Dose dependence of glutaraldehyde-induced changes in the electrical properties of the amphibian skin.
The effects of the protein cross-linker glutaraldehyde (GA) on the transepithelial short-circuit current (Isc), conductance (Gt) and impedance of the isolated frog skin were investigated at GA concentrations between 0.1 and 10 mM, i.e. up to three orders of magnitude less than used in fixative procedures. Below 0.5 mM GA increases Isc, with large variations among preparata. Millimolar GA concentrations induce fairly reproducible irreversible inhibitions of Isc, which proceed for about 3 h. The rate of Isc decrease and the amplitudes of the initial drop and subsequent recovery depend on GA concentration in a sigmoidal dose-effect way, reaching saturation at 10 mM. At this GA concentration, Gt is increased up to 5 times the control value. Transepithelial impedance measurements confirm the decreases in epithelial resistance (Rm) and show significant increases in epithelial capacitance (Cm). Rm is diminished by 20% at 0.5 mM GA and by 75% at 10 mM GA, while Cm is maximally augmented by 55% at 2.5 mM GA. It is concluded that protein cross-linking by mild GA treatment is a convenient procedure for changing the electrical characteristics of epithelia.


Toxicity of copper intake: lipid profile, oxidative stress and susceptibility to renal dysfunction.
The present study was carried out to investigate the effects of copper (Cu) intake on lipid profile, oxidative stress and tissue damage in normal and in diabetic condition. Since diabetes mellitus is a situation of high-risk susceptibility to toxic compounds, we examined potential early markers of Cu excess in diabetic animals. Male Wistar rats, at 60-days-old were divided into six groups of eight rats each. The control(C) received saline from gastric tube, the no-diabetic(Cu-10), treated with 10 mg/kg of Cu(Cu(++)-CuSO4, gastric tube), no-diabetic with Cu-60 mg/kg(Cu-60), diabetic(D), diabetic low-Cu(DCu-10) and diabetic high-Cu(DCu-60). Diabetes was induced by an ip injection of streptozotocin (60 mg/kg). After 30 days of treatments, no changes were observed in serum lactate dehydrogenase, alanine transaminase and alkaline phosphatase, indicating no adverse effects on cardiac and hepatic tissues. D-rats had glucose intolerance and dyslipidemic profile. Cholesterol and LDL-cholesterol were higher in Cu-60 and DCu-60 than in C, Cu-10 and D and DCu-10 groups respectively. Cu-60 rats had higher lipid hydroperoxide (HP) and lower superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) serum activities than C and Cu-10 rats. LH was increased and GSH-Px was decreased, while no alterations were observed in SOD and catalase in serum of DCu-60 animals. DCu-60 rats had increased urinary glucose, creatinine and albumin. In conclusion, Cu intake at high concentration induced adverse effects on lipid profile, associated with oxidative stress and diminished activities of antioxidant enzymes. Diabetic animals were more susceptible to copper toxicity. High Cu intake induced dyslipidemic profile, oxidative stress and kidney dysfunction in diabetic condition. Copper renal toxicity was associated with oxidative stress and reduction at least, one of the antioxidant enzymes.


Stability, prognostic factors and survival of spinal bone metastases in malignant melanoma patients after palliative radiotherapy.
This retrospective analysis aimed to evaluate the stability of spinal metastases in malignant melanoma patients following radiotherapy (RT), and to assess prognostic factors for survival. Forty-one patients with malignant melanoma and osteolytic spinal bone metastases were irradiated at the university clinics of Heidelberg and Mainz between July 2003 and October 2013. Three and six months after palliative RT, only 20 and 15 patients, respectively, were still alive and were therefore assessed for spinal stability using the Taneichi score based on CT imaging. Additionally, overall survival (OS) and bone survival (BS) rates as well as prognostic factors for BS were evaluated for all study patients. Before RT, 19 patients (46.3%) were rated unstable. In the surviving patients, none of the unstable metastases were classified as stable 6 months after RT. Five-year OS was 23.3% and median BS was 4 months (range 0.5-29.8). Accordingly, only 36.6% of the patients were still alive 6 months after RT. Karnofsky performance score (KPS) <70%, visceral metastases and more than one bone metastasis were significantly predictive of poor BS. Our study population was characterized by poor BS and a lack of benefit with regard to stabilization of initially unstable spinal bone metastases 3 and 6 months after RT. This applies in particular to patients with a KPS <70%, visceral metastases and multiple bone metastases. Given the limited life expectancy, short fractionated treatment schedules of RT may be preferred in this population.


Varimax Rotation Based on Gradient Projection Is a Feasible Alternative to SPSS.
Gradient projection rotation (GPR) is an openly available and promising tool for factor and component rotation. We compare GPR toward the Varimax criterion in principal component analysis to the built-in Varimax procedure in SPSS. In a simulation study, we tested whether GPR-Varimax yielded multiple local solutions by creating population simple structure with a single optimum and with two optima, a global and a local one (double-optimum condition). The other conditions comprised the number of components (k = 3, 6, 9, and 12), the number of variables per component (m/k = 4, 6, and 8), the number of iterations per rotation (i = 25 and 250), and whether loadings were Kaiser normalized before rotation or not. GPR-Varimax was conducted with unrotated and multiple (q = 1, 10, 50, and 100) random start loadings. We found equal results for GPR-Varimax and SPSS-Varimax in most conditions. The few very small differences in favor of SPSS-Varimax were eliminated when Kaiser-normalized loadings and 250 iterations per rotation were used. Selecting the best solution out of multiple random starts in GPR-Varimax increased proximity to population components in the double-optimum condition with Kaiser normalized loadings, for which GPR-Varimax recovered population structure better than SPSS-Varimax. We also included an empirical example and found that GPR-Varimax and SPSS-Varimax yielded highly similar solutions for orthogonal simple structure in a real data set. We suggest that GPR-Varimax can be used as an alternative to Varimax rotation in SPSS. Users of GPR-Varimax should allow for at least 250 iterations, normalize loadings before rotation, and select the best solution from at least 10 random starts to ensure optimal results.


Robust regulatory architecture of pan-neuronal gene expression.
Pan-neuronally expressed genes, such as genes involved in the synaptic vesicle cycle or in neuropeptide maturation, are critical for proper function of all neurons, but the transcriptional control mechanisms that direct such genes to all neurons of a nervous system remain poorly understood. We show here that six members of the CUT family of homeobox genes control pan-neuronal identity specification in Caenorhabditis elegans. Single CUT mutants show barely any effects on pan-neuronal gene expression or global nervous system function, but such effects become apparent and progressively worsen upon removal of additional CUT family members, indicating a critical role of gene dosage. Overexpression of each individual CUT gene rescued the phenotype of compound mutants, corroborating that gene dosage, rather than the activity of specific members of the gene family, is critical for CUT gene family function. Genome-wide binding profiles, as well as mutation of CUT homeodomain binding sites by CRISPR/Cas9 genome engineering show that CUT genes directly control the expression of pan-neuronal features. Moreover, CUT genes act in conjunction with neuron-type-specific transcription factors to control pan-neuronal gene expression. Our study, therefore, provides a previously missing key insight into how neuronal gene expression programs are specified and reveals a highly buffered and robust mechanism that controls the most critical functional features of all neuronal cell types.


Superoxide anions in the paraventricular nucleus mediate cardiac sympathetic afferent reflex in insulin resistance rats.
Cardiac sympathetic afferent reflex (CSAR) participates in sympathetic over-excitation. Superoxide anions and angiotensin II (Ang II) mechanisms are associated with sympathetic outflow and CSAR in the paraventricular nucleus (PVN). This study was designed to investigate whether PVN superoxide anions mediate CSAR and Ang II-induced CSAR enhancement response in fructose-induced insulin resistance (IR) rats. CSAR was evaluated with the changes of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to the epicardial application of capsaicin (CAP) in anaesthetized rats. Compared with Control rats, IR rats showed that CSAR, PVN NAD(P)H oxidase activity, superoxide anions, malondialdehyde (MDA), Ang II and AT1 receptor levels were significantly increased, whereas PVN superoxide dismutase (SOD) and catalase (CAT) activities were decreased. In Control and IR rats, PVN microinjection of superoxide anions scavengers tempol, tiron and PEG-SOD (an analogue of endogenous superoxide dismutase) or inhibition of PVN NAD(P)H oxidase with apocynin caused significant reduction of CSAR, respectively, but DETC (a superoxide dismutase inhibitor) strengthened the CSAR. PVN pre-treatment with tempol abolished, whereas DETC potentiated, Ang II-induced CSAR enhancement response. Moreover, PVN pre-treatment with tempol or losartan prevented superoxide anions increase caused by Ang II in IR rats. PVN superoxide anions mediate CSAR and Ang II-induced CSAR response in IR rats. In IR state, increased NAD(P)H oxidase activity and decreased SOD and CAT activities in the PVN promote superoxide anions increase to involve in CSAR enhancement. Ang II may increase NAD(P)H oxidase activity via AT1 receptor to induce superoxide anion production.


Information processing of passive joint motion to spinal nervous system.
The purpose of this work was to investigate the information processing of passive joint motion of the rat hindlimb in the spinal nervous system in vivo. Action potentials using intracellular recordings and joint kinematics using video analysis were measured. The results show that the action potentials of the spinal nervous system-evoked passive joint motion were significantly changed. Therefore, physical therapy is one of the useful methods for the treatment of joint position and angular position sensitivity and spinal nervous system disorders.


PCED2.0--a computer program for the simulation of polycrystalline electron diffraction pattern.
A computer program for the simulation of polycrystalline electron diffraction patterns is described. PCED2.0, an upgraded version of the previous JECP/PCED, can be used as a teaching aid and research tool for phase identification, microstructure texture analysis, and phase fraction determination. In addition to kinematical theory for diffraction intensity calculation of polycrystalline samples, Blackman two-beam dynamical correction is included. March model is used for out-of-plane and in-plane texture simulation. A pseudo-Voigt function is used for the peak profile fitting of diffraction rings. User-friendly interface is improved in the handling of experimental diffraction data and the flexibility of indexing. Application of the program for the analysis of FePt thin films is given as an example.


Surfactant abnormality after endotoxin-induced lung injury in guinea-pigs.
Endotoxin (30 mg/kg) or saline was given endotracheally to guinea-pigs in order to investigate surfactant function in respiratory failure. Six hours later, bronchoalveolar lavage was performed. The lavage was analyzed for protein, phospholipids and surface activity, and fractioned into the phospholipid-rich sediment and the phospholipid-poor supernatant. The latter fraction was analyzed for surfactant inhibitor activity. After endotoxin, PaO2 and static lung-thorax compliance decreased. The lavage from endotoxin-treated animals revealed a 180% increase in protein, a 52 67% decrease in surfactant phospholipids, and increased minimum surface tension, as compared to the controls. After endotoxin, the supernatant contained a 58% higher activity of surfactant inhibitor, and the sediment had slower surface adsorption than after saline. We propose that abnormal surfactant function is important in the pathogenesis of respiratory failure in high-permeability pulmonary edema.


Dynamic culturing of smooth muscle cells in tubular poly(trimethylene carbonate) scaffolds for vascular tissue engineering.
Porous, tubular, flexible, and elastic poly(trimethylene carbonate) (PTMC) scaffolds (length 8 cm and inner diameter 3 mm) for vascular tissue engineering were prepared by means of a dip-coating and particulate leaching procedure. Using NaCl as porogen, scaffolds with an average pore size of 110 μm and a porosity of 85% were obtained. Before leaching the salt, the structures were made creep-resistant by means of crosslinking at 25 kGy gamma irradiation. To increase the efficiency of cell seeding, the scaffolds were provided with a microporous outer layer of 0.2 mm with an average pore size of 28 μm and a porosity of 65% (total wall thickness 1 mm). Human smooth muscle cells (SMCs) were seeded in these scaffolds with an efficiency of 43%, as determined after 24 h cell adhesion. SMCs were cultured in the scaffolds up to 14 days under stationary conditions or under pulsatile flow conditions in a bioreactor (pressure 70-130 mmHg, 69 pulsations/min, and average wall shear rate 320 s(-1)). Although SMCs proliferated under both conditions, cell numbers were three to five times higher in case of dynamic culturing. This was qualitatively confirmed by means of histology. Also, in terms of mechanical properties, the dynamically cultured constructs performed better than the statically cultured constructs. After culturing for 14 days, the maximum tensile strengths of the constructs, determined in the radial direction, had increased from 0.16 MPa (unseeded scaffold) to 0.48 MPa (dynamic culturing) and 0.38 MPa (static culturing). The results of this study indicate that a potentially useful medial layer for tissue-engineered vascular grafts can be prepared by dynamic culturing of human SMCs seeded in porous tubular poly(trimethylene carbonate) scaffolds.


Lessons learned from a 5-year experience with a 4-week experiential quality improvement curriculum in a preventive medicine fellowship.
Competency in practice-based learning and improvement (PBLI) and systems-based practice (SBP) empowers learners with the skills to plan, lead, and execute health care systems improvement efforts. Experiences from several graduate medical education programs describe the implementation of PBLI and SBP curricula as challenging because of lack of adequate curricular time and faculty resources, as well as a perception that PBLI and SBP are not relevant to future careers. A dedicated experiential rotation that requires fellow participation in a specialty-specific quality improvement project (QIP) may address some of these challenges. We describe a retrospective analysis of our 5-year experience with a dedicated 3-week PBLI-SBP experiential curriculum in a preventive medicine fellowship program at Mayo Clinic, Rochester, Minnesota. Between 2004 and 2008, 19 learners including 7 preventive medicine fellows participated in the rotation. Using just-in-time learning, fellows work together on a relatively complex QIP of community or institutional significance. Since 2004, all 19 learners (100%) participating in this rotation have consistently demonstrated statistically significant increase in their quality improvement knowledge application tool (QIKAT) scores at the end of the rotation. At the end of the rotation, all 19 learners stated that they were either confident or very confident of making a change to improve health care in a local setting. Most of the QIPs resulted in sustainable practice improvements, and resultant solutions have been disseminated beyond the location of the original QIP. A dedicated experiential rotation that requires learner participation in a QIP is one of the effective methods to address the needs of the SBP and PBLI competencies.


Tris(2-amino-pyridinium) hexa-chlorido-indate(III).
The Schiff base (E)-4-chloro-2-[(pyridin-2-yl-imino)-meth-yl]phenol was reacted with InCl(3)·4H(2)O, generating the title molecular salt, (C(5)H(7)N(2))(3)[InCl(6)]. The octa-hedral hexa-chlorido-indate(III) anion is located on an inversion centre, and one half of the anion and two crystallographically independent cations form the asymmetric unit. One of the cations is located on a twofold rotation axis and its intra-ring C and N atoms simulate this symmetry by exchanging their positions in statistical disorder. In the crystal, weak N-H⋯Cl hydrogen bonds and two types of π-π interactions with centroid-centroid separations of 4.047 (3) and 4.202 (3) Å are observed.


Dynamic tread wear measurement method for train wheels against vibrations.
Dynamic tread wear measurement is difficult but significant for railway transportation safety and efficiency. The accuracy of existing methods is inclined to be affected by environmental vibrations since they are highly dependent on the accurate calibration of the relative pose between vision sensors. In this paper, we present a method to obtain full wheel profiles based on automatic registration of vision sensor data instead of traditional global calibrations. We adopt two structured light vision sensors to recover the inner and outer profiles of each wheel, and register them by the iterative closest point algorithm. Computer simulations show that the proposed method is insensitive to noises and relative pose vibrations. Static experiments demonstrate that our method has high accuracy and great repeatability. Dynamic experiments show that the measurement accuracy of our method is about 0.18 mm, which is a twofold improvement over traditional methods.


68Ga-NODAGA-RGDyK PET/CT Imaging in Esophageal Cancer: First-in-Human Imaging.
Ga-NODAGA-RGDyK(cyclic) and FDG PET/CT were performed in a 39-year-old man for the work-up of a moderately differentiated carcinoma of the gastro-esophageal junction within a clinical study protocol. Although FDG PET images showed intense, diffuse hypermetabolic lesion activity, NODAGA-RGDyK illustrated the neo-angiogenesis process with tracer uptake clearly localized in non-FDG-avid perilesional structures. Neo-angiogenesis is characterized by ανβ3 integrin expression at the lesion surface of newly formed vessels. This case supports evidence that angiogenesis imaging might therefore be a crucial step in early disease identification and localization, metastatization potential, and in monitoring the efficacy of antiangiogenic therapies.


Role of amides, amino acids, and ureides in the nutrition of developing soybean seeds.
The various nitrogenous solutes important to embryo development in symbiotic soybean plants were determined during the midpodfilling stage. Glutamine was the principal form of nitrogen, contributing 55% of the embryo nitrogen requirement. Asparagine was the second most important, contributing 20%. The ureides allantoin and allantoic acid directly contributed only insignificantly to the total nitrogen requirement of the embryo. These conclusions were based upon analyses of tissue extracts, translocation studies of radiolabeled solutes, analysis of in vivo seed coat exudate collected from the freespace of attached, surgically altered seeds, and the in vitro culture of isolated immature soybean embryos.


Synthesis of proline-based diketopiperazine scaffolds.
A number of natural products with interesting biological properties are based on a diketopiperazine scaffold. In this context, we have developed a diversity oriented and efficient synthetic strategy to highly functionalized proline-based diketopiperazines. In this paper we describe the stereoselective synthesis of various scaffolds resembling abundant natural product core structures. These scaffolds can be conjugated to a solid phase and are thus platforms for the construction of small compound libraries and the synthesis of natural products with diketopiperazine cores.


De novo screening of disease-resistant genes from the chromosome-level genome of rare minnow using CRISPR-cas9 random mutation.
Mutants are important for the discovery of functional genes and creation of germplasm resources. Mutant acquisition depends on the efficiency of mutation technology and screening methods. CRISPR-Cas9 technology is an efficient gene editing technology mainly used for editing a few genes or target sites, which has not been applied for the construction of random mutant libraries and for the de novo discovery of functional genes. In this study, we first sequenced and assembled the chromosome-level genome of wild-type rare minnow (Gobiocypris rarus) as a susceptible model of hemorrhagic disease, obtained a 956.05 Mb genome sequence, assembled the sequence into 25 chromosomes, and annotated 26,861 protein-coding genes. Thereafter, CRISPR-Cas9 technology was applied to randomly mutate the whole genome of rare minnow with the conserved bases (TATAWAW and ATG) of the promoter and coding regions as the target sites. The survival rate of hemorrhagic disease in the rare minnow gradually increased from 0% (the entire wild-type population died after infection) to 38.24% (F3 generation). Finally, 7 susceptible genes were identified via genome comparative analysis and cell-level verification based on the rare minnow genome. The results provided the genomic resources for wild-type rare minnow, and confirmed that the random mutation system designed using CRISPR-Cas9 technology in this study is simple and efficient and is suitable for the de novo discovery of functional genes and creation of a germplasm resource related to qualitative traits.


Classification of bloodstream infections in patients recently discharged from acute-care facilities: Hospital acquired or healthcare-associated community onset?
Laboratory-identified bloodstream infections (LAB-ID BSIs) in recently discharged patients are likely to be classified as healthcare-associated community-onset (HCA-CO) infections, even though they may represent hospital-onset (HO) infections. A review of LAB-ID BSIs among patients discharged within 14 days revealed that 109 of 756 cases (14.4%) were HO infections. The BSI risk being misclassified as HCA CO may underestimate the hospital infection risk.


[A case of gastric antral vascular ectasia (GAVE) with chronic renal failure].
A 76-year-old woman was admitted to our hospital complaining of tarry stool, general fatigue and marked anemia(Hb 5.2 g/dl). Gastric endoscopic findings showed longitudinal red stripes and diffuse erythematous spots, indicating dilated vascular vessels. They resembled the stripes of a watermelon at the gastric antrum. The marked anemia was caused by chronic blood loss from the abnormally dilated mucosal and submucosal capillary veins in the gastric antrum. She was diagnosed as having gastric antral vascular ectasia(GAVE) with chronic renal failure(CRF). The association of GAVE and CRF is considered to be rare according to previous reports in Japan. Endoscopic argon plasma coagulation therapy was performed three times. After therapy, capillary dilatation disappeared, and the marked anemia was greatly improved. Argon plasma coagulation therapy was found to be a safe and effective procedure for this disease. Although GAVE is essentially a benign gastric disease, endoscopic therapy should be the treatment of first choice for this disease.


Optimization of aluminum treatment efficiency to control internal phosphorus loading in eutrophic lakes.
Historical accumulation of phosphorus (P) in lake sediment often contributes to and sustains eutrophic conditions in lakes, even when external sources of P are reduced. The most cost-effective and commonly used method to restore the balance between P and P-binding metals in the sediment is aluminum (Al) treatment. The binding efficiency of Al, however, has varied greatly among treatments conducted over the past five decades, resulting in substantial differences in the amount of P bound per unit Al. We analyzed sediment from seven previously Al treated Swedish lakes to investigate factors controlling binding efficiency. In contrast to earlier work, lake morphology was negatively correlated to binding efficiency, meaning that binding efficiency was higher in lakes with steeply sloping bathymetry than in lakes with more gradually sloping bottoms. This was likely due to Al generally being added directly into the sediment, and not to the water column. Higher binding efficiencies were detected when Al was applied directly into the sediment, whereas the lowest binding efficiency was detected where Al was instead added to the water column. Al dose, mobile sediment P and lake morphology together explained 87% of the variation in binding efficiency among lakes where Al was added directly into the sediment. This led to the development of a model able to predict the optimal Al dose to maximize binding efficiency based on mobile sediment P mass and lake morphology. The predictive model can be used to evaluate cost-effectiveness and potential outcomes when planning Al-treatment using direct sediment application to restore water quality in eutrophic lakes.


Disruption of the Golgi apparatus by brefeldin A inhibits the cytotoxicity of ricin, modeccin, and Pseudomonas toxin.
We have studied the cytotoxicity of ricin in cells treated with brefeldin A (BFA), which dramatically disrupts the structure of the Golgi apparatus causing Golgi content and membrane to redistribute to the ER. BFA inhibits the cytotoxicity of ricin in Chinese hamster ovary, normal rat kidney, and Vero cells and abolishes the enhancement of ricin cytotoxicity by NH4Cl, nigericin, swainsonine, and tunicamycin or by a mutation in endosomal acidification. BFA protects cells from the cytotoxicities of modeccin and Pseudomonas toxin, but has no effect on the intoxication by diphtheria toxin. Pretreatment of BFA does not protect cells from ricin treatment in the absence of BFA. Our results suggest that ricin, modeccin, and Pseudomonas toxin share a common pathway of intracellular transport from endosomes to the Golgi region where they are released into the cytosol. In contrast, the lack of protection of Vero cells from diphtheria toxin by BFA indicates that diphtheria toxin is released from acidified endosomes without involving the Golgi region.


Operative treatment of chronic distal biceps tendon ruptures.
Chronic biceps tendon ruptures typically involve tendon retraction, scarring, and even compromised tissue. Indirect repair, such as tenodesis to the brachialis, does not provide optimal functional recovery. Chronic biceps tendon ruptures can be reconstructed with autogenous grafts (semitendinosis, tensor fascia lata) or allografts (typically Achilles tendon). The complications associated with these grafts include harvest site morbidity and graft incorporation. Using a vascularized local soft tissue source could minimize complications of graft reconstructions. The authors provide a novel reconstructive technique, reconstruction using the lacertus fibrosis, as a local graft source for chronic distal biceps tendon ruptures.


Theoretical Study on Decomposition Mechanism of Insulating Epoxy Resin Cured by Anhydride.
High temperatures caused by partial discharge results in the decomposition of insulating epoxy resins in electrical equipment. In this paper, the ReaxFF force field is used to investigate the decomposition process of epoxy resins cured by anhydride and the formation mechanisms of small-molecule gases. Results show that the initiation reaction is the cleavage of an ester bond linked with an epoxy resin. Produced by the decomposition of ester groups, CO₂ is the first and most abundant product. Meanwhile, CH₂O can be generated through three main ways, although the process still depends on the decomposition of epoxy functional groups. H₂O is produced by free radical collision and dehydration. The production of small-molecule gases has the following sequence: CO₂, CH₂O, CO, and H₂O. The produced gases have the following order according to amount: CO₂, CH₂O, H₂O, and CO.


Review article: gastro-oesophageal reflux disease as a functional gastrointestinal disorder.
Gastro-oesophageal reflux disease encompasses a family of disorders united by a common pathogenesis: the excessive reflux of gastric contents. The best defined disorder is oesophagitis, but it is now evident that proton pump inhibitor therapy can resolve oesophagitis in virtually every case. The same cannot be said for gastro-oesophageal reflux disease symptoms, however, thus moving the frontier to symptom control. Endoscopy-negative reflux disease is a heterogeneous group, no longer bound by the common denominator of endoscopic findings. In fact, three distinct patient subgroups emerge: (i) individuals who in essence have oesophagitis, but are either in remission or simply fail to meet the endoscopic criteria; (ii) patients with hypersensitivity to oesophageal stimuli; and (iii) patients with 'functional heartburn' whose symptoms are not related to reflux. Given this heterogeneity, it is not surprising that the efficacy of antisecretory drugs is less impressive. This has led to new therapeutic approaches beyond acid control: mucosal protective agents, either central nervous system or peripherally acting compounds aimed at normalizing hyperalgesia, and reflux inhibitors and serotonergic agents, such as tegaserod.


Treatment of acute pulmonary embolism using rheolytic thrombectomy.
The AngioJet rheolytic thrombectomy (ART) system can quickly fragment and aspirate thrombi according to Bernoulli's principle. This retrospective study aimed to evaluate the therapeutic effects of the ART system in treating severe acute pulmonary embolism (APE), including high-risk pulmonary embolism (HR-PE) and intermediate-high-risk pulmonary embolism (IHR-PE). Forty-four APE patients (21 HR-PE and 23 IHR-PE) were enrolled and underwent pulmonary ART using the 6 Fr Solent Omni AngioJet device. Nineteen patients were diagnosed with APE and lower extremity deep venous thrombosis (LEDVT), and underwent thrombectomy of APE and LEDVT simultaneously using ART. All patients also received local thrombolysis with urokinase. The results showed that the mean length of stay in intensive care units was 2.4±1.9 days. Significant improvements in clinical, haemodynamic and angiographic parameters were observed in both groups; the improvements in shock index, PaO2, and angiographic parameters were more obvious in the IHR-PE group. Six of the 44 patients died in hospital. During the follow-up, 35 of 38 patients were functioning well and no recurrence of APE was observed. Pulmonary ART plus local thrombolysis of the pulmonary artery for HR-PE or IHR-PE is feasible and appears to be safe. Further studies are warranted to investigate comparative efficacy compared to existing treatments.


Classification of hypotheses on the advantage of amphimixis.
A classification of hypotheses on the advantage of amphimixis over apomixis is presented. According to "Immediate Benefit" hypotheses, amphimixis is advantageous regardless of reciprocal gene exchange, because either it directly increases fitness of the progeny, reduces the deleterious mutation rate, or makes selection more efficient. In contrast, "Variation and Selection" hypotheses attribute the advantage of amphimixis to the reciprocal gene exchange that alters genetic variability and response to selection among the progeny. Most such hypotheses assume that amphimixis increases variability and efficiency of selection, but some claim that amphimixis decreases response to selection. Variation and Selection hypotheses require that some factor, either random drift or epistatic selection, makes distributions of different alleles nonindependent, while another factor, either changes of the genotype fitnesses or deleterious mutations, makes overrepresented genotypes non-optimal. Numerous Variation and Selection hypotheses, dealing with either unstructured or spatially structured populations, are reviewed. Two of them seem most plausible: better responsiveness of the amphimictic population to widely fluctuating selection, and lower mutation load in the amphimictic population under synergistic selection against deleterious mutations. In both cases the large advantage of amphimixis requires rather stringent conditions, which could be falsified by careful experiment. Further progress in understanding the evolution of amphimixis will depend mostly on such experimental work.


Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs.
In the bone marrow, hematopoietic stem cells (HSCs) reside in specific niches near osteoblast-lineage cells at the endosteum. To investigate the regulation of these endosteal niches, we studied the mobilization of HSCs into the bloodstream in response to granulocyte colony-stimulating factor (G-CSF). We report that G-CSF mobilization rapidly depletes endosteal osteoblasts, leading to suppressed endosteal bone formation and decreased expression of factors required for HSC retention and self-renewal. Importantly, G-CSF administration also depleted a population of trophic endosteal macrophages (osteomacs) that support osteoblast function. Osteomac loss, osteoblast suppression, and HSC mobilization occurred concomitantly, suggesting that osteomac loss could disrupt endosteal niches. Indeed, in vivo depletion of macrophages, in either macrophage Fas-induced apoptosis (Mafia) transgenic mice or by administration of clodronate-loaded liposomes to wild-type mice, recapitulated the: (1) loss of endosteal osteoblasts and (2) marked reduction of HSC-trophic cytokines at the endosteum, with (3) HSC mobilization into the blood, as observed during G-CSF administration. Together, these results establish that bone marrow macrophages are pivotal to maintain the endosteal HSC niche and that the loss of such macrophages leads to the egress of HSCs into the blood.


68Ga-DOTATATE Radioisotope scan to detect neuroendocrine tumors; A Cross-Sectional Study.
Neuroendocrine tumors are a heterogeneous group of neoplasms that arise from the peptide-producing cells of the neuroendocrine system. Different functional imaging methods have been suggested to diagnose NETs. There is still not enough evidence to recommend 68Ga-DOTATATE as a standard diagnostic tool in NETs. Therefore, the aim of this study was to assess the value of 68Ga-DOTATATE scan in detecting NETs. This was a cross-sectional study. All patients with a pathologically confirmed NET tumor referred to Masih Daneshvari Hospital affiliated to Shahid Beheshti University of Medical Sciences entered the study. Patients underwent a 68Ga-DOTATATE PET/CT. All statistical analysis were performed by SPSS software version 18. Forty patients with a mean age of 48.1±15.80 years entered the study. Twenty-one (52.5%) were male and 19 (47.5%) female. In the studied patients, neuroendocrine tumor was present in 19 cases (47.5%) in pancreas and gastrointestinal tract, 9 (22.5%) in lung, 3 (7.5%) in mediastinum and adrenal gland, 6 cases (5%) in liver and 3 other sites. There was no significant association between mean age and gender with primary location of the tumor. The mean SUVmax was 11.62±20.02 and the the mean tumor size was 38.25±31.35 mm. The mean size of the metastasis was 40.55±24.53 mm. The mean percentage of ki-67 was 12.54±18.40. There was no significant correlation between SUVmax of the lesion and age (r=0.063, P=0.701), tumor size (r=-0.63, P=0.067) or Ki-67 (r=0.011, P=0.960). In 20 cases, metastases were reported, of which 14 were (70%) in the liver, 3 in the lungs (15%), 2 in the gastrointestinal and cervical lymph nodes, and 1 in the bones and pancreas(%5). 68Ga-DOTA-peptide PET/CT could find the primary or metastasis sites of NETs with good quality images. In general, this modality can enhance the management in patients with NETs.


Examination of two small-molecule antiperoxidative agents in a rabbit model of postischemic myocardial infarction.
Peroxidation of membrane phospholipid may be a causal contributor to the development of irreversible postischemic myocardial injury. In this study, two small-molecule antiperoxidative agents were tested for their ability to salvage reperfused rabbit myocardium and reduce infarct size as assessed by direct histological evaluation of hearts following a 30-min occlusion of a coronary arterial branch and a 72-h reperfusion period. The compounds tested are novel analogs of alpha-tocopherol (vitamin E), and share with the parent compound an ability to scavenge the peroxyl radicals that propagate and amplify lipid peroxidation initiated by partially reduced oxygen; however, the new analogs are significantly more potent peroxyl-radical scavengers that alpha-tocopherol. Each antiperoxidant (3 mg/kg) was administered by intravenous bolus injection in two stages: 20% of the total dose was given 15 min before occlusion, and the remaining 80% was given 5 min before reperfusion. The results revealed that neither antiperoxidant offered a sustained reduction in infarct size (expressed as a percentage of the region at risk) as compared to a nontreated vehicle control. The implications of the present study with respect to the purported cardioprotective effects of antiperoxidants in the setting of ischemia reperfusion and the pathogenic role of lipid peroxidation in the postischemic heart are discussed.


[Protein databank for several tissues derived from five instar of silkworm].
We attempted to construct protein databank of silkworm (Bombyx mori L.) for clarifying the gene expression and post-translational modification. Proteins from silkworm body wall, fat body and middle intestines were separated by two-dimensional electrophoresis. The N-terminal amino acid sequences of 40 proteins and their homology to proteins from other organisms were determined. 58.5% proteins were high homologous to the already reported proteins in D. melanogaster and 36.5% to those in other organisms. Only 5% of the proteins were homologous to the known protein in silkworm. The N-terminal sequences of 27 proteins were first found in silkworm, and all these data were registered in SWISS-PROT through the Internet. The results suggested that the information of gene expression and post-translational modification could be obtained by the information of protein databank.


216 cases of pancreaticoduodenectomy: risk factors for postoperative complications.
Surgical resection remains the best treatment for patients with periampullary tumors. Many series have been reported with low or zero mortality, however, high incidence of complications is the rule. This study aims to present the results of pancreaticoduodenectomy and factors predisposing to postoperative complications, especially pancreatic leak, at our center. Between January 2000 and December 2006, 216 periampullary tumors were treated by Whipple pancreaticoduodenectomy. Pancreaticogastrostomy was done in 183 patients and pancreaticojejunostomy in 33 patients. Hospital mortality and surgical complications were recorded with special emphasis on pancreatic leak. All specimens were histologically examined for the presence and origin of malignant tissue. The mean age was 58 years and male to female ratio was 2:1. The commonest symptom was jaundice (97.7%) followed by abdominal pain (74%). Operative mortality in 7 patients (3.2%). 71 (33%) patients developed 1 or more complications, pancreatic leak occurred in 23 (10.6%) patients, abdominal collection in 23 patients (10.6%) and delayed gastric emptying in 19 (8.8%) patients. Factors that influenced the development of postoperative complications included type of pancreaticoenteric anastomosis, pancreatic texture and intraoperative blood transfusion of 4 or more blood units. Pancreatic leak was commoner with PJ (p=0.001), soft pancreatic texture (p=0.008), intraoperative blood transfusion of 4 or more units (p<0.0001). Periampullary adenocarcinoma was found in 204 (94.4%) patients, chronic pancreatitis in 9 (4.2%) patients, 2 patients with solid and papillary neoplasm, and 1 patient with NHL (Non-Hodgkin's Lymphoma). Surgery is the only hope for patients with periampullary tumors. Postoperative complications after pancreaticoduodenectomy depend largely on surgical technique and can be reduced reasonably with the adoption of pancreaticogastrostomy, which is safer and easier to learn than pancreaticojejunostomy.


The emerging role of hepatitis B virus pre-S2 deletion mutant proteins in HBV tumorigenesis.
Chronic hepatitis B virus (HBV) infection can cause hepatocellular carcinoma (HCC). Several hypotheses have been proposed to explain the mechanisms of HBV tumorigenesis, including inflammation and liver regeneration associated with cytotoxic immune injuries and transcriptional activators of mutant HBV gene products. The mutant viral oncoprotein-driven tumorigenesis is prevailed at the advanced stage or anti-HBe-positive phase of chronic HBV infection. Besides HBx, the pre-S2 (deletion) mutant protein represents a newly recognized oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGH). The retention of pre-S2 mutant protein in ER can induce ER stress and initiate an ER stress-dependent VEGF/Akt/mTOR and NFκB/COX-2 signal pathway. Additionally, the pre-S2 mutant large surface protein can induce an ER stress-independent pathway to transactivate JAB-1/p27/RB/cyclin A,D pathway, leading to growth advantage of type II GGH. The pre-S2 mutant protein-induced ER stress can also cause DNA damage, centrosome overduplication, and genomic instability. In 5-10% of type II GGHs, there is co-expression of pre-S2 mutant protein and HBx antigen which exhibited enhanced oncogenic effects in transgenic mice. The mTOR signal cascade is consistently activated throughout the course of pre-S2 mutant transgenic livers and in human HCC tissues, leading to metabolic disorders and HCC tumorigenesis. Clinically, the presence of pre-S2 deletion mutants in sera frequently develop resistance to nucleoside analogues anti-virals and predict HCC development. The pre-S2 deletion mutants and type II GGHs therefore represent novel biomarkers of HBV-related HCCs. A versatile DNA array chip has been developed to detect pre-S2 mutants in serum. Overall, the presence of pre-S2 mutants in serum has implications for anti-viral treatment and can predict HCC development. Targeting at pre-S2 mutant protein-induced, ER stress-dependent, mTOR signal cascade and metabolic disorders may offer potential strategy for chemoprevention or therapy in high risk chronic HBV carriers.


[Structural mechanism of immune evasion of HIV-1 gp120 by genomic, computational, and experimental science].
The third variable region (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope gp120 subunit participates in determination of viral infection co-receptor tropism and host humoral immune responses. Positive charge of the V3 plays a key role in determining viral co-receptor tropism. In our previous papers, we showed a key role of the V3's net positive charge in the immunological escape and co-receptor tropism evolution in vivo. On the other hand, the several papers suggested that trimeric gp120s are protected from immune system by occlusion on the oligomer, by mutational variation, by carbohydrate masking and by conformational masking. If we can reveal the mechanism of neutralization escape, we expect that we will regulate the neutralization of HIV-1. In this review, we will overview the structural mechanism of neutralization escape of HIV-1 gp120 examined by computational science. The computational sciences for virology can provide more valuable information in combination with genomic and experimental science.


Incidence and risk factors associated with a second squamous cell carcinoma or basal cell carcinoma in psoralen + ultraviolet a light-treated psoriasis patients.
Psoralen + ultraviolet A-treated psoriasis patients are at increased risk for squamous cell carcinomas and basal cell carcinomas; however, the incidence and risk factors associated with second squamous cell carcinomas and basal cell carcinomas in this population are not well qualified. Incidence and risk factors for second squamous cell carcinomas and basal cell carcinomas were studied in a cohort of 1380 psoralen + ultraviolet A-treated psoriasis patients prospectively followed for over 20 y; 264 had a squamous cell carcinoma and 258 a basal cell carcinoma after beginning psoralen + ultraviolet A therapy. After a first squamous cell carcinoma, the risk of a second squamous cell carcinoma was 26% at 1 y, 62% at 5 y, and 75% at 10 y. Risk increased with high psoralen + ultraviolet A exposure prior to the first squamous cell carcinoma (hazard ratio 3.32, 95% confidence interval 1.53, 7.18). Higher rates of post-first squamous cell carcinoma psoralen + ultraviolet A treatment also were associated with greater risk (hazard ratio 1.56 for every additional 10 treatments per year for patients with low pre-first squamous cell carcinoma psoralen + ultraviolet A exposure, 95% confidence interval 1.35, 1.81). Patients exposed to high levels of tar and/or ultraviolet B before a first squamous cell carcinoma were also at higher risk (hazard ratio 1.72, 95% confidence interval 1.14-2.60). Risk of a second basal cell carcinoma was 21% at 1 y, 49% at 5 y, and 61% at 10 y. There was some evidence that high exposure to psoralen + ultraviolet A before a first basal cell carcinoma was associated with increased risk of second basal cell carcinoma (hazard ratio 1.45, 95% confidence interval 0.97-2.17). Higher post-first tumor psoralen + ultraviolet A treatment rates also increased risk (hazard ratio 1.24 for every additional 10 treatments per year, 95% confidence interval 1.06-1.47). Psoralen + ultraviolet A-treated psoriasis patients appear to have a greatly increased incidence of second squamous cell carcinoma compared with the general population. Patients who develop a squamous cell carcinoma after starting psoralen + ultraviolet A therapy should be closely monitored for a subsequent squamous cell carcinoma.


Prognostic relevance of micro-vessel density in cancer of the urinary bladder.
Angiogenesis is an important factor in tumour growth and metastasis. Degree of angiogenesis (microvascular density-MVD) has been found to correlate with tumour progression and disease outcome in a number of different malignancies. We studied 88 patients undergoing cystectomy for transitional cell bladder cancer to determine if angiogenesis was associated with cancer specific survival. Microvessels were identified by immunostaining of endothelial cells for CD31. Active areas of angiogenesis ("hot spots") were selected using low magnification. The vessel count was performed using a Chalkley point graticule. The mean of 3 counts was used for statistical analysis. The median count was 3.4. Univariate analysis revealed that higher MVD was associated with worsening prognosis (p = 0.02). When adjusted for clinical stage MVD continued to predict worsening prognosis (p = 0.02). MVD was not affected by age or sex or by previous radiotherapy. MVD was associated with the risk of patients dying following pelvic recurrence (p = 0.03) and MVD was significantly higher in patients with lymph node metastasis at surgery. In conclusion, microvessel density proved to be an independent prognostic marker in transitional cell carcinoma of bladder.


13C-NMR relaxation in glycogen.
This study is the first report on the multiexponential T2 relaxation of the 13C-1 carbon of glycogen. In contrast to T1 relaxation, which does not display observable multiexponential decay behavior, T2 relaxation is described by a continuous distribution of T2 times. Changes in molecular weight and sample viscosity, which affect the overall mobility of the glycogen particle have little influence on T1 and T2 relaxation times. This is in contradiction with earlier results that T2 is dominated by the overall motion of the glycogen particles [L.-H. Zang Biochemistry 29, 6815-6820 (1990)]. T1 depends strongly on the external field Bo and is almost temperature independent in the range 23-37 degrees C whereas T2 is field independent and varies appreciably with temperature. The experimental T1 and T2 relaxation data are shown to be consistent with existing theoretical models for relaxation, suitably modified to include a distribution of correlation times for the internal motions. The presence of fast decaying components (short T2) in the FID implies broad line components in the frequency spectrum and the corresponding need to appropriately set the integration limits for the quantification of the glycogen peak.


The aim of this study was to examine association between IFNL4 gene ss469415590 and treatment efficiency in group of Ukrainian PEG-interferon/ribavirin-treated chronic hepatitis C patients. Study group consisted of 92 unrelated hepatitis C virus genotype 1 mono-infected patients: case group - 29 patients with late or absent virological response; control group - 63 patients with sustained virological response. Study material was genomic DNA. Genotyping was performed using amplification-refractory mutation system PCR. Statistical analysis was performed using GenePop and OpenEpi statistical packages. Obtained results show that ss469415590 ΔG/ΔG genotype is associated with poor virological response (OR = 3.62; CI 95%: 1.12-11.67) in PEG-interferon/ribavirin-treated chronic hepatitis C patients from Ukraine.


Maternal mortality. A global perspective.
Despite difficulty in collecting data and prevailing underreporting and misclassification, data collection by the World Health Organization shows that more than half a million maternal deaths occur globally every year; 99% occur in developing countries and 1% occur in industrialized ones. The maternal mortality rate is highest in sub-Saharan African countries, followed by South Asian countries. Compelling evidence suggests that a reduction in maternal mortality on a short-term basis is possible only by providing modern obstetric care to the 15% of pregnancies that develop complications and making such care available in time. For long-term reduction and prevention of maternal death, preventive measures should be started before conception and should be continued during pregnancy and the postpartum period.


The role of unstructured highly charged regions on the stability and specificity of dimerization of two-stranded alpha-helical coiled-coils: analysis of the neck-hinge region of the kinesin-like motor protein Kif3A.
We investigated the folding, stability, and specificity of dimerization of the neck-hinge region (residues 356-416) of the kinesin-like protein Kif3A. We showed that the predicted coiled-coil on its own (residues 356-377) will fold autonomously in solution. We then explored the ability of oppositely charged regions to specify heterodimer formation in coiled-coils by synthesizing analogs of the neck coiled-coil region with and without various negatively and positively charged extensions to the C-terminus of the neck coiled-coil and characterizing these analogs by circular dichroism spectroscopy. The charged region alone (residues 378-416) adopted a random-coil structure and this region remained unfolded in the presence of the coiled-coil. Redox experiments demonstrated that oppositely charged regions specified the formation of a hetero-two-stranded coiled-coil. Denaturation studies with urea demonstrated a decrease in coiled-coil stability with the addition of negatively charged residues in the homostranded coiled-coil; conversely, the addition of the positively charged region (residues 403-416) of Kif3A C-terminally to the neck coiled-coil did not affect coiled-coil stability. Overall, our results suggest that electrostatic attractions drive the specificity of heterodimerization of the coiled-coil, not the removal of positive or negative charge-charge repulsions, while maintaining the stability of the heterodimer compared to that of the stablest homodimer.


Longitudinal changes in cognitive function and regional cerebral function in Alzheimer's disease: a SPECT blood flow study.
In Alzheimer's disease (AD), SPECT imagining of regional cerebral blood flow (rCBF) has emphasized deficits in the posterior association cortex. Previous studies have shown an association between these deficits and cognitive performance, both on overall cognitive tests and more specific tests such as praxis and language. Frontal deficits have been reported in more severe patients. This has led to the conclusion that the deficit in AD, at least with functional neuroimaging, starts in the posterior association cortex, and later in the disease process "spreads" to involve the frontal cortex. This study set out to measure, in a group of AD patients, the change over time of cognitive performance and the pattern of functional deficit measured by neuroimaging. Change in function was measured using 99TCm-HMPAO and SPECT and change in cognitive function using the CAMCOG. Two time points were used, 0 and 2 years. Twenty-four patients satisfying the DSM-III R criteria for probable AD were studied, nine of whom were subsequently diagnosed as having AD at post-mortem. The most striking finding was the effect that decreases in frontal lobe function had on cognitive function. A similar study by the same group, using the same techniques and many of the same patients but at only one time point, showed a correlation between cognitive function and rCBF in the parietal and posterior temporal lobes. This suggests that as AD patients deteriorate from unaffected to mild or moderately affected, the posterior association cortex exerts the greatest effect on cognitive deficit. In this longitudinal study, we found, using a MANOVA, that there were significant decreases over time for all the cortical regions studied, but that no region decreased significantly more than any other. In addition we found a correlation between change in frontal rCBF and change in cognitive function (both overall cognitive function and the CAMCOG sub tests of language and praxis). These data suggest, in contrast to the previous study, that as the disease progresses from mild or moderate to moderate or severe, the frontal cortex exerts the greatest effect on cognitive decline. These data support the concept of the deficit in functional imaging spreading from posterior to anterior as the disease progresses. However, both the initial pattern of deficit and the change over time were very heterogeneous when examined qualitatively. A posterior to anterior spread is the predominant pattern for the group as a whole, but individual patients, and possibly groups of patients, may well show alternative patterns.


Sequential administration of the native TERT572 cryptic peptide enhances the immune response initiated by its optimized variant TERT(572Y) in cancer patients.
The aim of this study was to investigate the best administration of telomerase reverse transcriptase (TERT572), an human leukocyte antigen-A*0201-restricted cryptic epitope of telomerase, and its optimized variant TERT(572Y) to elicit specific T cell immune responses in cancer patients. Forty-eight cancer patients with chemo-resistant tumors received 2 subcutaneous injections of TERT(572Y) at 2 mg followed at random by 4 subcutaneous injections of either TERT572 or TERT(572Y) peptides at 2 mg every 3 weeks. Specific immune response was evaluated by interferon-γ enzyme-linked immunosorbent spot. T cell responses after the sixth vaccination were detected more frequently (44% vs. 17%), and with higher number of peptide-specific reactive T cells (60 T cells/2 × 10(5) peripheral blood mononuclear cell vs. 10 T cells/2 × 10(5) peripheral blood mononuclear cell, P=0.04), and higher avidity in the patients who received 4 more vaccinations with the TERT572 peptide compared with patients who received only TERT(572Y) vaccinations. These results demonstrate that the best vaccination schedule involves first the administration of the optimized TERT(572Y) followed by the native TERT572 peptides in patients who are candidates for cancer immunotherapy.


MicroRNA-195-5p inhibits the progression of hemangioma via targeting SKI.
Hemangioma (HA), which is characterized by aberrant endothelial cell proliferation in blood vessels, is a common tumor during infancy. MicroRNAs (miRNAs/miRs) collectively participate in the development of HA; however, the potential roles of miR-195-5p in HA are not completely understood. The aim of the present study was to investigate the roles of miR-195-5p in HA. In the present study, miR-195-5p was found to be downregulated in HA cells, such as the XPTS-1 human infantile hemangioma-derived endothelial cell line and the EOMA hemangioendothelioma cell line. Overexpression of miR-195-5p was shown to suppress HA cell viability, colony formation and proliferation, and induced HA cell apoptosis. Furthermore, miR-195-5p downregulated Bcl-2 expression and upregulated Bax and Bcl-2 expression levels. V-ski sarcoma viral oncogene homolog (SKI) was identified as a target of miR-195-5p. Co-transfection of miR-195-5p mimics and SKI 3'-untranslated region wild-type decreased HA cell luciferase activity. SKI overexpression alleviated the miR-195-5p-induced decrease in HA cell proliferation and increased HA cell apoptosis. In addition, the regulatory role of miR-195-5p on the expression of Bcl-2, Bax and poly(ADP-ribose) polymerase was reversed by SKI. Collectively, the results of the present study demonstrated that miR-195-5p suppressed HA progression and its effects were mediated via SKI. Therefore, the miR-195-5p/SKI axis may represent a novel therapeutic target for HA.


DNA origami nanopores.
We demonstrate the assembly of functional hybrid nanopores for single molecule sensing by inserting DNA origami structures into solid-state nanopores. In our experiments, single artificial nanopores based on DNA origami are repeatedly inserted in and ejected from solid-state nanopores with diameters around 15 nm. We show that these hybrid nanopores can be employed for the detection of λ-DNA molecules. Our approach paves the way for future development of adaptable single-molecule nanopore sensors based on the combination of solid-state nanopores and DNA self-assembly.


A direct observation method for auditing large urban centers using stratified sampling, mobile GIS technology and virtual environments.
With the expansion and growth of research on neighbourhood characteristics, there is an increased need for direct observational field audits. Herein, we introduce a novel direct observational audit method and systematic social observation instrument (SSOI) for efficiently assessing neighbourhood aesthetics over large urban areas. Our audit method uses spatial random sampling stratified by residential zoning and incorporates both mobile geographic information systems technology and virtual environments. The reliability of our method was tested in two ways: first, in 15 Ottawa neighbourhoods, we compared results at audited locations over two subsequent years, and second; we audited every residential block (167 blocks) in one neighbourhood and compared the distribution of SSOI aesthetics index scores with results from the randomly audited locations. Finally, we present interrater reliability and consistency results on all observed items. The observed neighbourhood average aesthetics index score estimated from four or five stratified random audit locations is sufficient to characterize the average neighbourhood aesthetics. The SSOI was internally consistent and demonstrated good to excellent interrater reliability. At the neighbourhood level, aesthetics is positively related to SES and physical activity and negatively correlated with BMI. The proposed approach to direct neighbourhood auditing performs sufficiently and has the advantage of financial and temporal efficiency when auditing a large city.


Physiological models are good tools to predict rat bioavailability of EF5154 prodrugs from in vitro intestinal parameters.
There are only a few reports on the methods that predict in vivo bioavailability from in vitro intestinal parameters. In the present study, we constructed physiological models where we examined if in vivo rat bioavailability was predictable from in vitro intestinal parameters using prodrugs of EF5154, a potent glycoprotein IIb/IIIa receptor antagonist, and other prodrugs. Apparent fraction absorbed (F(a),pred) was calculated using the physiological models that consist of absorption number calculated from Caco-2 cell membrane permeability (P(app)), and Damkohler number calculated from apparent degradation rate constant (K(dapp)) in rat small intestinal fluid. The predicted rat bioavailability that was calculated from F(a),pred corresponded to the observed rat bioavailability, and root mean square error (RMSE) and squared correlation coefficient (r(2)) were 4.58 and 0.904, respectively, suggesting that the physiological models consisting of the membrane permeability and degradation rate constant are good tools for predicting rat bioavailability of EF5154 prodrugs. As for other prodrugs where the chemical structure of their active forms differs from EF5154, the predicted rat bioavailability was not different from fraction absorbed (or rat bioavailability), suggesting the physiological models are generalized to various prodrugs that are not the substrates for active transporters.


[Bacterial culture and drug sensitivity analysis of upper urinary tract calculi complicating with infection].
To investigate the bacteriology and drug sensitivity of upper urinary tract calculi patients, and to provide information for choosing suitable antibiotics. In the study, 21 patients who suffered from lithiasis in upper urinary tract and required an emergency drainage for acute obstruction and infection were the "acute group"; 64 patients with calculi in upper urinary tract and accompanied with no infectious symptoms were the "common group". The bacteriology and drug sensitivity of the two groups were investigated. Gram-negative bacteria infected the most common of upper urinary tract calculi patients with infection, accounting for 71.4% in the acute group and 65.7% in the common group, among which Escherichia coli were the predominant ones (35.7% in the acute group and 32.9% in the common group). No difference was found between these two groups in bacterial distribution (P>0.05). Although the average drug resistance rate of Gram-negative bacteria in the acute group was higher than that in the common group, it revealed no significant difference (P>0.05). The drug resistance rate to semisynthetic penicillin, cefuroxime and ceftriaxone were more than 50%, 60%, and 50%, respectively. Quinolones, such as ciprofloxacin and levofloxacin, got a 45% drug resistance. Aminoglycoside, carbapenema were sensitive to Gram-negative bacteria. Cefoperazone/sulbactam and piperacillin/tazobactam were more effective than ceftriaxone and piperacillin, respectively. There was no significant difference between upper urinary tract calculi patients with acute infection and common infection in bacteriology and drug sensitivity. Semisynthetic penicillin, the second generation of cephalosporin and quinolone were no longer the good choices of empirical use. Antibiotics combined with β-lactamase inhibitors would be an ideal empirical therapeutic choice.


The human footprint in the west: a large-scale analysis of anthropogenic impacts.
Anthropogenic features such as urbanization, roads, and power lines, are increasing in western United States landscapes in response to rapidly growing human populations. However, their spatial effects have not been evaluated. Our goal was to model the human footprint across the western United States. We first delineated the actual area occupied by anthropogenic features, the physical effect area. Next, we developed the human footprint model based on the ecological effect area, the zone influenced by features beyond their physical presence, by combining seven input models: three models quantified top-down anthropogenic influences of synanthropic predators (avian predators, domestic dog and cat presence risk), and four models quantified bottom-up anthropogenic influences on habitat (invasion of exotic plants, human-caused fires, energy extraction, and anthropogenic wildland fragmentation). Using independent bird population data, we found bird abundance of four synanthropic species to correlate positively with human footprint intensity and negatively for three of the six species influenced by habitat fragmentation. We then evaluated the extent of the human footprint in relation to terrestrial (ecoregions) and aquatic systems (major rivers and lakes), regional management and conservation status, physical environment, and temporal changes in human actions. The physical effect area of anthropogenic features covered 13% of the western United States with agricultural land (9.8%) being most dominant. High-intensity human footprint areas (class 8-10) overlapped highly productive low-elevation private landholdings and covered 7% of the western United States compared to 48% for low-intensity areas (class 1-3), which were confined to low-productivity high-elevation federal landholdings. Areas within 1 km of rivers were more affected by the human footprint compared to lakes. Percentage human population growth was higher in low-intensity human footprint areas. The disproportional regional effects of the human footprint on landscapes in the western United States create a challenge to management of ecosystems and wildlife populations. Using footprint models, managers can plan land use actions, develop restoration scenarios, and identify areas of high conservation value at local landscapes within a regional context. Moreover, human footprint models serve as a tool to stratify landscapes for studies investigating floral and faunal response to human disturbance intensity gradients.


Detection of potential cytokine gene(s) in an Alu-PCR library from the human chromosome 4.
Jumping and linking libraries have been constructed in order to have more information of chromosome 4. Two types of jumping libraries (Not I and Xma III jumping) and one linking library were prepared. The jumping clones represent DNA regions between two rare-cutting enzymes sites (such is Not I or Xma III) whereas linking clones represent only the area which surrounds the rare-cutting site. These clones were used as target DNA in Alu-PCR. The Alu-PCR fragments were cloned into pGEM-T vector and transformed into Escherichia coli JM 109 competent cells. The colonies were screened for inserts by restriction analysis. More than 50% of the colonies were shown to contain inserts. Inserts from each library were screened by PCR. One of the jumping libraries appeared to have inserts containing CpG islands and AT-rich sequences.


The novel coronary artery disease risk gene JCAD/KIAA1462 promotes endothelial dysfunction and atherosclerosis.
Recent genome-wide association studies (GWAS) have identified that the JCAD locus is associated with risk of coronary artery disease (CAD) and myocardial infarction (MI). However, the mechanisms whereby candidate gene JCAD confers disease risk remain unclear. We addressed whether and how JCAD affects the development of atherosclerosis, the common cause of CAD. By mining data in the Genotype-Tissue Expression (GTEx) database, we found that CAD-associated risk variants at the JCAD locus are linked to increased JCAD gene expression in human arteries, implicating JCAD as a candidate causal CAD gene. We therefore generated global and endothelial cell (EC) specific-JCAD knockout mice, and observed that JCAD deficiency attenuated high fat diet-induced atherosclerosis in ApoE-deficient mice. JCAD-deficiency in mice also improved endothelium-dependent relaxation. Genome-wide transcriptional profiling of JCAD-depleted human coronary artery ECs showed that JCAD depletion inhibited the activation of YAP/TAZ pathway, and the expression of downstream pro-atherogenic genes, including CTGF and Cyr61. As a result, JCAD-deficient ECs attracted fewer monocytes in response to lipopolysaccharide (LPS) stimulation. Moreover, JCAD expression in ECs was decreased under unidirectional laminar flow in vitro and in vivo. Proteomics studies suggest that JCAD regulates YAP/TAZ activation by interacting with actin-binding protein TRIOBP, thereby stabilizing stress fiber formation. Finally, we observed that endothelial JCAD expression was increased in mouse and human atherosclerotic plaques. The present study demonstrates that the GWAS-identified CAD risk gene JCAD promotes endothelial dysfunction and atherosclerosis, thus highlighting the possibility of new therapeutic strategies for CAD by targeting JCAD.


Observation of electrical switching, reverse rectification and hysteresis in nanostructured organic-organic heterojunction.
Nanostructured organic-organic (O-O) heterojunction was fabricated by using the thin films of a hole transporting material, copper phthalocyanine (CuPc) and an electron transporting material, copper hexadecafluoro-phthalocyanine (F16CuPc). The nanostructured thin films were characterized by optical absorption spectra, FESEM, AFM, X-ray diffraction, etc. Grain size of CuPc and F16CuPc on the substrate surface was different. XRD analysis shows that the crystallinity of the double layer films/heterojunction decreases as compared to the single layer film. The heterojunction sandwich structure ITO/F16CuPc/CuPc/Al, in the present study has shown a good diode like current-voltage (I-V) characteristics with reverse rectifying characteristics. In addition, electrical switching and hysteresis phenomena have also been observed in both sides of the voltage polarities. Interestingly, the single layer sandwich structure of the type ITO/CuPc/Al and ITO/F16CuPc/Al did not show any noticeable electrical switching and hysteresis in I-V characteristics as compared to double layer heterostructure. The reverse rectification has been explained on the basis of band bending due to the accumulation of charge carriers near the junction and the electrical switching has been explained considering the charge carriers trapping and detrapping at the O-O interface.


Reversible inactivation of purified leukocyte integrin CR3 (CD11b/CD18, alpha m beta 2) by removal of divalent cations from a cryptic site.
Integrins exhibit reversible changes in their ability to bind ligands and these changes enable transient cell adhesion. We recently showed that leukocyte integrin CR3 (complement receptor type three, CD11b/CD18, alpha m beta 2) may be purified in a form that is either capable or incapable of binding soluble, monomeric ligand and that "inactive" CR3 may be rendered capable of binding ligand by addition of an anti-CR3 mAb known as KIM-127 (Cai and Wright, JBC. 270: 14358, 1995). Here, we demonstrate that active CR3 may be rendered inactive by treatment of immobilized receptor with EDTA. EDTA-treated CR3 failed to bind ligand even in the presence of mM Ca2+ and Mg2+, suggesting that EDTA-treatment caused a change in the receptor that is not readily reversed. EDTA-treated receptor did, however, bind ligand upon addition of KIM-127 plus Mg2+ with an affinity (17.8 +/- 4.5 nM) similar to untreated, active receptor (12.5 +/- 4.7 nM). EDTA-treated CR3 thus exhibits the properties of inactive CR3, in which the ligand binding site is cryptic but subject to exposure by KIM-127. A candidate for the cryptic ligand binding site is the I-domain, a Mg2+-binding region in the alpha chain of CR3. We found that monomeric C3bi binds directly to recombinant I-domain in a Mg(2+)-dependent fashion with an affinity of 300 +/- 113 nM. These results thus suggest that CR3 may be inactivated by removing tightly bound divalent cation from a cryptic site in CR3.


Evidence for a major gene influencing 7-year increases in diastolic blood pressure with age.
The contribution of genetic factors to blood pressure levels is well established. The contribution of genes to the longitudinal change in blood pressure has been less well studied, because of the lack of longitudinal family data. The present study investigated a possible major-gene effect on the observed increase with age in diastolic blood pressure (DBP) levels. Subjects included 965 unmedicated adults (age > or = 18 years) in 73 pedigrees collected in Utah as part of a longitudinal cardiovascular family study. Segregation analysis of DBP change over 7.2 years of follow-up identified a recessive major-gene effect with a gene frequency of p = .23. There was also a significant age effect on the genotypic means, which decreased expression of the major gene at older ages. For those inferred to have the genotype responsible for large DBP increases, DBP increased 32.3%, compared with a 1.5% increase in the nonsusceptible group (P < .0001). The relative risk of developing hypertension between the susceptible and nonsusceptible groups after 7.2 years was 2.4 (P = .006). Baseline DBP reactivities to mental arithmetic (P < .0001), and isometric handgrip (P < .0001) stress tests were greatest in those assigned to the susceptible genotype. We conclude that age-related changes in DBP are influenced by a major gene. Characteristics of this major-gene effect for greater age-related blood pressure increases include greater reactivity to mental and physical stressors. The present study thus provides evidence for genetic control of changes in blood pressure, in addition to the previously suggested genetic control of absolute blood pressure level.


Functional and structural effects of ACE inhibitors on the cardiovascular system.
There is considerable interest in the ability of angiotensin-converting enzyme (ACE) inhibitors not only to lower blood pressure, but also to reverse hypertension-induced remodelling of the circulation. Recently published data would suggest that treatment of spontaneously hypertensive rats from an early age with ACE inhibitors will prevent the development of the expected changes in the resistance vessels as the animals age and that withdrawal of treatment is followed by a lag period before the blood pressure rises. Such findings appear to be contrary to those obtained with other hypertensive drugs where morphological changes are not as effectively attenuated and blood pressure rises rapidly after withdrawal of treatment. There is some evidence for a relationship between the efficacy of ACE inhibitors in this area and lipid solubility. This raises the possibility that the mechanism at work is related to the inhibition of tissue-located renin-angiotensin systems both in vascular smooth muscle and elsewhere, possibly in the central nervous system. An overall review of the literature indicates that treatment of spontaneously hypertensive rats with ACE inhibitors can result in prolonged reduction of blood pressure, even after treatment is withdrawn. Comparisons with other treatments suggest that it is easier to reduce blood pressure than to reverse vascular structure. However, achieving a reversal in morphological changes in resistance vessels as well as controlling blood pressure may be important for reducing the mortality from ischaemic heart disease. ACE inhibitors may have a direct effect on reversal of vascular structure, but other sites of action may also be important in this aspect of their action.


Quantitative one-step real-time RT-PCR for the fast detection of the four genotypes of PPRV.
A one-step real-time Taqman RT-PCR assay (RRT-PCR) for peste des petits ruminants virus (PPRV) was developed to detect the four lineages of PPRV by targeting the nucleoprotein (N) gene of the virus. This new assay was compared to a conventional RT-PCR on reference strains and field materials. Quantitation was performed against a standard based on a synthetic transcript of the NPPR gene for which a minimum of 32 copies per reaction were detected with a corresponding C(t) value of 39. Depending on the lineage involved, the detection limit of RRT-PCR was decreased by one to three log copies relative to the conventional method. The lower stringency occurred with lineage III because of minor nucleotide mismatches within the probe region. The assay did not detect phylogenetically or symptomatically related viruses of ruminants (such as rinderpest, bluetongue, and bovine viral diarrhea viruses). However, it was capable of detecting 20% more positive field samples with low viral RNA loads compared to the conventional PCR method. When compared on a proficiency panel to the method developed by Bao et al. (2008), the sensitivity of the in-house assay was slightly improved on lineage II. It proved significantly faster to perform and hence better adapted for monitoring large numbers of at risk or diseased animals.


Lubiprostone Induces Claudin-1 and Protects Intestinal Barrier Function.
Lubiprostone, a chloride channel activator, is said to reduce epithelial permeability. However, whether lubiprostone has a direct effect on the epithelial barrier function and how it modulates the intestinal barrier function remain unknown. Therefore, the effects of lubiprostone on intestinal barrier function were evaluated in vitro. Caco-2 cells were used to assess the intestinal barrier function. To examine the expression of claudins, immunoblotting was performed with specific antibodies. The effects of lubiprostone on cytokines (IFNγ, IL-6, and IL-1β) and aspirin-induced epithelial barrier disruption were assessed by transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) labeled-dextran permeability. IFNγ, IL-6, IL-1β, and aspirin significantly decreased TEER and increased epithelial permeability. Lubiprostone significantly improved the IFNγ-induced decrease in TEER in a dose-dependent manner. Lubiprostone significantly reduced the IFNγ-induced increase in FITC labeled-dextran permeability. The changes induced by IL-6, IL-1β, and aspirin were not affected by lubiprostone. The expression of claudin-1, but not claudin-3, claudin-4, occludin, and ZO-1 was significantly increased by lubiprostone. Lubiprostone significantly improved the IFNγ-induced decrease in TEER and increase in FITC labeled-dextran permeability. Lubiprostone increased the expression of claudin-1, and this increase may be related to the effect of lubiprostone on the epithelial barrier function.


Evaluation of head examinations produced with a mobile CT unit.
Recent years have seen the development of mobile CT units, designed for use in operating theatres, intensive care units and accident and emergency departments. One such unit is the Tomoscan M (Philips, Utrecht, The Netherlands). It operates with a maximum tube voltage of 130 kV, and a maximum tube current of only 50 mA. This study tested whether acceptable quality CT images of the brain could be produced on the mobile unit with these parameters. 44 consecutive normal head examinations performed on the mobile scanner were compared with 35 examinations from two conventional CT units. Two independent readers scored the examinations for noise and artefact. CT dose index (CTDI) values for the three CT units were obtained in free air as an estimate of patient dose. Differences in artefact score between CT units were generally small, but noise scores were worse when using the Tomoscan M with a 2 s slice time. The lowest CTDI values were obtained with the Somatom DRH (Siemens, Erlangen, Germany) unit and the highest with the SR 7000 (Philips, Utrecht, The Netherlands), with values from Tomoscan M, in all except one case, falling between these values for the protocols used in the study. The measured scattered radiation doses from the Tomoscan M are presented.


Smart self-tightening surgical suture from a tough bio-based hyperbranched polyurethane/reduced carbon dot nanocomposite.
Design and fabrication of a smart bio-based polymeric material with potent biocompatibility and high performance still remain a challenge in the biomedical realm. In this context, a potential smart suture was fabricated from starch modified hyperbranched polyurethane (HPU) nanocomposites with different weight percentages of reduced carbon dots for the first time. The desired mechanical (tensile strength: 32.14 MPa, elongation at break: 1576% and toughness 439.28 MJ m-3) and thermal (286 °C) attributes of the suture were achieved with 2 wt% of reduced carbon dots in an HPU matrix. The non-contact self-tightening behavior was observed just within 15 s at body temperature of 37 °C ± 1 °C with notable shape fixity (99.6%) and shape recovery (99.7%) effects. The nanocomposites displayed in vitro biodegradability and hemocompatibility. Low lactate dehydrogenase activity and minimal red blood cell lysis indicated the anti-thrombogenicity and anti-hemolytic properties of the nanocomposites. The suitability of the fabricated nanocomposites as a smart biomaterial was supported by the inherent biocompatibility as observed by the growth and proliferation of smooth muscle cells and endothelial cells. Furthermore, they exhibited minimal immunogenic response (TNF α release). Thus, the study paves the way to biodegradable HPU nanocomposites as advanced non-contact triggered rapid self-tightening surgical sutures for biomedical applications.


Molecular Cloning, Bioinformatic Analysis, and Expression of Bombyx mori Lebocin 5 Gene Related to Beauveria bassiana Infection.
A full-length cDNA of lebocin 5 (BmLeb5) was first cloned from silkworm, Bombyx mori, by rapid amplification of cDNA ends. The BmLeb5 gene is 808 bp in length and the open reading frame encodes a 179-amino acid hydroxyproline-rich peptide. Bioinformatic analysis results showed that BmLeb5 owns an O-glycosylation site and four RXXR motifs as other lebocins. Sequence similarity and phylogenic analysis results indicated that lebocins form a multiple gene family in silkworm as cecropins. Quantitative real-time PCR analysis revealed that BmLeb5 was highest expressed in the fat body. In the silkworm larvae infected by Beauveria bassiana, the expression level of BmLeb5 was upregulated in the fat body and hemolymph which are the most important immune tissues in silkworm. The recombinant protein of BmLeb5 was for the first time successfully expressed with prokaryotic expression system and purified. There are no reports so far that the expression of lebocins could be induced by entomopathogenic fungus. Our study suggested that BmLeb5 might play an important role in the immune response of silkworm to defend B. bassiana infection. The results also provided helpful information for further studying the lebocin family functioned in antifungal immune response in the silkworm.


Essential Data Elements for Reporters of Elder Abuse.
Most states' adult or elder protective services and aging agency personnel prepare annual reports about their protective services. These reports vary by state and have different terms for the reporter of abuse. Reviewing annual reports from 46 states and the District of Columbia, 248 different terms were used for the reporter of abuse. To develop essential data elements for reporters of abuse, a literature search, a compilation of state elder abuse annual report list of abuse reporters, and a sorting exercise were conducted. Eleven terms were recommended for the different reporters of abuse, encouraging all state administrators and caseworkers to reach consensus to standardize the language.


Reversible tricuspid stenosis. Demonstration with two-dimensional echocardiography and continuous-wave Doppler.
We report a case of pseudo-tricuspid stenosis as a result of extrinsic compression of the tricuspid valve by a large right-sided pericardial effusion. Two-dimensional echocardiography and continuous-wave Doppler enabled accurate noninvasive diagnosis and hemodynamic assessment.


Aberrant methylation impairs low density lipoprotein receptor-related protein 1B tumor suppressor function in gastric cancer.
DNA methylation plays a significant role in tumor progression. In this study, we used CpG microarray and differential methylation hybridization approaches to identify low density lipoprotein receptor-related protein 1B (LRP1B) as a novel epigenetic target in gastric cancer. LRP1B was hypermethylated in four gastric cancer cell lines, and low LRP1B mRNA expression was associated with high methylation levels in gastric cancer cell lines. Addition of a DNA methylation inhibitor (5-Aza-dC) restored the mRNA expression of LRP1B in these cell lines, indicating that DNA methylation is involved in regulating LRP1B expression. In 45 out of 74 (61%) clinical samples, LRP1B was highly methylated; LRP1B mRNA expression was significantly lower in 15 out of 19 (79%, P < 0.001) gastric tumor tissues than in corresponding adjacent normal tissues. In addition, ectopic expression of mLRP1B4 in gastric cancer cell lines suppressed cell growth, colony formation and tumor formation in nude mice. These results collectively indicate that LRP1B is a functional tumor suppressor gene in gastric cancer and that is regulated by DNA methylation.


Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation.
Minocycline protects animals against cerebral ischemia by inhibiting inflammation. To determine whether minocycline protects PC12 cells from in vitro ischemic-like injury and affects pro-inflammatory 5-lipoxygenase activation, the cell viability and 5-lipoxygenase translocation to nuclear membrane were observed after oxygen-glucose deprivation (OGD). We found that OGD reduced cell viability, which was attenuated by minocycline and 5-lipoxygenase inhibitor caffeic acid. 5-Lipoxygenase protein was detected in PC12 cells by immunohistochemical and Western blot analyses. OGD induced 5-lipoxygenase translocation to nuclear membranes, which was abolished by minocycline and caffeic acid. Thus, minocycline can protect PC12 cells from in vitro ischemic-like injury, and this effect may be partly related to the inhibition of 5-lipoxygenase activation.


Guiding strand passage: DNA-induced movement of the gyrase C-terminal domains defines an early step in the supercoiling cycle.
DNA gyrase catalyzes ATP-dependent negative supercoiling of DNA in a strand passage mechanism. A double-stranded segment of DNA, the T-segment, is passed through the gap in a transiently cleaved G-segment by coordinated closing and opening of three protein interfaces in gyrase. T-segment capture is thought to be guided by the C-terminal domains of the GyrA subunit of gyrase that wrap DNA around their perimeter and cause a DNA-crossing with a positive handedness. We show here that the C-terminal domains are in a downward-facing orientation in the absence of DNA, but swing up and rotate away from the gyrase body when DNA binds. The upward movement of the C-terminal domains is an early event in the catalytic cycle of gyrase that is triggered by binding of a G-segment, and first contacts of the DNA with the C-terminal domains, and contributes to T-segment capture and subsequent strand passage.


The effect of growth hormone on fibrinogen synthesis.
A method described by McFarlane (1963a) for the measurement of the absolute rate of synthesis of liver-made plasma proteins was used to show that, within a few hours of giving bovine growth hormone to rats, fibrinogen synthesis increased significantly without a change in albumin synthesis.


Development of sodium fluoride PET response criteria for solid tumours (NAFCIST) in a clinical trial of radium-223 in osteosarcoma: from RECIST to PERCIST to NAFCIST.
The development of osteosarcoma therapeutics has been challenging, in part because of the lack of appropriate criteria to evaluate responses. We developed a novel criteria in a clinical trial of radium-223 dichloride (223RaCl2) for response assessment in osteosarcoma, NAFCIST (Na18F PET response Criteria in Solid Tumors). Patients received one to six cycles of 223RaCl2, and cumulative doses varied from 6.84 MBq to 57.81 MBq. Molecular imaging with technetium-99m phosphonate scintigraphy, fluorine-18-fluorodeoxyglucose (18FDG) positron emission tomography (PET) or sodium fluoride-18 (Na18F) PET was used to characterise the disease. Correlation of biomarkers and survival was analysed with NAFCIST measure from Na18F PET. Of the 18 patients, 17 had bone lesions visible in at least one of the imaging studies. In four of seven patients with multiple skeletal lesions (>5), FDG PET and NaF PET studies could be compared. The skeletal tumour locations varied in our patient population: cranium=2, extremities=7, pelvis=10, spine=12 and thorax=9. The 18F-FDG PET and Na18F PET studies could be compared in all four patients who had multiple lung lesions (>5). Overall the Response Evaluation Criteria in Solid Tumors response was seen in one patient, but four patients experienced mixed responses better defined by Na18F PET. Changes in NAFCIST were correlated with changes in bone alkaline phosphatase levels (r=0.54) and negatively with cumulative dose of 223RaCl2 (r=- 0.53). NAFCIST correlated with overall survival (p value of 0.037) while the PERCIST (PET Response Criteria in Solid Tumors) did not (p value of 0.19). Our results indicate that Na18F PET should be further studied in osteosarcoma staging. NAFCIST may be a promising criteria for high-risk osteosarcoma response evaluation and correlates with survival. Further validation studies are needed.


Ovarian carcinoma: modification of T4 lymphocytes after surgery and during chemotherapy.
To examine the values of helper/inducer lymphocytes (T4), preoperatively, and during the chemotherapy, 1 and 3 months postoperatively in a prospective randomized study of women with cancer. The study included 30 surgically-treated patients with ovarian cancer at the Department of Obstetrics and Gynecology in Novi Sad, Yugoslavia. In the control group, 20 patients had no malignant ovarian tumor. Patients with ovarian cancer, besides surgical treatment, were treated with chemotherapy (CP protocol). Helper/inducer lymphocytes were defined by monoclonal antibody--CD4, conducted by laser flow cytometry. The average values of T4 lymphocytes in relation to control group (1.09 +/- 0.50), in IIIa, IIIb and IIIc stage of ovarian cancer decreased preoperatively (0.55 +/- 0.26), but increased in stages Ia and Ic (1.12 +/- 0.57) and in stage IV (0.31 +/- 0.51). Post surgery treatment (1 and 3 months) and during chemotherapy (CP protocol), the average values of T4 lymphocytes were lowered in relation to preoperative values.


Complications of and controversies associated with percutaneous endoscopic gastrostomy: report of a case and literature review.
Percutaneous endoscopic gastrostomy (PEG) is one of the most commonly performed gastrointestinal procedures, despite absence of benefit in many patients and risks associated with the procedure. Increased education of primary care physicians about the shortcomings of PEG may allow for better selection of patients to be referred for PEG placement. We performed a comprehensive literature review by searching PUBMED using the search headings percutaneous enteral gastrostomy, PEG, complications, dementia, stroke, dysphagia, malnutrition, and complications. We identified English language articles from 1980 onward. The highest quality data were considered to be randomized controlled trials although given the paucity of trials in this area, we used all of the various types of literature. We based the major conclusions of this review, where possible, on the most robust literature, namely, controlled trials. However, the majority of the available literature in this field is based on case series. We attempted to maximize the use of larger case series with longer term follow-up. Case reports were used only to report on rare complications where no other literature was available. Despite more than 30 years of experience with PEG, numerous questions remain regarding the utility of nutrition support in many of the clinical scenarios in which PEG placement is contemplated. There is a multitude of evidence that artificial nutrition does not improve outcome or quality of life in patients with dementia who have decreased oral intake. It is likely that ethical, moral, religious, and legal considerations of family members and caregivers play a role in the decision to place a PEG in a patient with dementia despite the medical evidence demonstrating lack of benefit.


Imaging Features of Primary Tumors and Metastatic Patterns of the Extraskeletal Ewing Sarcoma Family of Tumors in Adults: A 17-Year Experience at a Single Institution.
To comprehensively analyze the spectrum of imaging features of the primary tumors and metastatic patterns of the Extraskeletal Ewing sarcoma family of tumors (EES) in adults. We performed a computerized search of our hospital's data-warehouse from 1996 to 2013 using codes for Ewing sarcoma and primitive neuroectodermal tumors as well as the demographic code for ≥ 18 years of age. We selected subjects who were histologically confirmed to have Ewing sarcoma of extraskeletal origin. Imaging features of the primary tumor and metastatic disease were evaluated for lesion location, size, enhancement pattern, necrosis, margin, and invasion of adjacent organs. Among the 70 patients (mean age, 35.8 ± 15.6 years; range, 18-67 years) included in our study, primary tumors of EES occurred in the soft tissue and extremities (n = 20), abdomen and pelvis (n = 18), thorax (n = 14), paravertebral space (n = 8), head and neck (n = 6), and an unknown primary site (n = 4). Most primary tumors manifested as large and bulky soft-tissue masses (mean size, 9.0 cm; range, 1.3-23.0 cm), frequently invading adjacent organs (45.6%) and showed heterogeneous enhancement (73.7%), a well-defined (66.7%) margin, and partial necrosis/cystic degeneration (81.9%). Notably, 29 patients had metastatic disease detected at their initial diagnosis. The most frequent site of metastasis was lymph nodes (75.9%), followed by bone (31.0%), lung (20.7%), abdominal solid organs (13.8%), peritoneum (13.8%), pleura (6.9%), and brain (3.4%). Primary tumors of EES can occur anywhere and mostly manifest as large and bulky, soft-tissue masses. Lymph nodes are the most frequent metastasis sites.


Influence of vulnerability factors in panic disorder severity.
We studied herein the predictive value for panic severity of three well-based vulnerability factors: personality traits (neuroticism and extraversion; NEO-PI-R), anxiety sensitivity (ASI), and perceived control (ACQ-R). The sample was composed of 52 participants diagnosed with panic disorder, with or without agoraphobia, according to DSM-IV-TR criteria. Our results revealed that the anxiety facet is a better predictor of panic severity than neuroticism. Anxiety sensitivity increases the predictive value for panic severity and, finally, perception of control of emotions is the only perception control subscale that increases the predictive value for panic severity more than the anxiety facet and anxiety sensitivity. This finding supports the assumption of the importance of taking into account the assessment of the lower order dimensions of the vulnerability factors in the field of psychopathology studies. Furthermore, the predictive value of perception of control of emotions indicates the importance of this specific vulnerability factor in the etiology of panic disorder (with or without agoraphobia) and, thus, shows the necessity to include emotion regulation strategies in the psychological treatments.


A novel inhalation challenge set to study animal model of allergic alveolitis.
A novel inhalation challenge set for the study of experimental allergic alveolitis (hypersensitivity pneumonitis) in mice was designed. A finely dispersed aerosol of allergenic extract generated by the commercial ultrasonic nebulizer "TAJFUN MU1" (produced by Medbryt, Warsaw, Poland) was transported to the airtight inhalation chamber. In the chamber were placed 15 perforated containers made of transparent plastic, each containing one mouse. They were coupled in 3 units, each consisted of 5 containers. The constant flow of aerosol through the chamber was assured by commercial vacuum pump "PL 2/3" (AGA LABOR S.C., Warsaw, Poland). The applied set enabled the natural exposure of mice via the inhalation route to known quantities of allergen (usually microbial) suspended in saline, and then dispersed in form of fine aerosol by ultrasonic nebulizer. This method assures the penetration of allergen into the deep parts of lungs, alveoli and bronchioli. The detailed study of histopathological and biochemical changes in the lungs of exposed animals will be the subject of further publications. So far, the retention of endotoxin in the lungs of mice exposed to the extract of a Gram-negative bacterium Pantoea agglomerans and appearance of positive serologic reactions to this extract indicate the effectiveness of the method.


Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction.
Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, offers renoprotection in diabetes. However, potential for use in nondiabetic kidney disease remains unknown. Herein, we assessed whether dapagliflozin alleviates renal fibrosis by interfering with necroinflammation in a rat model of unilateral ureteral obstruction (UUO) and in vitro. After induction of UUO, rats were administered dapagliflozin daily for seven consecutive days. UUO induced significant renal tubular necrosis and overexpression of RIP1-RIP3-MLKL axis proteins; these coincided with NLRP3 inflammasome activation, and subsequent development of renal fibrosis. Oxidative stress caused by UUO is tightly associated with endoplasmic reticulum stress and mitochondrial dysfunction, leading to apoptotic cell death through Wnt3α/β-catenin/GSK-3β signaling; all of which were abolished by both dapagliflozin and specific RIP inhibitors (necrostatin-1 and GSK872). In H2O2-treated HK-2 cells, dapagliflozin and RIP inhibitors suppressed overexpression of RIP1-RIP3-MLKL proteins and pyroptosis-related cytokines, decreased intracellular reactive oxygen species production and apoptotic cell death, whereas cell viability was improved. Moreover, activated Wnt3α/β-catenin/GSK-3β signaling was inhibited by dapagliflozin and Wnt/β-catenin inhibitor ICG-001. Our findings suggest that dapagliflozin ameliorates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in UUO.