The Clinical Evidence Linking Helicobacter pylori to Gastric Cancer.
Gastric cancer has long been recognized to be accompanied and preceded by chronic gastritis, lasting decades. Arguably, the most important development in our understanding of gastric cancer pathogenesis over the past 50 years has been the realization that, for most cases of gastric cancer, Helicobacter pylori is the cause of the underlying gastritis. Gastritis can promote gastric carcinogenesis, typically via the Correa cascade of atrophic gastritis, intestinal metaplasia, and dysplasia. Nested case-control studies have shown that H pylori infection increases the risk of gastric cancer significantly, both of the intestinal and diffuse subtypes, and that H pylori is responsible for approximately 90% of the world's burden of noncardia gastric cancer. Based largely on randomized studies in high gastric cancer prevalence regions in East Asia, it appears that primary and tertiary intervention to eradicate H pylori can halve the risk of gastric cancer. Some public health authorities now are starting screening and treatment programs to reduce the burden of gastric cancer in these high-risk areas. However, there is currently much less enthusiasm for initiating similar attempts in the United States. This is partially because gastric cancer is a relatively less frequent cause of cancer in the United States, and in addition there are concerns about theoretical downsides of H pylori eradication, principally because of the consistent inverse relationship noted between H pylori and esophageal adenocarcinoma. Nevertheless, establishing a link between chronic H pylori infection and gastric cancer has led to novel insights into cancer biology, the gastrointestinal microbiome, and on individual and population-based gastric cancer prevention strategies.


Pylorus-preserving pancreatoduodenectomy. Experience in 20 patients.
Twenty patients underwent a pylorus-preserving pancreatoduodenectomy for benign or malignant periampullary and pancreatic disease. Eighteen patients had a partial and two patients a total pancreatectomy. There were 19 elective and 1 emergency operations. Post-operative mortality was 4% (1/20 patients) and the median follow up was 31 months (range, 15-75 months), during which period 8 patients with a malignant disease died. Pylorus-preserving pancreatoduodenectomy did not compromise survival in ampullary cancer. One patient developed a marginal ulcer during the study period and one of twelve patients, examined by technetium scintigraphy (done more than 3 months after the procedure), had delayed gastric emptying. Two patients presented with a gastric retention as the first sign of recurrent pancreatic cancer. The result of the operation was judged as excellent in 7 patients, good in 8 and as bad in only 2 of the 17 patients who survived more than 6 months. Body weight was studied in 15 patients surviving more than one year after operation; five patients had gained weight, two had lost weight and in 8 there was no difference. Pylorus-preserving pancreatoduodenectomy seems to be a valuable alternative in the treatment of patients with benign and selected malignant pancreaticobiliary disease.


Conformational changes in the DNA-binding domains of the ecdysteroid receptor during the formation of a complex with the hsp27 response element.
The ecdysone receptor (EcR) and the ultraspiracle protein (Usp) form the functional receptor for ecdysteroids that initiates metamorphosis in insects. The Usp and EcR DNA-binding domains (UspDBD and EcRDBD, respectively) form a heterodimer on the natural pseudopalindromic element from the hsp27 gene promoter. The conformational changes in the protein-DNA during the formation of the UspDBD-EcRDBD-hsp27 complex were analyzed. Recombined UspDBD and EcRDBD proteins were purified and fluorescein labeled (FL) using the intein method at the C-ends of both proteins. The changes in the distances from the respective C-ends of EcRDBD and/or UspDBD to the 5'- and/or 3'-end of the response element were measured using fluorescence resonance energy transfer (FRET) methodology. The binding of EcRDBD induced a strong conformational change in UspDBD and caused the C-terminal fragment of the UspDBD molecule to move away from both ends of the regulatory element. UspDBD also induced a significant conformational change in the EcRDBD molecule. The EcRDBD C-terminus moved away from the 5'-end of the regulatory element and moved close to the 3'-end. An analysis was also done on the effect that DHR38DBD, the Drosophila ortholog of the mammalian NGFI-B, had on the interaction of UspDBD and EcRDBD with hsp27. FRET analysis demonstrated that hsp27 bending was induced by DHR38DBD. Fluorescence data revealed that hsp27 had a shorter end-to-end distance both in the presence of EcRDBD as well as in the presence of EcRDBD together with DHR38DBD, with DNA bend angles of about 36.2° and 33.6°, respectively. A model of how DHR38DBD binds to hsp27 in the presence of EcRDBD is presented.


Genomics, domestication, and evolution of forest trees.
The forests of the world continue to be threatened by climate change, population growth, and loss to agriculture. Our ability to conserve natural forests and to meet the increasing demand for fuel, biomass, wood, and paper depends on our fundamental understanding of tree growth and adaptation (FAO 2001; Fenning and Gershenzon 2002; Campbell et al. 2003; Gray et al. 2006). Our knowledge of the unique biology of trees will be greatly advanced through the application of genomics. The purpose of this chapter is to describe this emergent genomic paradigm as it is being applied to trees.


DEDIFFERENTIATION AND REDIFFERENTIATION OF CELLS IN HYDRA VIRIDIS.
The interstitial cell of the green hydra is formed by dedifferentiation of specialized gastrodermal cells. Similarly, the epidermal epitheliomuscular cells are probably formed by direct difjerentiation of algae-laden digestive cells that lose their algae and enclosed food droplets, migrate to the periphery of the animal, and begin the mucous secretion characteristic of epidermal cells.


Theoretical value of pre-trade testing for Salmonella in Swedish cattle herds.
The Swedish Salmonella control programme includes mandatory action if Salmonella is detected in a herd. The aim of this study was to assess the relative value of different strategies for pre-movement testing of cattle. Three fictitious herds were included: dairy, beef and specialised calf-fattening. The yearly risks of introducing Salmonella with and without individual serological or bulk milk testing were assessed as well as the effects of sourcing animals from low-prevalence areas or reducing the number of source herds. The initial risk was highest for the calf-fattening herd and lowest for the beef herd. For the beef and dairy herds, the yearly risk of Salmonella introduction was reduced by about 75% with individual testing. Sourcing animals from low-prevalence areas reduced the risk by >99%. For the calf-fattening herd, the yearly risk was reduced by almost 50% by individual testing or sourcing animals from a maximum of five herds. The method was useful for illustrating effects of risk mitigation when introducing animals into a herd. Sourcing animals from low-risk areas (or herds) is more effective than single testing of individual animals or bulk milk. A comprehensive approach to reduce the risk of introducing Salmonella from source herds is justified.


[Optimization of experimental parameters for quantitative NMR (qNMR) and its application in quantitative analysis of traditional Chinese medicines].
Quantitative NMR (qNMR) is a technology based on the principle of NMR. This technology does not need the references of the determined components, which supplies a solution for the problem of reference scarcity in the quantitative analysis of traditional Chinese medicines. Moreover, this technology has the advantages of easy operation, non-destructiveness for the determined sample, high accuracy and repeatability, in comparison with HPLC, LC-MS and GC-MS. NMR technology has achieved quantum leap in sensitivity and accuracy with the development of NMR hardware. In addition, the choice of appropriate experimental parameters of the pre-treatment and measurement procedure as well as the post-acquisition processing is also important for obtaining high-quality and reproducible NMR spectra. This review summarizes the principle of qHNMR, the various experimental parameters affecting the accuracy and the precision of qHNMR, such as signal to noise ratio, relaxation delay, pulse width, acquisition time, window function, phase correction and baseline correction, and their corresponding optimized methods. Moreover, the application of qHNMR in the fields of quantitation of single or multi-components of traditional Chinese medicines, the purity detection of references, and the quality analysis of foods has been discussed. In addition, the existing questions and the future application prospects of qNMR in natural product areas are also presented.


The role of the conserved glycines of ATP-binding cassette signature motifs of MRP1 in the communication between the substrate-binding site and the catalytic centers.
A key element of the structural model of ABC-ATP-ases is the interaction of the two ABC domains. They complement each other's active sites in a way that the ABC signature motif (LSGGQ) of one subunit interacts with the gamma-phosphate of the ATP, bound at the Walker motifs of the opposite subunit. In the present study, the conserved glycines in the fourth position of the LSGGQ motifs of human MRP1 were substituted for aspartic acids (G771D and G1433D), the mutants were expressed in Sf9 insect cells, and the nucleotideas well as the transported substrate-protein interactions were studied. We found that these transport- and ATPase-incompetent mutants showed no nucleotide trapping under any of the conditions examined. However, when measuring the effect of nucleotide and transported substrates on the vanadate-induced cleavage reactions, we found that the effect of substrates on the cleavage reactions was significantly different in the mutant MRP1 proteins than in the wild type. Although the transported substrates (e.g. etoposide + oxidized glutathione) stimulated the formation of the posthydrolytic complex in the wild type, this reaction was inhibited in the signature mutants. Our study also revealed that a similar mutation in the ABC signature of either ABC unit resulted in the same effect. We suggest that the conserved glycine residues in both LSGGQ segments are part of the conformational network, which is responsible for the accelerated hydrolytic activity upon interaction of the protein with its transported substrates. This intramolecular communication between the substrate-binding site and the catalytic centers is assumed to be a general feature of the molecular mechanism of ABC transporters.


A cotton gene encoding MYB-like transcription factor is specifically expressed in pollen and is involved in regulation of late anther/pollen development.
In flowering plants, pollen development is a highly programmed process, in which a lot of genes are involved. In this study, a gene, designated as GhMYB24, encoding R2R3-MYB-like protein was isolated from cotton. GhMYB24 protein is localized in the cell nucleus and acts as a transcriptional activator. Northern blot analysis revealed that GhMYB24 transcripts were predominantly detected in anthers. It was further found that strong expression of GhMYB24 was mainly detected in pollen and was regulated during anther development by in situ hybridization. Overexpression of GhMYB24 in Arabidopsis caused flower malformation, shorter filaments, non-dehiscent anthers and fewer viable pollen grains. Further analysis revealed that the septum and stomium cells of anthers were not broken, and fewer fibrous bands were found in the endothecium cells in transgenic plants. A complementation test demonstrated that GhMYB24 was able to recover partially the male fertility of the myb21 myb24 double mutant. Expression levels of the genes involved in the phenylpropanoid biosynthetic pathway and reactive oxygen species homeostasis were altered in GhMYB24-overexpressing transgenic plants. Furthermore, the genes involved in jasmonate biosynthesis and its signaling pathway were up-regulated in the transgenic plants. Yeast two-hybrid assay indicated that GhMYB24 interacted with GhJAZ1/2 in cells. Taking the data together, our results suggest that GhMYB24 may play an important role in normal anther/pollen development.


Epigenetic Control of Human Endogenous Retrovirus Expression: Focus on Regulation of Long-Terminal Repeats (LTRs).
Transposable elements, including endogenous retroviruses (ERVs), comprise almost 45% of the human genome. This could represent a significant pathogenic burden but it is becoming more evident that many of these elements have a positive contribution to make to normal human physiology. In particular, the contributions of human ERVs (HERVs) to gene regulation and the expression of noncoding RNAs has been revealed with the help of new and emerging genomic technologies. HERVs have the common provirus structure of coding open reading frames (ORFs) flanked by two long-terminal repeats (LTRs). However, over the course of evolution and as a consequence of host defence mechanisms, most of the sequences contain INDELs, mutations or have been reduced to single LTRs by recombination. These INDELs and mutations reduce HERV activity. However, there is a trade-off for the host cells in that HERVs can provide beneficial sources of genetic variation but with this benefit comes the risk of pathogenic activity and spread within the genome. For example, the LTRs are of critical importance as they contain promoter sequences and can regulate not only HERV expression but that of human genes. This is true even when the LTRs are located in intergenic regions or are in antisense orientation to the rest of the gene. Uncontrolled, this promoter activity could disrupt normal gene expression or transcript processing (e.g., splicing). Thus, control of HERVs and particularly their LTRs is essential for the cell to manage these elements and this control is achieved at multiple levels, including epigenetic regulations that permit HERV expression in the germline but silence it in most somatic tissues. We will discuss some of the common epigenetic mechanisms and how they affect HERV expression, providing detailed discussions of HERVs in stem cell, placenta and cancer biology.


Posttransplant peripheral blood donor-specific interferon-γ enzyme-linked immune spot assay differentiates risk of subclinical rejection and de novo donor-specific alloantibodies in kidney transplant recipients.
Noninvasive diagnosis of kidney allograft inflammation in transplant recipients with stable graft function (subclinical rejection) could permit more effective therapy and prevent later development of de novo anti-donor HLA antibodies and/or graft dysfunction. Here we tested whether quantifying posttransplant donor-specific alloreactive T-cells by IFN-γ ELISPOT assay noninvasively detects subclinical T-cell mediated rejection and/or predicts development of anti-donor HLA antibodies. Using an initial cross-sectional cohort of 60 kidney transplant patients with six-month surveillance biopsies, we found that negative donor-specific IFN-γ ELISPOT assays accurately ruled out the presence of subclinical T-cell mediated rejection. These results were validated using a distinct prospective cohort of 101 patients where donor-specific IFN-γ ELISPOT results at both three- and six-months posttransplant significantly differentiated patients with subclinical T-cell mediated rejection at six months, independent of other clinical variables (odds ratio 0.072, 95% confidence interval 0.008-0.653). The posttransplant donor-specific IFN-γ ELISPOT results independently associated with subsequent development of significant anti-donor HLA antibodies (0.085, 0.008-0.862) and with significantly worse two-year function (estimated glomerular filtration rate) compared to patients with a negative test. Thus, posttransplant immune monitoring by donor-specific IFN-γ ELISPOT can assess risk for developing subclinical T-cell mediated rejection and anti-donor HLA antibodies, potentially limiting the need for surveillance biopsies. Our study provides a guide for individualizing immunosuppression to improve posttransplant outcomes.


High-flow nasal cannula oxygen therapy in acute hypoxemic respiratory failure in 22 dogs requiring oxygen support escalation.
To determine the effect of high-flow nasal cannula (HFNC) oxygen therapy on cardiorespiratory variables and outcome in dogs with acute hypoxemic respiratory failure. Prospective, sequential clinical trial. University veterinary teaching hospital. Twenty-two client-owned dogs that failed to respond to traditional oxygen support. Initiation of HFNC therapy after traditional oxygen supplementation failed to increase Spo2 > 96% and Pao2 > 75 mm Hg or improve respiratory rate/effort. Physiological variables, blood gas analyses, and dyspnea/sedation/tolerance scores were collected prior to HFNC initiation (on traditional oxygen support [time 0 or T0]), and subsequently during HFNC oxygen administration at time 30 minutes, 60 minutes, and 7 ± 1 hours. Relative to T0, use of HFNC resulted in a decreased respiratory rate at 1 hour (P = 0.022) and 7 hours (P = 0.012), a decrease in dyspnea score at all times (P < 0.01), and an increase in Spo2 at all times (P < 0.01). There was no difference in arterial/venous Pco2 relative to T0, although Paco2 was correlated with flow rate. Based on respiratory assessment, 60% of dogs responded to HFNC use by 30 minutes, and 45% ultimately responded to HFNC use and survived. No clinical air-leak syndromes were observed. HFNC use improved oxygenation and work of breathing relative to traditional oxygen therapies, without impairing ventilation. HFNC use appears to be a beneficial oxygen support modality to bridge the gap between standard oxygen supplementation and mechanical ventilation.


Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions.
Functionally altered biological mechanisms arising from disease-associated polymorphisms, remain difficult to characterize when those variants are intergenic, or, fall between genes. We sought to identify shared downstream mechanisms by which inter- and intragenic single nucleotide polymorphisms (SNPs) contribute to a specific physiopathology. Using computational modeling of 2 million pairs of disease-associated SNPs drawn from genome wide association studies (GWAS), integrated with expression Quantitative Trait Loci (eQTL) and Gene Ontology functional annotations, we predicted 3,870 inter-intra and inter-intra SNP pairs with convergent biological mechanisms (FDR<0.05). These prioritized SNP pairs with overlapping mRNA targets or similar functional annotations were more likely to be associated with the same disease than unrelated pathologies (OR>12). We additionally confirmed synergistic and antagonistic genetic interactions for a subset of prioritized SNP pairs in independent studies of Alzheimer's disease (entropy p=0.046), bladder cancer (entropy p=0.039), and rheumatoid arthritis (PheWAS case-control p<10-4). Using ENCODE datasets, we further statistically validated that the biological mechanisms shared within prioritized SNP pairs are frequently governed by matching transcription factor binding sites and long-range chromatin interactions. These results provide a "roadmap" of disease mechanisms emerging from GWAS and further identify candidate therapeutic targets among downstream effectors of intergenic SNPs.


Anesthesia staffing and anesthetic complications during cesarean delivery: a retrospective analysis.
Obstetrical anesthesia services may be provided by Certified Registered Nurse Anesthetists (CRNAs), anesthesiologists, or a combination of the two providers. Research is needed to assist hospitals and anesthesia groups in making cost-effective staffing choices. To identify differences in the rates of anesthetic complications in hospitals whose obstetrical anesthesia is provided solely by CRNAs compared to hospitals with only anesthesiologists. Washington State hospital discharge data were obtained from 1993 to 2004 for all cesarean sections, and were merged with a survey of hospital obstetrical anesthesia staffing. Anesthetic complications were identified via International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Resulting rates were risk-adjusted using regression analysis. Hospitals with CRNA-only staffing had a lower rate of anesthetic complications than those with anesthesiologist staffing (0.58% vs. 0.76%, p=.0006). However, after regression analysis, this difference was not significant (odds ratio for CRNA vs. anesthesiologist complications: 1.046 to 1, 95% confidence interval 0.649-1.658, p=.85). There is no difference in rates of complications between the two types of staffing models. As a result, hospitals and anesthesiology groups may safely examine other variables, such as provider availability and costs, when staffing for obstetrical anesthesia. Further study is needed to validate the use of ICD-9-CM codes for anesthesia complications as an indicator of quality.


Molecular epigenetics, chromatin, and NeuroAIDS/HIV: immunopathological implications.
Epigenetics studies factors related to the organism and environment that modulate inheritance from generation to generation. Molecular epigenetics examines non-coding DNA (ncdDNA) vs. coding DNA (cdDNA), and pertains to every domain of physiology, including immune and brain function. Molecular cartography, including genomics, proteomics, and interactomics, seeks to recognize and to identify the multi-faceted and intricate array of interacting genes and gene products that characterize the function and specialization of each individual cell in the context of cell-cell interaction, tissue, and organ function. Molecular cartography, epigenetics, and chromatin assembly, repair and remodeling (CARR), which, together with the RNA interfering signaling complex (RISC), is responsible for much of the control and regulation of gene expression, intersect.We describe current and ongoing studies aimed to apply these overlapping areas of research, CARR and RISC, to a novel understanding of the immuno-neuropathology of HIV-1 infection, as an example. Taken together, the arguments presented here lead to a novel working hypothesis of molecular immune epigenetics as it pertains to HIV/AIDS, and the immunopathology of HIV-1-infected CD4+ cells. Specifically, we discuss these views in the context of the structure-function relationship of chromatin, the cdDNA/ncdDNA ratio, and possible nucleotide divergence in the untranslated regions (UTRs) of mature mRNA intronic and intergenic DNA sequences, and putative catastrophic consequences for immune surveillance and the preservation of health in HIV/AIDS. Here, we discuss the immunopathology of HIV Infection, with emphasis on CARR in cellular, humoral and molecular immune epigenetics.


Multidisciplinary Approach to the Management of Esophageal Malignancies.
A multidisciplinary approach in the management of complex malignancies is becoming more common, and likewise, adopting such an approach to the care of patients with locally advanced esophageal is recommended in order to optimize clinical outcomes. In this review, we discuss both the surgical and medical oncology perspectives in the management of patients with locally advanced esophageal cancer. We review the data supporting the current standard-of-care approach, namely trimodality therapy with neoadjuvant chemo-radiotherapy followed by surgery. Other aspects of managing these patients including the control of dysphagia and pain as well as nutritional support are discussed. Finally, we review data that support the importance of incorporating a multidisciplinary streamlined approach in the management of these patients. Rather than having patients see each provider separately, a multidisciplinary approach to esophageal cancer allows for the seamless flow of communication and proactive management of the patient's symptoms. These benefits include increasing the likelihood of evidence-based decision making, shorter time to treatment, and increased patient quality of life, all of which can result in improved patient outcomes. The use of a multidisciplinary team can lead to a more accurate staging paradigm and thereby, better management decisions that translate to improved clinical outcomes. Therefore, optimizing the multidisciplinary approach for the care of patients with locally advanced esophageal cancer is essential for successful and individualized patient care.


Unilateral Pterional Polycraniosynostosis Treated with Craniectomy and Helmet Therapy.
Craniosynostosis is a condition in which one or more of the cranial sutures have fused prematurely, affecting the growth pattern and contours of the infant skull. The pterion is the junction of temporal, frontal, parietal, and sphenoid bones of the skull. We present a case of unilateral pterional craniosynostosis, which was treated with strip craniectomy and helmet therapy.


Novel Computerized Method for Measurement of Retinal Vessel Diameters.
Several clinical studies reveal the relationship between alterations in the topologies of the human retinal blood vessel, the outcrop and the disease evolution, such as diabetic retinopathy, hypertensive retinopathy, and macular degeneration. Indeed, the detection of these vascular changes always has gaps. In addition, the manual steps are slow, which may be subjected to a bias of the perceiver. However, we can overcome these troubles using computer algorithms that are quicker and more accurate. This paper presents and investigates a novel method for measuring the blood vessel diameter in the retinal image. The proposed method is based on a thresholding segmentation and thinning step, followed by the characteristic point determination step by the Douglas-Peucker algorithm. Thereafter, it uses the active contours to detect vessel contour. Finally, Heron's Formula is applied to assure the calculation of vessel diameter. The obtained results for six sample images showed that the proposed method generated less errors compared to other techniques, which confirms the high performance of the proposed method.


Intraoperative Extracorporeal Membrane Oxygenation Rescue of a Polytrauma Patient With a Complete Right Mainstem Bronchus Avulsion: A Pediatric Case Report.
In pediatric patients experiencing blunt chest trauma, tracheobronchial avulsion injuries are rare but frequently fatal. We report the case of a 13-year-old boy who presented to our trauma center following a semitruck versus pedestrian collision. During his operative course, he developed refractory hypoxemia requiring emergency venovenous (VV) extracorporeal membrane oxygenation (ECMO) support. After stabilization, a complete right mainstem bronchus avulsion was identified and treated.


Studies on the pharmacology of central opioid-induced increases in plasma catecholamines in conscious rats.
Centrally-administered opioid peptides produce elevations in levels of catecholamines in plasma in conscious rats. To investigate the opioid receptor involved in mediating this response, morphine (3.5-105 nmol), [D-Ala2-D-Leu5]enkephalin (DADL, 1.05-35 nmol) and U50, 488H (35-1160 nmol), relatively selective ligands for the mu, delta and kappa receptors respectively, were injected intracerebroventricularly into conscious rats and the levels of catecholamines in plasma determined at the peak of the response. Each agonist produced dose-dependent elevations in levels of noradrenaline and adrenaline, the order of potency being DADL approximately equal to morphine greater than U50,488H. These results exclude involvement of the kappa receptor but do not distinguish between an effect mediated by a mu or delta receptor. The responses to morphine were blocked in the presence of 300 nmol naloxone but were not altered by 41.5 nmol RX 781094, a selective alpha 2-adrenoceptor antagonist. The elevation in levels of adrenaline in plasma produced by small doses of the agonists was not related to behavioural changes.


Simultaneous and comprehensive in vivo analysis of cytochrome P450 activity by using a cocktail approach in rats.
A cocktail approach can detect the activities of multiple cytochrome P450 (CYP) isoforms following the administration of multiple CYP-specific substrates in a single experiment. This study aimed to develop a simultaneous and comprehensive in vivo analysis of CYP activity in rats. The rats received an oral administration of losartan (10 mg/kg) and omeprazole (40 mg/kg). Caffeine (1 mg/kg), dextromethorphan (10 mg/kg) and midazolam (10 mg/kg) were administered 15 min later. In the drug-interaction phase, the rats were treated orally with dexamethasone (80 mg/kg) 24 h before, or with ketoconazole (10 mg/kg), fluvoxamine (100 mg kg) or fluconazole (10 mg/kg) 1 h before the administration of cocktail drugs. The concentrations of the drugs and their metabolites were determined by LC/MS/MS. Plasma concentrations of five CYP substrates and their metabolites were simultaneously evaluated after the oral drug administration. Fluvoxamine and fluconazole significantly increased the Cmax and AUC of caffeine, and the AUC of omeprazole and midazolam. Dexamethasone significantly increased Cmax and AUC of losartan, while it decreased the Cmax of midazolam. Ketoconazole showed no significant effect on the pharmacokinetic parameters of the tested drugs. In conclusion, a cocktail approach was developed for simultaneous and comprehensive analysis of the activities of multiple CYP isoforms in rats. In this approach, the effects of inhibitors and an inducer of various CYP isoforms were examined. Although further studies are necessary to predict the effects in humans, this approach may be expected to serve as a convenient method for detecting drug-drug interactions in rats.


Peptide-mediated delivery of nucleic acids into mammalian cells.
Control of gene expression using RNA interference (RNAi) technology constitutes a method of choice for investigating gene function in mammalian cells. However, like most oligonucleotide-based strategies, the major limitation of interfering RNA is their poor cellular uptake due to low permeability of the cell membrane to nucleic acids. Several strategies have been developed to improve delivery of oligonucleotides both in cultured cells and in vivo. So far, there is no universal method for their delivery, as they all present several limitations. Peptide-based strategies have been demonstrated to improve the cellular uptake of nucleic acids both in cultured cell and in vivo. This chapter describes a new peptide-based gene delivery system, MPG, which forms stable noncovalent complexes with oligonucleotides and promotes their delivery into a large panel of cell lines without the need for prior chemical covalent coupling. Protocols are described for both adherent and suspension cell lines.


Cutaneous vasculitis in a patient with ankylosing spondylitis: A case report.
Cutaneous vasculitis is usually found in patients with rheumatoid arthritis (RA) as an extra-articular manifestation, but rare in patients with ankylosing spondylitis (AS). In this case, we describe an AS patient who developed large skin lesions, of which the histological findings were consistent with cutaneous vasculitis. A 22-year-old male who was diagnosed as HLA-27 positive AS for 5 years. However, in the last year, he suffered a recurrent skin lesion in both lower extremities especially the dorsum of feet, accompanying with intense pruritus. The originally diagnosis of the skin lessons was dermatitis, and then a skin biopsy pathology showed it was consistent with cutaneous vasculitis. At first he was treated with gentamycin and ethacridine for nearly 2 weeks, the symptoms were relieved. But then he suffered severe cutaneous lesions with swell at the ulcerous margin in his dorsum of right foot. The patient was treated with dexamethasone 10 mg intravenous drip daily for 2 weeks, and followed by methylprednisolone 160 mg oral administration daily after discharge. The skin lesions were gradually healed in several months OUTCOMES:: This patient was followed up at 1-month, 5-month, and 10-month after discharged, the skin lessons was gradually healed and never occurred. This case indicated that cutaneous vasculitis might be an extra-articular manifestation of AS in which IgA may plays a pathogenic part. All this may be associated with the damage of cytokines and autoantibodies to vascular endothelial wall caused by active inflammatory phase.


Stacking interactions and intercalative DNA binding.
The DNA-binding properties of many ligands can be rationalized on the basis of their structural and electronic complementarity with the functional groups present in the minor and major grooves of particular DNA sequences. Specific hydrogen bonding patterns are particularly useful for the purpose of sequence recognition. Less obvious, however, is the influence of base composition on the conformational preferences of individual base steps and on the binding of intercalating moieties which become sandwiched between contiguous base pairs. Improved knowledge of stacking interactions may lead to a better understanding of the architecture and inherent flexibility of particular DNA sequences and may provide insight into the principles that dictate the structural changes and specificity patterns observed in the binding of some intercalating ligands to DNA.


Rapid induction of carcinoma in situ in dog urinary bladder by sequential treatment with N-methyl-N'-nitrosourea and N-butyl-N-(4-hydroxybutyl)-nitrosamine.
A highly atypical intraepithelial proliferation, which was interpreted as carcinoma in situ, developed in the urinary bladder of 2 beagle dogs after repeated intravesical instillations of N-methyl-N'-nitrosourea followed by oral administration of N-butyl-N-(4-hydroxybutyl)nitrosamine. The latent period was 37 weeks. The technique may provide a useful model to study the natural history of bladder cancer, particularly carcinoma in situ.


Misuse of booster cushions - an observation study of children's performance during buckling up.
Booster cushions are effective tools to protect children from injuries in car crashes, but there remains a large amount of misuse. The aim of this study was to assess potential misuse of booster cushions in an observational laboratory study, and to identify whether booster cushion design, age or clothing had any effect. 130 Swedish children from the ages of 4-12 years participated. Each child buckled up on an integrated and on an aftermarket booster cushion in the rear seat. The older children also buckled up with seat belt only. Interviews, observations and body measurements were performed. Time to buckle up and amount of belt slack were registered. Photographs were taken to document misuse. Results showed that 77% failed to perform correct belt routing on the aftermarket cushion, independent of age, although they were familiar with this system. The misuse rate for the integrated cushion was only 4%. No misuse was found for seat belt only. Few children tightened the belt. The belt slack increased when wearing winter jackets. This indicates the importance of adding pretensioners to the rear seat. Sled tests with HIII&TNO 6y dummies were also performed for the most frequent misuse situations found. The main conclusion is that an integrated booster cushion has many advantages compared to an aftermarket cushion regarding both safety and comfort. It is easy and quick to handle, has few possibilities for misuse, has an intuitive design, the buckling up sequence is equal to buckling up with an ordinary seat belt, and younger children can buckle up correctly.


The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels.
The Tweety proteins comprise a family of chloride ion channels with three members identified in humans (TTYH1-3) and orthologues in fly and murine species. In humans, increased TTYH2 expression is associated with cancer progression, whereas fly Tweety is associated with developmental processes. Structurally, Tweety proteins are characterized by five membrane-spanning domains and N-glycan modifications important for trafficking to the plasma membrane, where these proteins are oriented with the amino terminus located extracellularly and the carboxyl terminus cytoplasmically. In addition to N-glycosylation, ubiquitination mediated by the HECT type E3 ubiquitin ligase Nedd4-2 is a post-translation modification important in regulating membrane proteins. In the present study, we performed a comprehensive analysis of the ability of each of TTYH1-3 to interact with Nedd4-2 and to be ubiquitinated and regulated by this ligase. Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein. These data, indicating that Nedd4-2 differentially interacts with and regulates TTYH1-3, will be important for understanding mechanisms controlling Tweety proteins in physiology and disease.


Hydrogen production in the presence of oxygen by Escherichia coli K-12.
Escherichia coli is a facultative anaerobe that can grow in a variety of environmental conditions. In the complete absence of O2, E. coli can perform a mixed-acid fermentation that contains within it an elaborate metabolism of formic acid. In this study, we use cavity-enhanced Raman spectroscopy (CERS), FTIR, liquid Raman spectroscopy, isotopic labelling and molecular genetics to make advances in the understanding of bacterial formate and H2 metabolism. It is shown that, under anaerobic (anoxic) conditions, formic acid is generated endogenously, excreted briefly from the cell, and then taken up again to be disproportionated to H2 and CO2 by formate hydrogenlyase (FHL-1). However, exogenously added D-labelled formate behaves quite differently from the endogenous formate and is taken up immediately, independently, and possibly by a different mechanism, by the cell and converted to H2 and CO2. Our data support an anion-proton symport model for formic acid transport. In addition, when E. coli was grown in a micro-aerobic (micro-oxic) environment it was possible to analyse aspects of formate and O2 respiration occurring alongside anaerobic metabolism. While cells growing under micro-aerobic conditions generated endogenous formic acid, no H2 was produced. However, addition of exogenous formate at the outset of cell growth did induce FHL-1 biosynthesis and resulted in formate-dependent H2 production in the presence of O2.


Integrated paramagnetic resonance of high-spin Co(II) in axial symmetry: chemical separation of dipolar and contact electron-nuclear couplings.
Integrated paramagnetic resonance, utilizing electron paramagnetic resonance (EPR), NMR, and electron-nuclear double resonance (ENDOR), of a series of cobalt bis-trispyrazolylborates, Co(Tp ( x )) 2, are reported. Systematic substitutions at the ring carbons and on the apical boron provide a unique opportunity to separate through-bond and through-space contributions to the NMR hyperfine shifts for the parent, unsubstituted Tp complex. A simple relationship between the chemical shift difference (delta H - delta Me) and the contact shift of the proton in that position is developed. This approach allows independent extraction of the isotropic hyperfine coupling, A iso, for each proton in the molecule. The Co..H contact coupling energies derived from the NMR, together with the known metrics of the compounds, were used to predict the ENDOR couplings at g perpendicular. Proton ENDOR data is presented that shows good agreement with the NMR-derived model. ENDOR signals from all other magnetic nuclei in the complex ( (14)N, coordinating and noncoordinating, (11)B and (13)C) are also reported.


Cardiac function and glycogen content after twenty-four-hour preservation with various metabolic substrates.
Previous work has suggested that recovery of cardiac function after long preservation periods is improved if a suitable exogenous substrate is provided. However, interpretation of existing data on the benefit of added substrate is complicated by differing preservation media and protocols studied, as well as differing models used to evaluate postpreservation recovery. These experiments were designed to evaluate glucose, pyruvate, aspartate, and glutamate as exogenous substrates for prolonged perfusion preservation of hearts with a rat heart model preserved with crystalloid medium and with function quantified in an isolated working heart preparation. Cardiac function (n = 5/group) and tissue glycogen content (n = 5/group) were measured in fresh control rat hearts and four groups of hearts preserved for 24 hours in an extracellular-type cardioplegic medium containing 11 mmol/L glucose and either 20 mmol/L sodium aspartate, 20 mmol/L sodium glutamate, 20 mmol/L sodium pyruvate, or no other substrate. Postpreservation cardiac function was measured in an isolated working rat heart preparation for a 4-hour reperfusion period. Exogenous substrate consumption during preservation and tissue glycogen content at the end of preservation were measured with spectrophotometric assays. All hearts in the aspartate- and glutamate-preserved groups functioned for the full 4-hour period with stroke work that was 50% to 60% of control. Hearts preserved with only glucose substrate had inconsistent recovery: two of five hearts in that group did not recover, whereas three recovered similar to the aspartate and glutamate groups. None of the pyruvate-preserved hearts recovered contractile function. There was no association between postpreservation tissue glycogen content and extent of cardiac function recovery. Aspartate or glutamate plus glucose was the best substrate mixture among those tested for long-term perfusion preservation of hearts. These amino acids offer advantages over pyruvate because they produced better recovery of the hearts and because they are chemically more stable than pyruvate. Aspartate or glutamate plus glucose also produced better postpreservation function compared with glucose alone.


Coxsackievirus B3 elicits a sex-specific CD8+ T cell response which protects female mice.
Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, often attributed to weaker immune responses. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex difference in the CD8+ T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8+ T cells in female mice but not in male mice. CVB3 also increased the proportion and number of CD11ahiCD62Llo CD8+ T cells in female mice, indicative of activation. This response was independent of the inoculation route and type I interferon. Using a recombinant CVB3 virus expressing a model CD8+ T cell epitope, we found that the expansion of CD8+ T cells in females is viral-specific and not due to bystander activation. Finally, the depletion of CD8+ T cells, prior to infection, led to enhanced mortality, indicating that CD8+ T cells are protective against CVB3 in female mice. These data demonstrate that CVB3 induces a CD8+ T cell response in female mice and highlight the importance of sex-specific immune responses to viral pathogens.


Novel synchronization of discrete-time chaotic systems using neural network observer.
This paper presents a new approach to solve the synchronization problem of a large class of discrete chaotic systems. The chaotic systems can be reformulated as an appropriate class of linear parameter varying (LPV) systems. The synchronization problem for this class of nonlinear systems is revisited from a control perspective and it is argued that the problem can be viewed as an observer design problem. Then, based on the LPV representation, a neural network observer-based approach is proposed to solve the synchronization problem. The simulation results show the advantages of combining the LPV techniques and the neural networks to determine the appropriate observer gain within the context of chaotic system synchronization.


[Using multiple-fragment amplification combined with Gibson assembly to clone genes with site-directed mutations].
In order to develop a simple and efficient site-directed mutagenesis solution, the Gibson assembly technique was used to clone the cyclin dependent kinase 4 gene with single or double site mutations, with the aim to simplify the overlap extension PCR. The gene fragments containing site mutations were amplified using a strategy similar to overlap extension PCR. Meanwhile, an empty plasmid was digested by double restriction endonucleases to generate a linearized vector with a short adaptor overlapping with the targeted gene fragments. The gene fragments were directly spliced with the linearized vector by Gibson assembly in an isothermal, single-reaction, creating a recombinant plasmid. After the recombinant plasmids were transformed into competent Escherichia coli DH5α, several clones were screened from each group. Through restriction analysis and DNA sequencing, it was found that the randomly selected clones were 100% target mutants. Since there was neither tedious multiple-round PCR amplification nor frequent DNA extraction operation, and there was no need to digest the original plasmid, this protocol circumvents many factors that may interfere with the conventional site-directed mutagenesis. Hence, genes with single or multiple mutations could be cloned easily and efficiently. In summary, the major defects associated with overlap extension PCR and rolling circle amplification were circumvented in this protocol, making it a good solution for site-directed mutagenesis.


An LRR-only protein promotes NLP-triggered cell death and disease susceptibility by facilitating oligomerization of NLP in Arabidopsis.
Necrosis- and ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) constitute a superfamily of proteins toxic to dicot plants, but the molecular basis of this toxicity remains obscure. Using quantitative trait locus (QTL) analysis we investigated the genetic variation underlying ion leakage in Arabidopsis plants elicited with MoNLP1 derived from Magnaporthe oryzae. The QTL conditioning MoNLP1 toxicity was positionally cloned and further characterized to elucidate its mode of action. MoNLP1-triggered cell death varied significantly across > 250 Arabidopsis accessions and three QTLs were identified conferring the observed variation. The QTL on chromosome 4 was uncovered to encode a leucine-rich repeat (LRR)-only protein designated as NTCD4, which shares high sequence identity with a set of nucleotide-binding LRR proteins. NTCD4 was secreted into the apoplast and physically interacted with multiple NLPs. Apoplastic NTCD4 facilitated the oligomerization of NLP, which was closely associated with toxicity in planta. The natural genetic variation causing D3N change in NTCD4 reduced the secretion efficiency of NTCD4 and the infection of Botrytis cinerea on Arabidopsis plants. These observations demonstrate that the plant-derived NTCD4 is recruited by NLPs to promote toxicity via facilitating their oligomerization, which extends our understanding of a key step in the toxic mode of action of NLPs.


Optical injection locking of a THz quantum-cascade VECSEL with an electronic source.
Optical injection locking of a metasurface quantum-cascade (QC) vertical-external-cavity surface-emitting laser (VECSEL) is demonstrated at 2.5 THz using a Schottky diode frequency multiplier chain as the injection source. The spectral properties of the source are transferred to the laser output with a locked linewidth of ∼1 Hz, as measured by a separate subharmonic diode mixer, and a locking bandwidth of ∼300 MHz is achieved. The large locking range is enabled by the microwatt power levels available from modern diode multipliers. The interplay between the injected signal and feedback from external reflections is studied and demonstrated to increase or decrease the locking bandwidth relative to the classic locking range depending on the phase of the feedback.


Silymarin, a polyphenolic flavonoid impede Plasmodium falciparum growth through interaction with heme.
A polyphenolic flavonoid, Silymarin isolated from Silybum marianum is widely known for its hepatoprotective action. In the present study anti-plasmodial activity of Silymarin has been demonstrated for the first time having IC50 of 14 ± 0.33 μM against the NF-54 strain of P. falciparum with high selectivity index (>100). The parasitostatic action is exerted through inhibition of β-hematin/hemozoin formation which is due to the interaction (Kd = 3.63 ± 0.9µM) of silymarin with free heme in a Stoichiometry of 1:1 Silymarin: heme complex resulting into heme-induced membrane damage in the parasite. Silymarin could hinder the glutathione and hydrogen peroxide-induced heme detoxification. Silymarin also induces apoptosis in the parasite through the elevation of caspase-3 level in a dose-dependent manner. Results from the docking studies suggest that Silymarin interacts with heme.


A torquing shearing interferometer for cylindrical wire array experiments.
In standard shearing interferometry, a single probing beam passes through a perturbing medium and is then split into two beams. A linear shift results in an overlap, an interference, and a fringe pattern yielding the perturbing medium density profile. The probing beam usually needs to be larger than the perturbing medium so that part of it passes through a well separated low density region. During early time axial (end-on) views of imploding cylindrical wire arrays low density regions lie in between the high density regions that are near the initial wire positions. In addition, for end-on viewing, the probing beam diameter is limited by electrodes and is comparable to the array diameter. In this case a linear translation will not work but the overlap can be accomplished by an azimuthal rotation of one beam with respect to the other. Such a torquing shearing interferometer has been set up on the COBRA experiment to give time resolved, radial, and azimuthal electron density profiles during early time cylindrical wire array implosions.


The Influence of Four Constructs of Social Support on Pregnancy Experiences in Group Prenatal Care.
Objective: This study aimed to identify the influence of the four constructs of social support on positive pregnancy experiences in CenteringPregnancy, a group prenatal care (GPNC) model. Methods: Using a qualitative descriptive design, semi-structured interviews were conducted with 11 women who had participated in at least 6 of 10 GPNC sessions at a family practice medicine residency. Participants were asked to describe their experiences in GPNC. Results: Using a standard content analysis, four constructs of social support (emotional, informational, instrumental, and appraisal) were identified through three major themes: (1) informational support, offered by peers in GPNC settings, promotes learning and prepares women for motherhood; (2) emotional and appraisal support, offered by peers in GPNC, improves emotional well-being and helps women build lasting, supportive connections with peers, and (3) emotional, informational, instrumental, and appraisal support work in tandem to create positive relationships between women and health care providers. Conclusion: Social support provided a means to a positive prenatal health care experience that facilitated the attainment of new knowledge and the formation of positive relationships with health care providers and peers. The findings of this study can provide health care providers with a framework to examine and enhance their practice and care of women in the perinatal period.


Dispersive solid-phase extraction for the determination of trace organochlorine pesticides in apple juices using reduced graphene oxide coated with ZnO nanocomposites as sorbent.
In this work, reduced graphene oxide coated with ZnO nanocomposites was used as an efficient sorbent of dispersive solid-phase extraction and successfully applied for the extraction of organochlorine pesticides from apple juice followed by gas chromatography with mass spectrometry. Several experimental parameters affecting the extraction efficiencies, including the amount of adsorbent, extraction time, and the pH of the sample solution, as well as the type and volume of eluent solvent, were investigated and optimized. Under the optimal experimental conditions, good linearity existed in the range of 1.0-200.0 ng/mL for all the analytes with the correlation coefficients (R2 ) ranging from 0.9964 to 0.9994. The limits of detection of the method for the compounds were 0.011-0.053 ng/mL. Good reproducibilities were acquired with relative standard deviations below 8.7% for both intraday and interday precision. The recoveries of the method were in the range of 78.1-105.8% with relative standard deviations of 3.3-6.9%.


Stx-Producing Shigella Species From Patients in Haiti: An Emerging Pathogen With the Potential for Global Spread.
Shiga toxins (Stx) are commonly produced by Shigella dysenteriae serotype 1 and Stx-producing Escherichia coli. However, the toxin genes have been detected in additional Shigella species. We recently reported the emergence of Stx-producing Shigella in travelers in the United States and France who had recently visited Hispaniola (Haiti and the Dominican Republic). In this study, we confirm this epidemiological link by identifying Stx-producing Shigella from Haitian patients attending clinics near Port-au-Prince. We also demonstrate that the bacteriophage encoding Stx is capable of dissemination to stx-negative Shigella species found in Haiti, suggesting that Stx-producing Shigella may become more widespread within that region.


Bovine Omasum-Inspired Interfacial Carbon-Based Nanocomposite for Saliva Metabolic Screening of Gastric Cancer.
Gastric cancer is one of the most common malignant digestive cancers, and its diagnostic has still faced challenges based on metabolic analysis due to complex sample pretreatment and low metabolite abundance. In this study, inspired by the structure of bovine omasum, we in situ synthesized a novel interfacial carbon-based nanocomposite of graphene supported nickel nanoparticles-encapsulated in the nitrogen-doped carbon nanotube (Ni/N-CNT/rGO), which was served as a novel matrix with enhanced ionization efficiency for the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) saliva metabolic analysis of gastric cancer. Benefiting from its high sp2 graphitic degree, large surface area, strong UV absorption, and rich active sites, Ni/N-CNT/rGO matrix exhibited excellent performances of reproducibility, coverage, salt-tolerance, sensitivity, and adsorption ability in MALDI-TOF MS. The differential scanning calorimetry (DSC) and thermal conversion behaviors explained the highly efficient LDI mechanism. Based on saliva metabolic fingerprints, Ni/N-CNT/rGO assisted LDI MS with cross-validation analysis could successfully distinguish gastric cancer patients from healthy controls through the screening of four potential biomarkers with an accuracy of 92.50%, specificity of 88.03%, and sensitivity of 97.12%. This work provided a fast and sensitive MS sensing platform for the metabolomics characterization of gastric cancer and might have potential value for precision medicine in the future.


Outcome and Prognostic Factors for Canine Splenic Lymphoma Treated by Splenectomy (1995-2011).
To assess the outcome of canine splenic lymphoma treated with splenectomy and to evaluate prognostic factors, including involvement of other sites, adjuvant chemotherapy, and the effect of World Health Organization (WHO) histological classification of canine malignant lymphoma. Multi-institutional, retrospective study. Client-owned dogs (n = 28). Medical records (1995-2011) of dogs with a histological diagnosis of splenic lymphoma and treated by splenectomy submitted by Veterinary Society of Surgical Oncology members were reviewed. Included were dogs treated with or without adjuvant therapy. Overall survival, disease-free interval, and cause of death were determined. Prognostic factors and the WHO histological classification of canine malignant lymphoma were evaluated with respect to outcome. Dogs with splenic lymphoma treated by splenectomy had a 1-year survival rate of 58.8%, after which no animals died of their disease. B cell lymphoma held a better prognosis for survival than other variants of splenic lymphoma. Marginal zone lymphoma and mantle cell lymphoma were the most common B cell lymphoma subtypes in our study. Hemoabdomen and clinical signs related to splenic lymphoma, including abdominal distention, lethargy, and anorexia, were poor prognostic indicators, whereas disease confined to the spleen was a positive prognostic indicator. Pre- or postoperative adjuvant chemotherapy did not provide a survival benefit. Based on our sample population, splenectomy alone was an effective treatment for splenic lymphoma in cases with disease confined to the spleen. Chemotherapy may not improve survival in cases of lymphoma restricted to the spleen.


Review and application of serine protease inhibition in coronary artery bypass graft surgery.
Current pharmacologic agents, aprotinin, epsilon aminocaproic acid, and tranexamic acid, used to decrease blood loss and transfusion requirements during coronary artery bypass graft (CABG) surgery are discussed. Aprotinin is the only agent that also modulates the systemic inflammatory responses that are generated by contact activation during CABG surgery. These responses are largely mediated by serine proteases such as kallikrein, thrombin, and plasmin. Aprotinin is a naturally occurring polypeptide that has a concentration-dependent effect to inhibit serine proteases. Two aprotinin dosing regimens are indicated in the United States (U.S.) for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass (CPB) during the course of CABG surgery. Serum concentrations achieved with the full-dose regimen inhibit both kallikrein and plasmin activity resulting in attenuation of the systemic inflammatory response to bypass, whereas serum concentrations achieved with the half-dose regimen only inhibit plasmin activity. The efficacy and safety of aprotinin have been studied in randomized controlled trials in over 5,000 patients. Aprotinin is well tolerated compared to placebo. Treatment-emergent adverse events are similar to those associated with CPB surgery. However, because aprotinin is a bovine protein, there is a small, but manageable risk of hypersensitivity reactions. Epsilon aminocaproic acid and tranexamic acid are lysine analogs that reduce bleeding by inhibiting the conversion of plasminogen to plasmin, a serine protease responsible for breaking down fibrinogen to fibrin. Although they are commonly used to decrease bleeding associated with CABG surgery with CPB, they are not currently approved by the U.S. Food and Drug Administration (FDA) for CABG surgery. Aprotinin is the only agent that has an FDA indication to prevent blood loss and transfusion during CABG surgery, and the additional benefit of attenuating the systemic inflammatory response associated with CABG with CPB.


Coronary microembolization.
Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the entire epicardial coronary artery with subsequent acute myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. This review summarizes the available morphological evidence for coronary microembolization in patients who died from coronary artery disease, most notably from sudden death. Then the experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes is detailed. Finally, the review presents the available clinical evidence for coronary microembolization in patients, highlights its key features--arrhythmias, contractile dysfunction, microinfarcts and reduced coronary reserve--, compares these features to those of the experimental model and addresses its prevention by mechanical protection devices and glycoprotein IIb/IIIa antagonism.


The development and validation of a simulation tool for health policy decision making.
Computer simulations have been used to model infectious diseases to examine the outcomes of alternative strategies for managing their spread. Methicillin resistant Staphylococcus aureus (MRSA) skin and soft tissue infections have become prominent in many communities and efforts are underway to reduce the spread of this organism both in hospitals and communities. Currently, there are few tools for policy makers to use to examine the outcome of various choices when making decisions about MRSA. Using the example of MRSA, we describe, in this paper, a rigorous approach for development and validation of a tool that simulates the spread of MRSA infections. We used sensitivity analyses in a novel way and validated the simulation results against local data over time. Our approach for simulation development and validation is generalizeable to simulations of other diseases.


Acute choroidal ischemia as a complication of photocoagulation.
Acute choroidal vascular insufficiency as a complication of photocoagulation has been little noticed. In 17 eyes of 16 patients photocoagulated with either xenon or argon sources for proliferative sickle cell retinopathy, gray lesions of the fundus developed peripheral to the photocoagulation sites. Histologic examination of similar gray lesions produced in monkeys showed necrosis and atrophy of the outer half of the retina. Intense photocoagulation of the human fundus, even with smaller spot sizes, may occlude a choroidal artery, producing separate gray lesions of distinctive shape. The lesions in both the patients and the monkeys progressed to granular hyperpigmentation by two to three weeks after photocoagulation.


Use of dental implants to improve unfavorable removable partial denture design.
This study aimed to determine whether the use of a limited number of dental implants, with no rigid connection between implants and teeth and as few as possible prosthetic element requirements, is a viable solution for improving unfavorable removable partial dentures (RPD) design. Fifteen partially edentulous patients with an unfavorable number and distribution of abutment teeth were treated, each with a limited number of implants, from 1997 to 2004, resulting in an improved RPD design. Implant survival rate was 100%, and prosthetic complications were minor. All patients reported great satisfaction with the partial dentures and good chewing efficiency. The results indicate that the use of dental implants to improve unfavorable RPD design is a viable and cost-effective treatment modality.


Mineralization of individual congeners of linear alkylbenzenesulfonate by defined pairs of heterotrophic bacteria.
Parvibaculum lavamentivorans DS-1(T) utilized the commercial surfactant linear alkylbenzenesulfonate (LAS) (20 congeners with C(10) to C(13) side chains) as a carbon and energy source by shortening the side chain, and sulfophenylcarboxylates (SPCs) and similar compounds (e.g., alpha,beta-unsaturated SPCs [SPC-2Hs]) were excreted with quantitative recovery of the sulfophenyl moiety. 2-(4-Sulfophenyl)decane (2-C10-LAS) was converted largely to 3-(4-sulfophenyl)butyrate (3-C4-SPC), as were 2-C12-LAS and 2-C14-LAS; the other products were 5-C6-SPC (SPC+2C) and 3-C4-SPC-2H. 2-C11-LAS was converted largely to 4-C5-SPC with the corresponding SPC+2C and SPC-2H; similarly, 3-C12-LAS yielded 4-C6-SPC with the corresponding SPC+2C and SPC-2H. This pattern of products confirmed that LAS is degraded by omega-oxygenation and chain shortening through beta-oxidation. At least nine major SPCs were formed from commercial LAS. The novel isolates Comamonas testosteroni SPB-2 and KF-1 utilized 3-C4-SPC; Delftia acidovorans SPH-1 utilized 4-C6-SPC enantioselectively. The substrate-dependent oxygen uptake of whole cells of strain SPB-2 indicated that there was inducible oxygenation of 3-C4-SPC and of 4-sulfophenol in whole cells of the strains of C. testosteroni during growth with 3-C4-SPC or 4-sulfophenol. The degradative pathways apparently involved 4-sulfocatechol and 4-sulfocatechol 1,2-dioxygenase. Strain SPB-2 and strain DS-1(T) grew together in LAS-salts medium, and only seven of the nine major SPCs were recovered. Strain SPB-2 utilized 3-C4-SPC, 3-C5-SPC, and 3-C4-SPC-2H. Strain SPH-1 grew together with strain DS-1(T) in LAS-salts medium, and a different set of seven major SPCs was recovered. Strain SPH-1 utilized 4-C6-SPC, 4-C5-SPC, 4-C6-SPC-2H, and 4-C5-SPC-2H. A three-member community consisting of strains DS-1(T), SPB-2, and SPH-1 utilized four major SPCs. We inferred that this community mineralized the major SPCs derived from 8 of the 20 LAS congeners.


[Surgery as a treatment modality for sleep disordered breathing].
The main characteristic of all types of sleep disordered breathing (SDB) is partial or complete obstruction in the upper airway. Patency of the pharyngeal airway is maintained by two opposing forces: negative intraluminal pressure and the activity of the upper airway musculature. Different anatomical abnormalities can disrupt this delicate balance with resultant compromise of the upper airway. Thus, the main goal of the medical and surgical therapy is to alleviate this obstruction and increase airway patency. If multilevel obstruction is noted, multilevel-surgery is needed. It can be done as one-stage or multi-stage procedure which depends on the current patient state and surgical skill. Technical developments and their implementation in everyday surgical practice made some of the surgical methods for SDB treatment more convinient for the patient. Surgery can be performed in ambulatory facility and the procedures are repeatable with no adverse effects which significantly decreases the postoperative morbidity. Almost all surgical techniques for SDB treatment have good results in properly selected patients. That is why the key for the successful SDB treatment is a proper multidisciplinary diagnostic algorithm and a team work.


Synthesis and processing of D2 dopamine receptors.
Dopamine receptors belong to a superfamily of neurotransmitter receptors that are functionally coupled to guanine nucleotide binding proteins. In this study, we have used Chinese hamster ovary (CHO) cells stably transfected with the rat D2L receptor, in conjunction with specific anti-peptide antibodies that we have developed, in order to visualize this protein and the course of its synthesis. The newly synthesized receptor exists as a 45-kDa protein which undergoes further processing to a 75-kDa glycosylated receptor in the CHO cells. In pulse-chase experiments it was noticed that a 35-kDa precursor was present which disappeared after 30 min. In order to determine whether this 35-kDa protein represents an unprocessed form of the receptor, we have employed an in vitro translation system with cDNA constructs coding for both the murine D2 and D3 dopamine receptor isoforms. In the absence of processing, the D2 and D3 receptors have an apparent molecular mass of 35 kDa. The translated proteins were shown to be the full length receptors by immunoprecipitation with various anti-peptide antibodies and by the demonstration that they can undergo glycosylation to apparent molecular masses of approximately 45 kDa in an in vitro system.


Empty pericarp5 encodes a pentatricopeptide repeat protein that is required for mitochondrial RNA editing and seed development in maize.
In flowering plants, RNA editing is a posttranscriptional mechanism that converts specific cytidines to uridines in both mitochondrial and plastidial transcripts, altering the information encoded by these genes. Here, we report the molecular characterization of the empty pericarp5 (emp5) mutants in maize (Zea mays). Null mutation of Emp5 results in abortion of embryo and endosperm development at early stages. Emp5 encodes a mitochondrion-targeted DYW subgroup pentatricopeptide repeat (PPR) protein. Analysis of the mitochondrial transcripts revealed that loss of the EMP5 function abolishes the C-to-U editing of ribosomal protein L16 at the rpl16-458 site (100% edited in the wild type), decreases the editing at nine sites in NADH dehydrogenase9 (nad9), cytochrome c oxidase3 (cox3), and ribosomal protein S12 (rps12), and surprisingly increases the editing at five sites of ATP synthase F0 subunit a (atp6), apocytochrome b (cob), nad1, and rpl16. Mutant EMP5-4 lacking the E+ and DYW domains still retains the substrate specificity and editing function, only at reduced efficiency. This suggests that the E+ and DYW domains of EMP5 are not essential to the EMP5 editing function but are necessary for efficiency. Analysis of the ortholog in rice (Oryza sativa) indicates that rice EMP5 has a conserved function in C-to-U editing of the rice mitochondrial rpl16-458 site. EMP5 knockdown expression in transgenics resulted in slow growth and defective seeds. These results demonstrate that Emp5 encodes a PPR-DYW protein that is required for the editing of multiple transcripts in mitochondria, and the editing events, particularly the C-to-U editing at the rpl16-458 site, are critical to the mitochondrial functions and, hence, to seed development in maize.


Selected cases of periapical changes treated with calcium hydroxide preparations.
Success in endodontic treatment with application of non-hardening calcium hydroxide preparations to periapical pathosis has been described. The clinical procedures consisted in elaboration of root canals and temporary filling with Biopulp preparation. Control clinical and radiological investigations were carried out after 3 and 6 months. In spite of occurrence of initial periapical pathosis, the method of treatment with calcium hydroxide preparations permitted to achive positive results of healing of periapical pathosis thus eliminating the necessity of surgical operation.


Estimating Accuracy at Exercise Intensities: A Comparative Study of Self-Monitoring Heart Rate and Physical Activity Wearable Devices.
Physical activity tracking wearable devices have emerged as an increasingly popular method for consumers to assess their daily activity and calories expended. However, whether these wearable devices are valid at different levels of exercise intensity is unknown. The objective of this study was to examine heart rate (HR) and energy expenditure (EE) validity of 3 popular wrist-worn activity monitors at different exercise intensities. A total of 62 participants (females: 58%, 36/62; nonwhite: 47% [13/62 Hispanic, 8/62 Asian, 7/62 black/ African American, 1/62 other]) wore the Apple Watch, Fitbit Charge HR, and Garmin Forerunner 225. Validity was assessed using 2 criterion devices: HR chest strap and a metabolic cart. Participants completed a 10-minute seated baseline assessment; separate 4-minute stages of light-, moderate-, and vigorous-intensity treadmill exercises; and a 10-minute seated recovery period. Data from devices were compared with each criterion via two-way repeated-measures analysis of variance and Bland-Altman analysis. Differences are expressed in mean absolute percentage error (MAPE). For the Apple Watch, HR MAPE was between 1.14% and 6.70%. HR was not significantly different at the start (P=.78), during baseline (P=.76), or vigorous intensity (P=.84); lower HR readings were measured during light intensity (P=.03), moderate intensity (P=.001), and recovery (P=.004). EE MAPE was between 14.07% and 210.84%. The device measured higher EE at all stages (P<.01). For the Fitbit device, the HR MAPE was between 2.38% and 16.99%. HR was not significantly different at the start (P=.67) or during moderate intensity (P=.34); lower HR readings were measured during baseline, vigorous intensity, and recovery (P<.001) and higher HR during light intensity (P<.001). EE MAPE was between 16.85% and 84.98%. The device measured higher EE at baseline (P=.003), light intensity (P<.001), and moderate intensity (P=.001). EE was not significantly different at vigorous (P=.70) or recovery (P=.10). For Garmin Forerunner 225, HR MAPE was between 7.87% and 24.38%. HR was not significantly different at vigorous intensity (P=.35). The device measured higher HR readings at start, baseline, light intensity, moderate intensity (P<.001), and recovery (P=.04). EE MAPE was between 30.77% and 155.05%. The device measured higher EE at all stages (P<.001). This study provides one of the first validation assessments for the Fitbit Charge HR, Apple Watch, and Garmin Forerunner 225. An advantage and novel approach of the study is the examination of HR and EE at specific physical activity intensities. Establishing validity of wearable devices is of particular interest as these devices are being used in weight loss interventions and could impact findings. Future research should investigate why differences between exercise intensities and the devices exist.


Prevalence of extreme detergent resistance among the Enterobacteriaceae.
The detergent-resistance properties of 208 independent isolates of the Enterobacteriaceae have been examined. Of these bacterial strains, 200 were able to grow in the presence of greater than or equal to 5% sodium dodecyl sulfate, including all members of the Klebsielleae tribe. This resistance does not appear to be plasmid encoded. It is proposed that detergent-resistant organisms be termed saponotolerant or saponophilic, by analogy with other microorganisms occupying harsh ecological niches. In contrast to their prevalent resistance to anionic detergents, not one of the 208 strains tested was found to grow in the presence of three different cationic detergents. This sensitivity to cationic detergents may be of significance in combating nosocomial infections.


Supramolecular assemblies of sulfonatocalixarenes with phenanthroline: factors governing capsule formation versus bilayer arrangements.
Four crystalline complexes were prepared by the inclusion complexation of the 1,10-phenanthrolinium ion (Phen) with p-sulfonatothiacalix[4]arene (TCAS) (2 from a solution at pH 1-2 and 4 from 1 M HCl) and with p-sulfonatocalix[5]arene (C5AS) (3 from a solution at pH 1-2 and 5 from 1 M HCl) upon varying the acidity of the solution. By combining the results obtained for complexes 2-5 with those for our previously reported complex (1), p-sulfonatocalix[4]arene (C4AS) complexed to Phen, it was revealed that p-sulfonatocalixarenes (CASs) form "bis-molecular" capsules (1, 2, and 3) around Phen at pH 1-2, whereas complexes 4 and 5 display distinct host-guest inclusion behavior at higher acid concentrations. The degree of compactness of the capsules increases with the enlargement of the calixarene cavity, which is affected significantly by both the penetration depth of Phen and the structure of the Phen dimer. Furthermore, the complexation behavior of TCAS/C5AS with Phen in 1 M DCl was investigated by using NMR spectroscopy, and was discussed in comparison with the previously reported results obtained from solutions at pH 2.0.


Joint Statistical Iterative Material Image Reconstruction for Spectral Computed Tomography Using a Semi-Empirical Forward Model.
By acquiring tomographic measurements with several distinct photon energy spectra, spectral computed tomography (spectral CT) is able to provide additional material-specific information compared with conventional CT. This information enables the generation of material selective images, which have found various applications in medical imaging. However, material decomposition typically leads to noise amplification and a degradation of the signal-to-noise ratio. This is still a fundamental problem of spectral CT, especially for low-dose medical applications. Inspired by the success for low-dose conventional CT, several statistical iterative reconstruction algorithms for spectral CT have been developed. These algorithms typically rely on detailed knowledge about the spectrum and the detector response. Obtaining this knowledge is often difficult in practice, especially if photon counting detectors are used to acquire the energy specific information. In this paper, a new algorithm for joint statistical iterative material image reconstruction is presented. It relies on a semi-empirical forward model which is tuned by calibration measurements. This strategy allows to model spatially varying properties of the imaging system without requiring detailed prior knowledge of the system parameters. We employ an efficient optimization algorithm based on separable surrogate functions to accelerate convergence and reduce the reconstruction time. Numerical as well as real experiments show that our new algorithm leads to reduced statistical bias and improved image quality compared with projection-based material decomposition followed by analytical or iterative image reconstruction.


S-equol enantioselectively activates cAMP-protein kinase A signaling and reduces alloxan-induced cell death in INS-1 pancreatic β-cells.
S-Equol is enantioselectively produced from the isoflavone daidzein by gut microflora and is absorbed by the body. An increase of pancreatic β-cell death is directly associated with defects in insulin secretion and an increased risk of type 2 diabetes mellitus. In the present study, we demonstrate that only the S-enantiomer has suppressive effects against alloxan-induced oxidative stress in INS-1 pancreatic β-cells. S-Equol reduced alloxan-induced cell death in a dose-dependent manner, whereas R-equol had no effects. In contrast, no significant differences were observed between the enantiomers in estrogenic activity. The cytoprotective effects of S-equol were stronger than those of its precursor daidzein and were blocked by the protein synthesis inhibitor cycloheximide. The cytoprotection was diminished when cells were incubated with a protein kinase A (PKA) inhibitor (H89), but not an estrogen receptor inhibitor. S-Equol increased intracellular cAMP levels in an enantioselective manner. S-Equol, but not R-equol, induced phosphorylation of cAMP-response element-binding protein at Ser 133, and induced cAMP-response element-mediated transcription, both of which were diminished in the presence of H89. Taken together, these results show that S-equol enantioselectively increases the survival of INS-1 cells presumably through activating PKA signaling. Thus, S-equol might have applications as an anti-type 2 diabetic agent.


[Regional comparison of patient-reported outcomes in Japanese cedar pollinosis].
There is little information about the relationship between local pollen counts and pollinosis symptoms of the local patients. In this study, we compared patient-reported outcomes (PROs) of Japanese cedar pollinosis (JCP) according to regions. The study was conducted between February 24 and March 8, 2003 (peak pollen season), and 1200 patients were recruited from 15 ENT clinical sites in 4 regions : central Osaka (n = 576), southern Osaka (n = 195), northern Wakayama (n = 234), and southern Wakayama (n = 195). PROs consisted of nasal symptoms, ocular symptom, learning and work impairment, and QOL (SF-36). In non-treatment group, there were significant differences in ocular symptom and learning and work impairment among regions. On the other hand, patients with longer duration of treatment had better symptom relief regardless of pollen level in early treatment group. As to QOL, SF-36 summary scores did not differ among regions in both groups. This study shows that patients without early treatment seemed to be affected by pollen level on their ocular symptom and its related outcomes. In patients with early treatment, however, the treatment duration had bigger impact on PROs than the local pollen counts.


Vascular Ehlers-Danlos syndrome without the characteristic facial features: a case report.
As a type of Ehlers-Danlos syndrome (EDS), vascular EDs (vEDS) is typified by a number of characteristic facial features (eg, large eyes, small chin, sunken cheeks, thin nose and lips, lobeless ears). However, vEDs does not typically display hypermobility of the large joints and skin hyperextensibility, which are features typical of the more common forms of EDS. Thus, colonic perforation or aneurysm rupture may be the first presentation of the disease. Because both complications are associated with a reduced life expectancy for individuals with this condition, an awareness of the clinical features of vEDS is important. Here, we describe the treatment of vEDS lacking the characteristic facial attributes in a 24-year-old healthy man who presented to the emergency room with abdominal pain. Enhanced computed tomography revealed diverticula and perforation in the sigmoid colon. The lesion of the sigmoid colon perforation was removed, and Hartmann procedure was performed. During the surgery, the control of bleeding was required because of vascular fragility. Subsequent molecular and genetic analysis was performed based on the suspected diagnosis of vEDS. These analyses revealed reduced type III collagen synthesis in cultured skin fibroblasts and identified a previously undocumented mutation in the gene for a1 type III collagen, confirming the diagnosis of vEDS. After eliciting a detailed medical profile, we learned his mother had a history of extensive bruising since childhood and idiopathic hematothorax. Both were prescribed oral celiprolol. One year after admission, the patient was free of recurrent perforation. This case illustrates an awareness of the clinical characteristics of vEDS and the family history is important because of the high mortality from this condition even in young people. Importantly, genetic assays could help in determining the surgical procedure and offer benefits to relatives since this condition is inherited in an autosomal dominant manner.


The Expanding Role of Ketogenic Diets in Adult Neurological Disorders.
The current review highlights the evidence supporting the use of ketogenic diet therapies in the management of adult epilepsy, adult malignant glioma and Alzheimer's disease. An overview of the scientific literature, both preclinical and clinical, in each area is presented and management strategies for addressing adverse effects and compliance are discussed.


Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms.
To document the natural history of von Recklinghausen neurofibromatosis, we followed up a nationwide cohort of 212 affected patients and families identified in Denmark 42 years ago. We obtained follow-up information on 99 percent. Because all 76 probands were identified through hospitals, they may include a disproportionate number of severe cases of neurofibromatosis. To diminish this effect of selection bias, we distinguished between the probands and their affected relatives. In a comparison with the general population, survival rates were significantly impaired in relatives with neurofibromatosis, worse in probands, and worst in female probands. Malignant neoplasms or benign central nervous system tumors occurred in 45 percent of the probands, giving a relative risk of 4.0 (95 percent confidence limits, 2.8 to 5.6) as compared with expected numbers. Multiple primary neoplasms were found in 15 probands, but only 1 relative. Compared with the general population, male relatives with neurofibromatosis had the same rate of neoplasms, whereas female relatives had a nearly twofold higher rate (relative risk, 1.9; 1.1 to 3.1). Nervous system tumors were disproportionately represented. We conclude that patients with severe neurofibromatosis requiring hospitalization often have a poor prognosis, but incidentally diagnosed relatives may have a considerably better outcome.


Clinical trial of weekly paclitaxel chemotherapy for papillary thyroid carcinoma with squamous cell carcinoma component.
Papillary thyroid carcinoma (PC) can occasionally include a squamous cell carcinoma (SCC) component. In this study, we evaluated the effect of weekly paclitaxel chemotherapy in 3 patients with PC including an SCC component. None of these patients had lesions of anaplastic carcinoma on pathological examination. Weekly paclitaxel chemotherapy was performed as an induction chemotherapy for 2 patients. All 3 patients underwent locally curative surgery and weekly paclitaxel chemotherapy after surgery as an adjuvant therapy. The response to the chemotherapy was evaluated based on the RECIST guideline (version 1.1). Two patients had partial responses (PRs) and the remaining 1 had stable disease (SD). The response rate was 67% and the clinical benefit rate (PR+SD) was 100%. One patient died of the growth of lung metastases that had been detected before surgery 22 months after the diagnosis. The remaining 2 are still alive, 14 and 22 months after the diagnosis, respectively. Taken together, weekly paclitaxel may be one of the effective adjuvant therapies for PC with an SCC component.


Effect of temperature and method of semen collection on the viability of turkey spermatozoa.
An experiment was conducted to determine the effect of semen collection temperature and semen collection method on the viability of turkey spermatozoa. When semen was collected into a dry tube maintained at 5 C, the fertilizing capacity of spermatozoa was lower (81%) than when semen was collected into dry tubes maintained at 15 (90%) and 25 C (93%) or a tube containing Beltsville Poultry Semen Extender ( BPSE ) maintained at 5 C (93%). When semen was collected into tubes containing BPSE , the fertilizing capacity of spermatozoa (92 to 96%) was not affected by collection temperature. Sperm motility and egg hatchability were not affected by semen collection temperature or semen collection method.


Conclusiveness of Cochrane Reviews in physiotherapy: a systematic search and analytical review.
Numerous Cochrane Reviews (CRs) in the field of physiotherapy have been published, but their conclusiveness has not been investigated. The purpose of this study was to provide an overview and describe the conclusiveness of evidence from CRs regarding physiotherapy. We conducted a systematic search using the Cochrane Database of Systematic Reviews in the Cochrane Library from 2008 through 2017 in the field of physiotherapy, the Physical Rehabilitation Evidence Database, and the CRs list on the Cochrane Rehabilitation website. Reviewers extracted the following data: year of publication, editorial group, number of articles meeting the criteria, number of patients enrolled, conclusiveness, and need for additional studies. Linear regression was used to determine whether the percentage of conclusive reviews was affected by the year of publication. Reviewers found 283 CRs in the field of physiotherapy, and only 16 (5.7%) of which were conclusive. The number of trials and participants enrolled in conclusive reviews were significantly higher than those in inconclusive reviews (P < 0.001). The percentage of conclusive reviews was significantly correlated with year of publication (P = 0.03). Almost all reviews recognized the need for additional studies. Most CRs in physiotherapy are inconclusive, and most emphasize the need for further research. The ability of a Cochrane Review to reach a conclusion is affected by the cumulative patient sample size and number of trials included in the analysis.


Dissolving microneedles for transdermal drug delivery: Advances and challenges.
Over the last number of years, a significant body of evidence has shown the benefit of using dissolving microneedles (DMNs) for transdermal drug delivery. These devices are prepared from a wide range of materials such as sugars and polymers. DMNs are mainly fabricated by micromolding, photopolymerization, drawing lithography and droplet-airborne blowing. In this review, we have focused on the advances made in the field in recent years using a representative set of studies. Although the list of studies is not exhaustive, they highlight the challenges encountered such as the need to increase mechanical strength as well as medication dose while ensuring fast release of the active ingredient. DMNs can be used to delivery low molecular drugs as well as peptides, proteins and other high molecular weight compounds.


Use of the metals data file (CRYSTMET) in XAFS analysis.
The X-ray absorption spectrometry (XAS) technique has been widely used to determine the local structure of materials that are poorly suited to study by ordinary diffraction methods, such as fine particles or amorphous matter. XAS is among the major applications at synchrotron radiation facilities and many existing beamlines perform the measurement of XAFS (X-ray absorption fine structure) spectra. XAFS spectra can also be measured with conventional X-ray sources. Measurement of XAFS spectra is relatively straightforward, but real difficulties arise in the analysis and interpretation of the data. Contrary to single-crystal diffraction techniques, the structure is not obtained directly from the measured XAFS data. Model structures must be assumed and the corresponding simulated XAFS spectra must be calculated, with determination of which models best fit the measured data. Model building is a most important part of XAFS analysis, but creation of three-dimensional structures from crystal-chemical considerations can be a very time-consuming task. Utilization of a database of crystal structures and of its built-in structure analysis and display tools can considerably reduce the time and effort required by this task. As XAS is often used to study metals, a database of alloys and intermetallic compounds, such as CRYSTMET, incorporating an array of powerful tools, is then very useful.


A PKG inhibitor increases Ca(2+)-regulated exocytosis in guinea pig antral mucous cells: cAMP accumulation via PDE2A inhibition.
In antral mucous cells, acetylcholine (ACh, 1 μM) activates Ca(2+)-regulated exocytosis, consisting of an initial peak that declines rapidly (initial transient phase) followed by a second slower decline (late phase) lasting during ACh stimulation. The addition of 8-bromo-cGMP (8-BrcGMP) enhanced the initial phase, which was inhibited by the protein kinase G (PKG) inhibitor guanosine 3',5'-cyclic monophosphorothoiate, β-phenyl-1,N(2)-etheno-8-bromo, Rp-isomer, sodium salt (Rp-8-BrPETcGMPS, 100 nM). However, Rp-8-BrPETcGMPS produced a delayed, but transient, increase in the exocytotic frequency during the late phase that was abolished by a protein kinase A (PKA) inhibitor (PKI-amide), suggesting that Rp-8-BrPETcGMPS accumulates cAMP. The cGMP-dependent phosphodiesterase 2 (PDE2), which degrades cAMP, may exist in antral mucous cells. The PDE2 inhibitor BAY-60-7550 (250 nM) mimicked the effect of Rp-8-BrPETcGMPS on ACh-stimulated exocytosis. Measurement of the cGMP and cAMP contents in antral mucosae revealed that ACh stimulates the accumulation of cGMP and that BAY-60-7550 accumulates cAMP similarly to Rp-8-BrPETcGMPS during ACh stimulation. Analyses of Western blot and immunohistochemistry demonstrated that PDE2A exists in antral mucous cells. In conclusion, Rp-8-BrPETcGMPS accumulates cAMP by inhibiting PDE2 in ACh-stimulated antral mucous cells, leading to the delayed, but transient, increase in the frequency of Ca(2+)-regulated exocytosis. PDE2 may prevent antral mucous cells from excessive mucin secretion caused by the cAMP accumulation.


[Combined Influence of Arisaematis Rhizoma Polysaccharide with Cisplatin on the Proliferation,Apoptosis and Epithelial Mesenchymal Transition of Breast Carcinoma MDA-MB-231 Cells].
To explore the combined influence of Arisaematis Rhizoma polysaccharide with cisplatin on the proliferation,apoptosis and epithelial mesenchymal transition of breast carcinoma MDA-MB-231 cells. MDA-MB-231 cells were divided into control group,Arisaematis Rhizoma polysaccharide group( 50 μg / m L),cisplatin group( 5 μg / m L) and combined group( Arisaematis Rhizoma polysaccharide + cisplatin); the cells proliferation were detected by MTT assay, the cells apoptosis were detected by Annexin V / PI flow cytometry, the mRNA expression levels of Vimentin, N-cadherinand E-cadherin were detected by Real time PCR, the levels of Fibronectin( FN) were detected by ELISA,and the levels of Akt and p-Akt were measured by western blotting. The proliferation of MDA-MB-231 cells were inhibited in Arisaematis Rhizoma polysaccharide group, cisplatin group and combined group with a time dependent manner. The early, late apoptosis rate and E-cadherin mRNA level in Arisaematis Rhizoma polysaccharide group, cisplatin group and combined group were higher,while Vimentin,N-cadherin mRNA,FN level and p-Akt / Akt were lower than those in control group( P < 0. 05). Compared with Arisaematis Rhizoma polysaccharide group and cisplatin group, there were higher in the early,late apoptosis rate and E-cadherin mRNA levels, lower the mRNA levels of Vimentin, N-cadherin, FN and p-Akt / Akt in combined group( P <0. 05). Both of Arisaematis Rhizoma polysaccharide and cisplatin can affect the proliferation, apoptosis and epithelial-mesenchymal transition, and inhibit activation of PI3 K / Akt signaling pathway and the combined effect is better.


Response to low-dose bortezomib in plasma cell leukemia patients with malignant pleural effusion and ascites: a case report and a review of the literature.
Pleural effusion or ascites complicating plasmacytoma is rare and has a poor prognosis. A 70-year-old man was diagnosed as plasma cell leukemia and one course of ranimustine-vindesine, melphalan, and prednisolone followed by melphalan and prednisone (MP) maintained a very good partial response. After MP he was diagnosed to have pleural effusion and ascites as a complication of the plasmacytoma. Low-dose bortezomib caused disappearance of the malignant effusion. The malignant effusions recurred after the end of the second course of bortezomib. High-dose dexamethasone vincristine, doxorubicin, cyclophosphamide, and prednisone yielded no benefit, the patient died of Aspergillus pneumonia.


Methadone replacement therapy: tried, tested, effective?
Methadone prescription is a controversial topic. While many believe that it is an effective treatment for opiate dependency, others argue that it is not successful in reducing either the addiction or even injecting behaviour. In this debate, Dr Robertson makes the case that methadone has been well tested, is cheap and acceptable to the patient and results in visible improvement. Dr Daniels argues that methadone treatment is philosophically ill-conceived, ethically dubious, and costly. He also highlights evidence that the treatment is potentially harmful to both patients and those in contact with them.


[Turning point in quality control in Japan--current status & problems and future issues].
Some authorities suggest that quality control in Japan is now at a turning point. During the 30 years since its introduction in the 1960s, quality control has improved dramatically, and a number of new quality control techniques have been designed and applied to routine examination. In actual practice, however, people tend to become insensitive to abnormalities or to ignore them, causing an increase in the number of abnormal results. This article will review a survey of quality control and describe the current status, problems and future issues in quality assurance.


Nephro-urological complications of epidermolysis bullosa in paediatric patients.
A small but important proportion of patients with epidermolysis bullosa (EB) may develop significant renal and urological complications which can have a major impact on their morbidity and mortality. During the last 10 years, five of a large group of children with EB under our care, with either dystrophic or junctional types of disease, experienced major nephro-urological complications. Two patients with recessive dystrophic EB (REDB) developed macroscopic haematuria - one had renal failure and underwent a renal biopsy showing IgA nephropathy. A third patient with RDEB also developed renal failure and his biopsy demonstrated postinfectious glomerulonephritis/type III membranoproliferative (mesangiocapillary) glomerulonephritis. Both patients with renal failure underwent peritoneal dialysis. Two patients with junctional EB developed obstructive uropathies, which required bladder reconstruction and the fashioning of a Mitrofanoff channel in one.


Preservation of fertility in reproductive-age women with the diagnosis of cancer.
Over the past few decades the number of young, reproductive age cancer survivors has increased as a result of improved and less destructive cancer treatments. Certain types of cancers are predominantly diagnosed among reproductive age women and a small proportion of cancers originating in the reproductive tract are also detected in this age group. Treatment in the past used to be definitive and in most cases led to sterility. In recent years, improved medical treatments and more conservative surgical approaches have been introduced increasing the number of young survivors of cancer treatment. These less invasive treatments seem to be associated with similar survival rates and fertility can be preserved in most cases. This has led to studies evaluating the reproductive options of these women. Conservative surgical techniques, the use of chemotherapeutic agents with a reduced gonadotoxic side-effect profile, and the application of more focused radiation therapy are associated with maintenance of fertility. In addition, assisted reproductive technology (ART) has undergone tremendous improvements and now offers several alternatives to those who wish to maintain fertility before or even after cancer therapy. This review summarizes the fertility sparing medical and surgical as well as ART options that reproductive age women desiring to maintain fertility may utilize if they face cancer therapy.