples. We observed a high concordance (96.96%) between tissue biopsy and ctDNA for oncogenic driver mutations in Exon 19 and Exon 21 of the EGFR gene. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the assay were 91.1%, 100% 100%, 95.6%, and 97%, respectively. A false negative rate of 3% was observed. A subset of mutations was also verified on droplet digital PCR. Sixteen percent EGFR mutation positivity was observed in patients where only liquid biopsy was available, thus creating options for targeted therapy. This is the first and largest study from India, demonstrating successful validation of circulating cell-free DNA as a clinically useful material for molecular testing in NSCLC.


Inter-patient ECG heartbeat classification for arrhythmia classification: a new approach of multi-layer perceptron with weight capsule and sequence-to-sequence combination.
Objective: The objective of this research is to construct a method to alleviate the problem of sample imbalance in classification, especially for arrhythmia classification. This approach can improve the performance of the model without using data enhancement. Methods: In this study, we have developed a new Multi-layer Perceptron (MLP) block and have used a Weight Capsule (WCapsule) network with MLP combined with sequence-to-sequence (Seq2Seq) network to classify arrhythmias. Our work is based on the MIT-BIH arrhythmia database, the original electrocardiogram (ECG) data is classified according to the criteria recommended by the American Association for Medical Instrumentation (AAMI). Also, our method's performance is further evaluated. Results: The proposed model is evaluated using the inter-patient paradigm. Our proposed method shows an accuracy (ACC) of 99.88% under sample imbalance. For Class N, sensitivity (SEN) is 99.79%, positive predictive value (PPV) is 99.90%, and specificity (SPEC) is 99.19%. For Class S, SEN is 97.66%, PPV is 96.14%, and SPEC is 99.85%. For Class V, SEN is 99.97%, PPV is 99.07%, and SPEC is 99.94%. For Class F, SEN is 97.94%, PPV is 98.70%, and SPEC is 99.99%. When using only half of the training sample, our method shows that the SEN of Class N and V is 0.97% and 5.27% higher than the traditional machine learning algorithm. Conclusion: The proposed method combines MLP, weight capsule network with Seq2seq network, effectively addresses the problem of sample imbalance in arrhythmia classification, and produces good performance. Our method also shows promising potential in less samples.


Multichannel radiometer calibration: a new approach.
The error in irradiance measured with Sun-calibrated multichannel radiometers may be large when the solar zenith angle (SZA) increases. This could be particularly detrimental in radiometers installed at mid and high latitudes, where SZAs at noon are larger than 50 degrees during part of the year. When a multiregressive methodology, including the total ozone column and SZA, was applied in the calculation of the calibration constant, an important improvement was observed. By combining two different equations, an improvement was obtained at almost all the SZAs in the calibration. An independent test that compared the irradiance of a multichannel instrument and a spectroradiometer installed in Ushuaia, Argentina, was used to confirm the results.


[An experiment study of protection and treatment of Kudan granule on rats of pulmonary fibrosis induced by pinyangmycin].
To explore the protection and treatment effects of Kudan granule on rats of pulmonary fibrosis induced by pinyangmycin. In asepsis condition, rat was anaesthetized by 3.5% chloral hydrate, inserted the needle above the bifurcation of trachea and injecting 5 mg x kg(-1) pinyangmycin normal saline solution. For model-group rats, after injecting pinyangmycin at 7, 14, 28, 56 days, there were mass inflammation cell infiltration at pulmonary alveoli and interstitial, the pulmonary alveolar wall and interstitial thickened obviously, and the pulmonary interval broadened distinctly. The structure of collagen fiber was destroyed, and the pulmonary alveoli disappeared. By Masson dyeing, there were hunk collagen fiber and the consolidation of lung had come into being. Compared with the model group, the rats of Kudan granule big-dose group, at 7, 14, 28, 56 days after injecting pinyangmycin, there were still much inflammation cell infiltration at pulmonary alveoli and interstitial, pulmonary interstitial edema and spotty necrosis, thickened alveolar wall, broadened pulmonary interval, and much collagen fiber in pulmonary interstitial, but there was not bunk the consolidation of lung. The curative effect of Kudan granule small-dose group was not better than that of Kudan granule big-dose group, because there were still bunk collagen fiber and the consolidation of lung in pulmonary interstitial. Although the destroyed area was more than 50%, it was better than that of the model-group. The big-dose Kudan granule show the better function of protection and treatment for pulmonary fibrosis of rats induced by pinyangmycin.


Association of traditional Chinese medicine therapy and the risk of dementia in patients with hypertension: a nationwide population-based cohort study.
Patients with hypertension (HTN) reportedly have a higher risk of developing dementia. However, it remains unclear if use of Traditional Chinese Medicine (TCM), the most common form of complementary and alternative medicine, can help lower the risk of dementia for these patients. So the aim of the study was to investigate the effects of TCM on dementia risk among patients with hypertension. This longitudinal cohort study used the Taiwanese National Health Insurance Research Database (NHIRD) to identify 143,382 newly diagnosed hypertension patients aged 20-90 years who received treatment between 1998 and 2007. Among them, 52,365 (36.52%) had received TCM after the onset of hypertension (TCM users), and the remaining 91,017 patients (63.48%) were designated as a control group (non-TCM users). All enrollees were followed until the end of 2012 to record the incidence of dementia. A Cox proportional hazards regression model was used to compute the hazard ratio (HR) of dementia in patients who received TCM. During the 15-year follow-up, 3933 TCM users and 10,316 non-TCM users developed dementia, representing an incidence rate of 8.41 and 11.55%, respectively, per 1000 person-years. TCM users had a significantly reduced risk of dementia compared to non-TCM users (adjusted HR = 0.76; 95% confidence interval [CI] = 0.74-0.81). The predominant effect was observed among those treated with TCM longer than 180 days (adjusted HR = 0.65; 95% CI = 0.62-0.69). Among the commonly used TCM products, Tian-Ma-Gou-Teng-Yin, Dan-Shen (Radix Salviae Miltiorrhizae), Chuan-Niu-Xi (Radix Cyathulae), Ge-Gen (Radix Puerariae), Jia-Wei-Xiao-Yao-San, and Jue-Ming-Zi (Semen Cassiae) were significantly associated with a lower risk of dementia. Results from this population-based study support the effects of TCM on reducing dementia risk, which may provide a reference for dementia prevention strategies.


Comprehensive anticancer drug response prediction based on a simple cell line-drug complex network model.
Accurate prediction of anticancer drug responses in cell lines is a crucial step to accomplish the precision medicine in oncology. Although many popular computational models have been proposed towards this non-trivial issue, there is still room for improving the prediction performance by combining multiple types of genome-wide molecular data. We first demonstrated an observation on the CCLE and GDSC datasets, i.e., genetically similar cell lines always exhibit higher response correlations to structurally related drugs. Based on this observation we built a cell line-drug complex network model, named CDCN model. It captures different contributions of all available cell line-drug responses through cell line similarities and drug similarities. We executed anticancer drug response prediction on CCLE and GDSC independently. The result is significantly superior to that of some existing studies. More importantly, our model could predict the response of new drug to new cell line with considerable performance. We also divided all possible cell lines into "sensitive" and "resistant" groups by their response values to a given drug, the prediction accuracy, sensitivity, specificity and goodness of fit are also very promising. CDCN model is a comprehensive tool to predict anticancer drug responses. Compared with existing methods, it is able to provide more satisfactory prediction results with less computational consumption.


[Efficacy of hyperbaric oxygen therapy in the treatment of ischemic toe ulcer in a patient presenting systemic sclerosis].
The medical treatment of ischemic ulcers in patients with systemic sclerosis remains difficult. Despite the major help provided by vasodilator treatments, the risk of spontaneous or surgical amputation remains high. A 48-year-old female patient from Guadeloupe was treated in our department for diffuse systemic sclerosis present for 15 years complicated by lung, joint and digestive involvement, and associated with severe Raynaud's phenomenon. The clinical course was marked by the occurrence of multiple ischemic ulcers, which were resistant to conventional medical treatment and resulted in two surgical amputations (to the 2nd and 3rd interphalangeal joints of the toes of the left foot). Treatment with an endothelin-receptor antagonist and a calcium inhibitor was then introduced for secondary prevention. Two years later, the patient consulted for a further ischemic ulcer of the left 4th toe. She refused the proposed treatment with iloprost. Because of the unfavorable outcome and the absence of therapeutic alternative to amputation, hyperbaric oxygen therapy was initiated. Thirty 90-minutes sessions of pure oxygen at 2.5 ATA were conducted over a 10-week period. Complete healing was obtained after 8 months. We report herein a clinical case illustrating the efficacy of hyperbaric oxygen therapy for the treatment of ischemic ulcers of the toes in systemic sclerosis. It could offer an alternative therapeutic option, in particular for patients presenting resistant ischemic ulcers and a contraindication for or intolerance to the conventional medical treatment.


Role of vasoactive intestinal peptide on the proximal and distal parts from the dentate line in the normal human internal anal sphincter.
To clarify the functional differences of vasoactive intestinal peptide (VIP) in the human internal anal sphincter (IAS) between the proximal and distal parts from the dentate line, we investigated the VIPergic nerve responses of normal proximal and distal IAS in vitro. Normal IAS specimens derived from 20 patients with lower rectal cancer (14 men and 6 women aged from 48 to 77 years, average 66.5 years) were used. These IAS muscles were divided into 2 parts [oral site IAS from dentate line; proximal part (PIAS; n=20), anal site IAS from dentate line; distal part (DIAS; n=20)]. A mechanogram was used to evaluate in vitro muscle strip responses to VIP after treatment with various autonomic nerve blockers. 1) Response to VIP after blockade of the adrenergic and cholinergic nerves: VIP showed relaxation reaction in both PIAS and DIAS. The percentage of relaxation responses via VIP nerves in the PIAS was significantly greater than that in the DIAS (p=0.0350). 2) VIP responses in the PIAS and DIAS were not completely blocked by tetrodotoxin. These results indicated that VIP acts through both nerves and directly on the IAS muscle. There are functional differences in the regulation of VIPergic nerves between the PIAS and DIAS. Relaxation reaction via VIPergic nerves was mainly involved in the regulation of enteric nerve responses in the PIAS.


Eigenvector statistics of the product of Ginibre matrices.
We develop a method to calculate left-right eigenvector correlations of the product of m independent N×N complex Ginibre matrices. For illustration, we present explicit analytical results for the vector overlap for a couple of examples for small m and N. We conjecture that the integrated overlap between left and right eigenvectors is given by the formula O=1+(m/2)(N-1) and support this conjecture by analytical and numerical calculations. We derive an analytical expression for the limiting correlation density as N→∞ for the product of Ginibre matrices as well as for the product of elliptic matrices. In the latter case, we find that the correlation function is independent of the eccentricities of the elliptic laws.


Effects of Conscious Control of Scapular Orientation in Oral Cancer Survivors With Scapular Dyskinesis: A Randomized Controlled Trial.
Spinal accessory nerve dysfunction is one of the complications of neck dissection in patients with oral cancer. This study aimed to explore the effects of long-term scapular-focused exercises and conscious control of scapular orientation on scapular movement and quality of life (QoL). This study was a randomized controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Thirty-six patients with oral cancer were randomly allocated to the motor-control group (scapular-focused exercise + conscious control of scapular orientation) or the regular-exercise group (scapular-focused exercises only). Both groups received conventional physical therapy after neck dissection for 3 months. Shoulder pain intensity, active range of motion (AROM) of shoulder abduction, scapular muscle strength and activity under maximal voluntary isometric contraction (MVIC), scapular muscle activity when performing scapular movements, and QoL were measured at baseline, 1 month after the start of the intervention, and the end of the intervention. Both groups showed significant improvement in all outcomes except shoulder pain intensity. After the 3-month intervention, the motor-control group had more significant improvement in AROM of shoulder abduction with a 19° difference (95% CI: 10-29, P < .001), muscle strength of upper trapezius with an 11 N difference (95% CI: 2-20; P = .021), and QoL than the regular-exercise group. When performing shoulder horizontal adduction and flexion, the relative value (%MVIC) of serratus anterior was smaller in the motor-control group with a 106%MVIC difference (95% CI: 7-205, P = .037). Scapular-focused exercises have promising effects on spinal accessory nerve dysfunction. Combining scapular-focused exercises with conscious control of scapular orientation has more remarkable benefits on AROM of shoulder abduction, UT muscle strength, and muscle activation pattern than the scapular-focused exercises alone. Conscious control of scapular orientation should be considered to integrate into scapular-focused exercises in patients with oral cancer and scapular dyskinesis.Trial registry name and URL, and registration number: ClinicalTrials.gov (URL: https://clinicaltrials.gov; Approval No: NCT03545100).


Template-guided implantation of the Bonebridge: clinical experience.
The surgical procedure for Bonebridge implantation cannot be done in some cases without exposing the dura mater or sigmoid sinus. Surgical simulation technology can help to identify such difficulties prior to surgery and be used to clarify the optimal location and orientation of the device to be implanted. However, there has not been a simple strategy to drill the temporal bone at exactly the same location as that simulated on the computer. Based on our previous development of the surface template-assisted marker positioning (STAMP) method for performing image-guided otologic surgery, we recently developed a noninvasive guiding method, the BB-STAMP method, for performing image-guided Bonebridge implantation. Three patients underwent Bonebridge implantation at our surgical center during the years of 2013-2014. The authors in the simulation center supported the surgery using the BB-STAMP method. The time and effort required to prepare for the surgery were evaluated. In addition, a postoperative analysis was performed to assess the accuracy of placing the device in the planned location. The BB-STAMP method enabled the surgeon to precisely replicate the computer simulation in the real patient with submillimetric accuracy without complexity. Thus, the use of experienced and elaborative simulation coupled with the creation of a tailor-made three-dimensional template (BB-STAMP) enables surgeons to perform quick, precise and safe surgical procedures at distant institutions.


DNA Duplex Formation with a Coarse-Grained Model.
A middle-resolution coarse-grained model of DNA is proposed. The DNA chain is built of spherical and planar rigid bodies connected by elastic virtual bonds. The bonded part of the potential energy function is fit to potentials of mean force of model systems. The rigid bodies are sets of neutral, charged, and dipolar beads. Electrostatic and van der Waals interactions are parametrized by our recently developed procedure [Maciejczyk, M.; Spasic, A.; Liwo, A.; Scheraga, H.A. J. Comp. Chem.2010, 31, 1644]. Interactions with the solvent and an ionic cloud are approximated by a multipole-multipole Debye-Hückel model. A very efficient R-RATTLE algorithm, for integrating the movement of rigid bodies, is implemented. It is the first coarse-grained model, in which both bonded and nonbonded interactions were parametrized ab initio and which folds stable double helices from separated complementary strands, with the final conformation close to the geometry of experimentally determined structures.


Effects of mu- and delta-opioid-receptor antagonists on the stimulus properties of cholecystokinin.
Melton and Riley recently reported that the relatively selective mu-opioid-antagonist naloxone potentiated the stimulus properties of the gut peptide cholecystokinin (CCK). To assess whether such opioid potentiation is limited to activity at the mu-receptor subtype, in the present experiment the effects of the highly selective delta-antagonist naltrindole on CCK's stimulus properties were examined. Because in the initial report of naloxone's potentiation of CCK a relatively high, nonphysiologic dose of CCK (i.e., 13 micrograms/kg) was used as the training drug, in the current analysis subjects were trained to discriminate 5.6 micrograms/kg CCK from its vehicle and the assessments and comparisons of the effects of naloxone and naltrindole were based on this dose. Specifically, rats were administered 5.6 micrograms/kg CCK before saccharin-LiCl pairings and the CCK vehicle before saccharin alone. With such training, they rapidly acquired the drug discrimination, avoiding saccharin consumption when it was preceded by CCK and consuming the same saccharin solution when it was preceded by its vehicle. In subsequent generalization tests, doses of CCK that were ineffective in suppressing saccharin consumption (i.e., did not substitute for the training dose of CCK) did result in the suppression of saccharin consumption when combined with doses of the mu antagonist naloxone that alone had no effect on saccharin intake. On the other hand, the highly selective delta-opioid-receptor antagonist naltrindole was ineffective in potentiating the effects of CCK. Specifically, when naltrindole was combined with ineffective doses of CCK, subjects drank at control levels. The ability of naloxone to potentiate CCK's stimulus effects is consistent with a range of other demonstrations of the role of the mu-opioid-receptor subtype in CCK-opioid interactions, although the specific basis for the interaction remains unknown. Given recent findings on the effects of delta agonists and antagonists on CCK-induced activity, the failure of naltrindole to potentiate CCK's stimulus effects may be due to the absence of delta activity within this preparation, rather than the absence of delta mediation of CCK-opioid interactions in general.


ARP/wARP's model-building algorithms. I. The main chain.
Algorithms underlying the automatic model-building functionality of the ARP/wARP software suite are presented. Finding the most likely set of Calpha atoms from a given set of atoms is formulated as a constrained integer programming problem. The objective function is a density-weighted score for the match between observed and expected chain conformation. Graph-search algorithms are presented that find solutions to this problem in an efficient manner.


[Experiments on prosody perception with cochlear implants].
Prosody has a myriad of linguistic functions and involves specific aspects of speech, such as stress, intonation and pauses. The underlying acoustic quantities (amplitude envelope, pitch frequency, and temporal structure) can be processed and transmitted by cochlear implants (CI) only to a limited extent. At present, no adequate tests are available in the German-speaking world for evaluation of the perception of prosodic elements. Different experiments have been conducted to address several prosodic cues, and the results are to be used as a basis for appropriate tests. Various prosodic materials were used for the experiments. Discrimination was measured for minimal pairs differing in frequency and/or duration, accents in words and phrases, questions versus statements and phrasing. Measurements were performed in ten normal-hearing subjects and five with cochlear implants. In all test modules, the subjects with normal hearing proved to have high discrimination rates of 96-100%. The test of word stresses was problematic because the results were influenced by different confounders. The other measurements did prove to be basically suitable for use in the subjects with implants. Early results revealed that the subjects with CI had few problems with prosodic cues based on the temporal structure, the outcome being similar to that of the subjects with normal hearing in these tests. In contrast, the performance of subjects with CI in perceiving prosodic cues based on amplitude variations and, especially, on alterations in pitch frequency was worse, even though some of them achieved very good results in these tests too. These preliminary tests can form the basis for development of a German-language prosody test battery with a limited number of subtests addressing different prosodic cues.


Mechanisms of Change in Treatments of Personality Disorders: Commentary on the Special Section.
Ueli Kramer has assembled an eclectic and original set of articles on mechanisms of change in the treatment of borderline personality disorder. They largely focus on patient variables. Several authors make the point that developmentally based variables may have more predictive power than symptom-based variables. Several other articles illustrate that changes occur early in treatments and studying their mechanisms is a promising approach that could have longer term significance. These articles document the variety of research methodologies that can be used to study mechanisms of change and the potential clinical significance of doing this. For showing the field the potential of such research, we owe Dr. Kramer our gratitude.


Structure and functional characterization of the periplasmic N-terminal polypeptide domain of the sugar-specific ion channel protein (ScrY porin).
The structure of the sucrose-specific porin (ScrY) from Salmonella typhimurium has been elucidated by X-ray crystallography to consist of 18 antiparallel beta-strands, associated as a trimer complex similar to ion-transport channels. However, the 71-amino-acid-residue N-terminal periplasmic domain was not determined from the crystal structure due to the absence of sufficient electron density. The N-terminal polypeptide contains a coiled-coil structural motif and has been assumed to play a role in the sugar binding of ScrY porin. In this study the proteolytic stability and a specific proteolytic truncation site at the N-terminal domain were identified by the complete primary structure characterization of ScrY porin, using MALDI mass spectrometry and post-source-decay fragmentation. The secondary structure and supramolecular association of the coiled-coil N-terminal domain were determined by chemical synthesis of the complete N-terminal polypeptide and several partial sequences and their spectroscopic, biophysical, and mass spectrometric characterization. Circular dichroism spectra revealed predominant alpha-helical conformation for the putative coiled-coil domain comprising residues 4-46. Specific association to both dimer and trimer complexes was identified by electrospray ionization mass spectra and was ascertained by dynamic light scattering and electrophoresis data. The role of the N-terminal domain in sugar binding was examined by comparative TR-NOE-NMR spectroscopy of the complete ScrY porin and a recombinant mutant, ScrY(delta1-62), lacking the N-terminal polypeptide. The TR-NOE-NMR data showed a strong influence of ScrY porin on the sugar-binding affinity and suggested a possible function of the periplasmic N terminus for supramolecular stabilization and low-affinity sugar binding.


Which anthropometric indices best predict metabolic disorders in Taiwan?
The aim of this survey was to assess the association between the three simple anthropometric indices (body mass index [BMI], waist-to-hip ratio (WHR), and waist circumference [WC]) and various metabolic disorders, and to identify which indices can best predict metabolic disorders in Taiwan. A cross-sectional hospital-based survey was carried out from January to December 2000. We retrospectively analyzed the medical records of all the patients receiving periodic health examination with scheduled items at China Medical University Hospital. Anthropometric indices, metabolic profiles, and abdominal sonography were performed. A total of 746 people aged 19 to 87 were recruited as subjects for this study. The t test, chi2 test, and stepwise multivariate logistic regression were used. The subjects included 44.5% women and 55.5% men, with a mean age of 50.74 +/- 12.68 years. After controlling for the other covariables, stepwise multivariate logistic regression showed considerable statistical significance between overall obesity and hypertension, hypertriglyceridemia, hyperuricemia, and fatty liver. There is also statistical significance between abdominal obesity and abnormal ratio of total cholesterol HDL (high-density lipoprotein), hyperuricemia, and fatty liver. None of the indices revealed any association with hyperglycemia, hypercholesterolemia, abnormal low-density lipoprotein, or abnormal HDL. BMI and WC can best predict some metabolic disorders. For practical reasons, the combined measurement of BMI and WC is the simple and inexpensive anthropometric index for primary health care settings in the routine physical examinations of adults. We hope this study can establish the background data for further investigation on the epidemiology of anthropometric indices in Taiwan.


Agent-based modeling for understanding social intelligence.
The advantages of agent-based modeling for a general theory of intelligence at the individual and social level are emphasized over other existing approaches mainly relying on rationality theories. As was pointed out during the National Academy of Sciences Sackler Colloquium session "Implications of Agent-Based Modeling for Understanding Human Rationality and Learning," held in October 2001, properties of social intelligent agents include adaptability and learning capacity, as well as the capacity to produce and employ artifacts and manipulate symbols.


Synthesis of camphor thiazole derivates from Dryobalanops aromatica and its bioactivity as antioxidants and antidiabetes against alpha glucosidase enzymes.
Camphor is synthesized from the Sumatran camphor plant (Dryobalanops aromatica) in previous experiments. It can be synthesized with thiosemicarbazide, ethy-2‑chloro acetoacetate, and sodium acetate (catalyze) to form camphor derivate with thiazole ring structure. Hydrazine and phenylhydrazine were both used to make the thiazole ring variations. All the compounds were purified by recrystallization method and characterized by TLC, FTIR, UV-vis, and LC-MS. Camphor thiazole (Product 1), camphor thiazole hydrazine (Product 2), and camphor thiazole phenylhydrazine (Product 3) were successfully synthesized with%yields of 73.24 %; 77.36 %; and 72.91 % respectively. Furthermore, their antioxidant activity was measured using the DPPH free radical method. Product 2 had the strongest antioxidant activity with IC50 value of 6.93 ppm. The antidiabetic activity was measured using the α-glucosidase enzyme. This indicated that product 1 had the best inhibitory activity against the α-glucosidase enzyme with IC50 values of 869.06 ppm.•We developed an alternative method to utilize camphor extracted from the D. aromatica plant to be used as an alternative medicinal ingredient related to antioxidants and antidiabetes.•All products were successfully synthesized and have the potential to be used as antioxidants with an IC50 value of 6.93 ppm for Product 2 and as antidiabetics by means of an α-glucosidase inhibitor with an IC50 value of 869.06 ppm for Product 1.


A machine learning-based multimodal electrochemical analytical device based on eMoSx-LIG for multiplexed detection of tyrosine and uric acid in sweat and saliva.
Multiplexed detection of biomolecules is of great value in various fields, from disease diagnosis to food safety and environmental monitoring. However, accurate and multiplexed analyte detection is challenging to achieve in mixtures using a single device/material. In this paper, we demonstrate a machine learning (ML)-powered multimodal analytical device based on a single sensing material made of electrodeposited molybdenum polysulfide (eMoSx) on laser induced graphene (LIG) for multiplexed detection of tyrosine (TYR) and uric acid (UA) in sweat and saliva. Electrodeposition of MoSx shows an increased electrochemically active surface area (ECSA) and heterogeneous electron transfer rate constant, k0. Features are extracted from the electrochemical data in order to train ML models to predict the analyte concentration in the sample (both singly spiked and mixed samples). Different ML architectures are explored to optimize the sensing performance. The optimized ML-based multimodal analytical system offers a limit of detection (LOD) that is two orders of magnitude better than conventional approaches which rely on single peak analysis. A flexible and wearable sensor patch is also fabricated and validated on-body, achieving detection of UA and TYR in sweat over a wide concentration range. While the performance of the developed approach is demonstrated for detecting TYR and UA using eMoSx-LIG sensors, it is a general analytical methodology and can be extended to a variety of electrochemical sensors to enable accurate, reliable, and multiplexed sensing.


[Endoscopy in the diagnosis and treatment of abdominal adhesions].
Therapeutic and diagnostic laparoscopy was performed in 48 patients with chronic abdominal pain due to an adhesive process in the abdominal cavity. Laparoscopic treatment was applied only in patients who experienced pain when the adhesions were pulled with instruments. The adhesions were divided, the vessels were coagulated, and the organs were separated from the adhesions with instruments introduced into the abdominal cavity through additional punctures made in the anterior abdominal wall. The immediate results of the treatment were good in 44 out of 48 patients (91.6%). The late-term results were studied in 46 patients in follow-up periods of 12 months to 6 years. Recurrences were found in only 4 cases. Complications requiring special treatment were not encountered. Therapeutic and operative endoscopy is an effective and safe method for treating patients with adhesive disease manifested by abdominal pain.


Clinical prognostic factors and expression of cathepsin D in endometrioid adenocarcinoma.
The aim of our study was to evaluate the association between the expression of cathepsin D and clinical prognostic data in endometrioid adenocarcinoma of different histological grade. We studied 104 postmenopausal women with diagnosis of endometrioid adenocarcinoma. We evaluated the presence of obesity and vaginal bleeding. Surgical specimens were fixed in 10% neutral buffered formalin solution and embedded in paraffin. 4 mm sections were stained by hematoxylin and eosin, von Gieson, and histological type of cancer, metastatic lesion of lymph nodes and depth of myometrial invasion were evaluated. Histological grade of cancer was assessed by FIGO grading system. All samples were analysed by immunohistochemistry for cathepsin D (Dakocytomation). We assessed the number of cathepsin D-positive stromal and tumor cells and degree of positivity (low, moderate, high). Histological study by hematoxylin and eosin showed grade 1 endometrioid carcinoma in 35 cases (33,7%, group 1), grade 2 in 44 cases (42,3%, group 2), grade 3 in 25 cases (24%, grade 3). Our results suggest that the expression of cathepsin D is associated with the higher histological grade of endometrioid adenocarcinoma, depth of myometrial invasion, lymph node positivity, coexistence of obesity and vaginal bleeding. It seems that local invasion and metastatic spread of tumor should be preceeded by the expression of cathepsin D in stromal cells which can be assessed in grade 1 and 2 endometrioid adenocarcinomas. The expression of cathepsin D can be used as a prognostic factor and more aggressive chemothepery regimen should be used.


Integrative medicine as adjunct therapy in the treatment of atopic dermatitis--the role of traditional Chinese medicine, dietary supplements, and other modalities.
Atopic dermatitis (AD) is becoming increasingly prevalent in the pediatric population, with rates reportedly as high as 18-25 %. Westernized medicine has traditionally used a combination of emollients, antihistamines, corticosteroids, and immunomodulating agents to combat this often frustrating disease. Of late, integrative medicine has become the subject of more research as concerns grow regarding prolonged use of corticosteroids and their side effects in pediatric patients. Probiotics have been extensively studied to define their role in the treatment and prevention of AD in children. Unfortunately, results are varying showing significant improvement in some patients but not all. With regard to prevention, studies show that the use of probiotics during pregnancy does decrease the incidence of AD in children. Prebiotics and synbiotics are also a conceivable option for prevention of AD. A number of studies on Chinese herbal medicine have been performed, with a collective result of symptom improvement and decreased levels of inflammatory cytokines. However, there were reports of asymptomatic transaminitis in a few patients that warrant further testing. While the herbs tested in more recent randomized clinical trials were free from corticosteroids, a previous study showed high levels of dexamethasone in unlabeled herbal eczema creams. Vitamins and minerals have also been suggested as an alternative treatment of AD. Studies however have not yet demonstrated improvement of AD with vitamin or mineral supplementation. Topical vitamin B(12) is the exception to this; however, no topical vitamin B(12) preparation is available for use. Finally, relaxation techniques are also being investigated as adjunctive methods of treatment, but well-designed scientific studies are lacking.


Spectroscopic studies of single-stranded DNA ligands and oxazole yellow dyes.
Interactions between short single-stranded DNA ligands and fluorescent DNA indicator dyes were used to investigate binding selectivity of the ligands. Conformational differences among four DNA ligands of different sequence and structure, including two that form a G-quartet and two that do not, were confirmed by circular dichroism spectroscopy. Their interactions with indicator dyes YO-pro-1 iodide (YO) and YOYO-1 iodide (YOYO) were probed using measurements of dye absorbance; induced circular dichroism; and fluorescence spectra, anisotropy, and lifetime. Equilibrium binding constants and stoichiometry were determined as well. Results indicate significant differences among the dye interactions and binding stoichiometries of the four ligands. One of the G-quartet forming ligands, a 20-mer of sequence 5'-GGTTTTGGTTTTGGTTTTGG-3', shows distinctly different interactions from the other three ligands, all of which are 15-mers. These studies illustrate the importance of sequence and conformation in determining the binding interactions of short single-stranded DNA.


Liquid chromatography with electrochemical detection for monitoring mebendazole and hydroxymebendazole in echinococcosis patients.
A sensitive method is described for the simultaneous determination of mebendazole and hydroxymebendazole using flubendazole as an internal standard. The analytes were isolated with a single chloroform extraction from 1.0 ml of alkalinized plasma or cyst liquid samples. Separation and quantitation were performed with high-performance liquid chromatography with electrochemical detection. The limit of detection for mebendazole and hydroxymebendazole was approximately 5 and 2.5 ng/ml, respectively. The accuracy of the method was confirmed for mebendazole by a good correlation with an existing radioimmunoassay method. The method was applied for monitoring mebendazole therapy in echinococcosis patients. The results presented support the necessity of such monitoring, as most of the observed peak plasma concentrations did not reach the level regarded as minimal for therapeutic effect.


[Association of DNA with the nuclear skeleton].
A significant functional role is ascribed to DNA association with the nuclear skeleton. Specific proteins tightly bound to DNA have been discovered. According to one point of view these proteins perform constant attachment of DNA to the nuclear matrix, however, according to other authors this complex exists in transcribed genes only. In proliferating cell DNA is anchored by DNA-topoisomerase II and DNA-polymerase alpha. Except for proteins this function is performed by glycoproteins, neutral and phospholipids, RNA. Three types of specific DNA sequences have been elucidated: 1. AT-rich enhancers (SAR); 2. GC-rich origins of replication; 3. centromere and satellite DNA. In places of binding to the nuclear matrix DNA bears the numerous defects of secondary structure. Based on different criteria several types of DNA complexes with nuclear matrix proteins are distinguished: 1. resistant (lamina) and sensitive (intramolecular fibrils) to chelating agents; 2. formed by transcriptional complexes (transitory) and origins of replication (constant); 3. tight (resistant to salt-urea solutions, formed by replicative complex proteins) and weak (sensitive).


How to engineer the unknown: Advancing a quantitative and predictive understanding of plant and soil biology to address climate change.
Our basic understanding of carbon cycling in the biosphere remains qualitative and incomplete, precluding our ability to effectively engineer novel solutions to climate change. How can we attempt to engineer the unknown? This challenge has been faced before in plant biology, providing a roadmap to guide future efforts. We use examples from over a century of photosynthesis research to illustrate the key principles that will set future plant engineering on a solid footing, namely, an effort to identify the key control variables, quantify the effects of systematically tuning these variables, and use theory to account for these observations. The main contributions of plant synthetic biology will stem not from delivering desired genotypes but from enabling the kind of predictive understanding necessary to rationally design these genotypes in the first place. Only then will synthetic plant biology be able to live up to its promise.


Bridge Heteroarylation of Bicyclo[1.1.1]pentane Derivatives.
Herein, we report the decarboxylative Minisci heteroarylation of bicyclo[1.1.1]pentane (BCP) and 2-oxabicyclo[2.1.1]hexane (oBCH) derivatives at the bridge positions. In an operationally simple, photocatalyst-free process, free bridge carboxylic acids are directly coupled with nonprefunctionalized heteroarenes to provide rare examples of polysubstituted BCP and oBCH derivatives in synthetically useful yields. Additionally, the impact of the BCP core on the physicochemical properties of a representative example compared to those of its all-aromatic ortho- and meta-substituted analogues is evaluated.


Inhibition of lymphocyte blastogenesis caused by suppression of interleukin-2 receptor sites after thermal injury.
Burn patients often exhibit prolonged cell-mediated immune suppression. Of the mechanisms proposed to account for this, one invokes an inability on the part of T lymphocytes to undergo blastogenesis, clonal expansion, and differentiation--a process partially mediated by interleukin-2. Triplicate samples of 10% dilutions of burn serum from nine burn patients (three with greater than 60% burn) were analyzed for their ability to suppress mitogen-induced lymphocyte blastogenesis. A separate aliquot of stimulated cultured lymphocytes was tagged with a monoclonal antibody to interleukin-2 receptors. The serum of patients with greater than 60% burn was significantly more suppressive (as measured by depressed tritiated thymidine incorporation by cultured lymphocytes) than that taken from patients with smaller burns. In addition, serum from those with larger burns caused a marked reduction in the interleukin-2 receptor-labeling index, suggesting that it possesses factor(s) that directly or indirectly block T lymphocyte interleukin-2 receptor expression.


The Brief Military Career of Dr. William H. Welch.
The purpose of this article is to examine the Army service of Dr. William H. Welch during World War I. Archival research utilizing prime source documents in the William H. Welch Collection of the Alan M. Chesney Medical Archives for the Johns Hopkins Medical Institutions. Welch joined the Army at the age of 67 after serving as one of the principal transformational forces for reforming medical education in the United States and founding the first academic institution for educating public health professionals in the United States, the Johns Hopkins School of Public Health and Hygiene. His longstanding relationship with Army Surgeon General William Gorgas served as the backdrop for Welch's service. Welch served as both a staff officer and as a traveling medical inspector general, assessing the medical care of troops preparing for overseas duty. He did not adapt particularly well to military dress and decorum but his status as one of the icons of American medicine rendered these shortcomings insignificant. Welch was joined in Army service by a number of American medical luminaries-both Mayo brothers, George Crile, and Harvey Cushing among them. Although Welch remained on active duty for only 13 months, he maintained a nominal relationship with Army medicine through appointment to the Medical Officer Reserve Corps until the time of his death. 2016 marks the centennial of the establishment of the first independent academic institution in America dedicated to education and training of professionals focused on public health and hygiene issues. 2017 marks the centennial of U.S. entry into World War I. Dr. William H. Welch played an important role in both of these historic events and, although his active service was brief, the impact of his example was substantial. Analysis of his military career in its full historical context provides insight into the relationship between academic medicine and military medicine during periods of armed conflict.


Structure, aggregation dynamics and crystallization of superfolder green fluorescent protein: Effect of long alkyl chain imidazolium ionic liquids.
Green fluorescent protein (GFP) and its variants are widely used in medical and biological research, especially acting as indicators of protein structural integrity, protein-protein interactions and as biosensors. This study employs superfolder GFP (sfGFP) to investigate the impact of varying alkyl chain length of 1-Cn-3-methylimidazolium chloride ionic liquid (IL) series ([Cnmim]Cl, n = 2, 4, 6, 8, 10, 12) on the protein fluorescence, structure, hydration, aggregation dynamics and crystallization behaviour. The results revealed a concentration-dependent decrease in the sfGFP chromophore fluorescence, particularly in long alkyl chain ILs ([C10mim]Cl and [C12mim]Cl). Tryptophan (Trp) fluorescence showed the quenching rate increased with longer alkyl chains indicating a nonpolar interaction between Trp57 and the alkyl chain. Secondary structural changes were observed at the high IL concentration of 1.5 M in [C10mim]Cl and [C12mim]Cl. Small-angle X-ray scattering (SAXS) indicated relatively stable protein sizes, but with IL aggregates present in [C10mim]Cl and [C12mim]Cl solutions. Dynamic light scattering (DLS) data showed increased protein size and aggregation with longer alkyl chain ILs. Notably, ILs and salts, excluding [C2mim]Cl, promoted sfGFP crystallization. This study emphasizes the influence of the cation alkyl chain length and concentration on protein stability and aggregation, providing insights into utilizing IL solvents for protein stabilization and crystallization purposes.


Processing of expressions by individuals with autistic traits: Empathy deficit or sensory hyper-reactivity?
Individuals with autistic traits display impaired social interaction and communication in everyday life, but the underlying cognitive neural mechanisms remain very unclear and still remain controversial. The mind-blindness hypothesis suggests that social difficulties in individuals with autistic traits are caused by empathy impairment in individuals; however, the intense world theory suggests that these social difficulties are caused by sensory hyper-reactivity and sensory overload, rather than empathy impairment. To further test these two theories, this study investigated event-related potentials (ERPs) to explore the cognitive neural processing of repetitive expressions in individuals with autistic traits. This study employed the Mandarin version of the autism-spectrum quotient (AQ) to assess autistic traits in 2,502 healthy adults. Two subset groups were used, e.g., the participants of a high-AQ group were randomly selected among the 10% of individuals with the highest AQ scores; similarly, the participants in the low-AQ group were randomly selected from the 10% of participants with the lowest AQ scores. In an experiment, three different facial expressions (positive, neutral, or negative) of the same person were presented successively and pseudo-randomly in each trial. Participants needed to define the expression of the face that was presented last. The results showed that compared with the low-AQ group, the high-AQ group exhibited higher P1 amplitudes induced by the second and third presented expressions, as well as higher P3 amplitudes induced by the third presented negative expressions. This indicates that individuals with autistic traits may experience overly strong perception, attention, and cognitive evaluation to repetitive expressions, particularly negative expressions. This result supports the intense world theory more strongly than the mind-blindness hypothesis.


Effect of metabolic changes on force generation in skeletal muscle during maximal exercise.
During vigorous, strong contractions there is a rapid decline in the mechanical output or tension development in skeletal muscle. Several studies have indicated that this rapid decline in force development (often referred to as fatigue), is caused by metabolic changes in the muscles. During brief intense exercise there is a rapid breakdown of phosphocreatine and glycogen and a concomitant increase in the lactate and hydrogen ion concentration. The muscle lactate concentration is increased from about 1-2 mmol kg-1 wet weight at rest before exercise to approximately 25-30 mmol kg-1 wet weight immediately after intensive brief exercise to exhaustion. The muscle pH (i.e. the pH of muscle homogenates) falls from about 7.0 at rest to approximately 6.4 at exhaustion. The changes in the concentrations of ATP, ADP, and AMP are small. It is suggested that the changes in intracellular pH might affect the force generation of skeletal muscle by two different mechanisms: (1) The fall in intracellular pH reduces the activity of key enzymes in glycolysis, thus reducing the rate of ATP resynthesis, and (2) the increased hydrogen ion concentration has a direct effect on the contractile processes, thus reducing the rate of ATP utilization. It is suggested that the increased hydrogen ion concentration might be the common regulator for the maximal rate at which ATP is being utilized and the maximal rate at which it is being resynthesized.


Gene expression modulation of ABC transporter genes in response to permethrin in adults of the mosquito malaria vector Anopheles stephensi.
Living organisms have evolved an array of genes coding for detoxifying enzymes and efflux protein pumps, to cope with endogenous and xenobiotic toxic compounds. The study of the genes activated during toxic exposure is relevant to the area of arthropod vector control, since these genes are one of the targets upon which natural selection acts for the evolution of insecticide resistance. ATP-binding cassette (ABC) transporters participate to insecticide detoxification acting as efflux pumps, that reduce the intracellular concentration of toxic compounds, or of their metabolic derivatives. Here we analyzed the modulation of the expression of six genes coding for ABC transporters, after the exposure of adult females and males of the mosquito Anopheles stephensi, a major malaria vector in Asia, to permethrin. Male and female mosquitoes were exposed to insecticide for one hour, then the expression profiles of the ABC transporter genes AnstABCB2, AnstABCB3, AnstABCB4, AnstABCBmember6, AnstABCC11, and AnstABCG4 were analysed after one and 24h. Our results showed that three genes (AnstABCB2, AnstABCBmember6, AnstABCG4) were up-regulated in both sexes; two of these (AnstABCBmember6 and AnstABCG4) have previously been shown to be up-regulated also in larval stages of An. stephensi, supporting a role for these genes in permethrin defence in larvae as well as in adults. Finally, the same ABC transporter genes were activated both in females and males; however, the timing of gene induction was different, with a prompter induction in females than in males.


Detection of allergic disease in adenoid tissue.
Allergic adenoiditis is defined as the presence of numerous brightly fluorescent IgE mast cells (FIEMC) demonstrated in formalin-fixed adenoid tissue by the trypsin-immunofluorescent method. A prospective study of 606 routinely accessioned cases seen during a 39-month period revealed 98 positive cases. Correlation with clinical and other allergic diagnostic testing revealed a sensitivity of 58% and a specificity of 89%. The pathogenetic role of allergy in chronic otitis media with effusion appears to be related to an exaggerated immediate hypersensitivity response to an allergen and/or infectious agent leading to dysfunction of the eustachian tube. The proximity and shared mucosa of adenoid tissue and eustachian tube allow the recognition of this inflammatory event.


Early combination therapy with bromocriptine and levodopa in Parkinson's disease.
The use of early combination therapy with bromocriptine (Br) and levodopa (LD) in Parkinson's disease is controversial. It has been suggested that treatment with this regimen would prevent or delay the onset of motor fluctuations and dyskinesia. Thus, some have recommended it as a standard of care. This recommendation is based on the theory that LD may accelerate the progression of PD and clinical experience using Br monotherapy in early Parkinson's disease, which suggested that Br causes fewer late complications. This article reviews these arguments and shows that the theories are unproven. A single, uncontrolled trial is often referred to as evidence for efficacy of early combination therapy. We critically review this and five other studies which have evaluated the treatment strategy. We show that the literature is often misleading and that these trials do not support the efficacy of early combination therapy. We conclude that there is no justifiable reason to use a combination of Br and LD in early parkinsonian patients.


[Anesthetic management of tracheobronchial stent insertion in patients who underwent laser resection, balloon dilatation and tracheostomy in advance].
We report successful management of tracheobronchial stent insertion under general anesthesia. In thirty-two cases, tracheobronchial stent insertion was performed under general anesthesia. The technique for airway management was chosen depending on the type of stent or the constriction level of the airway portion. We employed tracheostomy in order to avoid repeated intubations during the insertion of Dumon or Dynamic stent. In case of severe airway stenosis, laser resection or balloon dilatation was performed before stent insertion. We had 32 successful cases in 36 trials. Four trials failed due to insufficient expansion in one, mismatches of stent angle in one and pneumomediastinum in one. There was no exacerbation of respiratory condition in failed cases. There was no case who needed percutaneous cardiopulmonary support system. We managed tracheobronchial stent insertion under general anesthesia. Both the airway expansion by laser resection or balloon dilatation before stent insertion and also the insertion of Dumon or Dynamic stent through a tracheostomy were helpful strategies. These techniques facilitated more definitive airway maintenance and stable anesthetic management.


Biliary endoprosthesis dysfunction in patients with malignant hilar tumors: successful treatment by percutaneous replacement of the stent.
Symptoms caused by malignant hilar bile duct tumors are often palliated by the insertion of a percutaneous biliary endoprosthesis. However, these often occlude early and may be difficult to replace. We have reviewed our experience with percutaneous replacement of endoprostheses in 17 patients with 31 episodes of stent dysfunction. The stent was changed successfully in 30 of the 31 attempts. The average durations of initial and subsequent stent patencies were 28 and 20 weeks, respectively. Significant acute complications occurred in three patients, one of whom had a perihepatic abscess and two of whom had septicemia. Two patients died within 30 days of their last stent change. The one patient in whom attempted insertion of a new stent was unsuccessful had to remain on continuous external catheter drainage. The occluded or migrated endoprosthesis was successfully removed either percutaneously (55%) or endoscopically (26%) in 25 of the 31 cases. Successful removal of the stent and reinsertion after blockage or migration is possible in most patients. Our experience suggests that patients with malignant obstruction of the bile duct should not be refused an indwelling endoprosthesis just because of the frequent occurrence of early occlusion of the stent.


[Tuberculosis of the lung bases].
Tuberculosis of the lung bases is a rare condition that can mimic pneumonia, bronchial carcinoma, lung abscess or bronchiectasis. Diagnostic delays, that can lead to serious complications not amenable to surgical resection, are often the result of repeatedly negative bacteriological examinations. We report a series of 10 cases of tuberculosis of the lung bases collected between 1993 and 1998 that were examined by computerised tomography. The chest x-ray most commonly showed a heterogeneous opacity. On the CT scan this corresponded with an area of alveolar consolidation which, when it was associated with centrilobular micronodules and cavitated nodules and masses, suggested the diagnosis of basal tuberculosis. Indeed the absence of apical lesions and the frequency of involvement of mediastinal and bronchial lymph nodes support the hypothesis of bronchial dissemination of the bacilli from tuberculous nodes. This explanation is supported by the high incidence of endobronchial lesions found at bronchoscopy in this form of tuberculosis.


Helicity, circular dichroism and molecular dynamics of proteins.
In protein unfolding studies, reduction in circular dichroism (CD) at 222 nm has been interpreted as loss of helicity. Estimates of the helicity of a protein from its CD spectrum are calibrated by reference to X-ray crystal structures, based on the assumption that the mean residue ellipticity at 222 nm is directly proportional to the number of residues in a helix. We have examined various influences on the CD at 222 nm, using molecular dynamics simulations to provide the structural detail required. We have found that the fragmentation of long helices, without a reduction in the number of helical residues, significantly reduces the mean residue ellipticity at 222 nm. The dynamical motion of the protein and the precise conformation of helical residues also play an important role. We discuss the implications of these factors to the interpretation of CD for the partial unfolding of apomyoglobin.


P2X(7) receptors: properties and relevance to CNS function.
Among seven members of P2X ionotropic receptors activated by extracellular ATP, the P2X(7) subtype is unique in that it can function as a cation channel, a nonselective pore, or even a signaling complex coupled with multiple downstream components. Several roles of P2X(7) receptors have been described in CNS cells in the past decade, including release of cytokines and transmitters, modulation of presynaptic transmitter release, and activation of multiple signaling pathways. The finding that P2X(7) pores may directly mediate efflux of cytosolic glutamate, GABA, and ATP in glial cells is particularly interesting, as it provides a novel mechanism of glial transmitter release that may play important roles not only in physiological intercellular communication but also in pathological neural injury.


The DNA binding pattern of the retinoid X receptor is regulated by ligand-dependent modulation of its oligomeric state.
The retinoid X receptor (RXR) regulates target gene transcription via its association with cognate DNA response elements either as a homodimer or as a heterodimer with a number of other nuclear receptors. We previously demonstrated that, in solution, RXR forms tetramers with a high affinity and that ligand binding leads to dissociation of receptor tetramers to smaller species. Here it is shown that RXR tetramers form stable complexes with direct repeats (DR-1 or DR-5) or palindromic (TREpal) response elements. Binding of RXR tetramers to cognate DNA occurs with a significantly higher affinity as compared with dimers. Ligand binding by DNA-bound RXR tetramers results in their dissociation to DNA-bound dimers, a process that is completely reversed upon removal of the ligand. Formation of stable tetramer-DNA complexes requires binding of two oligonucleotides/tetramer. It is proposed that ligand-dependent modulation of the oligomeric state of RXR is a regulatory feature of this nuclear receptor.


Familial risk of asthma among adolescents and their relatives in Taiwan.
Although family studies have established that asthma has a hereditary basis, little evidence has been presented about the family risk of simple asthma (AS or nonatopic asthma) and asthma with other atopic diseases (AWAD or atopic asthma) after adjusting for potential risk factors. In this study, data were collected on demographic variables and a wide range of known risk factors for asthma. Study participants were asthmatic adolescents and controls, and their relatives. The role of a familial history of asthma and atopic diseases in predicting asthma risk among asthmatic adolescents and their relatives was evaluated in a population-based family study conducted in southern Taiwan. Asthma risk factor data were collected through telephone interviews with students' parents for 207 asthmatic adolescents 11-16 years of age, their 1600 relatives, and 207 nonasthmatic adolescents in the control group and their 1638 relatives. The results show (after adjusting potential confounders) that a family history of asthma is highly associated with asthma in adolescents. Having two or more family members with asthma was associated with a 3.4-fold (95% confidence interval [CI] = 1.0-12.0) increased risk of asthma among adolescents. Logistic regression was used to assess the effects of having an asthmatic relative and the effect of atopic diseases among relatives of cases. Having a family history of asthma and other atopic conditions, such as rhinitis and atopic dermatitis (adjusted odds ratio [AOR] = 3.64, 95% CI = 2.29-5.74 and AOR = 1.94, 95% CI = 1.53-2.46, respectively), was found to be a significant predictor of asthma in children. Along with a history of allergic rhinitis or atopic dermatitis, familial risks of asthma occurring in adolescents with and without other atopic diseases will be analyzed separately. A critical finding was the significant difference in a risk of asthma and atopic diseases among the relatives of asthma cases with atopic diseases and controls. However, for relatives of asthma cases without atopic diseases compared to control probands, AORs were highly significant for family history of asthma, but not for the family history of atopic diseases. These findings suggest that both forms of asthma may be hereditary, but there are differences in their modes of inheritance. Atopic status itself did not predispose a child to AS. A concomitant inheritance of a predisposition to asthma and atopic condition for AWAD cases was suggested.


The in-vitro response of CD2-positive acute myelogenous leukemia to proliferation and differentiation inducing agents.
Acute mixed lineage leukemias (MLL) are a heterogeneous group of acute leukemias that express morphologic and/or immunophenotypic features of more than one hematopoietic cell line. The ontogenetic significance of this mixed lineage expression is unclear. We therefore studied the conviction of the lineage commitment in a group of MLL by examining the in-vitro response of five CD2+ (E-rosette receptor) acute myelogenous leukemia (AML) to a panel of proliferation and differentiation-inducing agents. Three of the five CD2+ AML were TdT-positive. Antigen receptor gene studies revealed no rearrangements at either the T beta or immunoglobulin heavy chain gene loci in any case. When blast-enriched cell populations were placed in short term suspension cultures with PHA, IL-2, PHA + IL-2, GM-CSF or TPA, three of the leukemias responded in a similar fashion while the remaining two cases showed no response. In the three MLL that responded to the in-vitro culture manipulations, features indicative of differentiation along the monocytic lineage pathway were observed. This differentiation was not pronounced in the presence of the phorbol ester TPA, and was manifested by loss of CD2 and CD7 expression, continued expression of myeloid antigens, and the development by the blasts of morphologic and cytochemical characteristics of monocytic cells. None of the five MLL showed any evidence of induced maturation along the T-lymphocyte line of differentiation with any of the agents used. rGM-CSF was the only exogenously added agent to induce proliferation; the proliferative response was slight and was seen in only one of the five leukemias. Therefore, the phenotypic expression of CD2 and CD7 in blasts from MLL is not indicative of irreversible commitment to T-lymphocyte development. The in-vitro loss of T-cell antigens in concert with the development of monocytic features in three of the five CD2+ AML in this study suggests the leukemic cells were preferentially committed to a non-lymphoid lineage differentiation pathway.


Synthesis of new Hantzsch adducts showing Ca2+ channel blockade capacity, cholinesterase inhibition and antioxidant power.
Background: Alzheimer's disease is a chronic neurodegenerative chronic disease with a heavy social and economic impact in our developed societies, which still lacks an efficient therapy. Method: This paper describes the Hantzsch multicomponent synthesis of twelve alkyl hexahydro-quinoline-3-carboxylates, 4a-l, along with the evaluation of their Ca2+ channel blockade capacity, cholinesterase inhibition and antioxidant power. Results: Compound 4l showed submicromolar inhibition of butyrylcholinesterase, Ca2+ channel antagonism and an antioxidant effect. Conclusion: Compound 4l is an interesting compound that deserves further investigation for Alzheimer's disease therapy.


Pharmacists and travel advice for tropics in Lisbon (Portugal).
In Portugal, little is known about the quality of advice given to international travelers by pharmacists. The aim of this study was to determine pharmacists' training, experience, and interest in travel medicine and to assess the technical quality of the information given. We sent a postal questionnaire to all pharmacies in the Lisbon area. The technical director or another graduate pharmacist was asked to complete the questionnaire. A total of 251 pharmacists participated in the study. Most of them (93.2%) did not have any training in travel medicine, and most of them expressed a wish to be informed and/or updated on this subject. The number of advised travelers was low. The use of repellent, protective clothes, and mosquito bed nets was the most frequent advice on protection against mosquito bites. From a subgroup of 170 pharmacists, 43.5% indicated mefloquine and 44.1% indicated chloroquine as malaria chemoprophylaxis to African countries. A significant association existed between the variables "to indicate mefloquine" and "seeks to be informed/updated on travel medicine." Those who indicated chloroquine tended to like travel medicine less. Concerning diarrhea prevention and treatment, the consumption of bottled and/or treated water and the administration of antibiotics during the episode were the most reported advice. Concerning vaccination against yellow fever, only 8 of 91 pharmacists correctly indicated all Portuguese-speaking countries with and without the risk of this disease. Studied pharmacists need training in travel medicine. Travel advice was incomplete and/or incorrect and must be improved.


Trans-scaphoid, Transcapitate, Transhamate Injury: A Case Report.
Traumatic axial dislocation of the carpus in a 20-year-old man is described. This injury was accompanied by a crushing injury to the hand. The disruption pattern was different from those of previously reported cases. Despite the restoration of painless wrist motion postoperatively, grip strength remained below normal. Early accurate reduction, fixation, and range of motion exercise are the treatments of choice in such complex injuries.


A Succinct History of Sleep Medicine.
Although sleep and sleep disorders have been studied for centuries, it was the development of sophisticated tools to monitor eye movements, brain waves, and muscle tone in the mid-20th century that led to modern sleep research. These tools allowed neuroscientists to distinguish between different "states" or "phases" of sleep, and to relate these findings to sleep disorders. This review chronicles the groundbreaking work of the pioneers in this field, and the impact their findings have had on patients today.


Prevalence of Health App Use Among Older Adults in Germany: National Survey.
Health apps are increasingly becoming an integral part of health care. Especially in older adults, the self-management of chronic diseases by health apps might become an integral part of health care services. The aim of this explorative study was to investigate the prevalence of health app use and related demographic factors, as well as health status among older adults in Germany. A nationwide postal survey was conducted. Of the 5000 individuals contacted, a total of 576 participants completed this survey. On the basis of their self-indicated assignment to one of the three predefined user groups (health app users, general app users, and nonusers of apps), participants answered various questions regarding app and health app use, including frequency of use and number of installed apps, demographic factors, and health status. In total, 16.5% (95/576) used health apps, whereas 37.5% (216/576) indicated only using general apps, and 46.0% (265/576) reported using no apps at all. The number of installed health apps was most frequently reported as between 1 and 5 apps per participant, which were usually used on a weekly basis. The most frequently cited type of health apps were exercise-related ones. Individuals using health apps were found to be younger (MeanmHealth 66.6, SD 4.7) and to have a higher level of technical readiness compared with general app users and nonusers of apps (adjusted odds ratio, AOR=4.02 [95% CI 2.23-7.25] for technical readiness, and AOR=0.905 [95% CI 0.85-0.97] for age). The most frequently mentioned sources of information about apps within the group of health and general app users were family and friends. Identified barriers against the use of health apps were a lack of trust, data privacy concerns, and fear of misdiagnosis. Health apps are already used by older adults in Germany. The main type of apps used are exercise-related ones. Barriers to and incentives for the use of health apps and associations with health status and users' demographics were revealed.