DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality.
Cytokine release syndrome (CRS) immune effector cell-associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell-mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.


Persistence with first line anticholinergic medication in treatment-naïve overactive bladder patients.
The aim of this study was to evaluate the persistence of first line anticholinergic medication use by patients with overactive bladder (OAB). Data from a hospital outpatient database were matched with information obtained by a telephone survey of patients to determine which patients discontinued use of anticholinergic medication and to identify the reasons underlying discontinuation. The study group included 377 OAB patients (52 men, 325 women) with a mean age of 60.29 ± 13.84 years. In total, 189 patients (50.1%) were treated with trospium (median dose 27.86 ± 12.73 mg), 41 patients (10.9%) with propiverine (28.17 ± 4.97 mg), nine patients (2.4%) with extended-release tolterodine (4.0 ± 0 mg), 48 patients (12.7%) with solifenacin (5.94 ± 1.97 mg) and 90 patients (23.9%) with fesoterodine (6.09 ± 2.01 mg). The median time for persistence with the first line anticholinergic treatment was 6.53 ± 3.84 months. Persistence was significantly higher in patients treated with anticholinergic medication with an extended-release formulation than in patients treated with immediate-release anticholinergics. The most common reasons for termination of treatment were healing/resolution of symptoms (35.9%), low effectiveness (30.9%) and side-effects (23.7%). More than half of the OAB patients were not satisfied with their first line treatment. Other treatment options should be sought, such as changing the medication or dosage, or possibly combining treatments.


Microrheometry of semiflexible actin networks through enforced single-filament reptation: frictional coupling and heterogeneities in entangled networks.
Magnetic tweezers are applied to study the enforced motion of single actin filaments in entangled actin networks to gain insight into friction-mediated entanglement in semiflexible macromolecular networks. Magnetic beads are coupled to one chain end of test filaments, which are pulled by 5 to 20 pN force pulses through entangled solutions of nonlabeled actin, the test filaments thus acting as linear force probes of the network. The transient filament motion is analyzed by microfluorescence, and the deflection-versus-time curves of the beads are evaluated in terms of a mechanical equivalent circuit to determine viscoelastic parameters, which are then interpreted in terms of viscoelastic moduli of the network. We demonstrate that the frictional coefficient characterizing the hydrodynamic coupling of the filaments to the surrounding network is much higher than predicted by the tube model, suggesting that friction-mediated interfilament coupling plays an important role in the entanglement of non-cross-linked actin networks. Furthermore, the local tube width along the filament contour (measured in terms of the root-mean-square displacement characterizing the lateral Brownian motion of the test filament) reveals strong fluctuations that can lead to transient local pinching of filaments.


Microbial treatment of bis (2-ethylhexyl) phthalate in polyvinyl chloride with isolated bacteria.
In this study, we investigated the use of microbes to degrade and remove bis (2-ethylhexyl) phthalate (DEHP), a common plasticizer and a suspected endocrine disruptor, exuding from polyvinyl chloride. Four species of bacteria that utilize DEHP as their sole carbon source were isolated from garden soil, one of which, strain NK0301, was markedly more efficient than the others in degrading DEHP and was chosen for further studies. Strain NK0301 was a coryneform bacterium (1.5x1.0 microm) identified as Mycobacterium sp. from its 16S rDNA sequencing homology. It readily degraded DEHP to two major products determined by gas chromatography/mass spectrometry to be 2-ethylhexanol and 1,2-benzenedicarboxylic acid. Other phthalate esters, suspected of being endocrine disruptors, were also tested and all except two could be utilized by strain NK0301 as their sole source of carbon. When strain NK0301 was cultivated on polyvinyl chloride sheets containing DEHP as the plasticizer, it removed up to 90% of DEHP in 3 d. Following this treatment, the polyvinyl chloride sheets did not exude DEHP to artificial saliva.


[Comparison of the effect of ambroxol and dexamethasone on the expression of pulmonary surfactant proteins in the fetal rat lungs].
To investigate the effects of maternally administered dexamethasone and ambroxol on the mRNA levels of surfactant proteins (SP-A, SP-B and SP-C) expression in fetal rat lungs at gestational age day 19. A 19-day fetal rat lung model was employed. In situ hybridization was used to detect the expression of SP-B mRNA in alveolar type II cell, and the levels of SP-A, SP-B and SP-C mRNAs were detected by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). (1) SP-B mRNA was detected in situ in alveolar type II cells in fetal rat lung of day 19 gestational age; (2) In the late developmental period of fetal rat lungs, alveolar type II cells were also found around bronchus; (3) Comparing to beta-actin mRNA, the relative values of SP-A, SP-B and SP-C mRNAs were 0.81 +/- 0.26, 0.97 +/- 0.20 and 0.88 +/- 0.11 in fetal lung in the control group. The relative values of mRNAs of SP-A, SP-B and SP-C to beta-actin were 1.04 +/- 0.16, 1.28 +/- 0.29, 1.09 +/- 0.25 in fetal lungs of the ambroxol injected rats, and were 1.08 +/- 0.25, 1.23 +/- 0.35, 1.21 +/- 0.25 in fetal lungs of the dexamethasone injected rats, respectively. Both ambroxol and dexamethasone-treated rats had significantly higher mRNA expression of surfactant proteins compared to the control saline injected animals (P < 0.05). (4) There were no significant differences between ambroxol and dexamethasone in the effects of increasing expressions of surfactant protein mRNAs (P > 0.05). Antepartum administration of both ambroxol and dexamethasone can significantly increase fetal lung SP-A, SP-B and SP-C mRNAs expression.


Beta-blocker treatment of chronic heart failure: comparison of carvedilol and metoprolol.
Beta blockers have been shown to prolong survival in chronic heart failure. It is currently a matter of debate whether any beta blocker is superior to the other in terms of improving symptoms, left ventricular function, or prognosis. A number of comparative studies have been performed with metoprolol, a beta1-selective second-generation beta blocker, and carvedilol, a nonselective and vasodilatative third-generation beta blocker. This review will focus on the different pharmacological profiles of carvedilol and metoprolol as well as on the clinical consequences derived from these differences. The results indicate that in some studies carvedilol is superior to metoprolol in improving left ventricular ejection fraction. However, because there is no conclusive evidence that carvedilol is superior to metoprolol in terms of prognosis, it is not justified to substitute metoprolol with carvedilol. Comparative data on mortality reduction are not available before termination of the Carvedilol or Metoprolol European Trial. Nevertheless, the different effects of both beta blockers on the beta-adrenergic system have an impact on tolerability and beta-adrenergic responsiveness and thus exercise tolerance in heart-failure patients.


HPLC assay for atropine in serum and protein solutions after in vitro addition of the tropane alkaloid.
A simple and sensitive method for the determination of atropine in serum and protein solutions is presented. Atropine and procaine (internal standard) were extracted with diethylether from protein containing solutions after alkalinization. The residue of the evaporized ether phase, redissolved in diluted sulfuric acid, was injected directly onto a LiChrosorbR column. Atropine, procaine and serum constituents were separated by HPLC using an ion-pair containing mobile phase. The limit for the detection of atropine was 200 ng/ml. The method was used for the determination of atropine in a binding study. Percent binding values to human serum, human serum albumin and human alpha 1-acid glycoprotein were evaluated by equilibrium dialysis.


Phospholipase D activation by sphingosine 1-phosphate regulates interleukin-8 secretion in human bronchial epithelial cells.
Sphingosine 1-phosphate (S1P), a potent bioactive sphingolipid, has been implicated in many critical cellular events, including a regulatory role in the pathogenesis of airway inflammation. We investigated the participation of S1P as an inflammatory mediator by assessing interleukin-8 (IL-8) secretion and phospholipase D (PLD) activation in human bronchial epithelial cells (Beas-2B). S1P(1), S1P(3), S1P(4), S1P(5), and weak S1P(2) receptors were detected in Beas-2B and primary human bronchial epithelial cells. S1P stimulated a rapid activation of PLD, which was nearly abolished by pertussis toxin (PTX) treatment, consistent with S1P receptor/G(i) protein coupling. S1P also markedly induced Beas-2B secretion of IL-8, a powerful neutrophil chemoattractant and activator, in a PTX-sensitive manner. This S1P-mediated response was dependent on transcription as indicated by a strong induction of IL-8 promoter-mediated luciferase activity in transfected Beas-2B cells and a complete inhibition by actinomycin D. Beas-2B exposure to 1-butanol, which converts the PLD-generated phosphatidic acid (PA) to phosphatidylbutanol by a transphosphatidylation reaction, significantly attenuated the S1P-induced IL-8 secretion, indicating the involvement of PLD-derived PA in the signaling pathway. Inhibition of 12-O-tetradecanoyl-phorbol-13-acetate-stimulated IL-8 production by 1-butanol further strengthened this observation. Blocking protein kinase C and Rho kinase also attenuated S1P-induced IL-8 secretion. Our data suggest that PLD-derived PA, protein kinase C, and Rho are important signaling components in S1P-mediated IL-8 secretion by human bronchial epithelial cells.


Ganglion Cyst Presenting as an External Auditory Canal Mass.
A ganglion cyst of the temporomandibular joint is a benign lesion that may present as a mass on the anterior wall of the external auditory canal and should be differentiated from other skull base pathology prior to management.


Heavy Metal and Rice in Gluten-Free Diets: Are They a Risk?
A gluten-free diet (GFD) is the treatment of choice for gluten-related disorders. It has been associated with macro- and micronutrient deficiencies. Recently, consumption of arsenic-contaminated rice has raised concern because of the potential greater risk that it may represent for people on GFDs, whose rice consumption is high, since it is a fundamental cereal in GFDs. We reviewed the data published over the last 20 years in Medline and Scielo, in English, French and Spanish, on four metals (As, Hg, Cd, and Pb), to assess whether the evidence suggests that celiac disease or consumption of a GFD is associated with increased levels of blood/urinary metal concentrations. The review revealed a few articles that were directly related to the four metals and their relationships with a GFD. The evidence supports that rice-based products are a relevant source of As and other metals. Clinical studies and evaluations based on NHANES have indicated that persons on GFDs have higher As and Hg blood/urinary levels, suggesting that the diet and not the disease is responsible for it. The levels described are statistically significant compared to those of persons on complete diets, but far from toxic levels. The question of whether higher exposure to heavy metals associated with a GFD is biologically relevant remains unanswered and deserves study.


Primary Health Care Reform in the cities of Lisbon and Rio de Janeiro: context, strategies, results, learning and challenges.
On the 30th anniversary of Alma-Ata, the World Health Organization published in 2008 the "Primary Health Care Now More Than Ever" Report, calling on all governments to reflect on the need to reflect on four sets of reforms. These included: (i) universal coverage reforms; (ii) service delivery reforms; (iii) public policies reforms that would ensure healthier communities; and (iv) leadership reforms. In this context, in the period 2005-2016, the cities of Rio de Janeiro and Lisbon developed a profound primary healthcare reform, and did so by sharing many of the solutions based on the best internationally recognized organizational practices. Several factors were fundamental throughout Lisbon and Rio de Janeiro's path of reforms, namely: (i) teamwork with professional motivation; (ii) internal and external communication; (iii) strengthening of training activities; (iv) investment in facilities and equipment; (v) commitment to the information system and computerization; (vi) pay-for-performance; (vii) health care contractualisation between funders and providers; (viii) technical leadership; (ix) political leadership; and finally (x) quality and accreditation of facilities by public agency.


Macromolecular transport in jejunal mucosa of children with severe malnutrition: a quantitative study.
Small intestinal permeability to horseradish peroxidase (HRP) was assessed in jejunal biopsies of malnourished children. Clinical examination, intestinal function (D-Xylose test), and the histological appearance of the mucosa were assessed in 14 children during the malnutrition phase and in eight children after 3 months of nutritional rehabilitation. Macromolecular permeability was evaluated by measuring transepithelial HRP fluxes from mucosa to serosa (JHRPms) using Ussing chambers. Intact HRP transport, i.e., nondegraded protein transport, was measured by enzyme assay, and tritiated HRP was concomitantly used to measure intact and degraded HRP fluxes (J[3H]HRPms). Electrical parameters (short-circuit current, potential difference, and ionic conductance) were also recorded. Transepithelial HRP fluxes were significantly higher during malnutrition (JHRPms = 8.85 +/- 1.44; J[3H]HRPms = 77.11 +/- 10.66 pmol X h-1 X cm-2) than in the same children after 3 months of nutritional rehabilitation (JHRPms = 2.94 +/- 1.10; J[3H]HRPms = 22.93 +/- 8.15 pmol X h-1 X cm-2). The total ionic conductance, which is an index of paracellular permeability, did not change significantly. Calculated intratissue degradation of the protein did not appear to alter during malnutrition. These results point to a clinical situation in which malnutrition with diarrhea in children is associated with increased intestinal permeability to macromolecules by a mechanism not related to any paracellular leak of the protein, but rather to increased transcellular absorption.


Amphiphiles based on D-glucose: efficient low molecular weight gelators.
A series of novel amphiphiles were synthesized based entirely on renewable resources. Besides their efficacy as supramolecular gelators in a wide variety of organic solvents and also water, their surface properties as surfactants and emulsifiers have been determined. A methodical study revealed that the length of the hydrocarbon chains has a dramatic and decisive influence on the thermal stabilities of the obtained hydrogels.


Metal-free carbonylations by photoredox catalysis.
The synthesis of benzoates from aryl electrophiles and carbon monoxide is a prime example of a transition-metal-catalyzed carbonylation reaction which is widely applied in research and industrial processes. Such reactions proceed in the presence of Pd or Ni catalysts, suitable ligands, and stoichiometric bases. We have developed an alternative procedure that is free of any metal, ligand, and base. The method involves a redox reaction driven by visible light and catalyzed by eosin Y which affords alkyl benzoates from arene diazonium salts, carbon monoxide, and alcohols under mild conditions. Tertiary esters can also be prepared in high yields. DFT calculations and radical trapping experiments support a catalytic photoredox pathway without the requirement for sacrificial redox partners.


Innervation of the muscularis mucosa in the canine stomach and colon.
A preliminary report is presented of studies into the innervation of the canine muscularis mucosa. In vitro experiments have investigated the mechanical response to electrical stimulation and the release of gut peptides known to modulate gastrointestinal function. Exogenous substance P increased tone and amplitude of phasic contractions while neurotensin and vasoactive intestinal polypeptide (VIP) relaxed the muscularis mucosa. Immunoreactive VIP was released into the superfusate during transmural electrical stimulation of the antrum while VIP and substance P were present in superfusate from the colon. The significance of these findings has been discusses briefly.


31P MRS of tumour metabolism in anaesthetized vs conscious mice.
The injectable anaesthetics Hypnorm/Hypnovel, chloral hydrate and etomidate, were examined for their effects on C3H/He mouse core temperature and on the in vivo 31P MR spectra of KHT and SCCVII/Ha transplantable tumours, compared with conscious mice gently restrained in jigs. Hypnorm/Hypnovel at 0.1 mL/mouse i.p. reduced core temperature by 6 degrees C at 30 min after injection, returning to control levels by 100 min, but did not significantly alter the 31P MR spectra of either KHT or SCCVII/Ha tumours. Chloral hydrate at 300 mg/kg i.p. produced a 5 degrees C fall in mouse core temperature, at 25 min after injection, again returning to control levels by 100 min. This agent increased the Pi/total ratio to 155% of control at 15 min after injection in the KHT tumour, and to 170% of control at 45 min in SCCVII/Ha. Etomidate at 25 mg/kg i.p. reduced mouse core temperature by 7.5 degrees C by 20 min after injection, returning to only 84% of control by 100 min. This agent increased the Pi/total ratio by 260% in the KHT tumour 15 min after injection, without recovery to control values by 100 min. In SCCVII/Ha, a maximum increase in Pi/total of 360% was observed at 15 min after injection, with a return to control levels by 60 min. In addition, etomidate caused convulsions in the mice during the induction phase, and myoclonic jerking within 15 min of anaesthesia.


Reduced systolic blood pressure in fingers of patients with generalized scleroderma (acrosclerosis).
Segmental systolic blood pressure was measured on upper arm, wrist, proximal and middle pahlanx in 10 patients suffering from generalized scleroderma of the acrosclerosis type and in 5 normal. Systolic pressure was measured by the strain-gauge technique before and after abolition of sympathetic vasoconstrictor activity by local heating and by nerve block. Arm and wrist pressures were equal in the two groups, but a significant reduction in finger pressure was found in the patients. Finger pressure was unaltered after sympathetic blockade, both in the patients and in the normals. The pressure drop from wrist to finger in the patients suggests an increased flow resistance in the palmer arch and digital arteries which was probably not caused by an augmented sympathetic vasoconstrictor activity, as sympathetic blockade did not influence finger systolic pressure. Sympathectomy cannot be expected to relieve Raynaud's attacks in these patients.


Prognostic index to identify patients who may not benefit from whole brain radiotherapy for multiple brain metastases from lung cancer.
Palliative whole brain radiotherapy (WBRT) is often recommended in the management of multiple brain metastases. Allowing for WBRT waiting time, duration of the WBRT course and time to clinical response, it may take 6 weeks from the point of initial assessment for a benefit from WBRT to manifest. Patients who die within 6 weeks ('early death') may not benefit from WBRT and may instead experience a decline in quality of life. This study aimed to develop a prognostic index (PI) that identifies the subset of patients with lung cancer with multiple brain metastases who may not benefit from WBRT because of 'early death'. The medical records of patients with lung cancer who had WBRT recommended for multiple brain metastases over a 10-year period were retrospectively reviewed. Patients were classified as either having died within 6 weeks or having lived beyond 6 weeks. Potential prognostic indicators were evaluated for correlation with 'early death'. A PI was constructed by modelling the survival classification to determine the contribution of these factors towards shortened survival. Of the 275 patients recommended WBRT, 64 (23.22%) died within 6 weeks. The main prognostic factor predicting early death was Eastern Cooperative Oncology Group (ECOG) status >2. Patients with a high PI score (>13) were at higher risk of 'early death'. Twenty-three per cent of patients died prior to benefit from WBRT. ECOG status was the most predictive for 'early death'. Other factors may also contribute towards a poor outcome. With further refinement and validation, the PI could be a valuable clinical decision tool.


Elevated expression of hypoxia inducible factor-2alpha in terminally differentiating growth plate chondrocytes.
Growth plate chondrocytes exist in a hypoxic environment where it is recognized that hypoxia-inducible factor-1alpha (HIF-1alpha) is essential for their survival. Its regulation of chondrocyte viability may be mediated by the increased expression of vascular endothelial growth factor (VEGF) and glycolytic enzymes. However, the full chondrocyte response to hypoxia and the molecular control of VEGF expression in relation to growth plate differentiation and vascularization remains poorly understood. Using Percoll density gradient centrifugation, chick chondrocytes were separated into populations of different maturational phenotype. A differential display analysis of the populations showed highly upregulated expression of HIF-2alpha mRNA during chondrocyte differentiation. HIF-2alpha is a homologue of the HIF-1alpha transcription factor, both of which play a role in the activation of a number of hypoxia responsive genes. HIF-1alpha mRNA was also found to be expressed, although levels of expression were found to be similar in all of the chondrocyte fractions. The elevated expression of HIF-2alpha during chondrocyte differentiation was accompanied by increased VEGF expression. Analysis of the murine chondrocyte cell line, ATDC5, which undergoes ordered maturation indicated that HIF-2alpha, VEGF, placental growth factor, and glucose transporter-1 expression all increased in parallel with chondrocyte differentiation. This observation was supported by immunohistochemistry on sections of mouse bone which showed staining corresponding to the presence of HIF-2alpha in hypertrophic growth plate chondrocytes. The presence of HIF-2alpha was also observed in articular chondrocytes but was restricted to the superficial tangential zone. HIF-2alpha is, therefore, likely to be involved in the initiation of blood vessel formation and a metabolic shift in the growth plate, processes crucial for endochondral ossification.


In vitro binding of amantadine to plasma proteins.
In vitro binding of amantadine to plasma protein was assessed by ultrafiltration of plasma samples (from a blood bank) to which amantadine hydrochloride had been added. Approximately two-thirds of the amantadine was found to be protein-bound. The degree of protein binding was constant over a plasma amantadine concentration range of 100-2,000 ng/ml.


Healthy shiftwork, healthy shiftworks.
Reflecting diversifying shift systems, extensive effort is put into managing shiftwork and reducing safety and health risks. It is accepted that shiftworkers are exposed to particular risks inherent in their irregular work schedules. This raises the question of how and to what extent we can ensure healthy work life for shiftworkers. In answering the question, we need to identify effective measures to improve both shiftworking conditions and the health of shiftworkers. Based on recent experiences in managing shiftwork, we note three directions of such measures: (a) comprehensive action to avoid risk-enhancing conditions based on general guidelines, (b) risk control as to workload, worksite ergonomics and risk reduction, and (c) support for flexible and restful working life. International standards are obviously relevant to these three aspects. Our own experiences in applying a set of ergonomic checkpoints to plant maintenance shiftwork demonstrate the usefulness of focusing on flexible work schedules and on multiple job-related factors such as night workload, ergonomic environment, resting conditions and training. There is a strong need for participatory planning and implementation of multi-area improvements as well as for relying on flexible schedules and autonomic teamwork. We may conclude that healthy shiftwork and healthy shiftworkers are compatible with each other only when certain conditions are met. In achieving this end, we need to combine (a) comprehensive measures to improve work schedules and job life, (b) strict risk management and (c) locally adjusted participatory steps for continual improvement.


A Rare Periprosthetic Knee Joint Infection With Clostridium perfringens, the Result of 2-Stage Exchange Treatment: A Case Report and Review of Current Literature.
Prosthetic joint infections (PJIs) commonly result from aerobic gram-positive organisms and can lead to detrimental outcomes. However, it is rare for Clostridium perfringens to cause a PJI. Owing to its rarity, current literature lacks a comprehensive guide for the proper management of these PJIs. We report on the case of an 80-year old man who presented to our institution with concerns for sepsis secondary to a PJI with C. perfringens 25 years status post total knee arthroplasty. The patient was managed with two-stage revision and exchange. After stage one, the patient developed cholecystitis, which has been reported in prior cases of PJI due to C. perfringens. After concerns for sepsis had resolved and stage 1 was complete, the patient was managed with 6 weeks of IV antibiotics. Treatment was directed at gram-positives with IV vancomycin along with anerobic coverage determined by anerobic susceptibility testing. After the second stage, the patient was discharged with 3 months of oral antibiotic therapy. At the final 1-year follow-up, the patient was doing well without residual infection. This report reviews previous evidence on the management of C. perfringens PJI and presents a case demonstrating the successful diagnostic, surgical, and antimicrobial management of a PJI with C. perfringens.


Biochemical characterization of an S-adenosyl-l-methionine-dependent methyltransferase (Rv0469) of Mycobacterium tuberculosis.
Tuberculostearic acid (l0-methylstearic acid, TSA) is a major constituent of mycobacterial membrane phospholipids, and its biosynthesis involves the direct methylation of oleic acid esterified as a component of phospholipids. The methyltransferases of mycobacteria were long proposed to be involved in the synthesis of methyl-branched short-chain fatty acids, but direct experimental evidence is still lacking. In this study, we identified the methyltransferase encoded by umaA in Mycobacterium tuberculosis H37Rv as a novel S-adenosyl-l-methionine (SAM)-dependent methyltransferase capable of catalyzing the conversion of olefinic double bond of phospholipid-linked oleic acid to biologically essential TSA. Therefore, UmaA, catalyzing such modifications, offer a viable target for chemotherapeutic intervention.


EFFECTS OF DETOMIDINE AND DEXMEDETOMIDINE ON PHYSIOLOGICAL PARAMETERS AND ANESTHETIC RECOVERY IN TAPIRUS TERRESTRIS ANESTHETIZED WITH KETAMINE, GLYCERYL GUAIACOL ETHER, AND MIDAZOLAM.
The aim of this study was to compare the effects of two anesthetic induction protocols for long procedures carried out in the field in Tapiridae. Sixteen tapirs were divided into two groups (n=8) receiving either detomidine (DET) or dexmedetomidine (DEX) for anesthetic induction. All animals were anesthetized by intramuscular administration of a combination of ketamine (1.5 mg/kg), midazolam (0.2 mg/kg), plus either DET (0.04 mg/kg) or DEX (0.007 mg/kg). Anesthetic maintenance was by continuous infusion of ketamine, midazolam, and glyceryl guaiacol ether at 2 mg/kg per hour, 0.1 mg/kg per hour, and 100 mg/kg per hour, respectively). The animals were kept anesthetized for a total of 50 min to allow physical examination and collection of biological material as part of a research program, and physiological variables (heart rate [HR], respiratory rate, oxyhemoglobin saturation [SpO2], rectal temperature [RT], mean arterial pressure [MAP], blood glucose [GLI], and cortisol) and electrocardiogram were recorded during anesthesia. Anesthetic recovery was monitored by two researchers who were not informed of the induction protocol group. The recorded results were statistically evaluated. In both groups there was an initial increase in MAP, which subsequently decreased; RT gradually decreased during anesthesia; HR and GLI increased throughout the procedure; SpO2 was below normal throughout the procedure. Cortisol levels were significantly higher in the DEX group than in the DET group. Also, the animals in the DEX group had a longer recovery time than those in the DET group. On the basis of the results, we conclude that the combination of alpha-2 agonists and midazolam, ketamine, and glyceryl guaicol ether is an appropriate protocol for the anesthesia of tapirs in the field. However, in moderately extended procedures oxygen supplementation is recommended. Additionally, DEX resulted in fewer cardiovascular effects and longer-lasting sedation than DET.


A cross-sectional survey to study the relationship of periodontal disease with cardiovascular disease, respiratory disease, and diabetes mellitus.
Periodontal deterioration has been reported to be associated with systemic diseases such as cardiovascular disease (CVD), diabetes mellitus, respiratory disease, liver cirrhosis, bacterial pneumonia, nutritional deficiencies, and adverse pregnancy outcomes. The present study assessed the periodontal disease among patients with systemic conditions such as diabetes, CVD, and respiratory disease. The study population consisted of 220 patients each of CVD, respiratory disease, and diabetes mellitus, making a total of 660 patients in the systemic disease group. A control group of 340 subjects were also included in the study for comparison purpose. The periodontal status of the patients with these confirmed medical conditions was assessed using the community periodontal index of treatment needs (CPITNs) index. The prevalence of CPITN code 4 was found to be greater among the patients with respiratory disease whereas the mean number of sextants with score 4 was found to be greater among the patients with diabetes mellitus and CVD. The treatment need 0 was found to be more among the controls (1.18%) whereas the treatment need 1, 2, and 3 were more among the patients with respiratory disease (100%, 97.73%, and 54.8%), diabetes mellitus (100%, 100% and 46.4%), and CVD (100%, 97.73%, and 38.1%), in comparison to the controls (6.18%). From the findings of the present study, it can be concluded that diabetes mellitus, CVD, and respiratory disease are associated with a higher severity of periodontal disease.


Fourier Spot Volatility Estimator: Asymptotic Normality and Efficiency with Liquid and Illiquid High-Frequency Data.
The recent availability of high frequency data has permitted more efficient ways of computing volatility. However, estimation of volatility from asset price observations is challenging because observed high frequency data are generally affected by noise-microstructure effects. We address this issue by using the Fourier estimator of instantaneous volatility introduced in Malliavin and Mancino 2002. We prove a central limit theorem for this estimator with optimal rate and asymptotic variance. An extensive simulation study shows the accuracy of the spot volatility estimates obtained using the Fourier estimator and its robustness even in the presence of different microstructure noise specifications. An empirical analysis on high frequency data (U.S. S&P500 and FIB 30 indices) illustrates how the Fourier spot volatility estimates can be successfully used to study intraday variations of volatility and to predict intraday Value at Risk.


Nucleotide regulatory protein-mediated activation of phospholipase C in human polymorphonuclear leukocytes is disrupted by phorbol esters.
Polymorphonuclear leukocytes (PMNs) activate phospholipase C via a guanine nucleotide regulatory (G) protein. Pretreatment of the PMNs with pertussis toxin (PT) or 4-beta-phorbol 12-myristate 13-acetate (PMA) inhibited chemoattractant-induced inositol trisphosphate generation. To determine the loci of inhibition by PT and PMA, G protein-mediated reactions in PMN plasma membranes were examined. Plasma membranes prepared from untreated and PMA-treated PMNs demonstrated equivalent ability of a GTP analogue to suppress high affinity binding of the chemoattractant-N-formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe) to its receptor. The rate, but not the extent, of high affinity binding of GTP gamma[35S] to untreated PMN membranes was stimulated up to 2-fold by preincubation with 1 microM fMet-Leu-Phe. The ability of fMet-Leu-Phe to stimulate the rate of GTP gamma S binding was absent in membranes prepared from PT-treated PMNs, but remained intact in membranes from PMA-treated cells. Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) via phospholipase C could be activated in untreated PMN membranes by either fMet-Leu-Phe plus GTP or GTP gamma S alone at low concentrations of Ca2+ (0.1-1 microM). Membranes prepared from PT-treated PMNs degraded PIP2 upon exposure to GTP gamma S, but not fMet-Leu-Phe plus GTP. In contrast, membranes prepared from phorbol ester-treated PMNs did not hydrolyze PIP2 when incubated with GTP gamma S. Treatment with PT or PMA did not affect the ability of 1 mM Ca2+ to activate PIP2 hydrolysis in PMN membranes, indicating that neither treatment directly inactivated phospholipase C. Therefore, PT appears to block coupling of the chemoattractant receptors to G protein activation, while phorbol esters disrupt coupling of the activated G protein to phospholipase C. The phorbol ester-mediated effect may mimic a negative feedback signal induced by protein kinase C activation by diacylglycerol generated upon activation of phospholipase C.


First results of Lichtenstein hernia repair with Ultrapro-mesh as cost saving procedure--quality control combined with a modified quality of life questionnaire (SF-36) in a series of ambulatory operated patients.
There are about 200,000 hernia repairs per year in Germany and about 770,000 in the U.S. In the United States most hernia repairs (80-90%) are performed as day surgery procedure; 90% of operations are open herniorrhaphies with mesh. Quality control includes the registration of complications, recurrence, and quality of life. In a prospective study 50 consecutive patients with inguinal hernia eligible for open mesh repair (modified Lichtenstein hernia repair), mostly Nyhus III and IV classification, were operated using light-weight Ultrapro-mesh (monocryl-prolene-composite, Ethicon Products), and interviewed 10 days after the operation according to a modified SF-36 questionnaire. Patients were examined three months later. There were 29 direct hernias, 21 combined (direct and indirect) hernias, 8 indirect hernias; 8 patients had hernias on both sides. 8 patients (16%) presented with recurrent hernias, mostly suture or laparoscopic repairs before. There were no intra-operative complications. 2 patients suffered from a moderate haematoma, which did not necessitate a surgical repair, after accidental intake of aspirin preoperatively in one case and after preoperative low-molecular-weight heparin prophylaxis. There were no other complications. All 50 patients (100%) had returned the questionnaire. 38 patients (78%) reported no or mild pain; only one patient (2%) suffered from severe pain, none had very severe pain. 32 patients (64%) applied no pain medication or only for 48 hours; only one patient (2%) used pain medication for more than 14 days. 34 patients (68%) admitted that their health status improved after the operation; 11 patients (22%) with good or very good health status indicated no change in health. Follow-up examination of the patients three months after the operation did not detect any recurrence. 49 patients (98%) were free of pain or restriction; one patient (2%) continued to have chronic pain which developed after two laparoscopic herniotomies performed at a different clinic before. There was no sign of mesh-related complication. The Ultrapro-mesh has been well accepted by the patients. In conclusion, open mesh repair according to Lichtenstein is safely done in specialised ambulatory day surgery clinics. Most patients benefit from this form of treatment according to a quality of life audit. The new light-weight mesh Ultrapro contributes to the improvement of hernia repair. There is evidence that ambulatory open mesh repair should be the method of choice for primary inguinal hernia. If in Germany an equal proportion of hernia repair as in the United States would be done as ambulatory procedure (80-90%), there would be an annual cost saving of several hundred million Euro.


Acral necrotizing mycosis fungoides.
A 65-year-old male with long-standing acral "eczema" and patches of mycosis fungoides suddenly developed a transformed, necrotizing ulcerative cutaneous T-cell lymphoma manifesting as necrotic lesions of the toe and lip. The tumor had brown and/or black eschars on the surface and grew multiple opportunistic organisms. Markers CD3, Epstein-Barr virus-encoded small RNA, and T-cell receptor g gene rearrangement were positive, with CD4, 8, 30, 56, and TIA-1 negative. In spite of initial response to radiation, the patient succumbed to infection within 3 months.


Influence of hepatopetal flow of the retroportal artery on efficiency of repeated hepatic arterial infusion chemotherapy.
Few reports have described the influence of the retroportal artery on the distribution of anticancer drugs in the liver during repeated hepatic arterial infusion chemotherapy. This report describes two patients in whom poor distribution was observed in the right lobe of the liver, which was confirmed at superior mesenteric arteriography to be caused by inflow of the retroportal artery to the right hepatic artery. The retroportal artery was successfully embolized, resulting in improvement of distribution in the right lobe of the liver in both cases.


Synaptotagmin gene content of the sequenced genomes.
Synaptotagmins exist as a large gene family in mammals. There is much interest in the function of certain family members which act crucially in the regulated synaptic vesicle exocytosis required for efficient neurotransmission. Knowledge of the functions of other family members is relatively poor and the presence of Synaptotagmin genes in plants indicates a role for the family as a whole which is wider than neurotransmission. Identification of the Synaptotagmin genes within completely sequenced genomes can provide the entire Synaptotagmin gene complement of each sequenced organism. Defining the detailed structures of all the Synaptotagmin genes and their encoded products can provide a useful resource for functional studies and a deeper understanding of the evolution of the gene family. The current rapid increase in the number of sequenced genomes from different branches of the tree of life, together with the public deposition of evolutionarily diverse transcript sequences make such studies worthwhile. I have compiled a detailed list of the Synaptotagmin genes of Caenorhabditis, Anopheles, Drosophila, Ciona, Danio, Fugu, Mus, Homo, Arabidopsis and Oryza by examining genomic and transcript sequences from public sequence databases together with some transcript sequences obtained by cDNA library screening and RT-PCR. I have compared all of the genes and investigated the relationship between plant Synaptotagmins and their non-Synaptotagmin counterparts. I have identified and compared 98 Synaptotagmin genes from 10 sequenced genomes. Detailed comparison of transcript sequences reveals abundant and complex variation in Synaptotagmin gene expression and indicates the presence of Synaptotagmin genes in all animals and land plants. Amino acid sequence comparisons indicate patterns of conservation and diversity in function. Phylogenetic analysis shows the origin of Synaptotagmins in multicellular eukaryotes and their great diversification in animals. Synaptotagmins occur in land plants and animals in combinations of 4-16 in different species. The detailed delineation of the Synaptotagmin genes presented here, will allow easier identification of Synaptotagmins in future. Since the functional roles of many of these genes are unknown, this gene collection provides a useful resource for future studies.


Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors.
Venocclusive disease (VOD) of the liver, a fibrous obliteration of small hepatic venules, can be caused by chemoradiation therapy. We reviewed 255 consecutive patients undergoing bone marrow transplantation for malignancy during 1978 to 1980 in order to determine the incidence of VOD and the predisposing factors. Fifty-three of 255 patients met our criteria for VOD, for an incidence of 21%. Multivariate analysis showed that the most significant risk factors for VOD were age over 15, an underlying malignancy other than acute lymphocytic leukemia and hepatitis prior to transplantation. Patients with hepatitis had a 3.4-fold risk of developing VOD, as compared to patients with normal SGOT values (p = 0.0004). Hepatitis in this setting is probably of non-A, non-B viral etiology and represents a relative contraindication to marrow transplantation because of enhanced toxicity from conditioning chemoradiotherapy.


Temporal Trends and Rural-Urban Differences in Hospital Length of Stay for Alzheimer Disease and Related Disorders.
The aim of this study was to assess rural-urban differences and temporal trends in length of inpatient stay among patients diagnosed with Alzheimer disease and related dementia (ADRD). The study sample comprised 27,313 ADRD and 27,313 matched non-ADRD inpatient discharges from Nebraska hospitals from 2005 to 2011. Descriptive statistics and multivariable regression models were used to assess rural-urban variations and temporal trends in length of stay (LOS). LOS was found to be similar for ADRD and non-ADRD-related hospitalizations. No rural-urban differences in LOS were observed for ADRD-related hospitalizations. However, there was a temporal decline in LOS for ADRD-related hospitalizations. LOS for ADRD-related hospitalizations was found to be influenced mostly by patient-level demographic and clinical factors. Hospital-level factors were not associated with LOS.


ICAM-1 expression on epidermal keratinocytes in cutaneous graft-versus-host disease.
An immunohistological study of epidermal keratinocytes for the intercellular adhesion molecule, ICAM-1 (CD54), was undertaken on skin biopsies from allogeneic bone marrow transplant recipients. In control biopsies from normal donors and patients prior to transplantation, staining was weak and confined to relatively few cells. After transplantation there was a significant increase in both the number of positive cells and their staining intensity in biopsies showing histological evidence of GVHD but not in those exhibiting normal appearances or epidermal abnormalities that could be attributed to cytotoxic drugs or irradiation. There was a strong positive correlation between ICAM-1 and HLA-DR expression by keratinocytes. All cases exhibiting increased ICAM-1 also exhibited an increase in HLA-DR antigens. The converse was not true, however, as 6 biopsies exhibited HLA-DR positivity without detectable increases in ICAM-1. Both ICAM-1 and HLA-DR antigen synthesis may be stimulated by local cytokine release following interactions between donor and recipient cells in the early posttransplant period. Our present findings suggest that immunostaining for ICAM-1 has little value in the early diagnosis of cutaneous GVHD but further, more detailed prospective studies would be of value.


[Robotic hernia repair : Part III: Robotic incisional hernia repair with transversus abdominis release (r-TAR). Video report and results of a cohort study].
The principle of targeted separation or weakening of individual components of the abdominal wall to relieve tension in the median line during major abdominal reconstruction has been known for over 30 years as anterior component separation (aKS) and is an established procedure. In search of alternatives with lower complication rates, posterior component separation (pKS) was developed; transversus abdominis release (TAR) is a nerve-sparing modification of pKS. With the ergonomic resources of robotics (e.g., angled instruments), TAR can be performed in a minimally invasive manner (r-TAR): hernia gaps of up to 14 cm can be closed and a large extraperitoneal mesh implanted. In this video article, the treatment of large incisional hernias using the r‑TAR technique is presented. Exemplary results of a cohort study in 13 consecutive patients are presented. The procedure is challenging, but our own results-as well as reports from the literature-are encouraging. The r‑TAR is becoming the pinnacle procedure for abdominal wall reconstruction.


Klotho regulates the myogenic response of muscle to mechanical loading and exercise.
What is the central question of this study? Does the hormone Klotho affect the myogenic response of muscle cells to mechanical loading or exercise? What is the main finding and its importance? Klotho prevents direct, mechanical activation of genes that regulate muscle differentiation, including genes that encode the myogenic regulatory factor myogenin and proteins in the canonical Wnt signalling pathway. Similarly, elevated levels of klotho expression in vivo prevent the exercise-induced increase in myogenin-expressing cells and reduce exercise-induced activation of the Wnt pathway. These findings demonstrate a new mechanism through which the responses of muscle to the mechanical environment are regulated. Muscle growth is influenced by changes in the mechanical environment that affect the expression of genes that regulate myogenesis. We tested whether the hormone Klotho could influence the response of muscle to mechanical loading. Applying mechanical loads to myoblasts in vitro increased RNA encoding transcription factors that are expressed in activated myoblasts (Myod) and in myogenic cells that have initiated terminal differentiation (Myog). However, application of Klotho to myoblasts prevented the loading-induced activation of Myog without affecting loading-induced activation of Myod. This indicates that elevated Klotho inhibits mechanically-induced differentiation of myogenic cells. Elevated Klotho also reduced the transcription of genes encoding proteins involved in the canonical Wnt pathway or their target genes (Wnt9a, Wnt10a, Ccnd1). Because the canonical Wnt pathway promotes differentiation of myogenic cells, these findings indicate that Klotho inhibits the differentiation of myogenic cells experiencing mechanical loading. We then tested whether these effects of Klotho occurred in muscles of mice experiencing high-intensity interval training (HIIT) by comparing wild-type mice and klotho transgenic mice. The expression of a klotho transgene combined with HIIT synergized to tremendously elevate numbers of Pax7+ satellite cells and activated MyoD+ cells. However, transgene expression prevented the increase in myogenin+ cells caused by HIIT in wild-type mice. Furthermore, transgene expression diminished the HIIT-induced activation of the canonical Wnt pathway in Pax7+ satellite cells. Collectively, these findings show that Klotho inhibits loading- or exercise-induced activation of muscle differentiation and indicate a new mechanism through which the responses of muscle to the mechanical environment are regulated.


Dietary measures and exercise training contribute to improvement of endothelial function and atherosclerosis even in patients given intensive pharmacologic therapy.
Atherosclerosis contributes to cardiovascular mortality and morbidity even with aggressive lipid management. Our objective is to determine whether a combined pharmacological and lifestyle intervention can improve atherosclerosis. We conducted a 2-year observational study at a specialized clinic in a tertiary care hospital. One hundred fifty-six subjects with coronary disease were enrolled in an intensive pharmacological management and lifestyle measures (including counseling and exercise training) program designed to reach specific targets. The main outcome measures were carotid intima media thickness and plaque area; brachial artery flow-mediated dilation; nitroglycerin-mediated dilation; flow-mediated dilation-nitroglycerin-mediated dilation ratio; laboratory parameters including lipids, glucose, creatinine, and homocysteine; and physical fitness. At completion, there were improvements in lipids and physical fitness. There were no overall changes in flow-mediated dilation, nitroglycerin-mediated dilation, or carotid intima media thickness in the entire cohort. However, multivariate logistic regression showed that dietary and exercise variables, such as increasing fiber intake and reducing body weight and body fat percentage, were independent predictors of improvements in endothelial function and carotid plaque burden. Even in the setting of intensive pharmacological therapy, lifestyle interventions, including exercise training and dietary changes, are important determinants of improved endothelial function and atherosclerosis.


Clinical education model for staff training in orthopedic manual therapy.
We designed a clinical education model for training staff orthopedic physical therapists to provide basic skills in orthopedic manual therapy. The program evolved in a health maintenance organization, where a large number of patients with acute and chronic musculoskeletal disorders receive care. As physical therapy became primary in the treatment of these patients, the staff needed to develop specialized clinical skill. We divided the program into four phases: Phase I--Lecture Series, Phase II--Evaluation of Clinical Skill, Phase III--Self-directed Study, and Phase IV--Re-evaluation. This clinical education assures the staff physical therapist of a supportive learning environment. The program enhances clinical development by identifying individual strengths and weaknesses and providing a positive framework for improvement and self-evaluation.


Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats.
The influence of icing on muscle regeneration after crush injury was examined in the rat extensor digitorum longus. After the injury, animals were randomly divided into nonicing and icing groups. In the latter, ice packs were applied for 20 min. Due to the icing, degeneration of the necrotic muscle fibers and differentiation of satellite cells at early stages of regeneration were retarded by ∼1 day. In the icing group, the ratio of regenerating fibers showing central nucleus at 14 days after the injury was higher, and cross-sectional area of the muscle fibers at 28 days was evidently smaller than in the nonicing group. Besides, the ratio of collagen fibers area at 14 and 28 days after the injury in the icing group was higher than in the nonicing group. These findings suggest that icing applied soon after the injury not only considerably retarded muscle regeneration but also induced impairment of muscle regeneration along with excessive collagen deposition. Macrophages were immunohistochemically demonstrated at the injury site during degeneration and early stages of regeneration. Due to icing, chronological changes in the number of macrophages and immunohistochemical expression of transforming growth factor (TGF)-β1 and IGF-I were also retarded by 1 to 2 days. Since it has been said that macrophages play important roles not only for degeneration, but also for muscle regeneration, the influence of icing on macrophage activities might be closely related to a delay in muscle regeneration, impairment of muscle regeneration, and redundant collagen synthesis.


Mental performance in extreme environments: results from a performance monitoring study during a 438-day spaceflight.
During their stay in a space habitat, astronauts are exposed to many different stressors that may entail detrimental effects on mood and performance. In order to monitor the effects of the space environment on different human information processing functions during an extraordinary long-term space mission, the cognitive. visuo-motor and time-sharing performance of one Russian cosmonaut was repeatedly assessed (29 times) during his 438-day stay in space. The performance tasks used were chosen from the AGARD-STRES battery and included grammatical reasoning, Sternberg memory-search, unstable tracking, and a dual-tasks consisting of unstable tracking with concurrent memory-search. In addition to performance assessment, several subjective ratings concerning mood and workload were collected. Comparisons of pre-flight, in-flight, post-flight and two follow-up assessments 6 months after the mission revealed, (1) no impairments of basic cognitive functions during the flight, (2) clear impairments of mood, feelings of raised workload, and disturbances of tracking performance and time-sharing during the first 3 weeks in space and the first 2 weeks after return to Earth, (3) an impressive stability of mood and performance during the second to fourteenth month in space, where mood and performance had returned to pre-flight baseline level, and (4) no long-lasting performance deficits at follow-up assessments. From these results it is concluded that the first 3 weeks of long-term spaceflights and the first 2 weeks back on Earth represent critical periods where adverse effects on attentional processes are to be expected, induced by the demands to adjust to the extreme environmental changes. The stability of mood and performance observed after successful adaptation to the space environment indicates that mental efficiency and emotional state can be maintained on a level as high as on Earth even during extraordinary long-term space missions.


Probing Multidimensional Structural Information of Single Molecules Transporting through a Sub-10 nm Conical Plasmonic Nanopore by SERS.
Probing the orientation and oxygenation state of single molecules (SMs) is of great importance for understanding the advanced structure of individual molecules. Here, we manipulate molecules transporting through the hot spot of a sub-10 nm conical gold nanopore and acquire the multidimensional structural information of the SMs by surface enhanced Raman scattering (SERS) detection. The sub-10 nm size and conical shape of the plasmonic nanopore guarantee its high detection sensitivity. SERS spectra show a high correlation with the orientations of small-sized single rhodamine 6G (R6G) during transport. Meanwhile, SERS spectra of a single hemoglobin (Hb) reveal both the vertical/parallel orientations of the porphyrin ring and oxygenated/deoxygenated states of Hb. The present study provides a new strategy for bridging the primary sequence and the advanced structure of SMs.


A minimalist fluorescent MOF sensor array for Baijiu identification.
The beverage industry is in the market tuyere, and grasps the lifeline of the social economy, so it is particularly vital to supervise it. Herein, we report a minimalist fluorescence metal-organic framework (MOF) sensor array for Baijiu identification. The original MOF was modified by rare-earth elements to obtain Eu-MOFs and Tb-MOFs. They exhibited multiple fluorescence characteristic peaks in the range of 400-700 nm when excited at 325 nm. The organic molecules in the Baijiu reacted with Eu-MOF and Tb-MOF, affecting the energy transfer of the entire system and the electronic transition of Eu3+ and Tb3+, which were accompanied by various changes in the fluorescence intensity. For each analyte, a unique fluorescence fingerprint and heat map would be formed, which could be discriminated by pattern recognition. With this method, 11 kinds of organic molecules were identified accurately. A good stepwise bilinear function between the fluorescence intensity and concentrations of ferulic acid was obtained at 0.2-3.13 μM and 6.25-100 μM. Crucially, 16 kinds of Baijius of different brands were accurately identified with an accuracy of 100%. The sensor array showed the advantages of strong maneuverability and fast response, exhibiting good application value in Baijiu detection.


Ifosfamide-containing regimens for treating patients with osteosarcomas.
This systemic analysis was conducted to evaluate the efficacy and safety of an ifosfamide- containing regimen in treating patients with osteosarcoma. Clinical studies evaluating the efficacy and safety of Ifosfamide-containing regimen on response and safety for patients with osteosarcoma were identified by using a predefined search strategy. Pooled response rate (RR) of treatment were calculated. When ifosfamide-containing regimens were evaluated, 4 clinical studies which including 134 patients with osteosarcoma were considered eligible for inclusion. Systemic analysis suggested that, in all patients, pooled RR was 44.8% (60/134) in ifosfamide-containing regimens. Major adverse effects were neutropenia, leukopenia, and fatigue inIfosfamide-containing regimens; No treatment related death occurred in cantharidin combined regimens. This systemic analysis suggests that ifosfamide-containing regimens are associated with good response rate and acceptable toxicity in treating patients with osteosarcoma, but this result should be confirmed by randomized clinical trials.


Dexamethasone treatment in patients with brain metastases and primary brain tumors: do the benefits outweigh the side-effects?
In order to minimize neurological symptoms and treatment-related side-effects, patients with primary or secondary brain tumors receive dexamethasone. The goal of this study was to analyze dosage and duration of dexamethasone intake and to compare the advantages and disadvantages of this medication during the course of radiation therapy (RT). Data from 138 consecutive patients were therefore analyzed retrospectively. During the course of therapy, the dosage of dexamethasone was evaluated, as were the indications for and duration of this treatment, its side-effects and any clinical changes reported during dexamethasone intake. The dosage of dexamethasone was higher at the outset and during RT (median 7-12 mg/day) than at the end of RT (median 1-6 mg/day). The average duration of dexamethasone intake was 23 weeks for patients with primary, and 7 weeks for patients with secondary brain tumors. The most frequent side-effects were a rise in serum glucose level, peripheral edema, psychiatric disorders, and Cushing's syndrome. Life-threatening complications remained rare. Initially, dexamethasone led to good clinical improvement with few side-effects of RT, whereas by the end of RT the symptom relief was slight and toxicity increased. In a group of 13 patients who received no dexamethasone during RT, 12 showed neither RT-related side-effects nor of neurological impairment. Dexamethasone effectively minimizes neurological symptoms and RT-related side-effects in patients with primary and secondary brain tumors. Nevertheless, the side-effects of dexamethasone itself increase over time. For this reason, a generalized dose scheme should not be used. Instead, dosage should be adapted to each patient's individual needs. Future prospective studies will have to determine whether dexamethasone is advantageous on balance or not.


A rare incidence of mandibular metastasis of papillary thyroid carcinoma: A case report and review of literature.
Papillary Thyroid Carcinoma (PTC) primarily metastasizes via regional lymphatics making its spread to the oral cavity exceedingly rare. Although this disease remains the most common endocrine malignancy, comprising roughly 85%-90% of all thyroid cancers, its occurrence within the oral cavity happens in less than 1% of oral malignancies. This study identifies a case involving a 77-year-old male with a history of well-differentiated PTC that was initially treated with a total thyroidectomy and adjuvant radioactive iodine. Five years after his initial treatment, surveillance imaging demonstrated a 3 cm expansile mass of the left mandible. An incisional biopsy then confirmed the diagnosis of metastatic PTC. A segmental resection of his mandible was completed with final reconstruction utilizing a fibula free flap. Given the limited number of cases involving metastatic spread of PTC to the oral cavity, a standardized treatment algorithm does not exist. Thus, this case serves to provide a documented report of this rare occurrence and to review literature that may help other clinicians treat patients with this malignancy type. There remains a need for future studies to create risk stratification models for patients with metastatic PTC that consider margin analysis, genetic characteristics, and risk factors to tailor individual treatment plans.


Circulating androgens and SHBG during the normal menstrual cycle in two ethnic populations.
The objective of this study was to study possible ethnic differences in steroid hormones and sex hormone-binding globulin (SHBG) during the menstrual cycle. Serum levels of the ovarian steroids estradiol (E2) and progesterone (P) and of follicle-stimulating hormone (FSH), luteinizing hormone (LH), SHBG, dehydroepiandrosterone (DHEA) and testosterone (T-ria) were all measured by immunoassay during the menstrual cycle in 15 Swedish and 11 West Asian regularly menstruating women. Testosterone (T-ms) was also measured by LC-MS/MS and so were 4-androstene-3,17-dione (A-4) and 17-alpha-hydroxyprogesterone (17-OHP). There were no ethnic differences in levels of ovarian steroids, gonadotrophins, A-4, 17-OHP and T-ms. DHEA were significantly higher and SHBG significantly lower in West Asian than in Swedish women. Surprisingly, T-ria was significantly higher in West Asian than in Swedish women and higher than T-ms (47% in Swedish and 107% in West Asian women). The difference (T-ria - T-ms) showed strong positive correlations to DHEA in the total and in West Asian but not in Swedish women, indicating an influence of DHEA/DHEAS metabolites on the T-ria results. In conclusion, ethnic differences in cross reacting steroids may cause erroneous results in one ethnic group by a steroid immunoassay having reasonable specificity in another. The reasons for the lower SHBG and the higher DHEA levels in West Asian women are not known. The results raise the question about establishing different reference values for certain analytes in different ethnic groups.


Mechanisms of protection of trehalase against heat inactivation in Neurospora.
The half-life of trehalase and invertase at 65 and 60 C was found to be much greater when intact ascospores of Neurospora tetrasperma were heated, as compared with extracts. By contrast, no protection was afforded these enzymes when they were heated in intact conidia and mycelium of N. crassa or N. tetrasperma. The protective effect of ascospores for trehalase was further investigated by heating ascospore extracts before and after dialysis. The removal of small molecules by dialysis lowered the heat resistance of trehalase significantly in such extracts. When the dialysate from extracts of mycelium, conidia, or ascospores was added to dialyzed enzyme extracts, that from ascospores was by far the most active. However, the same dialysates had only a small protective effect on invertase. The addition of ashed dialysates did not protect trehalase, and trehalose and glucose protected less effectively than the dialysate.


Effect of chlorhexidine-coated dressings on plaque formation after gingivectomy.
The aim of this clinical study was to evaluate the effect on plaque formation after gingivectomy when the periodontal dressing Coe-Pak was coated with chlorhexidine-hydrochloride powder. The study indicates that no additional plaque-inhibiting effect can be obtained by this method.


Chlorofluorocarbon CFCs, potential alternative HCFCs and HFCs, and related chlorinated compounds: mass spectral study, Part II.
In a previous publication, mass spectrometry was applied to the study of several ions formed by dissociative ionization of ethanes, partially substituted with fluorine and chlorine, and to the determination of the fragmentation pattern of each related compound. The aim of the present investigation was to extend this mass spectral study (70 eV and low ionization energy) to a group of closely related analogs, hydrofluorocarbons (HCFCs), HFCs, chlorinated fluorocarbons, and chlorinated hydrocarbons--halogenated methane, ethane, and propane molecules--to make an attempt to predict the relative bond strength and then the behavior--metabolic pathway and tropospheric degradation--of new HCFCs and HFCs.


Prevalence of congenital dental anomalies of the deciduous dentition in Japanese children.
We examined the prevalence of anomalies in deciduous dentition in 2,733 Japanese three-year-old children. The results showed that fused teeth occurs in 4.10%, congenital missing teeth in 2.38%, enamel hypoplasia in 1.50%, peg-shaped teeth in 0.55%, palatal cusps in upper deciduous incisors in 0.37%, supernumerary teeth in 0.07%, and color anomalies in 0.07%. Sixty-nine boys and 43 girls had fused teeth, percentages of 4.88 and 3.26, respectively. This difference was significant. All the fused teeth were located in the anterior region and were more frequent in the mandibular than in the maxillary arch. In the mandibular arch, 50 cases involved the lateral incisor and canine; the central incisor and lateral incisor were fused in 48 instances. There were 30 boys (2.12%) and 35 girls (2.65%) with congenitally missing deciduous teeth. This difference was not significant. Unilateral missing teeth were more frequently observed than bilateral missing ones. The lower lateral deciduous incisor was the most frequently missing tooth. The prevalences of fused teeth and congenital missing teeth were significantly higher in this study than in studies of American and Scandinavian children. These two anomalies are tending to increase in frequency in Japan.


The virion host shutoff function of herpes simplex virus type 1 plays a role in corneal invasion and functions independently of the cell cycle.
A significant restriction was demonstrated in the ability of herpes simplex virus type 1 virion host shutoff (vhs) mutant viruses to invade the corneal epithelium. Viral replication and invasion was confined to the areas of the cornea which were scarified prior to infection. Differences between wild-type and vhs mutant replication in corneas in vivo were 100- to 1000-fold at all timepoints postinfection. Smaller but still significant growth restrictions were observed in cultured corneal cells. This difference between in vitro and in vivo is not likely to be due to differences in cell cycle status since vhs-induced RNA degradation can occur in both cycling and noncycling cells in vitro. The vhs function is therefore important for invasion of the cornea and secondarily the nervous system and is thereby required for efficient establishment of latency.


Ultrasound appearance of fetal greater omentum.
Fetal ascites results in the ultrasonographic demonstration of normal structures within the fetal abdomen that are otherwise not seen. One such structure is a membrane that, when surrounded by intraperitoneal fluid, may simulate a loculated area of fluid or a fluid-filled viscus. On the basis of its configuration and site of insertion observed during real-time and static ultrasonography, we believe that this membrane is the greater omentum. Recognition of the typical appearance of greater omentum floating in fetal ascites will prevent the erroneous diagnosis of an abnormal intra-abdominal fluid collection.


Chromosome Segregation in Fertilized Eggs From Triploid Pacific Oysters, Crassostrea gigas (Thunberg), Following Inhibition of Polar Body 1.
Chromosome segregation in fertilized eggs from triploid Pacific oysters, following inhibition of the first polar body (PB1), was studied with acetic orcein staining techniques. To block the release of PB1, fertilized eggs were treated with 0.5 mg/l of cytochalasin B (CB). Four types of segregation were observed, namely, "tripolar segregation" (54.5%), "united bipolar segregation" (12%), "separated bipolar segregation" (2.5%), and "incomplete united bipolar segregation" (4%). The remaining 23% could not be classified because of chromosome disorganization, but appeared to be variants of the above. It seemed clear that the predominant pattern that gave rise to tetraploids was united bipolar segregation, although certain separated bipolar segregations might also lead to the formation of tetraploids. The sequential events of meioses observed in CB-treated eggs are described. The asynchrony of meiotic events and possible mechanisms for the various types of chromosome segregation are discussed.


Evidence for changing nerve growth factor signalling mechanisms during development, maturation and ageing in the rat molar pulp.
To examine rat molar pulp innervation and identify complex cellular signalling systems involving nerve growth factor (NGF) and its p75 receptors (NGFR) at different stages of development, maturation and ageing. Decalcified mandibular first molar mesial cusps from Wistar rats of ages 0 day; 1, 2, 3, 4, 6, 9, 12 and 24 weeks (n = 5 per group) were sectioned (10 μm) and incubated with antibodies for NGF, NGFR, calcitonin gene-related peptide (CGRP) and neurofilament. Nerve densities in worn and intact regions of 3- to 24-week-old rats were compared by anova, Bonferroni and t-tests. During odontogenesis, differences in NGF and NGFR expression were observed, with no evidence of nerve fibres, suggesting a signalling mechanism controlling cellular differentiation and dentine formation. Tooth wear in 4-week rats was associated with reduced NGF expression and significantly decreased CGRP axons within affected odontoblast regions. The underlying subodontoblasts started expressing NGF which continued until 9 weeks. This may promote a significant increase in CGRP nerve density in affected regions. Nerve density in intact odontoblast regions increased gradually and reached significant levels in 12-week rats. Reduction in nerve densities within worn and intact regions of cusps was observed at 24 weeks. Age-related changes and responses to tooth wear may be controlled by the NGF signalling mechanism, with roles in odontoblast/subodontoblast communication and control of sensory innervation at different stages of tooth development, maturation and ageing. Greater understanding of cellular and nerve regulation in the injured pulp may promote therapeutic strategies for pulp survival.


DNA sequence and transcript mapping of MOD5: features of the 5' region which suggest two translational starts.
A mutation in the yeast nuclear gene MOD5 drastically reduces the biosynthesis of the modified base isopentenyladenosine in tRNAs located in different cellular compartments: the mitochondria and the nucleus or cytoplasm. Several lines of evidence strongly suggest that MOD5 is the structural gene encoding the tRNA-modifying enzyme delta 2-isopentenyl pyrophosphate:tRNA isopentenyl transferase. DNA sequence analysis of MOD5 reveals an open reading frame of 428 amino acids. A set of mRNAs heterogeneous at both the 5' and 3' termini are transcribed from this gene. Although all of these transcripts initiate upstream of the first AUG codon of the open reading frame, a subset has an extremely short (greater than or equal to 1 base) 5' leader. Furthermore, in positions important for efficient initiation of translation and generally occupied by purines, this first AUG codon is flanked by a U (position -3) and a C (position +4). It is possible that two proteins, one with an amino-terminal extension of basic charge, could be generated from the MOD5 gene via differential translational starts.


Improved quality of anorectal endoluminal ultrasonography using emulsion of dimethicone.
This study was designed to show the benefits of filling echography probes with water mixed with dimethicone to preclude artifacts caused by bubbles. One hundred consecutive healthy volunteers (42 males; mean age, 46 years; range, 17-72 years) were blindly randomized to undergo rectal ultrasonography using conventional degassed water or degassed aqueous solution made of 40 ml of water and 10 ml of dimethicone emulsion (1 ml/100 mg). All examinations performed by the same surgeon-unaware of nature of filler liquid-for ten minutes, and number of rectal ultrasonographies with artifacts attributable to air bubbles was recorded. Endoluminal ultrasonography performed with conventional degassed water presented artifacts attributed to presence of air bubbles in 30 of 50 examinations (60 percent). When degassed aqueous solution was used, only 5 of 50 examinations showed artifacts caused by presence of air bubbles (10 percent). This difference was statistically significant (P < 0.0005). The use of conventional fluid was associated with artifacts secondary to the presence of air bubbles, adjusted odds ratio 13.5 (95 percent confidence interval, 4.56-39.88). During this experience, the solution did not damage ultrasound scanner. We found that use of a dimethicone-degassed water mixture is simple, not expensive, safe, effective, and may reduce frequency of sonographic distortion in presence of air bubbles.


Pain in primary Sjögren's syndrome: the role of catastrophizing and negative illness perceptions.
Pain is a major factor in health quality in Sjögren's syndrome (SS), but little is known about the factors that contribute to pain severity. Because pain perception has been linked to catastrophizing in other diseases, we assessed subjects with primary SS (pSS) to explore a possible link between pain, illness appraisal, and catastrophizing. A total of 92 subjects who met American-European consensus criteria for the diagnosis of pSS completed a questionnaire that included health history, medication use, illness perceptions, pain severity, mood, fatigue, pain anxiety, and pain catastrophizing. Linear regression was used to test the effect of each variable on pain severity. Multivariate models were constructed using backwards elimination to assess the significant predictors of pain severity. From linear regression analysis, catastrophizing was more strongly predictive of pain severity than age, fatigue, depression, or anxiety in both seropositive and seronegative pSS patients. In the multivariate model identified using backwards selection, four variables (pain catastrophizing, fibromyalgia status, serological status, and the conviction that illness would have severe consequences) predicted 55% of the variance in pain severity. Pain catastrophizing was a significant predictor of pain severity in both seropositive and seronegative pSS patients. This study suggests that behavioural interventions designed to reduce pain catastrophizing and negative appraisal of illness could be of benefit in pSS patients. Research is needed to test the effect of psycho-educational therapies on key patient-reported outcomes, particularly pain, depression, and fatigue, in pSS.


Weight change and androgen levels during contraceptive treatment of women affected by polycystic ovary.
The aim of this study was to investigate the effect of oral contraceptive Diane 35 (ethinylestradiol + cyproteroneacetate EE/CPA) which is widely used in the treatment of PCOS in Europe, on body weight, lipid levels and endocrine parameters in non-obese women with PCOS. Nineteen PCOS women were examined in the early follicular phase of menstrual cycle, blood samples for the estimation of cholesterol (C), HDL cholesterol (HDL-C), triglycerides (TG), testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were taken before the start of treatment with Diane 35 and again after 7 +/- 3.8 months of treatment with Diane 35. Body weight (W) was recorded at the time of both examinations. After the treatment with Diane 35 the levels of W (p<0.05), total C (p<0.05), TG (p<0.004) and SHBG (p<0.0001) increased significantly. In addition, significant negative correlation between SHBG levels before treatment and increase of W after Diane 35 was found (r= -0.56; p<0.02). Increase of W correlated negatively with T before treatment (r= 0.58; p< .02) and positively with the change in T level after treatment (r=0.50; p<0.05). Increase of body weight in a significant number of PCOS-affected women was seen after treatment with Diane 35 and it is assumed to blunt ameliorating effects of this treatment on androgen levels. Considering our findings, we conclude that the treatment with CPA/EE can result in significant weight gain ameliorating positive effects of the treatment on androgen levels. These findings could underline the necessity of the finding new therapeutical options for PCOS, besides contraception. Studies concerning body composition during contraceptive treatment in PCOS would be also useful in the future.


Online identification of functional regions in deep brain stimulation based on an unsupervised random forest with feature selection.
The identification of functional regions, in particular the subthalamic nucleus, through microelectrode recording (MER) is the key step in deep brain stimulation (DBS). To eliminate variability in a neurosurgeon's judgment, this study presents an online identification method for identifying functional regions along the electrode trajectory. Functional regions can be identified through offline clustering and online identification based on the unsupervised random forest (RF) algorithm. We took 106 features from MER and the estimated anatomical distance to target as the dataset to train the RF model. To improve the prediction performance and reduce the computation time, a wrapper feature selection (FS) method was added into the algorithm. The method contains feature ranking based on out-of-bag error or silhouette index and feature subset search based on the roulette selection algorithm. To evaluate the optimization effect of the FS method on the unsupervised RF algorithm, we compared the results of the algorithm with or without FS on the DBS dataset. In addition, the optimization effect of FS on the computation time is evaluated. The results show that for offline clustering, the accuracy obtained with the selected features is higher than that obtained with all features, and the running time decreased from 259.7 s to 60.8 s in the iteration of the FS. The accuracy in online identification improved from 76.19% to 92.08% through FS. In addition, the functional region online identification time is 41.5 ms, which can meet the requirements of DBS surgery. In conclusion, using the FS method can improve the accuracy and reduce the computation time of the online identification of functional regions. In addition, the online identification method can provide valuable assistance for both neurosurgeons and stereotactic surgery robots in guiding implantation of the electrode in real time.


Contribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease.
Nonalcoholic fatty liver disease has been defined by the presence of hepatic steatosis in the absence of other chronic liver diseases. We sought to determine whether obesity, insulin resistance, and the metabolic syndrome, which are the main risk factors for nonalcoholic fatty liver disease, are associated with similar elevations in serum alanine aminotransferase activity in persons with and those without other causes of chronic liver disease. Adult participants of the third National Health and Nutrition Examination Survey were divided into those with causes of chronic liver disease (n = 1037), defined as viral hepatitis, excessive alcohol consumption, or increased transferrin-iron saturation, and those without (n = 8004). Among persons with other causes of chronic liver disease, obesity (adjusted odds ratio, 4.9; 95% confidence interval, 2.5-9.4), insulin resistance (adjusted odds ratio, 6.8; 95% confidence interval, 3.0-15.5, comparing the highest and the lowest quartile), and the metabolic syndrome (adjusted odds ratio, 3.3; 95% confidence interval, 1.4-8.0) were all strongly associated with increased alanine aminotransferase activity (>43 IU/L). Among persons without other causes of chronic liver disease, statistically similar associations were identified. Obesity, insulin resistance, and the metabolic syndrome are strong predictors of increased alanine aminotransferase activity in the US population, both in persons with and in persons without other causes of chronic livers disease. We hypothesize that metabolic fatty liver disease related to these conditions is the cause of the increased alanine aminotransferase activity and may be underrecognized in persons with other causes of chronic liver disease.


Treatment of Uncomplicated Acute Diverticulitis Without Antibiotics: A Systematic Review and Meta-analysis.
Despite low-quality and conflicting evidence, the Association of Coloproctology of Great Britain and Ireland recommends the routine use of antibiotics in the treatment of uncomplicated acute diverticulitis. Recent studies have shown that treatment without antibiotics did not prolong recovery. Some new guidelines currently recommend selective use of antibiotics. The purpose of this study was to compare the safety, effectiveness, and outcomes in treating uncomplicated acute diverticulitis without antibiotics with treatment with antibiotics. PubMed, Embase, Clinicaltrials.gov, and the Cochrane Library were searched with the key words antibiotics and diverticulitis. All studies published in English on treating uncomplicated acute diverticulitis without antibiotics and containing >20 individuals were included. Treatment without antibiotics versus treatment with antibiotics were compared. The primary outcome was the percentage of patients requiring additional treatment or intervention to settle during the initial episode. The secondary outcomes were duration of hospital stay, rate of readmission or deferred admission, need for surgical or radiological intervention, recurrence, and complication. Search yielded 1164 studies. Nine studies were eligible and included in the meta-analysis, composed of 2505 patients, including 1663 treated without antibiotics and 842 treated with an antibiotic. The no-antibiotics group had a significantly shorter hospital stay (mean difference = -0.68; p = 0.04). There was no significant difference in the percentage of patients requiring additional treatment or intervention to settle during the initial episode (5.3% vs 3.6%; risk ratio = 1.48; p = 0.28), rate of readmission or deferred admission (risk ratio = 1.17; p = 0.26), need for surgical or radiological intervention (risk ratio = 0.61; p = 0.34), recurrence (risk ratio = 0.83; p = 0.21), and complications (risk ratio = 0.70-1.18; p = 0.67-0.91). Only a limited number of studies were available, and they were of variable qualities. Treatment of uncomplicated acute diverticulitis without antibiotics is associated with a significantly shorter hospital stay. There is no significant difference in the percentage of patients requiring additional treatment or intervention to settle in the initial episode, rate of readmission or deferred admission, need for surgical or radiological intervention, recurrence, or complications.


Recommendations for frequency of visits to monitor systemic lupus erythematosus in asymptomatic patients: data from an observational cohort study.
The aim of our study was to determine the optimal frequency of followup visits in patients with systemic lupus erythematosus (SLE). Patients followed in the lupus clinic over a 2-year period who had at least 3 visits and at least 18 months of followup were included. At each visit patients undergo a complete history, physical examination, and laboratory evaluation. The following variables that would not have been recognized by the patient were identified: proteinuria, hematuria, pyuria, casts, low hemoglobin, leukopenia, thrombocytopenia, elevated serum creatinine, positive anti-DNA antibodies, and low complement. When one of these variables was detected, it was determined whether it was new, and whether other features of activity were present. Thus isolated new variables of interest were identified. Descriptive statistics were used. A total of 515 patients (89% female, 61% white) met the inclusion criteria, with an average of 6.1 ± 1.5 for a total of 3126 visits. The average length of time between visits was 3.8 ± 1.0 months. In the 515 patients, the variables of interest were the sole manifestation of SLE in 126 (24.5%) patients (in a total of 175 visits). The commonest manifestations were renal, low complement, and DNA antibodies followed by thrombocytopenia, low hemoglobin, and elevated creatinine. One in 4 patients with SLE seen over a 2-year period will have a solitary silent variable of interest that could be detected only by routine laboratory followup. Patients with mild or inactive disease should be followed with clinical and laboratory measures at 3-4 month intervals.


Targeting the Key Enzymes of Abnormal Fatty Acid β-oxidation as a Potential Strategy for Tumor Therapy.
Fatty acid metabolism has attracted extensive attention for its key role in the occurrence and development of tumors. Fatty acids not only participate in the biosynthesis of phospholipids in the membrane to overcome the demand for rapidly proliferating membrane lipids but also provide ATP, signaling molecules, and NADPH through β-oxidation to maintain tumor survival and growth. However, the specific role of fatty acid β-oxidation in tumors and the description of multiple potential targets in this process are not comprehensive and systematic. Therefore, this review summarizes the function of fatty acid β-oxidation in tumors and studies of key enzymes that catalyze related reactions in various stages to improve the overall understanding of fatty acid β-oxidation and search for novel tumor treatment strategies and ideas.


Reprogramming alternative pre-messenger RNA splicing through the use of protein-binding antisense oligonucleotides.
Alternative pre-messenger RNA splicing is a major contributor to proteomic diversity in higher eukaryotes and represents a key step in the control of protein function in a large variety of biological systems. As a means of artificially altering splice site choice, we have investigated the impact of positioning proteins in the vicinity of 5' splice sites. We find that a recombinant GST-MS2 protein interferes with 5' splice site use, most efficiently when it binds upstream of that site. To broaden the use of proteins as steric inhibitors of splicing, we have tested the activity of antisense oligonucleotides carrying binding sites for the heterogeneous nuclear ribonucleoprotein A1/A2 proteins. In a HeLa cell extract, tailed oligonucleotides complementary to exonic sequences elicit strong shifts in 5' splice site selection. In four different human cell lines, an interfering oligonucleotide carrying A1/A2 binding sites also shifted the alternative splicing of the Bcl-x pre-mRNA more efficiently than oligonucleotides acting through duplex formation only. The use of protein-binding oligonucleotides that interfere with U1 small nuclear ribonucleoprotein binding therefore represents a novel and powerful approach to control splice site selection in cells.


[Nasal glioma (author's transl)].
Rare tumors are sometimes encountered in maxillofacial surgical practice and the operative approach, external, intranasal, or endocranial, may be difficult to choose. Preliminary angiography and particularly computer tomography can be of invaluable assistance in making the decision, especially in cases of nasofrontal glioma with heterotopic localization of glial tissue but without brain connections.


Stentless aortic valves. Current aspects.
The design of stentless valve prostheses is intended to achieve a more physiological flow pattern and superior hemodynamics in comparison to stented valves. First - generation stentless bioprosthesis were the Prima valve, the Freestyle valve and the Toronto stentless porcine valve. The second generation of stentless valves, as the Super stentless aortic porcine valve, need only one suture line. The Sorin Pericarbon Freedom and the Equine 3F heart Valve belong to the third generation of stentless valve pericardial bioprostheses. A stentless valve to replace a full root can be implanted by several surgical techniques: complete or modified subcoronary, root inclusion and full root. The full root technique is accompanied by the lowest incidence of patient-prothesis mismatch. Our own clinical experience reflects more than 3000 stentless valve implantations since April 1996. Randomized study trials showed a hemodynamic advantage for stentless valves, but several could not reach a significant level. Also reported was a significant advantage of stentless bioprostheses concerning transvalvular gradients, effective valve area and quicker regression of the left ventricular mass 6 months after the operation, but at 12 months. Advantages are obvious in patients with a decreased left ventricle ejection fraction of less than 50% and in smaller implanted valve size, concomitant aortic root pathology (e.g. dissection) and aortic valve endocarditis. A survival advantage for stentless bioprostheses in comparison to stented ones has been reported by all studies in the literature. Stentless valves enrich the surgical armamentarium. Time will define the place of stentless valves in the future.


The Use of Point-of-Care Ultrasound to Evaluate for Intestinal Foreign Bodies in the Pediatric Emergency Department.
We present the use of point-of-care ultrasound to evaluate two patients with examinations concerning for appendicitis who were found to have multiple magnets ingested and subsequent bowel perforations. These cases illustrate the consequences of magnet ingestion as well as the application of point-of-care ultrasound for the identification of intestinal foreign bodies in children.


Analysis of Phase 3 telavancin nosocomial pneumonia data excluding patients with severe renal impairment and acute renal failure.
Telavancin is approved in Europe for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus when other alternatives are not suitable. The approved European prescribing information contraindicates the use of telavancin in patients with severe renal impairment (creatinine clearance <30 mL/min, including patients on haemodialysis) and pre-existing acute renal failure owing to the higher observed mortality in these patients. Data from the ATTAIN studies were reanalysed, excluding patients with these contraindicating conditions at baseline. (At the time of submission of this article, the European marketing authorization of telavancin for the treatment of nosocomial pneumonia was suspended pending evidence of a new European Medicines Agency-approved supplier. Clinigen Healthcare Ltd, Theravance's commercialization partner for telavancin in Europe, is in the process of seeking approval of a new manufacturing source.) A post hoc analysis of data from two Phase 3 ATTAIN trials of telavancin for the treatment of Gram-positive nosocomial pneumonia assessing clinical outcomes and safety. The all-treated population for this analysis represented 84.2% (1266/1503) of the ATTAIN all-treated population. The cure rates in the clinically evaluable population were similar in the telavancin (82.5%, 231/280) and vancomycin (81.3%, 243/299) groups [treatment difference (95% CI): 1.3% (-5.0% to 7.6%)], and were consistent with the overall ATTAIN study results. The cure rate was higher in the telavancin than the vancomycin treatment group in microbiologically evaluable patients with only Gram-positive pathogens isolated at baseline [85.0% (130/153) versus 75.2% (109/145), respectively; treatment difference (95% CI): 9.7% (0.6%-18.8%)]. The incidences of adverse events were similar between treatment groups and consistent with the overall findings of the ATTAIN study. This analysis demonstrated that in the subset of patients without severe renal impairment or pre-existing acute renal failure, clinical and safety outcomes were similar in the telavancin and vancomycin treatment groups.


Evaluations of Corneas in Eyes with Isolated Iris Coloboma.
We aimed to evaluate the differences in the corneas of eyes with isolated iris coloboma. This study was designed as a prospective study. Among patients who applied to our hospital within the last 3-year period, those with isolated iris coloboma in one eye and a completely normal contralateral eye were included in the study. In addition to a complete ophthalmologic examination, all patients were scanned by Pentacam Scheimpflug camera in the dark, and a corneal endothelium cell count was taken using a Topcon Specular Microscope. Data entered using SPSS software were then evaluated by paired t-test; p < 0.05 value was considered statistically significant. Nine patients, seven men and two women, with a mean age of 35.77 ± 22.50 (range 8-60) years, were included in the study. In comparison to normal eyes, the colobomatous eyes were statistically found to have lower keratometry values in diopters (43.82 ± 2.17, 44.46 ± 1.86; p = 0.040), a greater negative asphericity (Q value) (-0.38 ± 0.07, -0.22 ± 0.20; p = 0.042), increased corneal thickness (569.78 ± 25.42, 537.33 ± 27.36; p < 0.001), decreased anterior chamber depth (2.50 ± 0.32, 2.81 ± 0.50; p = 0.005), a shallower angle (30.51 ± 10.68, 35.29 ± 9.99; p = 0.057), higher best-fit sphere (BFS) values of the anterior and posterior corneal surfaces (7.88 ± 0.39, 7.67 ± 0.37; p = 0.001; 6.40 ± 0.26, 6.23 ± 0.19; p = 0.006), larger pupil diameter (3.48 ± 0.49, 2.80 ± 0.34; p = 0.001), smaller horizontal corneal diameter (HCD) (11.06 ± 0.42; 11.26 ± 0.45; p = 0.009), and higher value of endothelial cell density (ECD) (3161 ± 431; 2923 ± 590; p = 0.031). We have determined that a number of factors such as keratometry values, particularly of the corneal endothelium, are different from those of normal eyes. These differences should be taken into account in the follow-up and treatment of eyes with iris coloboma.


Membrane receptors for oestrogen in the brain.
Oestrogen is important for the development of neuroendocrine centres and other neural networks including limbic and motor systems. Later in adulthood, oestrogen regulates the functional performance of different neural systems and is presumably implicated in the modulation of cognitive efficiency. Although still a matter of controversial discussion, clinical and experimental studies point at a potential neuroprotective role of oestrogen. Concerning the concept of cellular oestrogen action, it is undisputed that it comprises the binding and activation of nuclear receptors. The last decades have, however, immensely broadened the spectrum of steroid signalling within a cell. Novel steroid-activated intracellular signalling mechanisms were described which are usually termed 'non-classical' or 'non-genomic'. The brain appears to be a rich source of this new mode of oestrogen action. Studies from the past years have pinpointed non-classical oestrogen effects in many CNS regions. All available data support the view that non-classical oestrogen action requires interactions with putative membrane binding sites/receptors. In this article, we aim at compiling the most recent findings on the nature and identity of membrane oestrogen receptors with respect to the brain. We also attempt to turn readers attention to the coupling of these 'novel' receptors to distinct intracellular signalling pathways.