Comparative Analysis of Bioactivity of the Russian-Made Antitumor Substances of the Nitrosourea Group.
We performed an in vivo comparative study of activity of three substances of the nitrosourea group produced in Russia. All substances demonstrated high antitumor activity against various solid and leukemic tumors. Aranosa significantly enhanced life duration in mice with leukemia (by 65-194%) and inhibited the growth of solid tumors (by 49-99.6%). Lisomustine and ormustine showed higher activity than aranose. Single administration of lisomustine increased life span of mice (by 22-114%) and resulted in cure of all animals in four models: lymphoblastic leukemia L-1210, lymphocytic leukemia P-388, Lewis lung carcinoma, and cervical cancer RShM-5. After ormustine treatment, full recovery was observed only in groups with lymphocytic leukemia P-388 and cervical cancer RShM-5. These findings attest to higher activity of lisomustine in the studied models.


Unconsciousness indication using time-domain parameters extracted from mid-latency auditory evoked potentials.
The mid-latency auditory evoked potential (MLAEP) has been used to indicate depth of anaesthesia, and is usually analysed in time-domain. This work compares three techniques: Wave Deformation Parameters (PDO), Auditory Evoked Potential Index (AEPidx) and an automatic Nb-wave latency estimator (Nb), in the assessment of unconsciousness onset based on EEG under auditory stimulation. Ten normal adult volunteers, under no pre-anaesthetic drug administration, received propofol during two successive periods of 45 min each one (3 mg/Kg/h and 9 mg/Kg/h), being the EEG collected from 10 min previous to infusion beginning until the subjects woke up. From the time-evolution of MLAEP (averaging of successive sets of 1000 epochs) all the parameters were compared to thresholds (unconsciousness onset indication time) and the results were compared to the instant of pressing interruption of a soft-touch switch, when one assumed the volunteer became unconscious. The Wilcoxon Signed-Rank test points equivalence between each of the parameters and the switch for, say, alpha = 5%. Bland-Altman diagrams revealed that the Attenuation-PDO has better agreement to the switch than Nb and AEPidx. The results suggest that, at least to indicate unconsciousness, the most reliable effect of the anaesthetic drug on MLAEP would be the amplitude attenuation. Despite the high dependence on noise due to its time-domain basis, the Attenuation-PDO seems to be adequate to assess depth of anaesthesia.


Diagnosis of Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage and Triggers for Intervention.
Delayed cerebral ischemia (DCI) is a major determinant for poor neurological outcome after aneurysmal subarachnoid hemorrhage (aSAH). Detection and treatment of DCI is a key component in the neurocritical care of patients with aSAH after initial aneurysm repair. Narrative review of the literature. Over the past 2 decades, there has been a paradigm shift away from macrovascular (angiographic) vasospasm as a main diagnostic and therapeutic target. Instead, the pathophysiology of DCI is hypothesized to derive from several proischemic pathomechanisms. Clinical examination remains the most reliable means for monitoring and treatment of DCI, but its value is limited in comatose patients. In such patients, monitoring of DCI is usually based on numerous neurophysiological and/or radiological diagnostic modalities. Catheter angiography remains the gold standard for the detection of macrovascular spasm. Computed tomography (CT) angiography is increasingly used instead of catheter angiography because it is less invasive and may be combined with CT perfusion imaging. CT perfusion permits semiquantitative cerebral blood flow measurements, including the evaluation of the microcirculation. It may be used for prediction, early detection, and diagnosis of DCI, with yet-to-prove benefit on clinical outcome when used as a screening modality. Transcranial Doppler may be considered as an additional noninvasive screening tool for flow velocities in the middle cerebral artery, with limited accuracy in other cerebral arteries. Continuous electroencephalography enables detection of early signs of ischemia at a reversible stage prior to clinical manifestation. However, its widespread use is still limited because of the required infrastructure and expertise in data interpretation. Near-infrared spectroscopy, a noninvasive and continuous modality for evaluation of cerebral blood flow dynamics, has shown conflicting results and needs further validation. Monitoring techniques beyond neurological examinations may help in the detection of DCI, especially in comatose patients. However, these techniques are limited because of their invasive nature and/or restriction of measurements to focal brain areas. The current literature review underscores the need for incorporating existing modalities and developing new methods to evaluate brain perfusion, brain metabolism, and overall brain function more accurately and more globally.


Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease.
Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 -/-) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 -/- infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 -/- mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 -/- littermates. CCL5 and MMP-2 induction occurred preferentially (P<0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P<0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.


A method for measuring monoamine turnover in animals using an irreversible inhibitor of aromatic L-amino acid decarboxylase, DL-alpha-mono fluoromethyldopa.
DL-alpha-monofluoromethyldopa (MFMD) is a potent enzyme-activated irreversible inhibitor of aromatic L-amino acid decarboxylase which, when given to rats or mice at 100 and 250 mg/kg i.p., respectively, causes a linear accumulation of L-DOPA and 5HTP and an exponential decline of noradrenaline, dopamine, and 5HT concentrations in the brain. Rates of change of these parameters can be used to calculate the turnover of the three principle monoamine neurotransmitters. Experiments with haloperidol (1 mg/kg s.c.) and the central 5HT agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (0.25 mg/kg s.c.), have been performed to validate the use of MFMD to measure monoamine turnover. MFMD has several advantages over classical methods for the determination of comparative turnovers using enzyme inhibitors.


Investigation of gene evolution in vertebrate genome reveals novel insights into spine study.
Vertebrate genomes have been considered to have undergone a complicated evolution during their early period and to have generated a large number of genetic templates with novel functions, such as an extended spinal cord and a dorsal central nervous system. However, consistent gene evolution in vertebrate genomes has not been fully elucidated. In this study, we have systematically investigated the gene evolution in vertebrates utilizing a series of comparative genomics tools. We determined that three critical genes were consistently lost in vertebrate genomes, and 14 genes initially emerged in vertebrate formation. Furthermore, another 29 genes were identified with consistent amino acid variation between the vertebrates and invertebrates. A function analysis of five genes (TEP3, ABLIM2, ABLIM3, GAD1 and GAD2) was performed, and their evolution mechanisms in vertebrate genomes further investigated. These findings provide novel insights for studying the vertebrate evolution and spine development.


Backbone amide linker strategies for the solid-phase synthesis of C-terminal modified peptides.
This chapter describes backbone amide linker (BAL) strategies for the Nalpha-Fmoc solid-phase synthesis of C-terminal modified peptides. Most solid-phase protocols for the assembly of such peptides have limited generality, because they rely on the Calpha-carboxyl for attachment to the solid support. In the BAL approach, the growing peptide chain is anchored through a backbone nitrogen, thus allowing significant flexibility for chemical modification of the C-termini. In effect, any peptide containing C-terminal variations can be prepared in overall good purity and yield, with minimal side reactions, by using one or more of three variations (original and two modifications) of the BAL strategy.


Recovery from peripartum cardiomyopathy after treatment with bromocriptine.
Peripartum cardiomyopathy (PPCM) is a potentially devastating cause of heart failure that affects women late in pregnancy or in early puerperium. Recent findings showed that a 16 kDa fragment of prolactin may induce myocardial damage, and this offered a new option of treating PPCM by blocking prolactin with bromocriptine. We report on a 35-year-old woman with a twin gravidity who gave birth to two healthy boys at day 36/6 and developed a potentially fatal PPCM. Within 3 days since delivery she suffered from severe symptoms of heart failure (orthopnoea, pleural and pericardial effusion, reduced systolic function LVEF 15%). Bromocriptine 2.5 mg bid was added to standard heart failure therapy at day 6 after delivery, and within a week the patient recovered to NYHA functional class II. 2 months later she presented in a good state, NYHA class I, and MRI confirmed an LVEF of 60%. Balancing the potential side effects of bromocriptine against the very poor prognosis in severe PPCM our case supports the use of bromocriptine as a specific novel therapy.


Nutritional evaluation of phosphorylated pumpkin seed (Cucurbita moschata) protein concentrate in silver catfish Rhamdia quelen (Quoy and Gaimard, 1824).
An 8-week feeding trial was conducted to evaluate the effect of replacing fish meal with pumpkin seed meal (PSM) or phosphorylated protein concentrate of pumpkin seed meal (PPCPS) on growth and metabolic responses of silver catfish. Five isonitrogenous and isocaloric diets were formulated. Control diet contained fish meal as the main protein source. The treatment groups contained 25 and 50% of either PSM or PPCPS protein replaced the fishmeal protein. A total of 400 silver catfish, with initial mean weight of 24 ± 0.46 g, were distributed into 20 tanks. For data four orthogonal contrasts were applied: control diet versus PSM diets; control diets versus PPCPS diets; control versus other diets; PSM diets versus PPCPS diets. The results indicated that the fish fed PSM diets had lower weight gain when compared to either control diet or PPCPS. The PPCPS do not affect growth and protein efficiency ratio. Lower albumin contents were found for the control diet fish for the contrasts control diet versus PPCPS diet and control diet versus other diets. The hepatic ALAT enzyme activity was higher in the fish fed the control diet (P < 0.05). The hepatic ALP was most active in fish that received the PPCPS diets, when comparing control diet versus PPCPS diets and control diet versus other diets. The hepatosomatic index was higher for fish fed the PPCPS. Our results indicated that PPCPS presents relevant nutritional quality for fish and can replace the fish meal protein up to 50% without affecting growth, PER and intermediate metabolites in silver catfish.


Retraction Note: Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.
An amendment to this paper has been published and can be accessed via the original article.


Surgical Reconstruction Options in Chronic Distal Biceps Tendon Ruptures - Case Report and Literature Review.
Chronic distal biceps tendon ruptures are rare and conservative or operative treatment options are suitable. There is a consensus in the literature in case of acute traumatic ruptures the operative refixation should be preferred. Disagreement exists in the best way of care of old ruptures (> 4 weeks) of distal biceps tendon. Several kinds of refixation possibilities up to tendon grafts are described. Aim of this publication is showing an overview of the literature of the approved methods in reconstruction of the distal biceps tendon using autogenous and allogenic grafts, comparing the outcomes and transferring them on an own case. A literature research was carried out using the online medical database "PubMed" with the following keywords "chronic rupture distal biceps tendon, surgical techniques". 59 citations were found concerning the topic, 37 publications were relevant for this work. There is consensus that even in chronic ruptures the operative management of the distal biceps tendon generates the best results. Consistently the experiences and results of only little patient collectives are reported. Numerous techniques of surgery are described without predominance of one method. Reinsertions of the tendon butts are reported in different techniques: with achilles, palmaris longus, fascia lata, triceps, quadriceps and semitendinosus tendon grafts. All together they showed postoperative satisfactory results. With surgical treatment of chronic ruptured distal biceps tendons comparable outcomes can be achieved by primary refixation and graft augmentations. In case of graft augmentations several tissue options are available which showed in all cases satisfactory functional results in the end.


Controlling the feed rate of propanol to optimize erythromycin fermentation by on-line capacitance and oxygen uptake rate measurement.
The aim of the present study was to optimize the feeding proportion of glucose and propanol for erythromycin biosynthesis by real-time monitoring and exploring its limited ratio by the on-line multi-frequency permittivity measurement. It was found that the capacitance values were sensitive to the variation of biomass concentration and microbial morphology as well as the true state of cell growth. It was most favorable to both cell growth and secondary metabolism to keep the ratio of glucose to propanol at 4.3 (g/g). The specific growth rate calculated by the capacitance measurement correctly and accurately reflected the cell physiological state. An appropriate feed rate of propanol was crucial for cell growth and secondary metabolism, as well as to improve the quality of erythromycin-A. In addition, the erythromycin production titer (10,950 U/mL) was further enhanced by 4 % when the propanol feed was regulated by step-down strategy based on both OUR (oxygen uptake rate) and the on-line monitoring capacitance.


The biological and electrical trade-offs related to the thickness of conducting polymers for neural applications.
Poly(3,4-ethylenedioxythiophene) (PEDOT) films have attracted substantial interest as coatings for platinum neuroprosthetic electrodes due to their excellent chemical stability and electrical properties. This study systematically examined PEDOT coatings formed with different amounts of charge and dopant ions, and investigated the combination of surface characteristics that were optimal for neural cell interactions. PEDOT samples were fabricated by varying the electrodeposition charge from 0.05 to 1 C cm(-2). Samples were doped with either poly(styrenesulfonate), tosylate (pTS) or perchlorate. Scanning electron micrographs revealed that both thickness and nodularity increased as the charge used to produce the sample was increased, and larger dopants produced smoother films across all thicknesses. X-ray photoelectron spectroscopy confirmed that the amount of charge directly corresponded to the thickness and amount of dopant in the samples. Additionally, with increased thickness and nodularity, the electrochemical properties of all PEDOT coatings improved. However, neural cell adhesion and outgrowth assays revealed that there is a direct biological tradeoff related to the thickness and nodularity. Cell attachment, growth and differentiation was poorer on the thicker, rougher samples, but thin, less nodular PEDOT films exhibited significant improvements over bare platinum. PEDOT/pTS fabricated with a charge density of <0.1Ccm(-2) provided superior electrochemical and biological properties over conventional platinum electrodes and would be the most suitable conducting polymer for neural interface applications.


Retinal vascular function in asymptomatic individuals with a positive family history of cardiovascular disease.
To compare retinal microvascular function in healthy individuals with and without a positive family history (FH) of cardiovascular disease (CVD). Retinal vessel reactivity was assessed by means of dynamic retinal vessel analysis in 38 healthy subjects aged between 30 and 66 years with a positive FH of CVD and 37 age- and gender-matched control subjects. Other assessments included blood pressure (BP) profiles, blood glucose and lipid metabolism markers, Framingham risk scores (FRS), carotid intima-media thickness (c-IMT) and brachial flow-mediated dilation (FMD). Family history-positive subjects showed decreased retinal arterial baseline diameter fluctuation, dilation amplitude, percent dilation, and overall constriction response slope (p = 0.001; p = 0.015; p = 0.001; and p < 0.001, respectively) and increased percent constriction (p = 0.008). On the venous side, baseline-corrected flicker response and dilation response slope were decreased in the FH-positive group (p = 0.009 and p = 0.010, respectively). There were no significant differences between groups in c-IMT scores or FMD parameters (all p > 0.05). The arterial MC% correlated negatively with decreased high-density lipoprotein cholesterol (r = -0.52, p = 0.002) in only FH-positive group. Although macrovascular function is preserved in individuals with FH positive for CVD but with low FRS, there are, however, functional impairments at the retinal microvascular level that correlate with established plasma markers for cardiovascular risk.


Cytogenetic evaluation of mesenchymal stem/stromal cells from patients with myelodysplastic syndromes at different time-points during ex vivo expansion.
Mounting evidence suggests that in myelodysplastic syndromes (MDSs) bone marrow (BM) mesenchymal stem/stromal cells (MSCs) possess abnormal characteristics and are actively involved in disease pathogenesis. Nevertheless, it is controversial whether these cells harbor clonal cytogenetic aberrations. To probe more deeply into this issue, in the present study we used conventional G-banding and FISH analysis to assess the clonal chromosomal abnormalities of hematopoietic cells (HCs) and cultured MSCs, from 29 MDS patients and 25 healthy individuals, at early, intermediate and late passage. Variable clonal cytogenetic aberrations were detected in HCs from 31% and in MSCs from 34% of MDS patients. Clonal chromosomal abnormalities in MSCs were detected even in patients without aberrations in HCs. They were mostly numerical and always differed from those in HCs from the same individual. Clonal chromosomal abnormalities did not seem to confer a proliferative and/or survival advantage to MSCs. HCs from normal donors harbored no cytogenetic abnormalities, whereas trisomy of chromosome 5 was detected in MSCs from 16% of healthy individuals, in line with other studies. Our results suggest that MDS-derived BM-MSCs are genetically unstable. The significance of this observation in the biology of MSCs and MDS pathogenesis is still unknown and warrants further evaluation.


Restless legs symptoms without periodic limb movements in sleep and without response to dopaminergic agents: a restless legs-like syndrome?
Patients fulfilling the essential criteria for restless legs syndrome (RLS), but in whom the response to conventional dopaminergic treatment and the presence of periodic limb movements in sleep (PLMS) are lacking, are occasionally encountered. The aim of this study was to systematically characterize this population. In a consecutive series of 117 patients fulfilling the essential criteria for RLS, we assessed the presence of the following supportive criteria: PLMS >15/h on polysomnography, and favourable response to dopaminergic treatment. We differentiated patients with 'classical RLS' (RLS-C; fulfilling at least one of the selected supportive criteria) from those with 'RLS-like syndrome' (RLS-L) in whom supportive criteria were not fulfilled. There were 103 RLS-C and 14 RLS-L patients. Compared with RLS-C patients, RLS-L patients were significantly younger, more severely affected by RSL symptoms, and were more probably to suffer from psychiatric comorbidities, than RLS-C patients. This study proves the existence of patients with severe RLS symptoms, but without PLMS and without response to dopaminergic treatment, who are clinically distinct from patients with 'classical RLS'.


Role of the retrorubral nucleus in striatally elicited orofacial dyskinesia in cats: effects of muscimol and bicuculline.
Orofacial dyskinesia (OFD) is a disorder characterized by involuntary movements of the oral and facial muscles. OFD attacks can be elicited acutely in cats by local injections of dopaminergic agents into the anterodorsal part (r-CRM) of the caudate nucleus. Because the dopaminergic A8 cell group, being embedded in the retrorubral nucleus (RRN), gives rise to fibres which terminate in the r-CRM, two questions arose: (1) whether the A8 cell group forms part of the circuitry that directs and/or modulates OFD, and (2) whether GABA-ergic compounds in the RRN play a role in OFD, and if so, whether a pharmacological GABA-ergic intervention of the activity in the RRN modulates or mediates OFD. For this purpose, the activity of the RRN was manipulated with local injections of the GABA(A) agonist muscimol and antagonist bicuculline. These local injections into the RRN were subsequently combined with manipulations of dopamine transmission in the r-CRM with local injections of the selective DAi receptor agonist (3,4-dihydroxyphenylimino)-2-imidazoline. The present study shows that local injections of GABA-ergic compounds into the RRN do not elicit OFD attacks in cats, but can modulate oral behaviour elicited from the r-CRM. The latter effect is dose dependent and GABA-ergic specific.


Electron-microscopical study of a Rathke's cleft cyst.
The electron-microscopical appearance of a Rathke's cleft cyst is described. The cyst lining is seen to consist predominantly of secretory columnar epithelium, both ciliated and non-ciliated. There are also epidermoid cells occurring singly or in squamae. The histogenesis of Rathke's cleft cysts, in relation to craniopharyngiomas, is discussed.


Characterization of a molt-related myostatin gene (FmMstn) from the banana shrimp Fenneropenaeus merguiensis.
Myostatin is an important member of the transforming growth factor (TGF) family that functions to regulate muscle growth in animals. In this study, the myostatin gene (FmMstn) and two slightly different (short and long forms) cDNAs of the banana shrimp Fenneropenaeus merguiensis were cloned and characterized. Similar to Mstn gene of the scallop, fish and mammal, FmMstn gene consists of 3 exons and 2 introns. The 2kb upstream promoter region of the FmMstn gene consists of putative response elements for myocyte enhancing factor (MEF2) and E-box factors. The longest open reading frame of the short Mstn consists of 1260bp encoding for a protein with 420 amino acid residues. The long FmMstn is almost identical to the short FmMstn with the exception of 8 amino acid insertions. FmMstn is most similar to the Mstn of Litopenaeus vannamei and Penaeus monodon sharing >92-98% amino acid sequence identity. Multiple sequence alignment results revealed high degree of amino acid conservation of the cysteine residues and mature peptide of the FmMstn with Mstn from other animals. FmMstn transcript was detected in the heart, muscle, optic nerve and thoracic ganglion. FmMstn transcript level in muscle is higher in early postmolt, decreases in intermolt and increases again towards ecdysis. Higher expression level of FmMstn is also observed in smaller shrimp of the same age. Knock-down of FmMstn gene by RNAi can cause a significant increase in molt cycle duration and failure of some shrimp to undergo ecdysis. Direct DNA sequencing results revealed that FmMstn gene is highly polymorphic and several potential SNPs have been identified. Some SNPs are associated with the size difference of the shrimp. In summary, the result of this study indicates that shrimp FmMstn gene is molt/growth-related and the presence of SNP suggests that it could be a candidate gene for shrimp genetic improvement research.


Is the assumption of normality or log-normality for continuous response data critical for benchmark dose estimation?
Continuous responses (e.g. body weight) are widely used in risk assessment for determining the benchmark dose (BMD) which is used to derive a U.S. EPA reference dose. One critical question that is not often addressed in dose-response assessments is whether to model the continuous data as normally or log-normally distributed. Additionally, if lognormality is assumed, and only summarized response data (i.e., mean±standard deviation) are available as is usual in the peer-reviewed literature, the BMD can only be approximated. In this study, using the "hybrid" method and relative deviation approach, we first evaluate six representative continuous dose-response datasets reporting individual animal responses to investigate the impact on BMD/BMDL estimates of (1) the distribution assumption and (2) the use of summarized versus individual animal data when a log-normal distribution is assumed. We also conduct simulation studies evaluating model fits to various known distributions to investigate whether the distribution assumption has influence on BMD/BMDL estimates. Our results indicate that BMDs estimated using the hybrid method are more sensitive to the distribution assumption than counterpart BMDs estimated using the relative deviation approach. The choice of distribution assumption has limited impact on the BMD/BMDL estimates when the within dose-group variance is small, while the lognormality assumption is a better choice for relative deviation method when data are more skewed because of its appropriateness in describing the relationship between mean and standard deviation. Additionally, the results suggest that the use of summarized data versus individual response data to characterize log-normal distributions has minimal impact on BMD estimates.


TL-118-anti-angiogenic treatment in pancreatic cancer: a case report.
Pancreatic cancer is one of the most aggressive malignant tumors. In recent years, little progress has been made in understanding and treatment of the disease. The two most commonly used chemotherapy drugs approved for the treatment of pancreatic cancer are gemcitabine and fluorouracil. Anti-angiogenic treatment is one of the current promising approaches in cancer translational research. Its aim is to inhibit development of new blood vessels and thereby prevent further tumor growth. We present a first description of a pancreatic cancer patient treated with standard chemotherapy and TL-118, an anti-angiogenic combination of 4 drugs that target non-overlapping aspects of the angiogenic process (Provided by Tiltan Pharma Ltd for compassionate use). Our patient, treated with standard chemotherapy combined with TL-118, was diagnosed about 16 months ago and is still considered progression free, while being treated with that combination. Moreover, when the treatment with TL-118 was stopped, there was a clear elevation of tumor marker which dropped again with the renewal of TL-118. This effect was not achieved by gemcitabine treatment alone. Recently, a phase II clinical trial of TL-118 for pancreatic cancer patients that have not yet been treated with chemotherapy was initiated. (Tiltan Pharma Ltd). The study objective is to evaluate the efficacy, safety, and tolerability of TL-118 in gemcitabine-treated metastatic pancreatic cancer patients. This report describes a new approach in treating pancreatic cancer, enabling patients to obtain a longer progression-free survival using this new anti-angiogenic drug combination, added on standard chemotherapy.


Long-term outcomes of endoscopic papillary balloon dilation and endoscopic sphincterotomy for bile duct stones.
We recently reported that endoscopic papillary balloon dilation (EPBD) might suppress biliary bacterial contamination better than endoscopic sphincterotomy (EST) in patients with small bile duct stones (diameter ≤8 mm). In the present study, we evaluated immediate and long-term outcomes of endoscopic papillary balloon dilation with regard to stone size. We allocated 474 patients alternately to the two procedures. The patients were classified according to stone diameter (≤8 mm or >8 mm) and outcomes (i.e. complete stone removal, early complications, and late complications) were compared. The predictive risk factors for late complications were also investigated. In patients with small stones, complete stone removal rate and early complication rate were similar between the two procedures; the incidence of pancreatitis was higher after EPBD, although the difference was not significant. Late complication rate and stone recurrence rate were significantly lower after EPBD than after EST (5.3% vs 17.3%, P = 0.009; 4.4% vs 12.7%; P = 0.048, respectively). In patients with large stones who underwent EPBD complete stone removal rate and late complication rate were lower, but the incidence of pancreatitis was higher. However, these differences were not statistically significant. Multivariate analysis showed that the increased risk of bactobilia following EPBD for large stones or EST, and the gallbladder with stones in situ were independent risk factors for late complications. EPBD produced significantly better long-term outcomes than EST in patients with small bile duct stones.


Combination of tumour-infarction therapy and chemotherapy via the co-delivery of doxorubicin and thrombin encapsulated in tumour-targeted nanoparticles.
Drugs that induce thrombosis in the tumour vasculature have not resulted in long-term tumour eradication owing to tumour regrowth from tissue in the surviving rim of the tumour, where tumour cells can derive nutrients from adjacent non-tumoral blood vessels and tissues. Here, we report the performance of a combination of tumour-infarction therapy and chemotherapy, delivered via chitosan-based nanoparticles decorated with a tumour-homing peptide targeting fibrin-fibronectin complexes overexpressed on tumour-vessel walls and in tumour stroma, and encapsulating the coagulation-inducing protease thrombin and the chemotherapeutic doxorubicin. Systemic administration of the nanoparticles into mice and rabbits bearing subcutaneous or orthotopic tumours resulted in higher tumour growth suppression and decreased tumour recurrence than nanoparticles delivering only thrombin or doxorubicin, with histological and haematological analyses indicating an absence of detectable toxicity. The co-administration of a cytotoxic payload and a protease to elicit vascular infarction in tumours with biodegradable tumour-targeted nanoparticles represents a promising strategy for improving the therapeutic index of coagulation-based tumour therapy.


Tissue transglutaminase protects against apoptosis by modifying the tumor suppressor protein p110 Rb.
Tissue transglutaminase (TGase) is involved in the regulation of several biological events including cellular differentiation and apoptosis. The expression and activation of TGase are up-regulated in response to retinoic acid (RA), leading to the protection of several cell lines against N-(4-hydroxyphenyl)retinamide (HPR)-induced apoptosis. The anti-apoptotic mechanisms of TGase are poorly understood at this time. We examined the interaction of TGase with the retinoblastoma (Rb) protein, a substrate of TGase that is also implicated in cell survival functions. In cells undergoing HPR-induced apoptosis, Rb is degraded. This degradation is blocked when cells are pretreated with RA, an important regulator of TGase. In vitro studies revealed that TGase protects Rb from caspase-induced degradation in a transamidation-dependent manner. Experiments performed with fibroblasts from Rb(-/-) mice further demonstrated that the presence of Rb was required for TGase to exhibit anti-apoptotic activity in response to RA treatment. Microinjection of Rb(-/-) cells with a transamidation-defective TGase mutant and Rb afforded no protection from HPR-induced apoptosis. Taken together, these findings suggest that the ability of TGase to modify Rb via transamidation underlies the ability of TGase to provide protection against apoptotic insults and to ensure that cells remain viable during differentiation.


Evaluation of stability of osteosynthesis with K-wires on an artificial model of tibial malleolus fracture.
Paediatric ankle fractures comprise approximately 4% of all paediatric fractures and 30% of all epiphyseal fractures. Integrity of the ankle "mortise", which consists of tibial and fibular malleoli, is significant for stability and function of the ankle joint. Tibial malleolar fractures are classified as SH III or SH IV intra-articular fractures and, in cases where the fragments are displaced, anatomic reposition and fixation is mandatory. Type SH III-IV fractures of the tibial malleolus are usually treated with open reduction and fixation with cannulated screws that are parallel to the physis. Two K-wires are used for temporary stabilisation of fragments during reduction. A third "guide wire" for the screw is then placed parallel with the physis. Considering the rules of mechanics, it is assumed that the two temporary pins with the additional third pin placed parallel to the physis create a strong triangle and thus provide strong fracture fixation. To prove this hypothesis, an experiment was conducted on the artificial models of the lower end of the tibia from the company "Sawbones". Each model had been sawn in a way that imitates the fracture of medial malleoli and then reattached with 1.8mm pins in various combinations. Prepared models were then tested for tensile and pressure forces. The least stable model was that in which the fractured pieces were attached with only two parallel pins. The most stable model comprised three pins, where two crossed pins were inserted in the opposite compact bone and the third pin was inserted through the epiphysis parallel with and below the growth plate. A potential method of choice for fixation of tibial malleolar fractures comprises three K-wires, where two crossed pins are placed in the opposite compact bone and one is parallel with the growth plate. The benefits associated with this method include shorter operating times and avoidance of a second operation for screw removal.


Ligand-aided 1H Nuclear Magnetic Resonance Spectroscopy for Non-destructive Estimation of Sulfate Content in Sulfated Saccharides.
Sulfated saccharides exhibit diverse physiological activities, but a lack of any convenient assay hinders their evaluation. Herein, an assay for the analysis of sulfated saccharides is described using 1H nuclear magnetic resonance (NMR) spectroscopy by employing ligands that can form ionic complexes with the sulfate groups. Based on the change in the chemical shift (Δδ) of the ligands by sulfated mono- to tetrasaccharide, imidazole was found to be a good ligand, showing the maximum Δδ; neutral saccharides do not show any change in the δ value. A marked and constant downfield δ value observed was changed dramatically at a molar ratio of >1:1 (imidazole:sulfated saccharides), allowing a sulfate content estimation based on the concentration of imidazole at the Δδ inflection point. By the proposed ligand-aided 1H NMR assay, the sulfate content of natural sulfated polysaccharide, fucoidan, was non-destructively estimated to be 2.1 mmol/g-fucoidan.


Economics of alternative energy sources.
An important part of the oil and natural gas at present consumed in the UK is used for the heating of buildings, a demand which shows large diurnal, day-to-day and annual fluctuations. The replacement of this energy by nuclear-generated electricity, as at present envisaged, would require the construction of some 250 GW of additional capacity by the end of the century, a progamme which does not seem feasible. By incorporating relatively cheap, short term storage in the form of low-grade heat, the generating capacity required to fulfil peak demand could be reduced by more than 50%. As soon as such storage is provided, however, other sources of energy become viable and attractive alternatives, and the UK is well situated to make use of wind, wave, and tidal power. It seems likely that the value of North Sea oil/gas reserves as feedstock to the chemical industry will rise sufficiently to make an early reduction in their consumption as fuel of great economic importance.


Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling.
Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. A retrospective review of MUP was performed at a tertiary referral cancer center. Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.


Resting-state functional connectivity in multiple sclerosis: an examination of group differences and individual differences.
Multiple sclerosis (MS) is a neurodegenerative, inflammatory disease of the central nervous system, resulting in physical and cognitive disturbances. The goal of the current study was to examine the association between network integrity and composite measures of cognition and disease severity in individuals with relapsing-remitting MS (RRMS), relative to healthy controls. All participants underwent a neuropsychological and neuroimaging session, where resting-state data was collected. Independent component analysis and dual regression were employed to examine network integrity in individuals with MS, relative to healthy controls. The MS sample exhibited less connectivity in the motor and visual networks, relative to healthy controls, after controlling for group differences in gray matter volume. However, no alterations were observed in the frontoparietal, executive control, or default-mode networks, despite previous evidence of altered neuronal patterns during tasks of exogenous processing. Whole-brain, voxel-wise regression analyses with disease severity and processing speed composites were also performed to elucidate the brain-behavior relationship with neuronal network integrity. Individuals with higher levels of disease severity demonstrated reduced intra-network connectivity of the motor network, and the executive control network, while higher disease burden was associated with greater inter-network connectivity between the medial visual network and areas involved in visuomotor learning. Our findings underscore the importance of examining resting-state oscillations in this population, both as a biomarker of disease progression and a potential target for therapeutic intervention.


Pilot study of treatment of biochemotherapy-refractory stage IV melanoma patients with autologous dendritic cells pulsed with a heterologous melanoma cell line lysate.
Eleven AJCC stage IV melanoma patients with progressive disease after treatment with biochemotherapy were treated with autologous dendritic cells pulsed with heterologous tumor cell lysates. The vaccine used mature DCs (CD1a+++, CD40++, CD80++, CD83+, and CD86+++) generated from peripheral blood monocytes in the presence of GM-CSF and IL-4. After 7 days, DCs were matured with a defined cocktail of cytokines (IL-1+IL-6+TNF-alpha+PGE2) and simultaneously pulsed with lysates of heterologous melanoma cell lines, for 2 days. A total of 4 x 10(6) DCs was injected monthly under ultrasound control in an inguinal lymph node of normal appearance. The study was closed when all patients died as a consequence of tumor progression. No sign of toxicity was observed during the study. One patient experienced a partial response lasting 5 months, and two patients showed a mixed response which lasted 3 months. The median survival of the whole group was 7.3 months (range 3-14 months). This vaccination program had specific antitumoral activity in highly pretreated and large tumor burden stage IV melanoma patients and was well tolerated. The clinical responses and the median survival of the group of patients, together with the low toxicity of our DC vaccine, suggest that this approach could be applied to earlier AJCC stage IV melanoma patients.


Phase II trail of nab-paclitaxel in metastatic breast cancer patients with visceral metastases.
Visceral metastases account for 48-67% of metastatic breast cancer (MBC) patients and presage a worse overall survival. Previous study suggested potential effect of nab-paclitaxel on patients with visceral metastases subgroups. This phase II trial was conducted to explore the efficacy and safety of nab-paclitaxel in such a high-risk group of patients. In this prospective, single-center, open-label, phase II study, MBC patients with visceral metastases (N = 80) received nab-paclitaxel (Abraxane, 125 mg/m2, D1, D8, D15 every 28 days). The median PFS was 5.1 months (95% CI: 4.2-6.0 months), with an ORR of 33.8% (95% CI 21.3-43.8%) and CBR of 66.2% (95% CI 56.3-75.0%). In univariate analysis, patients with premenopausal status had a trend of better treatment outcome. Multivariate analysis demonstrated non brain metastasis (adjusted HR 0.31, 95% CI 0.12-0.83, P = 0.019) and first line treatment (adjusted HR 0.37, 95% CI 0.17-0.81, P = 0.013) as independent predictors of longer PFS. The overall safety was acceptable with most common treatment-related, grade ≥ 3 toxicities of neutropenia (16.3%) and sensory neuropathy (3.7%). This phase II trial documented satisfactory efficacy and safety of nab-paclitaxel in MBC patients with visceral metastases, providing evidence for relative clinical practice. Patients in first line therapy had better treatment outcome. For patients with premenopausal status or brain metastasis, further alternatives (for example, combined chemotherapy or targeting therapy) might be required. This study also demonstrated the efficacy and safety of 125 mg/m2 nab-paclitaxel among Asian patients. This research is registered under clinicaltrials.gov (NCT02687490, February 22, 2016).


Two million hours of science.
After over a quarter of a century, the doors of the world's first synchrotron radiation source have closed. Its contribution to materials science in the past and the future should not be underestimated.


Ozone structure in Caribbean hurricanes.
Using ozone data from model-assimilated satellite measurements in the eastern Caribbean 15-20N, 60-68W, cases were studied when upper tropospheric O3 values declined below 60 ppb. Secondary criteria on convection and circulation isolated two hurricanes for analysis (Irma and Maria 2017). Winds at 150 hPa (14 km) show divergence over the vortex characterized by ozone <50 ppb. Upper tropospheric O3 concentrations >100 ppb appear west of hurricanes, where sinking motions interact with vortex outflow. Past work suggests that high values are important, but here low ozone concentrations near the core are more conspicuous. The low O3 layer formed over the ocean and lifted by the hurricane circulation and convection, indicates vortex - environment interaction, vertical motion and storm intensity. Upper tropospheric O3 concentrations <50 ppb cover an area about double the radius of heavy rainfall >10 mm/h, appearing as a protective envelope around the core.


Treatment with lovastatin, cholestyramine or niacin alters K-ras membrane association in mouse lung in a strain-dependent manner: results in females.
Hypocholesterolemic drugs may themselves increase (cholestyramine, CS) or decrease (lovastatin, Lov) peripheral tissue de novo cholesterol biosynthesis. This will alter the abundance of prenyl groups and potentially increase (CS) or decrease (Lov) K-ras membrane localization, with possible pro- or anti-carcinogenic effects (K-ras is a proto-oncogene frequently mutated in lung cancer). Female A/J, Swiss, and C57BL/6 mice were fed 2 or 4% CS, 1% niacin, or injected with Lov three (Lov-3x) or five (Lov-5x) times per week. After three weeks, serum cholesterol and triglycerides were determined enzymatically. Total, membrane, and cytoplasmic K-ras proteins were determined in lung homogenates by immunoprecipitation followed by Western blotting with a K-ras specific antibody. CS feeding increased membrane K-ras as hypothesized in A/J and C57BL/6 mice, but had no effect in Swiss mice. Lov failed in all three strains to reduce membrane K-ras, and resulted in an increase in total K-ras in A/J and C57BL/6 mice, while again lacking effect in Swiss mice. Niacin had no effect on K-ras protein in any mouse strain. These results differ from our published results for male mice of the same strains, particularly for A/J mice. Increased amounts of K-ras protein in the membrane fraction of A/J females (but not males) treated with either Lov or CS imply that if K-ras were to become mutated, CS could result in increased lung tumorigenesis and Lov would be less likely to be protective in females. In the light of these data, both sexes should be included in future animal and human chemoprevention trials.


Network analysis of Bogotá's Ciclovía Recreativa, a self-organized multisectorial community program to promote physical activity in a middle-income country.
Conduct a social network analysis of the health and non-health related organizations that participate in Bogotá's Ciclovía Recreativa (Ciclovía). Cross-sectional study. Ciclovía is a multisectoral community-based mass program in which streets are temporarily closed to motorized transport, allowing exclusive access to individuals for leisure activities and physical activity. Twenty-five organizations that participate in the Ciclovía. Seven variables were examined by using network analytic methods: relationship, link attributes (integration, contact, and importance), and node attributes (leadership, years in the program, and the sector of the organization). The network analytic methods were based on a visual descriptive analysis and an exponential random graph model. Analysis shows that the most central organizations in the network were outside of the Health sector and include Sports and Recreation, Government, and Security sectors. The organizations work in clusters formed by organizations of different sectors. Organization importance and structural predictors were positively related to integration, while the number of years working with Ciclovía was negatively associated with integration. Ciclovía is a network whose structure emerged as a self-organized complex system. Ciclovía of Bogotá is an example of a program with public health potential formed by organizations of multiple sectors with Sports and Recreation as the most central.


[Influence of temperature on the population dynamics of the rotifer Brachionus calyciflorus pallas].
Experiments were designed to test the influence of temperature on the life table data of the rotifer Brachionus calyciflorus Pallas. It is examined how well the observed modifications agree with theoretical models, and how they influence the temporal changes of population densities in limited and unlimited laboratory populations. On the basis of the experimental results, the population dynamics of planktonic rotifers in several natural habitats were analysed and interpreted. Laboratory Studies at 15, 20, and 25° C. 1. In individual cultures, the duration of all developmental stages (eggs, juvenils, adults) decreased with increasing temperature (Table 1, Fig. 1). On the other hand, the rate of reproduction was positively correlated with temperature. As a result of this twofold influence of temperature, the mean number of offspring per female shows an optimum at 20° C. 2. Unlimited populations which grew exponentially were characterised by a stable age distribution. Within the temperature range under study, the intrinsic rate of natural increase of unlimited populations rose with increasing temperature. 3. In populations limited by food supply, the mean population densities as well as the type and the intensity of oscillations was determined (Table 4, Figs. 2-5). Egg ratios and proportions of immature animals were also determined. Highest mean population densities occured at low temperatures, highest maximum densities at high temperatures. The latter fact is the result of stronger oscillations at higher temperatures: at 15° C oscillations were damped, at 20° C permanent or just increasing (no extinction within 60 days), at 25° C clearly increasing (extinction within 30 days). Amplitude and frequence of the oscillations were positively correlated with temperature. 4. The optima for the population growth and abundance were apparently not at the same temperature (Table 4). 5. The mictic rate, measured as the proportion of sexual females in the population, was relatively small; in limited populations it was larger than in unlimited populations. Temperature had a positive influence at high population densities. Test of Population Models. 1. Using life table data of individuals, theoretical predictions about the growth rate and the age structure of populations during exponential growth have been made by several authors. It is shown that at all temperatures the predictive power of the well known demographic model of Lotka is about as good as that of a recent model by Edmondson (Table 2). It is suggested that both models give adequate causal descriptions of exponential growth inspite of their manifold and different simplifications. As a consequence it is concluded that the observed influences of temperature on exponential growth are the result of direct influences of temperature on the life table data. 2. When mean population densities were estimated by theoretical calculations of energy balance, a rather good agreement with the empirical data was found. 3. Determination of the animal's food efficiencies on the basis of the observed production of biomass suggest that the coefficient of efficiency is significantly larger at 15° C (37%) than at 20 and 25° C (27 and 28%, resp.). 4. According to Cook and to Ricker, the mean generation length T permits predictions about type and frequency of the oscillations. When T was calculated from the life table data, the predictions about the oscillations were in fairly good agreement with the results on limited populations. The meaning of the parameter T in species with overlapping generations is discussed. Field Observations. During 1967 measurements of temperature and population densities of Brachionus calyciflorus were carried out in 15 artificial basins (0.3-50 m3) and 7 ponds (Figs. 6-8). An analysis of these data gave the following results: 1. During sudden population explosions, the growth rates were, on the average, positively correlated with environmental temperature. The agreement with laboratory data is quite good (Fig. 9). It is concluded, that temperature co-determines this aspect of population dynamics in the field. 2. The largest maxima of population densities were found at 20-28° C. With about 105 individuals/liter they are in the same order of magnitude as the corresponding data of laboratory populations. Average population densities seem to be independent of temperature within the range of 12-28° C; outside this range they appear to decrease (Fig. 10). Average densities in the field were clearly lower (10-102 individuals/liter) than long-term means of population densities in experimental populations (about 104-105 individuals/liter). 3. Fluctuations were stronger at high than at low temperatures. The degree of temperature dependence is about the same in the laboratory and in the field. However, at all temperatures the absolute values were greater in the field than in laboratory populations of the same temperature (Fig. 11). Modifying influences of biotic factors (phytoplankton, competitors, predators) are discussed.


Effects of antibiotics on the endophyte and phyllosphere bacterial communities of lotus from above and below surface water in a typical shallow lake.
Antibiotics are ubiquitous pollutants that are widely found in aquatic ecosystems, where the bacterial community of aquatic plants is influenced by antibiotics. However, differences between endophyte and phyllosphere bacteria of Lotus from above and below surface water remains unclear. Lotus samples from above and below the surface water were collected to investigate the differences in endophyte and phyllosphere bacteria and dominant environmental factors in regions with low (L-) and high (H-) total antibiotic levels. There were significant differences in Shannon diversity between endophyte and phyllosphere bacteria except between the below-surface water phyllosphere bacteria and below-surface water endophytes in both L-antibiotic and H-antibiotic regions, with higher values for phyllosphere bacteria. The dominant phylum in all phyllosphere samples was Proteobacteria (76.1%-92.5%), while Cyanobacteria (47.8%-81.1%) was dominant in all endophyte samples. The dominant source of above-surface water endophytes was below-surface water endophytes (83.68-91.25%), below-surface water phyllosphere bacteria (48.43-55.91%) for above-surface water phyllosphere bacteria, and above-surface water endophytes (53.83-61.80%) for below-surface water endophytes, while the dominant contributor to the below-surface water phyllosphere bacteria was also below-surface water endophytes (52.96-61.00%) in two regions, indicating that antibiotic stress changed the sink‒source relationship between endophytes and phyllosphere bacteria. The physical-chemical properties of surface water and sediments could be responsible for the variations in the above- and below-surface water endophytes and phyllosphere bacteria in both regions. It is suggested that antibiotics may have a substantial effect on endophyte and phyllosphere bacterial community.


Nonprofessional and professional help-agents' views of interventions with young maladapting school children.
The expectations of nonprofessional and professional help-agents about helping interventions with young children experiencing different types of school adjustment problems (i.e., aggressive-acting out, shy-anxious, and learning problems) were studied. The two groups responded similarly. Shy-anxious children were seen as most appropriate for the intervention, the easiest and most enjoyable group to work with, and as having the best prognoses. These four sets of judgments were relatively independent of each other. A connection was made between the current data and prior findings suggesting that shy-anxious children have more favorable treatment outcomes than other groups.


[Talocrural angle and ankle joint mobility in Germans and Japanese].
1980 Krämer and Gudat introduced the talo crural angle, which provides exact measurement of the mobility of the ankle joint. In field studies in Germany we found a greater range of mobility in female compared with male persons. With advancing age range of mobility decreased in both sex. Same examinations in Japan were performed to determine influence of genetic and way of life pattern.


Immunoassay for functional human soluble interleukin-6 receptor in plasma based on ligand/receptor interactions.
Soluble forms of most cytokine receptors, able to bind effectively to their respective ligands, have now been described. A soluble interleukin-6-binding molecule derived from the gp80 component of the multichain IL-6 receptor can be detected in biological fluids, and can act as an agonist of IL-6 activity. The clinical significance of the soluble receptor levels still remains to be explored. We took advantage of the characterization of an anti-IL-6 monoclonal antibody and of an anti-IL-6R monoclonal antibody that both bound to IL-6/IL-6R complexes to design an immunometric assay for the measurement of soluble IL-6R complexed to IL-6. This reaction scheme was designated as ELIA (enzyme-ligand immunoassay). When exogeneous IL-6 was added in excess to an sIL-6R containing sample, all sIL-6R was present in a complexed form. Thus, the reaction scheme could also be used to determine total sIL-6R concentrations. A recombinant sIL-6R standard was prepared from the supernatant of murine thymoma cells transfected with a gene coding for an extracellular portion of the IL-6 receptor. The assay permitted the precise and reproducible measurement of sIL-6R in serum or plasma. This approach is of general relevance for the determination of soluble cytokine receptors in biological fluids, provided that adequate anti-cytokine and anti-receptor antibodies are available.


[The reasons for the resistance of Vibrio cholerae to diagnostic phages].
Phage resistance of 225 strains of cholera germs of O1 group obtained from different countries in 1988-1992 has been analyzed. Change of sensitivity to diagnostic phages was mostly connected with the decrease or loss of agglutinability in cholera sera. Phage resistance is rather conditioned by the change of the surface structures of the cell and by further change of phage reception zones. The increase in the number of strains sensitive to diagnostic phages after 6-12 months of storage evidenced for stabilization of cell wall structures and increase of their viability under relatively favourable conditions of storage.


Experience with plasmin inhibitors.
The involvement and role of the plasminogen activator-plasmin system in normal and pathological wound healing is reviewed. The methods currently available for demonstrating plasmin activity are briefly described. The article also reviews some other serine proteases potentially involved in pathological wound healing processes. The current ophthalmological therapeutic measures used to regulate tissue proteolysis are also described.


Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice.
Inhibition of lymphocyte trafficking by treatment with an anti-α4 integrin antibody has been clinically validated as a therapeutic approach for inflammatory bowel disease (IBD), and the orally effective 'anti-α4 integrin therapy' may be more convenient in clinical practice. The aim of this study was to investigate the pharmacological profile and anti-inflammatory effect of a novel, orally active small molecule α4 integrin antagonist, AJM300. The binding specificity/potency of HCA2969 (the active metabolite of AJM300) were investigated in vitro. The pharmacodynamics for α4 integrin antagonism of AJM300 was investigated in mice. The anti-inflammatory effect of AJM300 fed in a diet and the anti-α4 integrin monoclonal antibody was evaluated in a mouse colitis model induced by transfer of IL-10 deficient T cells. HCA2969 selectively inhibited the in vitro binding of α4 integrin (α4β7/α4β1) to the cell adhesion molecules. Oral treatment with AJM300 dose-dependently inhibited lymphocyte homing to Peyer's patches and increased the peripheral lymphocyte count in the same dose range. AJM300 dose-dependently prevented the development of experimental colitis in mice. A significant inhibition of colon weight increase was accompanied by inhibition of T-cell infiltration into the lamina propria of colon. The maximum efficacy of AJM300 (1% diet) was comparable to that achieved by the saturated α4 integrin blockade with antibody. Oral treatment with the selective small molecule α4 integrin antagonist (AJM300) prevented the development of colitis and its efficacy was comparable to that of the anti-α4 integrin antibody.


Quantification of photoreceptor layer thickness in normal eyes using optical coherence tomography.
To demonstrate the ability to segment and analyze individual intraretinal layers, including the outer retinal complex (ORC; outer nuclear layer and inner and outer segments of the photoreceptor cells), in healthy eyes using images acquired from the latest commercially available optical coherence tomography (OCT) system (StratusOCT; Carl Zeiss Meditec, Inc., Dublin, CA) and from the ultrahigh resolution OCT (UHR-OCT) prototype. Thirty-seven eyes from 37 healthy subjects underwent complete ophthalmologic examination using StratusOCT and UHR-OCT. ORC was identified and measured using a segmentation algorithm. For StratusOCT, mean weighted ORC thickness +/- SD was 91.1 +/- 7.9 microm, and mean weighted total retinal thickness +/- SD was determined to be 258.9 +/- 10.1 microm. For UHR-OCT, mean weighted ORC thickness +/- SD was 96.4 +/- 6.3 microm, and mean weighted total retinal thickness +/- SD was determined to be 263.4 +/- 9.2 mum. There was a higher rate of algorithm failure with UHR-OCT images. Photoreceptor layer thickness can be calculated by measuring ORC on OCT images using a macular segmentation algorithm. ORC values may serve as a useful objective parameter in determining the efficacy of various therapeutic modalities that target the photoreceptor layer in various diseases.


Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment.
18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.


[Quantitative and qualitative analysis of oral microbiota by orthopedic rehabilitation with full and partial removable dentures].
Microbiological analysis of biomaterial surface in dental prosthesis showed the most common colonizing gram-positive species to be S. aureus, Micrococcus spp., S. haemolyticus, E. faecalis, mainly massive colonization with S. aureus was seen. The highest concentration of C. albicans colonization was found in removable dentures and may have a destructive effect on prosthetic material.


Bloom's syndrome with porokeratosis of Mibelli and multiple cancers of the skin, lung and colon.
A 38-year-old Japanese male with Bloom's syndrome (BS) and porokeratosis of Mibelli (PM) developed multiple carcinomas of the skin and lung. There were multiple, spontaneous chromosomal aberrations and frequent sister chromatid exchanges (SCE). Cutaneous delayed-type hypersensitivity reactions were defective and serum IgM was decreased. The lung cancer was treated with radiation, which was effective but caused a severe pulmonary atelectasis and esophageal stricture. The patient expired one-and-a-half years later because of pneumonia. Autopsy disclosed an adenocarcinoma of the colon. The concurrent PM was considered responsible for the occurrence of multiple skin cancers.


Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol.
Feedback control of cholesterol synthesis is mediated in part by sterol-induced binding of HMG CoA reductase to Insig proteins in the endoplasmic reticulum (ER). Binding leads to ubiquitination and proteasomal degradation of reductase, a rate-controlling enzyme in cholesterol synthesis. Using in vitro and in vivo assays, we show that lanosterol, the first sterol intermediate in cholesterol synthesis, potently stimulates ubiquitination of reductase, whereas cholesterol has no effect at 10-fold higher concentrations. Lanosterol is not effective in mediating the other action of Insigs, namely to promote ER retention of SCAP-SREBP complexes, a reaction that is mediated directly by cholesterol. A pair of methyl groups located in the C4 position of lanosterol confers this differential response. These data indicate that buildup of cholesterol synthesis intermediates represses the pathway selectively at reductase and reveal a previously unappreciated link between feedback inhibition of reductase and carbon flow through the cholesterol synthetic pathway.


Stimulation of HLA-A,B,C by IFN-alpha. The derivation of Molt 4 variants and the differential expression of HLA-A,B,C subsets.
Spontaneous mutants with altered HLA-A,B,C response to interferon-alpha (IFN-alpha) were isolated from the human thymus leukemia cell line Molt 4. Using fluorescein isothiocyanate (FITC)-conjugated W6/32 (a monoclonal antibody to HLA-A,B,C) and the fluorescence-activated cell sorter, the cells with highest and lowest fluorescence after 24-48 h of IFN-alpha treatment were selected and expanded. After several cycles of selection, mutant clones with low (greater than 10% of wild-type) and high (three times better) response were obtained. A similar protocol was employed to derive high responder mutants with the monoclonal antibody YT76, which recognises a subset of HLA strongly induced by IFN-alpha. Stable clones were derived for which YT-HLA induction was 7-fold that of Molt 4 cells and for which HLA induction occurred at 100-fold lower concentrations of IFN-alpha. The high response phenotype of the mutants was not accompanied by a significant increase in the constitutive level of expression of HLA-A,B,C (in the absence of IFN). The increase in the level of HLA-A,B,C expression after IFN-alpha treatment is mostly accounted for by the increase in the expression of a subset of HLA molecules, detected by the monoclonal antibody YT76 including HLA-B molecules.


Endothelialization of over- and undersized flow-diverter stents at covered vessel side branches: An in vivo and in silico study.
Although flow-diverting devices are promising treatment options for intracranial aneurysms, jailed side branches might occlude leading to insufficient blood supply. Especially differences in the local stent strut compression may have a drastic influence on subsequent endothelialization. To investigate the outcome of different treatment scenarios, over- and undersized stent deployments were realized experimentally and computationally. Two Pipeline Embolization Devices were placed in the right common carotid artery of large white swine, crossing the right ascending pharyngeal artery. DSA and PC-MRI measurements were acquired pre- and post-stenting and after three months. To evaluate the stent strut endothelialization and the corresponding ostium patency, the swine were sacrificed and scanning electron microscopy measurements were carried out. A more detailed analysis of the near-stent hemodynamics was enabled by a realistic virtual stenting in combination with highly resolved Computational Fluid Dynamics simulations using case-specific boundary conditions. The oversizing resulted in an elongated stent deployment with more open stent pores, while for the undersized case a shorter deployment with more condensed pores was present. In consequence, the side branch of the first case remained patent after three months and the latter almost fully occluded. The virtual investigation confirmed the experimental findings by identifying differences between the individual velocities as well as stent shear stresses at the distal part of the ostia. The choice of flow-diverting device and the subsequent deployment strategy strongly influences the patency of jailed side branches. Therefore, careful treatment planning is required, to guarantee sufficient blood supply in the brain territories supplied those branches.


Utilization of Optical Coherence Tomography in the Evaluation of Cherry Hemangiomas.
Cherry hemangiomas are common vascular proliferative lesions that can be concerning from a cosmetic perspective. Laser therapy is often used to eradicate cherry hemangiomas, but some lesions require multiple treatments or do not resolve at all. The suboptimal response to laser treatment may be due to limitations in penetration depth by vascular lasers such as the pulsed dye laser. Optical coherence tomography is a low-energy, light-based imaging device that can evaluate the depth and extent of vascular lesions such as cherry hemangiomas by allowing visualization of tissue structure and blood vessel architecture, which cannot be appreciated by clinical or dermatoscopic examination alone. We present optical coherence tomography images of a cherry hemangioma to demonstrate the precision and resolution of this imaging modality. Optical coherence tomography provides valuable information that has the potential to predict response to laser therapy without unnecessary attempts. Future prospective studies will determine its value for this purpose.

 J Drugs Dermatol. 2016;15(6):713-714.


A Two-Step Orthogonal Chromatographic Process for Purifying the Molecular Adjuvant QS-21 with High Purity and Yield.
QS-21 is a triterpene glycoside saponin found in the bark of the Chilean soap bark tree Quillaja saponaria. It is a highly potent vaccine adjuvant that is included in two approved vaccines and has shown promise in numerous other vaccine candidates in the research and clinical pipelines. One major hurdle to the widespread use of this adjuvant is the difficulty of obtaining it in high yield and purity. Previously reported purification approaches either showed suboptimal purity and/or yield, lacked efficiency, or had strict requirement on the composition of the starting material. Here, we report the development of a new two-step orthogonal chromatographic process, consisting of a polar reversed-phase (RP) chromatography step followed by a hydrophilic interaction chromatography (HILIC) step, for purifying QS-21 from a commercially available Quillaja saponaria bark extract with high yield and > 97% purity. This process makes available a simple and efficient method for obtaining highly pure QS-21 from saponin-enriched bark extract.


The evaluation of free-L-carnitine, zinc and fructose in the seminal plasma of patients with varicocele and normozoospermia.
The function of the epididymis and of the sex accessory glands have been investigated in a selected group of varicocele patients with normal sperm count. In the seminal plasma of these patients free-L-carnitine, fructose and zinc levels were determined as functional markers respectively of epididymis, seminal vesicles and prostate. Despite the unvaried free-L-carnitine and fructose levels, zinc levels were significantly lower (p less than 0.001) than in the control group. The Zn/F ratio, an index of the ratio between the prostatic and vesicular secretions, resulted also lower (p less than 0.01) with respect to the controls. The authors suggest that the impaired prostatic function could arise from the decreased venous drainage in the vesico-prostatic plexus. In the same patients sperm motility resulted significantly lower than in the controls, and was positively related to zinc levels (r = 0.44, p less than 0.01) and, to a higher degree, to the Zn/F ratio (r = 0.62, p less than 0.001). Our data show that in this selected group of varicocele patients with a not yet altered tubular epididymal unit, sex accessory gland secretions can influence, per se, the motility of the ejaculated spermatozoa.


[Blood-borne infections and the pregnant health care worker. Risks and preventive measures].
Due to the increasing proportion of women in health care, as well as changes in working conditions (implementation of safety devices, minimally invasive/endoscopic procedures) the question arises whether the applicable laws and regulations for the protection of working mothers are outdated and should be updated.Individual risk analysis, as well as the inclusion of the pregnant health care worker in the decision-making process with regard to continuation or modification of the work practice serves as a protection of the expectant mother and unborn child and allows a continuation of the occupational activities.


Comparison of contact angle hysteresis of different probe liquids on the same solid surface.
Advancing and receding contact angles of water, formamide and diiodomethane were measured on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) layers deposited on three different solid supports-glass, mica and poly(methyl methacrylate). Up to five statistical monolayers were deposited on the surfaces by spreading DPPC solution. It was found that even on five statistical DPPC monolayers, the hysteresis of a given liquid depends on the kind of solid support. Also on the same solid support the contact angle hysteresis is different for each probe liquid used. The AFM images show that the heights of roughness of the DPPC films cannot be the primary cause of the observed hysteresis because the heights are too small to cause the observed hystereses. It is believed that the hysteresis is due to the liquid film present right behind the three-phase solid surface/liquid drop/gas (vapour) contact line and the presence of Derjaguin pressure. The value of contact angle hysteresis depends on both the solid surface and liquid properties as well as on intermolecular interactions between them.


Retroviral transfer and expression of human MDR-1 in a murine haemopoietic stem cell line does not alter factor dependence, growth or differentiation characteristics.
In view of the recent report of a myeloproliferative syndrome in mice that had received an MDR-1-transduced haemopoietic graft, we have investigated the potential effects of MDR-1 expression on primitive haemopoietic cell growth and differentiation. Retroviral gene transfer was used to achieve exogenous expression of either MDR-1 or truncated nerve growth factor receptor (tNGFR) in the multipotent murine haemopoietic progenitor cell line, FDCP-mix. Following gene transfer, clonal lines were derived and FACS analysis confirmed appropriate expression of each transgene. MDR-1 (but not tNGFR) expression was associated with verapamil-sensitive rhodamine efflux and resistance to killing by etoposide. When growth factor responsiveness, proliferative capacity and differentiation capacity were examined, MDR-1 expressing FDCP-mix cells exhibited a normal phenotype and mimicked the response of tNGFR-expressing or untransduced FDCP-mix cells. Thus, in the model system we have used, MDR-1 does not perturb haemopoietic cell growth and development and our data do not support a myeloproliferative role for MDR-1.


Immunological methods for quantifying free and total serum IgE levels in allergy patients receiving omalizumab (Xolair) therapy.
Omalizumab (humanized-IgG1 anti-human IgE Fc, Xolair) complexes circulating IgE, blocking IgE binding to high affinity epsilon Fc receptors (FcepsilonR1) on mast cells and basophils. Free (non-Omalizumab bound) IgE levels in serum are a measure of effective Omalizumab dosing. The goal of this study was to quantify free (non-Omalizumab-complexed) and total serum IgE levels in asthma patients on Xolair. The concentration of (non-Omalizumab bound) free IgE in human serum was measured using a solid phase immunoenzymetric assay (IEMA) in which IgE was captured from serum with monoclonal anti-human IgE (clone HP6061) and detected with labeled-FcepsilonR1alpha. In a companion total human serum IEMA, IgE was captured from serum with the same anti-human IgE (clone HP6061) and all bound IgE was detected with labeled monoclonal anti-human IgE Fc (clone HP6029). Free and total IgE levels were quantified in pre- and 1 and 3 months post Omalizumab therapy sera from 12 allergic asthma patients. In the absence of Omalizumab, working ranges of the free and total IgE IEMAs were comparable (10-1000 kIU/l), with excellent precision, reproducibility and parallelism. Pre-Omalizumab total and free IgE levels by IEMA were highly correlated (r2=0.99, Y=0.9X+0.32, p<0.001), as were total serum IgE levels by IEMA and ImmunoCAP-250 (r2=0.98, Y=1.1X-0.05, p<0.001, n=33). In vitro reduction of free IgE (>90%) occurred at [Omalizumab:IgE] molar ratios of 2-20. Total IgE levels in 12 asthmatics increased from pre-therapy levels (52-658 kIU/l) by 1.5-5.5-fold at 1 month and 1.7-8.6 fold at 3 months of uninterrupted Omalizumab treatment. Free IgE levels fell by 49%-97% at 1 month and 45%-98% by 3 months of Omalizumab treatment. Free and total IgE levels by IEMA aid in monitoring patients receiving Omalizumab therapy.


Combination radiofrequency (RF) ablation and IV liposomal heat shock protein suppression: reduced tumor growth and increased animal endpoint survival in a small animal tumor model.
To investigate the effect of IV liposomal quercetin (a known down-regulator of heat shock proteins) alone and with liposomal doxorubicin on tumor growth and end-point survival when combined with radiofrequency (RF) tumor ablation in a rat tumor model. Solitary subcutaneous R3230 mammary adenocarcinoma tumors (1.3-1.5 cm) were implanted in 48 female Fischer rats. Initially, 32 tumors (n=8, each group) were randomized into four experimental groups: (a) conventional monopolar RF alone (70°C for 5 min), (b) IV liposomal quercetin alone (1 mg/kg), (c) IV liposomal quercetin followed 24hr later with RF, and (d) no treatment. Next, 16 additional tumors were randomized into two groups (n=8, each) that received a combined RF and liposomal doxorubicin (15 min post-RF, 8 mg/kg) either with or without liposomal quercetin. Kaplan-Meier survival analysis was performed using a tumor diameter of 3.0 cm as the defined survival endpoint. Differences in endpoint survival and tumor doubling time among the groups were highly significant (P<0.001). Endpoint survivals were 12.5±2.2 days for the control group, 16.6±2.9 days for tumors treated with RF alone, 15.5±2.1 days for tumors treated with liposomal quercetin alone, and 22.0±3.9 days with combined RF and quercetin. Additionally, combination quercetin/RF/doxorubicin therapy resulted in the longest survival (48.3±20.4 days), followed by RF/doxorubicin (29.9±3.8 days). IV liposomal quercetin in combination with RF ablation reduces tumor growth rates and improves animal endpoint survival. Further increases in endpoint survival can be seen by adding an additional anti-tumor adjuvant agent liposomal doxorubicin. This suggests that targeting several post-ablation processes with multi-drug nanotherapies can increase overall ablation efficacy.


Pandemic risk of COVID-19 outbreak in the United States: An analysis of network connectedness with air travel data.
The United States has become the country with the largest number of COVID-19 reported cases and deaths. This study aims to analyze the pandemic risk of COVID-19 outbreak in the US. Time series plots of the network density, together with the daily reported confirmed COVID-19 cases and flight frequency in the five states in the US with the largest numbers of COVID-19 cases were developed to discover the trends and patterns of the pandemic connectedness of COVID-19 among the five states. The research findings suggest that the pandemic risk of the outbreak in the US could be detected as early as the beginning of March. The signal was prior to the rapid increase of reported COVID-19 cases and flight reduction measures. Travel restriction can be strengthened at an early stage of the outbreak while more focus of local public health measures can be addressed after community spread. The study demonstrates the application of network density on detection of pandemic risk and its relationship with air travel restriction in order to provide useful information for policymakers to better optimize timely containment strategies to mitigate the outbreak of infectious diseases.


Syndrome of inappropriate antidiuresis and cerebral salt wasting syndrome: are they different and does it matter?
The syndrome of inappropriate antidiudresis (SIAD) and cerebral salt wasting (CSW) are similar conditions with the main difference being the absence or presence of volume depletion. The two conditions may be indistinguishable at presentation, as volume status is difficult to assess, which can lead to under-diagnosis of CSW in patients with central nervous system (CNS) disease. Carefully conducted studies in patients with CNS disease have indicated that CSW may be more common than SIAD. CSW may be differentiated from SIAD based on the persistence of hypouricemia and increased fractional excretion of urate following the correction of hyponatremia. Hyponatremia should be prevented if possible and treated promptly when discovered in patients with CNS disease as even mild hyponatremia could lead to neurological deterioration. Fluid restriction should not be used for the prevention or treatment of hyponatremia in hospitalized patients with CNS disease as it could lead to volume depletion especially if CSW is present. 0.9% sodium chloride may not be sufficiently hypertonic for the prevention of hyponatremia in hospitalized patients with CNS disease and a more hypertonic fluid may be required. The preferred therapy for the treatment of hyponatremia in patients with CNS disease is 3% sodium chloride.


Vitamin D signaling increases nitric oxide and antioxidant defenses of bovine monocytes.
Vitamin D contributes to multiple aspects of bovine immunity and is reported to decrease the effects of mastitis and metritis in dairy cows. We hypothesized that vitamin D signaling in bovine monocytes increases antioxidant responses as part of its immunomodulatory actions. Our objectives were to assess the effects of vitamin D on oxidant and antioxidant responses of bovine monocytes. Monocytes from peripheral blood of nonpregnant, lactating Holstein cows between 90 and 300 d in milk were used for in vitro cell culture experiments. To test the effects of vitamin D on reactive oxygen metabolites (dROM) and antioxidant potential (AOP), monocytes from 14 cows were cultured in replicates for 16 h with 25-hydroxyvitamin D3 [25(OH)D3, 0 or 75 ng/mL] in a factorial arrangement with lipopolysaccharide (LPS, 100 ng/mL) or interferon-γ (IFN-γ, 10 ng/mL) or with no stimulation. Data were analyzed by ANOVA for main effects of 25(OH)D3, stimulant, and interactions between 25(OH)D3 and stimulant. Significant interactions between 25(OH)D3 and stimulant were observed for dROM and AOP of culture supernatants. In unstimulated cultures, 25(OH)D3 tended to increase dROM, but the opposite was observed in stimulated cultures. In contrast, LPS and IFN-γ treatments alone decreased AOP of culture supernatants, but 25(OH)D3 counteracted the decrease in AOP caused by IFN-γ. Abundances of transcripts of genes encoding antioxidant-related proteins were measured by quantitative PCR using RNA from monocytes from 4 cows treated with 25(OH)D3 (0 or 75 ng/mL) in a factorial arrangement with increasing concentrations of LPS (0 to 1,000 ng/mL) or IFN-γ (0 to 10 ng/mL). Treatment with 25(OH)D3 increased transcripts of genes encoding metallothionein 1A and metallothionein 2A in the presence of IFN-γ but not LPS. Furthermore, 25(OH)D3 increased transcripts of genes encoding thioredoxin and thioredoxin reductase, but the effect of 25(OH)D3 did not depend on IFN-γ or LPS stimulation. In conclusion, 25(OH)D3 increased antioxidant capacity of IFN-γ-stimulated bovine monocytes, potentially by increasing metallothionein and thioredoxin activities in monocytes.


The degradation and metabolism of chlorfluazuron and flonicamid in tea: A risk assessment from tea garden to cup.
Degradation and metabolism of chlorfluazuron and flonicamid from tea garden to cup were simultaneously investigated by a modified QuEChERS method coupled with UPLC-MS/MS quantification. The dissipation half-lives of chlorfluazuron, flonicamid, and total flonicamid (the sum of flonicamid and its metabolites TFNG, TFNA, and TFNA-AM) in fresh tea leaves during tea growth were 6.0 d, 4.8 d, and 8.1 d, respectively. TFNG and TFNA were generated during tea growth. After tea processing, the residues of chlorfluazuron, flonicamid, and its metabolites in black tea were higher than those in green tea. The average processing factors of chlorfluazuron, flonicamid, and total flonicamid in black tea were 2.54, 3.02, and 2.87, respectively, while in green tea they were 2.40, 2.93, and 2.79, respectively. TFNG, TFNA, and TFNA-AM were formed rapidly during the drying step. Considering the influence of water content at various processing steps, the average loss rates of chlorfluazuron, flonicamid, and total flonicamid residue from fresh tea leaves to black tea were 16.7%, 33.8%, and 20.7%, respectively, and 29.6%, 14.0% and 18.2%, respectively, in the case of green tea. The highest leaching rates of chlorfluazuron, flonicamid, and total flonicamid during tea brewing were 6.8%, 97.0%, and 97.4%, respectively, in black tea infusion, and 6.0%, 98.9%, and 98.6%, respectively, in green tea infusion. The metabolites, especially TFNG, had a higher leaching rate during tea brewing. The migration of chlorfluazuron from fresh leaves to tea infusion was low, and the migration of flonicamid was high. The RQc and RQa of chlorfluazuron and total flonicamid were less than 1. This result indicates that the potential dietary intake risk of chlorfluazuron from tea is negligible. However, the risk of total flonicamid intake is three times higher than that of chlorfluazuron. There is a potential risk of intake of flonicamid and its metabolites in tea for human consumption.


Considerations on BVD eradication for the Irish livestock industry.
Animal Health Ireland has produced clear guidelines for the control of Bovine Viral Diarrhoea (BVD) infection in Irish cattle herds. In the course of developing these guidelines it was clear that a framework for regional and/or national BVD control would be required to increase the uptake of BVD control at farm level and reduce the overall prevalence of the disease. This paper assessed the economic impact of BVD, epidemiological aspects of the disease to its control, models of BVD control, international experiences of BVD control programmes. The technical knowledge and test technology exists to eradicate BVD. Indeed, many countries have successfully and others are embarking on control of the disease. The identification and prompt elimination of PI cattle will form the basis of any control programme. The trade of such animals must be curtailed. Pregnant and potentially pregnant carrying PI foetuses pose a significant threat. International experience indicates systematic, well coordinated programmes have the most success, while voluntary programmes can make good initial progress but ultimately fail. The farming community must buy into any proposed programme, and without their support, failure is likely. To buy into the programme and create such a demand for BVD control, farmers must first be well informed. It is likely that stemming economic loss and improving productivity will be the primary motivator at individual farm level.


[Renal agenesia: angiographic diagnosis (author's transl)].
The existence of renal agenesia was noted in 25 cases of about 1,500 abdominal angiographic examinations. Clinical symptomatology and radiological findings are discussed and some cases reported.


Endovascular Treatment of Renal Artery Stenosis in the Post CORAL Era.
Atherosclerotic renal artery stenosis (RAS) is highly associated with hypertension and renal insufficiency. Determining causation and who may benefit from RAS treatment remains difficult. The role of endovascular management of atherosclerotic RAS was challenged by several recent randomized controlled trials (RCT) which failed to demonstrate benefit of stenting. In the largest RCT to date, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study did not find benefit of revascularization compared to medical therapy alone. While such RCTs represent the highest level of evidence to date, the conclusions drawn from them should be interpreted with caution due to substantial flaws in study design, inclusion, and exclusion criteria. The current AHA/ACC recommendations for RAS management are supported by many level-II evidence cohort studies which consistently found benefit of revascularization in groups with the highest likelihood of clinically significant RAS. Further study of these patient groups are needed to define a clear role for endovascular therapy of renal artery stenosis.


Cerebral palsy. Mechanical evaluation and conservative correction of limb joint contractures.
Studies in animals and in children with cerebral palsy (CP) allow precise evaluation of the physiologic and pathophysiologic adaptations in muscle and tendon. In the individual child with CP, clinical evaluation must be much more precise than a routine examination in order to clearly define the nature of the contractures and select the correct therapeutic program.


Comparison of undirected frequency-domain connectivity measures for cerebro-peripheral analysis.
Analyses of cerebro-peripheral connectivity aim to quantify ongoing coupling between brain activity (measured by MEG/EEG) and peripheral signals such as muscle activity, continuous speech, or physiological rhythms (such as pupil dilation or respiration). Due to the distinct rhythmicity of these signals, undirected connectivity is typically assessed in the frequency domain. This leaves the investigator with two critical choices, namely a) the appropriate measure for spectral estimation (i.e., the transformation into the frequency domain) and b) the actual connectivity measure. As there is no consensus regarding best practice, a wide variety of methods has been applied. Here we systematically compare combinations of six standard spectral estimation methods (comprising fast Fourier and continuous wavelet transformation, bandpass filtering, and short-time Fourier transformation) and six connectivity measures (phase-locking value, Gaussian-Copula mutual information, Rayleigh test, weighted pairwise phase consistency, magnitude squared coherence, and entropy). We provide performance measures of each combination for simulated data (with precise control over true connectivity), a single-subject set of real MEG data, and a full group analysis of real MEG data. Our results show that, overall, WPPC and GCMI tend to outperform other connectivity measures, while entropy was the only measure sensitive to bimodal deviations from a uniform phase distribution. For group analysis, choosing the appropriate spectral estimation method appears to be more critical than the connectivity measure. We discuss practical implications (sampling rate, SNR, computation time, and data length) and aim to provide recommendations tailored to particular research questions.


Effects of kinesiotaping on foot posture in participants with pronated foot: a quasi-randomised, double-blind study.
To investigate whether kinesiotaping improves excessive foot pronation compared with sham kinesiotaping. Quasi-randomised, double-blind study. One primary care centre. One hundred and thirty participants were screened for inclusion. Sixty-eight participants with pronated feet [Foot Posture Index (FPI)≥ 6] were enrolled, and the follow-up rate was 100%. Participants were allocated into one of two groups: an experimental kinesiotaping group (KT1) and a sham taping group (KT2). Measures were collected by a blinded assessor at baseline, and 1 minute, 10 minutes, 60 minutes and 24 hours after taping. The primary outcome was total FPI score, and the secondary outcome was rear-foot FPI score. There were no significant differences in total FPI score between kinesiotaping and sham taping at any time point. Similarly, there were no significant differences in rear-foot FPI score, apart from at 60-minute follow-up when the difference between groups was significant (P=0.04) but the effect size was very small (0.85 points on the rear-foot FPI score between -6 and +6). Kinesiotaping does not correct foot pronation compared with sham kinesiotaping in people with pronated feet.


Multimodal Electrocorticogram Active Electrode Array Based on Zinc Oxide-Thin Film Transistors.
Active electrocorticogram (ECoG) electrodes can amplify weak electrophysiological signals and improve anti-interference ability; however, traditional active electrodes are opaque and cannot realize photoelectric collaborative observation. In this study, an active and fully transparent ECoG array based on zinc oxide thin-film transistors (ZnO TFTs) is developed as a local neural signal amplifier for electrophysiological monitoring. The transparency of the proposed ECoG array is up to 85%, which is superior to that of the previously reported active electrode arrays. Various electrical characterizations have demonstrated its ability to record electrophysiological signals with a higher signal-to-noise ratio of 19.9 dB compared to the Au grid (13.2 dB). The high transparency of the ZnO-TFT electrode array allows the concurrent collection of high-quality electrophysiological signals (32.2 dB) under direct optical stimulation of the optogenetic mice brain. The ECoG array can also work under 7-Tesla magnetic resonance imaging to record local brain signals without affecting brain tissue imaging. As the most transparent active ECoG array to date, it provides a powerful multimodal tool for brain observation, including recording brain activity under synchronized optical modulation and 7-Tesla magnetic resonance imaging.


"Cold" Cognitive Control and Attentional Symptoms in Anxiety: Perceptions Versus Performance.
Clinically significant anxiety is associated with an array of attentional symptoms (e.g., difficulty concentrating; unwanted thought) that are subjectively experienced as severe. However, neuropsychological findings are mixed with respect to the presence of cognitive deficits that can account for these symptoms. Contextualizing predictions from established clinical theories (e.g., Attentional Control Theory) within contemporary, neurobiologically derived models of cognitive control (Dual Mechanisms of Control Theory), the present study investigated the relationship between "cold" proactive and reactive cognitive control, task effort, and subjective attentional symptoms (difficulty concentrating; unwanted thought) in a mixed clinical sample of individuals with generalized anxiety disorder (GAD) and/or obsessive-compulsive disorder (OCD) and a comparison sample of healthy controls. Clinical status moderated the relationship between attentional symptoms (attentional focusing and trait worry) and proactive cognitive control response time. Clinical status also moderated the relationship between trait worry and task effort. Higher trait worry was associated with slower proactive control and lower effort in healthy participants, but faster proactive control in clinical participants. Self-reported attentional focusing showed differential validity vis-à-vis proactive control response time in clinical versus healthy participants. Post-hoc conditional effects analysis suggested more accurate self-appraisals in healthy controls, but was not significant after correction for multiple comparisons. Preliminary evidence suggested that differences in task effort in anxious versus healthy adults may relate to subjective attentional symptoms in GAD and OCD.