Longterm outcomes and damage accrual in patients with childhood systemic lupus erythematosus with psychosis and severe cognitive dysfunction.
(1) To describe the clinical course and response to treatment; and (2) to evaluate and compare damage accrual of distinct phenotypic subgroups of patients with clinically important psychiatric illness of pediatric systemic lupus erythematosus (pSLE). A single-center cohort study of patients with pSLE followed at a pediatric lupus clinic from 1985 to July 2009. Clinical course and response to treatment were studied. Remission was defined by absence of psychiatric/cognitive symptoms while receiving minimal doses of prednisone. Disease activity and damage were measured using SLE Disease Activity Index and SLE Damage Index. Fifty-three children were included: 40 with psychosis and cognitive dysfunction (PSYC group) and 13 with isolated cognitive dysfunction (COG group). All received immunosuppressive treatment. Eighteen of 32 treated with azathioprine required a change to cyclophosphamide for poor response but none on cyclophosphamide required a change. The median times to remission were 72 weeks (PSYC) and 70 weeks (COG). Eight patients (7 PSYC, 1 COG) experienced flare following response/remission. New damage was noted in 50% of children at a median of 11 months: 57% of PSYC group, 31% of COG group. Persistent cognitive dysfunction was seen in 16% of PSYC patients and 15% of COG patients. Most patients responded to immunosuppressive treatment, although median time to remission was > 1 year. Roughly half the patients acquired a new damage item, most of which did not interfere with functional abilities. Fewer than 20% of patients developed neuropsychiatric damage. Both phenotypes of psychiatric pSLE responded equally well to current treatment.


The Birmingham Interlocking Pelvic Osteotomy for acetabular dysplasia: 13- to 21-year survival outcomes.
The aim of this study was to evaluate the long-term clinical and radiographic outcomes of the Birmingham Interlocking Pelvic Osteotomy (BIPO). In this prospective study, we report the mid- to long-term clinical outcomes of the first 100 consecutive patients (116 hips; 88 in women, 28 in men) undergoing BIPO, reflecting the surgeon's learning curve. Failure was defined as conversion to hip arthroplasty. The mean age at operation was 31 years (7 to 57). Three patients (three hips) were lost to follow-up. Survivorship was 76% at ten years and 57% at a mean of 17 years. Younger patients (< 20 years) had the best survivorship (20 hips at risk; 90% at 17 years; 95% confidence interval 65 to 97). Post-operative complications occurred after 12 operations (10.4%) over the duration of the study. Increasing patient age and hip arthritis grade were primary determinants of surgical failure. BIPO provides good to excellent survivorship in appropriately selected patients, with a relatively low rate of complications. Our results are comparable with other established methods of periacetabular osteotomy (PAO), such as the Bernese PAO, even during the surgeon's initial learning curve. Cite this article: Bone Joint J 2017;99-B:724-31.


Metabolic effects of tourniquet ischaemia studied by nuclear magnetic resonance spectroscopy.
A model of tourniquet ischaemia was developed in the hind limb of the rat, and the metabolic changes that occurred in the calf muscles were monitored by the non-invasive technique of phosphorus-31 nuclear magnetic resonance spectroscopy. During ischaemia the intramyocellular pH became acidic as the level of phosphocreatine declined and that of inorganic phosphate rose. Phosphocreatine was no longer detectable after approximately 2 hours and ATP was depleted after approximately 3.5 hours. Metabolic recovery was rapid (1 hour) if ATP was present when the tourniquet was released but was prolonged (3 or more hours) if ATP was depleted. Hourly release of the tourniquet for 10 minutes ensured the maintenance of ATP and rapid metabolic recovery. Release for intervals of only 5 minutes did not have the same protective effect and in fact worsened tissue pH during the period of tourniquet ischaemia. Heparin and corticosteroids were without effect during and after periods of tourniquet ischaemia.


π-Hydrogen Bonding of Aromatics on the Surface of Aerosols: Insights from Ab Initio and Molecular Dynamics Simulation.
Molecular level insight into the interaction between volatile organic compounds (VOCs) and aerosols is crucial for improvement of atmospheric chemistry models. In this paper, the interaction between adsorbed toluene, one of the most significant VOCs in the urban atmosphere, and the aqueous surface of aerosols was studied by means of combined molecular dynamics simulations and ab initio quantum chemistry calculations. It is revealed that toluene can be stably adsorbed on the surface of aqueous droplets via hydroxyl-π hydrogen bonding between the H atoms of the water molecules and the C atoms in the aromatic ring. Further, significant modifications on the electrostatic potential map and frontier molecular orbital are induced by the solvation effect of surface water molecules, which would affect the reactivity and pathway of the atmospheric photooxidation of toluene. This study demonstrates that the surface interactions should be taken into consideration in the atmospheric chemical models on oxidation of aromatics.


Seasonal periodicity of three species of caryophyllaeid cestodes in the creek chubsucker, Erimyzon oblongus (Mitchill), in North Carolina.
One hundred and seventy-two specimens of Erimyzon oblongus from Lake Raleigh, North Carolina, were examined for caryophyllaeid cestodes from December 1972 to July 1974. Monobothrium ulmeri, Biacetabulum meridianum, and an undescribed species of Penarchigetes were recovered from the "stomach," "pyloric bend," and the first loop of the small intestine of the suckers. Infections of M. ulmeri were limited to an 8-month period and were seasonally periodic in prevalence, mean intensity, maturation, and length distribution. A "temperature dependeant rejection response" is discussed as a possible factor involved in the periodicity of this species. The maturation of M. ulmeri corresponded closely to the host's reproductive cycle, and may have been affected by changes in the host's hormonal levels during the spring. Infections of R. meridianum were present throughout the year, and exhibited a seasonal periodicity in prevalence, maturation, and length distribution. The mean intensity of infection suggests that the establishment of this species is inhibited by heavy burdens of M. ulmeri. Penarchigetes sp. was nonseasonal in prevalence, mean intensity, and maturation. The continuous availability of infective procercoids and the lack of a sucker "rejection response" are discussed as possible explanations for this destribution. Unlike B. meridianum and Penarchigetes sp., the mean intensity of M. ulmeri showed a close relationship with host sex.


Pathophysiologic studies of experimental chronic pancreatitis in rats induced by injection of zein-oleic acid-linoleic acid solution into the pancreatic duct.
An experimental model of chronic pancreatitis was induced by a retrograde injection of a viscous solution consisting of zein-oleic acid-linoleic acid (0.05 ml/100 g body weight) into the rat pancreatic duct. Histologic and biochemical changes were investigated over a period of 6 months after induction of this model. The treated rats gained weight, but pancreatic weight decreased with time. Histologically, the widening of acinar lumen and cellular vacuolization occurred within 24 h at the parenchyma neighboring the small ducts filled with the injected solution. Degenerative parenchyma, interstitial edema, and inflammatory cell infiltration were pronounced 1 week later. Thereafter, duct-like tubular complex formation progressed, and the exocrine tissue exhibited marked atrophy of the gland with irregular fibrosis and fat replacement over a period of 6 months. Pancreatic contents of protein, amylase, DNA, and RNA markedly decreased, as did pancreatic weight, whereas hydroxyproline content increased. Oral administration of camostat did not affect pancreatic weight and contents of enzyme in this model. Urinary para-aminobenzoic acid (PABA) excretion in the BT-PABA test decreased to 54% at 6 weeks and 22% at 6 months. Although three quarters of pancreatic immunoreactive insulin (IRI) content was lost after 6 months, overt diabetes did not occur. The results suggest that an obstructive mechanism in the small ducts plays an important role in the genesis and development of chronic pancreatitis.


Effects of action potential prolongation via different cellular mechanisms on the electrophysiological properties of rat and guinea-pig ventricular myocardium.
The effects of d-sotalol and the sea anemone toxin ATXII on the electrophysiological properties of rat and guinea-pig ventricular myocardium in vitro and on arrhythmias following coronary artery ligation in rat hearts in vivo were studied. ATXII (1-5 nM) prolonged the cardiac action potential of isolated papillary muscles and the effective refractory period of perfused hearts from both rats and guinea-pigs. In rat hearts, ATXII induced gross action potential prolongation and early afterdepolarizations at concentrations above 1 nM. In contrast, d-sotalol prolonged the action potential and effective refractory period of guinea-pig, but not of rat myocardium. Neither drug prevented arrhythmias in anaesthetized rats following coronary ligation.


The Role of p16INK4a Pathway in Human Epidermal Stem Cell Self-Renewal, Aging and Cancer.
The epidermis is a self-renewing tissue. The balance between proliferation and differentiation processes is tightly regulated to ensure the maintenance of the stem cell (SC) population in the epidermis during life. Aging and cancer may be considered related endpoints of accumulating damages within epidermal self-renewing compartment. p16INK4a is a potent inhibitor of the G1/S-phase transition of the cell cycle. p16INK4a governs the processes of SC self-renewal in several tissues and its deregulation may result in aging or tumor development. Keratinocytes are equipped with several epigenetic enzymes and transcription factors that shape the gene expression signatures of different epidermal layers and allow dynamic and coordinated expression changes to finely balance keratinocyte self-renewal and differentiation. These factors converge their activity in the basal layer to repress p16INK4a expression, protecting cells from senescence, and preserving epidermal homeostasis and regeneration. Several stress stimuli may activate p16INK4a expression that orchestrates cell cycle exit and senescence response. In the present review, we discuss the role of p16INK4a regulators in human epidermal SC self-renewal, aging and cancer.


Wnt1 silencing enhances neurotoxicity induced by paraquat and maneb in SH-SY5Y cells.
Wingless (Wnt) signaling regulates the proliferation and differentiation of midbrain dopamine (DA) neurons. Paraquat (PQ) and maneb (MB) are environmental pollutants that can be used to model Parkinson's disease (PD) in rodents. A previous study demonstrated that developmental exposure to PQ and MB affects the expression of Wnt1, Wnt5a, nuclear receptor-related factor 1 (NURR1) and tyrosine hydroxylase (TH). However, how Wnt signaling regulates these developmental factors in vitro is yet to be determined. To explore this, SH-SY5Y cells were exposed to PQ and MB. The results of the current study indicated that exposure to PQ and MB decreased Wnt1, β-catenin, NURR1 and TH levels and increased Wnt5a levels. Furthermore, Wnt1 silencing has the same effect as exposure to PQ and MB. Additionally, the neurotoxicity induced by PQ and MB is more severe in siWnt1-SH-SY5Y cells compared with normal SH-SY5Y cells. Therefore, Wnt1 may serve an important role in regulating developmental DA factors, and may be a candidate gene for PD diagnosis or gene therapy.


Facet-Specific Adsorption of Tripeptides at Aqueous Au Interfaces: Open Questions in Reconciling Experiment and Simulation.
The adsorption of three homo-tripeptides, HHH, YYY, and SSS, at the aqueous Au interface is investigated, using molecular dynamics simulations. We find that consideration of surface facet effects, relevant to experimental conditions, opens up new questions regarding interpretations of current experimental findings. Our well-tempered metadynamics simulations predict the rank ordering of the tripeptide binding affinities at aqueous Au(111) to be YYY > HHH > SSS. This ranking differs with that obtained from existing experimental data which used surface-immobilized Au nanoparticles as the target substrate. The influence of Au facet on these experimental findings is then considered, via our binding strength predictions of the relevant amino acids at aqueous Au(111) and Au(100)(1 × 1). The Au(111) interface supports an amino acid ranking of Tyr > HisA ≃ HisH > Ser, matching that of the tripeptides on Au(111), while the ranking on Au(100) is HisA > Ser ≃ Tyr ≃ HisH, with only HisA showing non-negligible binding. The substantial reduction in Tyr amino acid affinity for Au(100) vs Au(111) offers one possible explanation for the experimentally observed weaker adsorption of YYY on the nanoparticle-immobilized substrate compared with HHH. In a separate set of simulations, we predict the structures of the adsorbed tripeptides at the two aqueous Au facets, revealing facet-dependent differences in the adsorbed conformations. Our findings suggest that Au facet effects, where relevant, may influence the adsorption structures and energetics of biomolecules, highlighting the possible influence of the structural model used to interpret experimental binding data.


Advances in the molecular and serological diagnosis of invasive fungal infection in haemato-oncology patients.
Current laboratory diagnostic methods for invasive fungal infection (IFI) in haemato-oncology patients are insensitive, resulting in late diagnosis and contributing to high mortality. In recent years, progress has been made in the development and evaluation of sensitive sero-diagnostic assays, including detection of genomic DNA sequences and fungal antigens, which aid in a rapid, early diagnosis of IFI. The sensitivity and specificity of the assays vary considerably between studies, highlighting the need to correlate serological results with conventional laboratory tests and clinical or radiological findings. As part of management protocols, these assays may help to confirm the diagnosis of suspected IFI; however, the impact on mortality from IFI may be greatest when they are used to screen high-risk patients. Persistently positive screening results could direct early aggressive antifungal therapy, guided further by radiological and microbiological findings combined with regular clinical review, while the excellent negative predictive value may allow treatment to be withheld in patients with antibiotic resistant neutropenic fever but no other signs of IFI. However, this pre-emptive approach requires evaluation in prospective randomized trials.


[Culture proven bacterial endophthalmitis: a 6-year review].
To assess the distribution of microorganisms isolated from patients with bacterial endophthalmitis and their antimicrobial susceptibility. Retrospective analysis of medical and microbiological records of patients with suspected diagnosis of endophthalmitis and bacterial culture-proven at the Department of Ophthalmology, UNIFESP, between January 1 2000 and December 31 2005. 153 (33.9%) of 451 patients showed positive bacterial culture. A total of 155 microorganisms were isolated, 79.35% were gram-positive and 20.65% gram-negative. Staphylococcus (CoNS) (41.94%) were the most frequently isolated. The antimicrobial susceptibility for gram-negative microorganisms was as follows: amikacin 87.10%, tobramycin 80.65%, ciprofloxacin 96.67%, levofloxacin, gatifloxacin and moxifloxacin 100%, ceftazidime 85.0%, and gentamicin 80.65%. Vancomycin sensitivity among gram-positive microorganisms was 100%. S. aureus and CoNS showed 83.33% of susceptibility to oxacillin, 89.61% to ciprofloxacin and 100% to gatifloxacin and moxifloxacin. The main acquisition mechanism was postoperative (60.65%). We detected a low sensitivity of vitreous/aqueous culture for the etiologic diagnosis of endophthalmitis. The empiric antimicrobial therapy or prophylaxis should be active against gram-positive bacteria, particularly staphylococci. Surveillance studies of bacterial resistance are important for a better utilization of antimicrobials in this clinical setting.


Efficacy and Feasibility of an Osteopathic Intervention for Neurocognitive and Behavioral Symptoms Usually Associated With Fetal Alcohol Spectrum Disorder.
The purpose of this study was to evaluate the efficacy and feasibility of a 4-week planned osteopathic manipulative treatment intervention on the improvement of neurocognitive and behavioral symptoms usually associated with fetal alcohol spectrum disorder. Thirty-two symptomatic children without fetal alcohol spectrum disorder aged 3-6 years with low level of attention from two schools and an osteopathic center were recruited in a prospective randomized pilot study in an osteopathic manipulative treatment group [osteopathic manipulative treatment (OMT)] or a control group (standard support measures). Neurocognitive maturity test results for attention (A), iconic memory (IM), spatial structuration (SS), and visual perception (VP) were recorded at baseline and post-intervention. No adverse effects were communicated and there were no dropouts. A significant increase in neurocognitive assessments was observed in children in the OMT group at post-treatment. Intergroup post-intervention statistical differences were found for A, SS, and IM were p = 0.005, p < 0.001, and p < 0.001, respectively; no differences were seen for VP (p = 0.097). This study shows that a 4-week osteopathic manipulative treatment intervention may be a feasible and effective therapeutic approach for neurocognitive and behavioral symptoms usually present in fetal alcohol spectrum disorder, justifying more studies on children affected by this condition.


Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system.
Interactions between neurons and astrocytes are critical for signaling, energy metabolism, extracellular ion homeostasis, volume regulation, and neuroprotection in the central nervous system. Astrocytes face the synapses, send end-foot processes that enwrap the brain capillaries, and form an extensive network interconnected by gap junctions. Astrocytes express several membrane proteins and enzymes that are critical for uptake of glutamate at the synapses, ammonia detoxification, buffering of extracellular K+, and volume regulation. They also participate in detection, propagation, and modulation of excitatory synaptic signals, provide metabolic support to the active neurons, and contribute to functional hyperemia in the active brain tissue. Disturbances of these neuron-astrocyte interactions are likely to play an important role in neurologic disorders including cerebral ischemia, neurodegeneration, migraine, cerebral edema, and hepatic encephalopathy.


What does not kill mesangial cells makes it stronger? The response of the endoplasmic reticulum stress and the O-GlcNAc signaling to ATP depletion.
Mesangial cells are modified smooth muscle cells with the ability to modulate glomerular filtration rate (GFR) - a marker of ischemic renal injury. We aimed to determine the role of intracellular O-GlcNAc levels and ER stress in mesangial cells subjected to ATP depletion. Immortalized mouse mesangial cells culture was incubated for 30, 45 and 60 min, or not (control group) with a buffer containing antimycin A and 2-deoxy-d-glucose, inhibitors of ATP synthesis. Mesangial cells subjected to ATPdepletion for 45 min followed by 24 h reperfusion (H45/R24 mesangial cells) promoted 30 % of cell death mainly by necrosis. ATP depletion was sustained throughout reperfusion until 24 h. Resistant H45/R24 mesangial cells presented: (i) low protein content of GFAT, OGT and OGA, however no modification of total O-GlcNAcylation and (ii) attenuation of protein synthesis related to a UPR response mediated by GRP78/PERK/p-eIF2α and a decrease in the protein content of ATF4. The lower activation of apoptosis was related to no alterations in the levels of CHOP and activated caspase 3. We also detected activation of intracellular mediators of necroptosis: IRE1, ATF6, GADD34, ERO1, Mdm2 and P53. The resistant H45/R24 mesangial cells can replenish the cell culture dish indicating that the UPR adaptative response permitted cell survival. Successive ATP depletion induced lower levels O-GlcNAcylation leading to a 30 % cell death in every H/R process. We concluded that lower levels of O-GlcNAcylation and the GRP78/PERK/p-eIF2α UPR response are the molecular mechanisms involved in H45/R24 mesangial cell survival.


Speech acts, communication problems, and fighter pilot team performance.
Two aspects of team communication, speech acts and communication problems, and their relation to team performance in a team air combat simulator were studied. The purpose was to enhance the understanding of how team performance is related to team communication. Ten Swedish fighter pilots and four fighter controllers of varying experience participated. Data were collected during fighter simulator training involving four pilots and one fighter controller in each of two teams. Speech acts were collapsed over seven categories and communication problems over five categories. Communication was studied from two perspectives: critical situation outcome and mission outcome. Some problems were closely related to particular speech acts. Speech act frequency, especially meta-communications and tactics, was highest when winning. However, the timing of tactics in critical situations needs further research. Communication problem frequency was highest for runs which ended equally. The most common problem was simultaneous speech, possibly because of the simulator radio system. The number of speech acts was related to enhanced performance but in a complex manner. Thus in order to work efficiently team members need to communicate, but to communicate sufficiently and at appropriate times. This work has applications for fighter pilot and controller team training and the development of communication standards.


Gastroprotective potential of hydro-alcoholic extract of Pattanga (Caesalpinia sappan Linn.).
Pattanga is botanically equated as Caesalpinia sappan Linn. (Family: Caesalpiniaceae) and is used in Ayurveda system of medicine since ages. According to Ayurveda, useful part is Heartwood, which is bitter, astringent and acrid and is useful in vitiated conditions of vata and pitta, burning sensation, wounds, ulcers, leprosy, skin diseases, menorrhagia, leucorrhea, and diabetes. It is used as a major ingredient in Ayurvedic formulations and preparations like Patrangasava, Chandanadya Thalia, and Karpuradyarka. The present study is planned to evaluate the gastroprotective activity of the selected Ayurvedic drug using three different in vivo gastric ulcer models, so as to provide scientific evidence for the Ayurvedic claims. For this study, Wistar albino rats fasted overnight were selected. The hydroalcoholic extract of Caesalpinia sappan heartwood at the dose level 250 and 500mg/kg body weight was selected and administered orally before necrotizing agents. Antioxidant and antiulcer parameters were evaluated and the stomach samples were subjected for histopathological studies. In addition, PGE2 estimation and protein expressions of COX-1, COX-2 and iNOS were analyzed by Western blot. The plant extract was subjected to LCMS/MS analysis. In addition, Cytoprotective effect in isolated gastric mucosal cells, TUNEL Assay, Acid neutralizing capacity assay, H+/K+ ATPase inhibitory assay were performed. The ulcer protection was found to be 92%, 86% and 64% against ethanol, NSAID and pylorus ligation induced ulcer respectively. The hydro-alcoholic extract of C. sappan heartwood exhibited cytoprotective effect with 76.82% reduction against indomethacin-induced cytotoxicity at the concentration of 25µg/ml. C. sappan showed 63.91% inhibition in H+/K+ ATPase inhibitory assay at the concentration 500µg/ml. Our results depict that Caesalpinia sappan heartwood possesses gastroprotective activity, possibly mediated through cytoprotection and antioxidant mechanisms. The data obtained in the present study provides scientific support for the traditional use of Caesalpinia sappan in the management of peptic ulcer.


Comparative genomic analysis of Mycobacterium tuberculosis drug resistant strains from Russia.
Tuberculosis caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (MTB) strains is a growing problem in many countries. The availability of the complete nucleotide sequences of several MTB genomes allows to use the comparative genomics as a tool to study the relationships of strains and differences in their evolutionary history including acquisition of drug-resistance. In our work, we sequenced three genomes of Russian MTB strains of different phenotypes--drug susceptible, MDR and XDR. Of them, MDR and XDR strains were collected in Tomsk (Siberia, Russia) during the local TB outbreak in 1998-1999 and belonged to rare KQ and KY families in accordance with IS6110 typing, which are considered endemic for Russia. Based on phylogenetic analysis, our isolates belonged to different genetic families, Beijing, Ural and LAM, which made the direct comparison of their genomes impossible. For this reason we performed their comparison in the broader context of all M. tuberculosis genomes available in GenBank. The list of unique individual non-synonymous SNPs for each sequenced isolate was formed by comparison with all SNPs detected within the same phylogenetic group. For further functional analysis, all proteins with unique SNPs were ascribed to 20 different functional classes based on Clusters of Orthologous Groups (COG). We have confirmed drug resistant status of our isolates that harbored almost all known drug-resistance associated mutations. Unique SNPs of an XDR isolate CTRI-4(XDR), belonging to a Beijing family were compared in more detail with SNPs of additional 14 Russian XDR strains of the same family. Only type specific mutations in genes of repair, replication and recombination system (COG category L) were found common within this group. Probably the other unique SNPs discovered in CTRI-4(XDR) may have an important role in adaptation of this microorganism to its surrounding and in escape from antituberculosis drugs treatment.


Spinal and muscle motor evoked potentials following magnetic stimulation in cats.
Motor evoked potentials (MEP) from transcranial magnetic stimulation were successfully recorded from the spinal cord and gastrocnemius muscle in cats. The spinal MEP consisted of four negative peaks, N1 through N4, and subsequent small, multiphasic waves. The conduction velocity calculated from N1 corresponded to that of the nonpyramidal cerebellar evoked potential. After ablation of the pyramidal tract at various levels, N1 through N3 persisted, whereas N4 disappeared. The muscle MEP showed the same latency as that of MEP obtained by direct cortical electrical stimulation and disappeared after similar ablation. These findings suggest that the first three peaks of the spinal MEP are responses of the nonpyramidal cerebellospinal pathways and that the fourth peak of the spinal MEP and the muscle MEP are pyramidal tract responses. Spinal and muscle MEP from magnetic stimulation may be valuable in the qualitative evaluation of the function of the pyramidal and nonpyramidal pathways.


Effect of short-term exercise training on intramyocellular lipid content.
The purpose of this study was to investigate the influence of exercise training on intramyocellular lipid (IMCL) content and test the hypothesis that the effect of endurance-oriented exercise training on IMCL is dependent on characteristics of the population studied. Lean (N = 11, body mass index (BMI) = 22.2 ± 0.7 kg·m⁻²), obese (N = 14, BMI = 38.8 ± 1.7 kg·m⁻²), and type 2 diabetic (N = 9, BMI = 35.5 ± 2.5 kg·m⁻²) participants were examined before and after 10 consecutive days of endurance-oriented (60 min·day⁻¹ at ~70% [Formula: see text]O(2peak)) exercise training. IMCL and muscle glycogen were measured by Oil-Red-O and periodic acid - Schiff staining, respectively. The results indicated that IMCL was elevated (p < 0.05) in the obese and diabetic groups compared with the lean subjects prior to training. After training, IMCL content decreased (-35%) in the participants with type 2 diabetes; there were no changes in IMCL in the lean or obese groups. Muscle glycogen content was lower in the diabetic subjects than in the lean subjects both before and after training. These data indicate that changes in IMCL with exercise training do not exhibit a universal response but rather depend on the metabolic status of the population studied.


Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves.
Approximately 5 million people are affected with aortic valve disease (AoVD) in the United States. The most common treatment is aortic valve (AoV) replacement surgery, however, replacement valves are susceptible to failure, necessitating additional surgeries. The molecular mechanisms underlying disease progression and late AoV calcification are not well understood. Recent studies suggest that genes involved in bone and cartilage development play an active role in osteogenic-like calcification in human calcific AoVD (CAVD). In an effort to define the molecular pathways involved in AoVD progression and calcification, expression of markers of valve mesenchymal progenitors, chondrogenic precursors, and osteogenic differentiation was compared in pediatric non-calcified and adult calcified AoV specimens. Valvular interstitial cell (VIC) activation, extracellular matrix (ECM) disorganization, and markers of valve mesenchymal and skeletal chondrogenic progenitor cells were observed in both pediatric and adult AoVD. However, activated BMP signaling, increased expression of cartilage and bone-type collagens, and increased expression of the osteogenic marker Runx2 are observed in adult diseased AoVs. They are not observed in the majority of pediatric diseased valves, representing a marked distinction in the molecular profile between pediatric and adult diseased AoVs. The combined evidence suggests that an actively regulated osteochondrogenic disease process underlies the pathological changes affecting AoVD progression, ultimately resulting in stenotic AoVD. Both pediatric and adult diseased AoVs express protein markers of valve mesenchymal and chondrogenic progenitor cells while adult diseased AoVs also express proteins involved in osteogenic calcification. These findings provide specific molecular indicators of AoVD progression, which may lead to identification of early disease markers and the development of potential therapeutics.


Intrapartum fetal asphyxia: definition, diagnosis, and classification.
Evidence of a significant metabolic acidosis, an umbilical artery base deficit > 12 mmol/L, confirms that an asphyxial exposure has occurred. This is observed at delivery in approximately 2% of all pregnancies. Classification of the severity of the asphyxial exposure is difficult because the duration and nature of the exposure and the characteristics of the fetal cardiovascular response to the asphyxia in the affected fetus is usually not known. A classification is proposed in which the exposure to asphyxia is confirmed by a blood gas and acid-base assessment with evidence of a significant metabolic acidosis and the severity is defined by newborn encephalopathy and other organ system complications. Outstanding issues that may enhance this classification are identified.


Mechanistic Insights Into Co-Administration of Allosteric and Orthosteric Drugs to Overcome Drug-Resistance in T315I BCR-ABL1.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, driven by the BCR-ABL1 fusion oncoprotein. The discovery of orthosteric BCR-ABL1 tyrosine kinase inhibitors (TKIs) targeting its active ATP-binding pocket, such as first-generation Imatinib and second-generation Nilotinib (NIL), has profoundly revolutionized the therapeutic landscape of CML. However, currently targeted therapeutics still face considerable challenges with the inevitable emergence of drug-resistant mutations within BCR-ABL1. One of the most common resistant mutations in BCR-ABL1 is the T315I gatekeeper mutation, which confers resistance to most current TKIs in use. To resolve such conundrum, co-administration of orthosteric TKIs and allosteric drugs offers a novel paradigm to tackle drug resistance. Remarkably, previous studies have confirmed that the dual targeting BCR-ABL1 utilizing orthosteric TKI NIL and allosteric inhibitor ABL001 resulted in eradication of the CML xenograft tumors, exhibiting promising therapeutic potential. Previous studies have demonstrated the cooperated mechanism of two drugs. However, the conformational landscapes of synergistic effects remain unclear, hampering future efforts in optimizations and improvements. Hence, extensive large-scale molecular dynamics (MD) simulations of wide type (WT), WT-NIL, T315I, T315I-NIL, T315I-ABL001 and T315I-ABL001-NIL systems were carried out in an attempt to address such question. Simulation data revealed that the dynamic landscape of NIL-bound BCR-ABL1 was significantly reshaped upon ABL001 binding, as it shifted from an active conformation towards an inactive conformation. The community network of allosteric signaling was analyzed to elucidate the atomistic overview of allosteric regulation within BCR-ABL1. Moreover, binding free energy analysis unveiled that the affinity of NIL to BCR-ABL1 increased by the induction of ABL001, which led to its favorable binding and the release of drug resistance. The findings uncovered the in-depth structural mechanisms underpinning dual-targeting towards T315I BCR-ABL1 to overcome its drug resistance and will offer guidance for the rational design of next generations of BCR-ABL1 modulators and future combinatory therapeutic regimens.


PHOTOSTENT-02: porfimer sodium photodynamic therapy plus stenting versus stenting alone in patients with locally advanced or metastatic biliary tract cancer.
Endobiliary stenting is standard practice for palliation of obstructive jaundice due to biliary tract cancer (BTC). Photodynamic therapy (PDT) may also improve biliary drainage and previous small studies suggested survival benefit. To assess the difference in outcome between patients with BTC undergoing palliative stenting plus PDT versus stenting alone. 92 patients with confirmed locally advanced or metastatic BTC, ECOG performance status 0-3 and adequate biliary drainage were randomised (46 per group) to receive porfimer sodium PDT plus stenting or stenting alone. The primary end point was overall survival (OS). Toxicity and progression-free survival (PFS) were secondary end points. Treatment arms were well balanced for baseline factors and prior therapy. No significant differences in grade 3-4 toxicities and no grade 3-4 adverse events due to PDT were observed. Thirteen (28%) PDT patients and 24 (52%) stent alone patients received subsequent palliative chemotherapy. After a median follow-up of 8.4 months, OS and PFS were worse in patients receiving PDT compared with stent alone group (OS median 6.2 vs 9.8 months (HR 1.56, 95% CI 1.00 to 2.43, p=0.048) and PFS median 3.4 vs 4.3 months (HR 1.43, 95% CI: 0.93 to 2.18, p=0.10), respectively). In patients with locally advanced or metastatic BTC, PDT was associated with worse outcome than stenting alone, explained only in part by the differences in chemotherapy treatments. We conclude that optimal stenting remains the treatment of choice for malignant biliary obstruction and the use of PDT for this indication cannot be recommended outside of clinical trials. ISRCTN 87712758; EudraCT 2005-001173-96; UKCRN ID: 1461.


A Review of Agents for Palliative Sedation/Continuous Deep Sedation: Pharmacology and Practical Applications.
Continuous deep sedation at the end of life is a specific form of palliative sedation requiring a care plan that essentially places and maintains the patient in an unresponsive state because their symptoms are refractory to any other interventions. Because this application is uncommon, many providers may lack practical experience in this specialized area and resources they can access are outdated, nonspecific, and/or not comprehensive. The purpose of this review is to provide an evidence- and experience-based reference that specifically addresses those medications and regimens and their practical applications for this very narrow, but vital, aspect of hospice care. Patient goals in a hospital and hospice environments are different, so the manner in which widely used sedatives are dosed and applied can differ greatly as well. Parameters applied in end-of-life care that are based on experience and a thorough understanding of the pharmacology of those medications will differ from those applied in an intensive care unit or other medical environments. By recognizing these different goals and applying well-founded regimens geared specifically for end-of-life sedation, we can address our patients' symptoms in a more timely and efficacious manner.


Comprehensive Bioinformatics Analysis Identifies POLR2I as a Key Gene in the Pathogenesis of Hypertensive Nephropathy.
Hypertensive nephropathy (HN), mainly caused by chronic hypertension, is one of the major causes of end-stage renal disease. However, the pathogenesis of HN remains unclarified, and there is an urgent need for improved treatments. Gene expression profiles for HN and normal tissue were obtained from the Gene Expression Omnibus database. A total of 229 differentially co-expressed genes were identified by weighted gene co-expression network analysis and differential gene expression analysis. These genes were used to construct protein-protein interaction networks to search for hub genes. Following validation in an independent external dataset and in a clinical database, POLR2I, one of the hub genes, was identified as a key gene related to the pathogenesis of HN. The expression level of POLR2I is upregulated in HN, and the up-regulation of POLR2I is positively correlated with renal function in HN. Finally, we verified the protein levels of POLR2I in vivo to confirm the accuracy of our analysis. In conclusion, our study identified POLR2I as a key gene related to the pathogenesis of HN, providing new insights into the molecular mechanisms underlying HN.


Influence of gestational weight gain on low birth weight in short-statured South Indian pregnant women.
India contributes to one-third of the global burden of low birth weight (LBW) neonates, which is associated with increased risk of mortality and adverse consequences on long-term health. Factors leading to LBW are multidimensional and maternal short stature is an important component with an inter-generational effect. On the contrary gestational weight gain (GWG) shows an independent positive influence on birth weight. The aim of the present study therefore was to determine the influence of GWG on birth weight in short pregnant women. A prospective observational cohort of 1254 pregnant women was studied. Total, second and third trimester GWG per week were computed. Women were divided into two groups, "short" and "not-short", using a cut off of 152 cm that corresponded to the 25th percentile for height in the cohort. Association of tertiles of GWG with LBW was examined using log binomial regression analysis. "Short" women in highest tertile of total GWG had a significantly reduced adjusted relative risk (ARR 0.37, 95% confidence interval 0.16-0.83, P = 0.016) for LBW, compared to the lowest tertile. However, there was no significant increase in risk for cesarean section (CS) with increasing tertiles of total GWG. In women with height <152 cm a significant reduced risk for LBW was observed with the greatest total GWG, without a significant increase in the risk for CS. This suggests that improving GWG in short women may be beneficial for the birth weight of the offspring.


Postjunctional alpha-adrenoceptors in the rabbit isolated distal saphenous artery: indirect sensitivity to prazosin of responses to noradrenaline mediated via postjunctional alpha 2-adrenoceptors.
1. Under normal experimental conditions, the rabbit isolated distal saphenous artery appears to contain a homogeneous population of postjunctional alpha 1-adrenoceptors. Prazosin competitively antagonized responses to noradrenaline (NA) with a pA2 value of 8.6, while a relatively high concentration of rauwolscine (1 microM), produced only a 2 fold rightward displacement of the NA cumulative concentration-response curve (CCRC). 2. Despite the fact that angiotensin II (AII) was without effect on responses to NA or phenylephrine in this preparation, this peptide made responses to NA less susceptible to the antagonistic action of prazosin. This was particularly evident on the lower portion of the CCRC for NA. These results suggest that in the presence of AII, NA produces contractile responses by an action mediated through a prazosin-resistant adrenoceptor. 3. An attempt was made to isolate a homogeneous population of postjunctional alpha 2-adrenoceptors by use of a receptor protection procedure involving the combination of rauwolscine and phenoxybenzamine. After the protection protocol no responses were observed to the alpha-adrenoceptor agonists NA, phenylephrine or UK-14304. In the presence of angiotensin II however, concentration-dependent contractions were observed to each of these agonists. Under these conditions the rank order of potency, UK-14304 greater than NA greater than phenylephrine, is consistent with that of an effect mediated through postjunctional alpha 2-adrenoceptors. 4. The responses to NA, after the protection protocol, in the presence of AII, were susceptible to the selective alpha 2-adrenoceptor antagonist, rauwolscine (1 microM), but resistant to the selective alpha 2-adrenoceptor antagonist prazosin (0.1 microM). Furthermore, the combination of rauwolscine (1 microM) and prazosin (0.1 I microM) was no more effective in blocking responses to NA than was rauwolscine (1 microM) alone. These results are consistent with the presence of a homogeneous population of postjunctional alpha 2-adrenoceptors. 5. Inducing a small degree of tone with a low concentration of the selective alpha 1-adrenoceptor agonist, phenylephrine, markedly increased the threshold sensitivity to the selective alpha 2-adrenoceptor agonist UK- 14304, in a manner analogous to that seen with All. 6. The results in the present study indicate that responses mediated via postjunctional alpha 2-adrenoceptors in the rabbit isolated distal saphenous artery are dependent upon a degree of vascular smooth muscle stimulation by some other receptor system. It is hypothesized that under normal experimental conditions, this function is fulfilled by stimulation of alpha l-adrenoceptors, while after alpha 1-adrenoceptor blockade the necessary positive influence can be provided by stimulation of All receptors. The implications for such an interaction between postjunctional alpha-adrenoceptor subtypes in demonstrating prazosin-resistant, rauwolscine- or yohimbine-sensitive responses in isolated blood vessels is discussed.


Organizational safety climate and work experience.
The study examined the relationships between work experience and (a) safety perceptions, (b) job satisfaction, (c) compliance with safety management policies and (d) accident frequency. Participants were Ghanaian industrial workers (N = 320). They were divided into 2 cohorts: experienced and inexperienced workers. Workplace safety perceptions were assessed with Hayes et al.'s 50-item work safety scale. MANOVA was used to test for differences of statistical significance. Posterior comparison with t test consistently revealed significant differences between experienced cohorts and their inexperienced counterparts. Experienced workers indicated the best perceptions on safety, expressed the highest level of job satisfaction, were the most compliant with safety procedures and recorded the lowest accident frequency. From a practical perspective, analysing differences in work experience in relation to safety perceptions could be useful for organizations as the workers' experience could indicate a need for special safety programmes for particular groups.


Blood pressure management in acute stroke: comparison of current guidelines with prescribing patterns.
Current recommendations for treating elevated blood pressure (BP) in the acute stroke are based largely on expert opinion and vary with regard to treatment thresholds and choice of antihypertensive agents. In this study we investigate the influence of these recommendations by comparing the management of hypertension in acute stroke at a tertiary care hospital with current guidelines. Retrospective chart review of patients admitted with acute stroke at The Ottawa Hospital-General Campus over six consecutive months. The use of antihypertensive medications (type, dose, routes of administration, BP recordings) in the first seven days after admission was noted. Transdermal nitroglycerin paste was the most commonly used antihypertensive agent. In contrast to the 15% reduction in BP over 24 hours recommended for lowering BP in hypertensive patients with ischemic stroke, nitroglycerin caused a >15% reduction of BP over the first 24 hours on 60% of the occasions used. Furthermore, despite concerns about sublingual nifedipine, this was the second most commonly prescribed agent. Surprisingly, the mean time to first BP measurement following initiation of antihypertensive therapy was 117 +/- 43 minutes in ischemic stroke and 88 +/- 89 minutes in hemorrhagic strokes. The current guidelines for management of acute poststroke hypertension appear to have little influence on prescribing patterns, leading to considerable variations in practice. Such variations, likely due to uncertainty caused by lack of evidence from randomised controlled trials, are intolerable as patients maybe submitted to nonstandardised, potentially harmful care such as inappropriate choice of antihypertensives and inadequate BP monitoring as observed in this study.


Vestibular migraine patients are more anxious than migraine patients without vestibular symptoms.
The link between vertigo and anxiety is well known. The aim of this study is to compare anxiety disorders in 3 groups: patients with vestibular migraine (VM), patients with migraine but without vertigo (MO) and healthy controls (HC).We performed cross-sectional analysis of following tests: (a) Hamilton Anxiety Rating Scale (HAMA); (b) State-Trait Anxiety Inventory (STAI-X1 and STAI-X2); (c) Beck Depression Inventory (BDI); (d) Panic-Agoraphobic Scale and (e) Penn State Worry Questionnaire (PSWQ). ANOVA, Kruskal-Wallis and Chi-square tests were used for comparisons and least significant difference was used for further post-hoc analysis. There were 35 definite VM patients, 31 MO patients and 32 volunteer HC. There were no significant differences between three groups in age, total years of education or duration of headaches in VM and MO patients. On the other hand, vertigo severity was moderately and positively correlated with headache severity and with headache duration. There were significant differences in scores of HARS, BDI, PSWQ, and various PAS-R sub-scales between the three groups. Our study shows that VM patients are significantly more anxious and agoraphobic than MO patients and HC, displaying higher sensitivity to separation and being more prone to seeking medical reassurance.


Personalized Offline and Pseudo-Online BCI Models to Detect Pedaling Intent.
The aim of this work was to design a personalized BCI model to detect pedaling intention through EEG signals. The approach sought to select the best among many possible BCI models for each subject. The choice was between different processing windows, feature extraction algorithms and electrode configurations. Moreover, data was analyzed offline and pseudo-online (in a way suitable for real-time applications), with a preference for the latter case. A process for selecting the best BCI model was described in detail. Results for the pseudo-online processing with the best BCI model of each subject were on average 76.7% of true positive rate, 4.94 false positives per minute and 55.1% of accuracy. The personalized BCI model approach was also found to be significantly advantageous when compared to the typical approach of using a fixed feature extraction algorithm and electrode configuration. The resulting approach could be used to more robustly interface with lower limb exoskeletons in the context of the rehabilitation of stroke patients.


Impact of a Casino Opening on Gambling Behaviors of People Engaged in Methadone Maintenance.
This study examined gambling behavior in the context of a newly opening casino, comparing disordered gamblers to non-disordered gamblers, in a population of individuals involved in methadone maintenance treatment. Disordered gamblers (N = 50) and non-disordered gamblers (N = 50) were surveyed before and after the opening of a new casino on gambling behaviors, substance use, and psychological symptoms. No statistically significant changes in gambling behaviors were observed for disordered gamblers or non-disordered gamblers across time points; however, non-disordered gamblers demonstrated non-significant increases in horse and dog race betting, electronic games, and casino table games. As expected, disordered gamblers were found to spend significantly more money on electronic games and casino table games (p < 0.05) and demonstrated higher rates of drug use and impulsivity than non-disordered gamblers. The introduction of a new casino did not appear to have a major impact on gambling behaviors of individuals attending methadone maintenance treatment, though the non-significant increases in gambling among non-disordered gamblers may indicate that this population is preferentially impacted by the opening of a new casino. Future investigation into the longer term effects of opening a new casino on this population may be warranted.


The anti-aging properties of a human placental hydrolysate combined with dieckol isolated from Ecklonia cava.
In the present study, we aimed to examine the anti-aging properties of human placental hydrolysate (HPE) and dieckol (DE) from Ecklonia cava against free radical scavenging, muscle hypertrophy-related follistatin mRNA expression, amelioration of cognition-related genes and proteins, inhibition of collagenase-regulating genes, and elastinase activity. The anti-aging effects were examined in human fibroblast (CCD986sk), mouse myoblast (C2C12), and neuroblastoma (N2a) cell models, by employing various assays such as 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) scavenging, hydroxyl radical-mediated oxidation, quantitative real-time polymerase chain reaction, enzyme activity, and immunocytochemistry observation. Our results show that HPE combined with DE (HPE:DE) strongly scavenged DPPH radicals and protected proteins against degradation by hydroxyl radical attack. HPE:DE effectively inhibited matrix metalloproteinase-1 expression, protein kinase C alpha expression, and elastinase activity. Furthermore, HPE:DE improved the expression of cognition-related genes (choline acetyltransferase and vesicular acetylcholine transporter). These events may proactively contribute to retard the aging processes and the abrupt physiological changes probably induced by mitochondrial dysfunction with aging. Based on these findings, we conclude that the combined treatment of HPE:DE may be useful for anti-aging therapy in which the accumulation of oxidative damage is the main driving force.


Intrahepatic expression of serum hepatitis virus-associated antigens.
SH virus-associated antigens have been identified in the liver and blood by immunofluorescence. This antigenic expression of the hepatitis agent or its genome is found in the cytoplasm of hepatocytes and other cells of the liver. Acute hepatitis is associated with hepatocellular localization of SH antigen, whereas alternative or additional SH antigen in the cytoplasm of nonhepatocytes is observed in chronic or recurrent hepatitis. Persistent intrahepatic SH antigen has also been observed in conversion from acute to chronic hepatitis, and the persistence of this virus-associated antigen in the liver may serve a significant pathogenetic role in mediating direct anti-tissue responses as well as local immune complex reactions. Competitive inhibition studies of SH antigen suggest at least two antigenically and sterically independent determinants on the SH particle.


Rates of HIV-1 virological suppression and patterns of acquired drug resistance among fisherfolk on first-line antiretroviral therapy in Uganda.
We examined virological outcomes, patterns of acquired HIV drug resistance (ADR), correlates of virological failure (VF) and acquired drug resistance among fisherfolk on first-line ART. We enrolled 1169 adults on ART for a median duration of 6, 12, 24, 36 and ≥48 months and used a pooled VL testing approach to identify VF (VL ≥1000 copies/mL). We performed genotyping among VF cases and determined correlates of VF and ADR by logistic regression. The overall virological suppression rate was 91.7% and ADR was detected in 71/97 (73.2%) VF cases. The most prevalent mutations were M184V/I (53.6%) for NRTIs and K103N (39.2%) for NNRTIs. Thymidine analogue mutations were detected in 21.6% of VF cases while PI mutations were absent. A zidovudine-based ART regimen, duration on ART (≥24 months) and secondary/higher education level were significantly associated with VF. A nevirapine-based regimen [adjusted OR (aOR): 1.87; 95% CI: 0.03-0.54)] and VL ≥10000 copies/mL (aOR: 3.48; 95% CI: 1.37-8.85) were ADR correlates. The pooling strategies for VL testing with a negative predictive value (NPV) of ≥95.2% saved US $20320 (43.5%) in VL testing costs. We observed high virological suppression rates among these highly mobile fisherfolk; however, there was widespread ADR among those with VF at the first VL testing prior to intensive adherence counselling. Timely treatment switching and adherence support is recommended for better treatment outcomes. Adoption of pooled VL testing could be cost effective, particularly in resource-limited settings.


Canine filariosis in Umbria: an update of the occurrence one year after the first observation of autochthonous foci.
Following the first observation of two autochthonous foci of canine filariosis occurred in Umbria region in the year 2001, a survey on prevalence and risk factors was conducted 12 months later to better understand the actual entity of the Dirofilaria problem in Umbria region. Blood samples were collected between January and December 2002 from 2406 dogs living in a total of 7 towns located in the identified areas at risk. Blood samples were tested by a modified Knott's technique to evaluate the microfilaraemia and, by a commercial ELISA kit, to detect in the sera adult antigens of D. immitis. The results were subject to statistical analysis. A total of 439 dogs were found to be infected. The true prevalence (LC 95%) was of 18%. Microfilariae of D. immitis were detected in 286 dogs (13%) while 112 dogs (6%) showed only microfilariae of D. repens and 41 dogs (1.6%) microfilariae of both D. immitis and D. repens. The prevalence ratio (PR) for each species of Dirofilaria (LC 95%) calculated in association with different risk factors (age, sex, use, outdoor night status, position, living together with other dogs, breed) and the statistical significance between the risk factors and the presence/absence of the infection, evaluated for each species of Dirofilaria, are discussed.


Health-related direct-to-consumer genetic tests: a public health assessment and analysis of practices related to Internet-based tests for risk of thrombosis.
Recent years have seen increased concern about direct-to-consumer (DTC) genetic testing (i.e., the sale and use of genetic tests without involving a health care provider). Numerous professional organizations have developed policies in this area. However, little systematic evidence exists to inform public policy about these tests. We conducted a systematic search to identify genetic tests that are sold DTC without involving a health care provider. We evaluated the practices of companies offering DTC genetic tests for risk of thrombosis using criteria from multiple sources and a minimal set of key practices. We identified 84 instances of currently available health-related DTC genetic tests sold on 27 Web sites; the most common were for pharmacogenomics (12), risk of thrombosis (10), and nutrigenomics (10). For the DTC genetic tests for risk of thrombosis, we found low adherence to recommendations. Online information was frequently incomplete and had low agreement with professional recommendations. Our findings document the rapid growth in the availability of health-related DTC genetic tests and highlight the need to improve the delivery of DTC genetic tests. A major implication of this study is the need for the scientific and medical community to develop consistent recommendations to increase their impact.


Physicochemical Properties and Dentin Bond Strength of a Tricalcium Silicate-Based Retrograde Material.
The aim of this study was to evaluate the physicochemical properties and the apical dentin bond strength of the tricalcium silicate-based Biodentine in comparison to white MTA and zinc oxide eugenol-based cement (ZOE). Setting time and radiopacity were evaluated according to ISO 6876:2012 specification. Final setting time, compressive strength and pH were also assessed. Material's bond strength to the apical root canal dentin was measured by the push-out assay. Data were analyzed by ANOVA and Tukey-Krammer post-hoc test. Biodentine presented the shortest initial (16.2±1.48 min) and final setting time (35.4±5.55 min). Radiopacity of Biodentine (2.79±0.27 mmAl) does not agree with ISO 6876:2012 specifications. On the other hand, Biodentine showed higher compressive strength after 21 days (37.22±5.27 MPa) and higher dentin bond strength (11.2±2.16 MPa) in comparison to white MTA (27.68±3.56 MPa for compressive strength and 2.98±0.64 MPa for bond strength) (p<0.05). Both MTA and Biodentine produced an alkaline environment (approximately pH 10) (p>0.05) compared to ZOE (pH 7). It may be concluded that Biodentine exhibited faster setting, higher long-term compressive strength and bond strength to the apical dentin than MTA and ZOE.


New method to calculate the anisotropies of polarizability and thermal expansion of uniaxial liquid crystals.
The anisotropy of molecular polarizability in liquid crystals is linked to the birefringence in these substances. The classic methods to compute the polarizabilities of liquid crystals assume an average number density of molecules that is equal in all directions. In the present work, a new model is proposed for the anisotropic molar polarization based on a virtual anisotropy of the number density of molecules in the liquid-crystalline material. This new strategy hence allows for the computation of both the anisotropic polarizabilities and the anisotropic thermal-expansion coefficients of liquid crystals. The model is applied to the liquid crystals 4-n-pentyl-4'-cyanobiphenyl and N-(4-methoxybenzylidene)-4-butylaniline, yielding polarizabilities similar to those reported for these materials. For these nematic liquid crystals, the results imply the existence of a positive thermal-expansion coefficient in the direction perpendicular to the director vector throughout the entire nematic temperature range and a negative thermal-expansion coefficient parallel to the director vector near the temperature of the nematic-isotropic transition. At the isotropization temperature, there exists divergent and critical behavior of the anisotropic thermal-expansion coefficients, consistent with the typical discontinuity of volume in first-order transitions.


A proposed histopathologic classification, scoring, and grading system for renal amyloidosis: standardization of renal amyloid biopsy report.
A disease associated with amyloid deposits, called amyloidosis, is associated with characteristic electron microscopic appearance, typical x-ray pattern, and specific staining. Renal involvement mainly occurs in AA amyloidosis and AL amyloidosis and usually progresses to renal failure. The renal histopathologic changes with amyloidosis comprise a spectrum. Clear relationships between the extent of amyloid deposition and the severity of clinical manifestations have not been demonstrated. Whether there is a lack of clinicopathologic correlation is not clear, but studies have revealed the need for standardization of the renal amyloid biopsy report. With these objectives in mind, we proposed a histopathologic classification, scoring, and grading system. Renal amyloidosis was divided into 6 classes, similar to the classification of systemic lupus erythematosus. Amyloid depositions and other histopathologic lesions were scored. The sum of these scores was termed the renal amyloid prognostic score and was divided into 3 grades. AA amyloidosis was detected in 90% of cases, mostly related to familial Mediterranean fever. Positive correlations between class I and grade I, class VI and grade III, and class III and grade II were observed. Also, a positive correlation was identified between severity of glomerular amyloid depositions, interstitial fibrosis, and inflammation. Because of the inadequacy of the patients' records and outcomes, different therapy regimes, and etiologies, clinical validation of this study has not been completed. Standardization of the renal amyloid pathology report might be critical for patients' medication and comparison of outcome and therapeutic trials between different clinics. Because of our AA to AL amyloidosis ratio and the predisposition of familial Mediterranean fever-related AA amyloidosis, there is a need for further international collaborative studies.


Conditional control of gene expression in the mouse retina.
Conditional knockout is a powerful research tool for specific deletion of target genes, especially for the genes that are widely expressed and developmentally regulated. The development of the retina involves multiple intrinsic and extrinsic factors, many are required for embryonic development or expressed in multiple tissue or cell types. To study their roles in a spatial- or temporal-specific fashion, Cre/loxP-based gene-targeting approach has been utilized successfully. This chapter describes the methodology of conditional knockout approach in studying the development of the retina, using LIM homeobox gene Isl1 as an example. It provides details on targeting vector design and construction, introducing the vector into embryonic stem (ES) cell, screening ES cell for the recombination events, injecting ES cells, and generating chimeric and null mice. It also discusses the current issues in the use of Cre/loxP-based gene-targeting approach.


[Target selectivity of anticancer drugs].
Since the first use of chemotherapy, many efforts were devoted to develop drugs with a specific anticancer activity. Nevertheless, although several approaches to this end were used leading to significant results in cancer treatment, chemotherapy has mainly a palliative effect. The remarkable scientific advances in the knowledge of molecular changes in neoplastic diseases brought to development of new drugs with a specific molecular target. In some cases, this approach against a single molecular target, has been extremely successful, like imatinib in GIST. However, since in most cases tumor growth involves multiple genetic changes, it seems more appropriate to develop multitargeted agents. A successful way to improve target selectivity of anticancer drugs and to better choose patients to treat could be the use phase 0 clinical trials. In the future, the hope is to discover all genetic changes in each cancer patient and to restore the normal function of the cell with the aid of more advanced technologies.


Collisionless plasma shocks in striated electron temperatures.
The existence of low frequency waveguide modes of ion acoustic waves is demonstrated in magnetized plasmas for electron temperatures striated along the magnetic field lines. At higher frequencies, in a band between the ion cyclotron and the ion plasma frequency, radiative modes develop and propagate obliquely to the field away from the striation. Arguments for the subsequent formation and propagation of electrostatic shock are presented and demonstrated numerically. For such plasma conditions, the dissipation mechanism is the "leakage" of the harmonics generated by the wave steepening.


Pathway selection by an active droplet.
We report the movement of an active 1-pentanol drop within a closed Y-shaped channel subjected to geometrical and chemical asymmetry. A Y-shaped channel was configured with an angle of 120° between any two arms, which serves as the closed area of movement for the active drop. The arm where the 1-pentanol drop is introduced in the beginning is considered the source arm, and the center of the Y-shaped structure is the decision region. The drop always selects a specific route to move away from the decision region. The total probability of pathway selection excludes the possibility of the drop choosing the source channel. Remarkably, the active drop exhibits a strong sense of navigation for both geometrically and chemically asymmetric environments with accuracy rates of 80% and 100%, respectively. The pathway selection in a chemically asymmetric channel is a demonstration of the artificial negative chemotaxis, where the extra confined drop acts as a chemo-repellent. To develop a better understanding of our observations, a numerical model is constructed, wherein the particle is subjected to a net force which is a combined form of - (i) Yukawa-like repulsive interaction force (acting between the drop and the walls), (ii) a self-propulsion force, (iii) a drag, and (iv) a stochastic force. The numerics can capture all the experimental findings both qualitatively and quantitatively. Finally, a statistical analysis validates conclusions derived from both experiments and numerics.


New family of lithium salts for highly conductive nonaqueous electrolytes.
New lithium salts of weakly coordinating anions were prepared by treating lithium imidazolates or LiN(CH3)2 with 2 equiv of BF(3). They are LiIm(BF3)2, Li 2-MeIm(BF3)2, Li 4-MeIm(BF3)2, LiBenzIm(BF3)2, Li 2-iPrIm(BF3)2, and LiN(CH3)2(BF3)2 (Im=imidazolate, Me=methyl, iPr=isopropyl, BenzIm=benzoimidazolate). The salts were characterized by NMR spectroscopy and mass spectrometry. The structure of LiBenzIm(BF3)2 consists of a dimeric centrosymmetric unit with each lithium atom forming a bridge between the two anions through one fluorine contact to each anion. The structure of a hydrate of LiN(CH3)2(BF3)2 consists of an infinite chain in which each anion chelates two different lithium atoms through Li-F bonds. The conductivities of electrolyte solutions of these salts were measured and are discussed in terms of different ion-pairing modes determined from the solid-state structures, the anion's ability to distribute charge, and solution viscosity. Organic carbonate solutions of LiIm(BF3)2 partially disproportionate at 85 degrees C forming LiBF4, LiBF2[Im(BF3)]2, and Li[(BF3)ImBF2ImBF2Im(BF3)], reaching equilibrium by 3 months at 85 degrees C but not disproportionating at room temperature after 9 months. A mechanism for the formation of these disproportionation products is proposed. The lower conductivity of the 1 M LiIm(BF3)2 solution that has undergone disproportionation is attributed to the formation LiBF4, which is less conductive, and LiBF2[Im(BF3)]2 and Li[(BF3)ImBF2ImBF2Im(BF3)], which increase solution viscosity.


ACE variants and association with brain Aβ levels in Alzheimer's disease.
ACE is a candidate gene for Alzheimer's disease (AD) and associations have been reported between ACE variants and plasma ACE levels, AD risk, AD age at onset of disease and cerebrospinal fluid levels of Aβ. Despite evidence that ACE can degrade Aβ, the relationships between ACE variants and the levels of different types of Aβ in the brain are not known. We have investigated the relationship between AD-associated ACE variants, for which the associations with brain activity of ACE were previously analysed, and brain homogenate levels of soluble, insoluble and oligomeric Aβ. Reported AD risk variants in the ACE indel (rs1799752) and its 'proxy' rs4343 were significantly associated with soluble Aβ level in AD only (p=0.001), as was rs1800764 but less so (p=0.014). In contrast, insoluble Aβ was associated with ACE indel and rs4343 variants in controls only (p < 0.01). No associations were found for oligomeric Aβ. These data indicate a complex relationship between ACE and Aβ that differs between AD and control brains.


Measuring Microtubule Supertwist and Defects by Three-Dimensional-Force-Clamp Tracking of Single Kinesin-1 Motors.
Three-dimensional (3D) nanometer tracking of single biomolecules provides important information about their biological function. However, existing microscopy approaches often have only limited spatial or temporal precision and do not allow the application of defined loads. Here, we developed and applied a high-precision 3D-optical-tweezers force clamp to track in vitro the 3D motion of single kinesin-1 motor proteins along microtubules. To provide the motors with unimpeded access to the whole microtubule lattice, we mounted the microtubules on topographic surface features generated by UV-nanoimprint lithography. Because kinesin-1 motors processively move along individual protofilaments, we could determine the number of protofilaments the microtubules were composed of by measuring the helical pitches of motor movement on supertwisted microtubules. Moreover, we were able to identify defects in microtubules, most likely arising from local changes in the protofilament number. While it is hypothesized that microtubule supertwist and defects can severely influence the function of motors and other microtubule-associated proteins, the presented method allows for the first time to fully map the microtubule lattice in situ. This mapping allows the correlation of motor-filament interactions with the microtubule fine-structure. With the additional ability to apply loads, we expect our 3D-optical-tweezers force clamp to become a valuable tool for obtaining a wide range of information from other biological systems, inaccessible by two-dimensional and/or ensemble measurements.


Atopic Manifestations: Dermatitis, Allergic Rhinitis and Asthma in Patients With Hypogammaglobulinemia.
Most of the hypogammaglobulinemic patients have a clinical history in favor of allergic respiratory disease. Nevertheless, in these patients the importance and prevalence of atopic disorders have not been completely explained. This study was aimed to evaluate atopic manifestations (dermatitis, allergic rhinitis and asthma) and pulmonary function in patients with hypogammaglobulinemia. We used the international study of asthma and allergies in childhood (ISAAC) questionnaire in forty-five patients diagnosed with hypogammaglobulinemia and spirometry was done in 41 patients older than 5 years. Spirometry results were normal in 21 (51%), and showed obstructive in 15 (37%) and restrictive pattern in 5 (12%) of the 41 patients who were evaluated. By the end of the study, asthma was diagnosed in nine (20%) patients and other atopies (rhinitis and dermatitis) identified in 10 (22%), and four (9%), respectively. Atopic conditions should be investigated in the hypogammaglobulinemic patients and the prevalence in these patients may be higher than in normal population. Also, it is recommended to perform a pulmonary function test as a routine procedure in patients with hypogammaglobulinemia and atopy should be assessed in these patients.


Antagonism of vecuronium paralysis: comparison between edrophonium and neostigmine.
The reversal of vecuronium paralysis was studied in three series of anesthetized (methohexital, fentanyl, N2O/O2) informed adult patients receiving either 40 micrograms/kg neostigmine (NEO40) (n = 6), either 500 micrograms/kg edrophonium (EDRO500) (n = 6) or 1000 micrograms/kg edrophonium (EDRO1000) (n = 6). These drugs were given randomly once the adductor pollicis twitch height regained 10% of its initial value. The neuromuscular transmission recovery was assessed during 15 minutes after the antagonist administration, by recording twitch height (TH), train of four--2 Hz--every 3 minutes (TOF Ratio) and finally tetanic fade--50 Herz (TET50) and 100 Hz (TET100), 5 seconds duration, one minute apart--. At 15 minutes, the TH values (mean +/- SEM) were for EDRO500 92% +/- 7, for EDRO1000 93% +/- 3 and for NEO40 100% +/- 4 percent (n.s.). For the TOF Ratio, a statistical difference (p less than 0.05) was found between NEO40 86% +/- 4 and the two other groups: EDRO500 73% +/- 3, EDRO1000 69% +/- 4. For the TET50, the values were: EDRO500 93% +/- 3, EDRO1000 86% +/- 5 and NEO40 94% +/- 2 (n.s.). At 100 Hz, the values were: NEO40 61% +/- 8, EDRO500 43 +/- 151 and EDRO1000 31 +/- 12 (p less than 0.01). In conclusion, in the conditions studied, 40 micrograms/kg neostigmine restores the neuromuscular transmission of the adductor pollicis at a higher level than edrophonium 500 micrograms/kg does. Edrophonium, 1000 micrograms/kg instead of 500 micrograms/kg does not change the neuromuscular transmission recovery.


Surgical alternatives in the treatment of polyposis coli.
The history of familial polyposis coli and its various surgical treatment alternatives are presented. Each form of treatment has advantages and disadvantages. The menu of alternatives allows the surgeon the freedom to choose the best option for each patient.


Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide.
The presence of measurable residual disease (MRD) prior to an allogeneic hematopoietic transplant (alloHCT) in Acute Myeloid Leukemia (AML) has been shown to be associated with an increased risk of post-transplant relapse. Since the Isocitrate Dehydrogenase genes (IDH1/2) are mutated in a considerable proportion of patients with AML, we studied if these mutations would serve as useful targets for MRD. Fifty-five IDH-mutated AML patients undergoing non-myeloablative alloHCT with post-transplant cyclophosphamide at a single center were sequenced at baseline using a multi-gene panel followed by targeted testing for persistent IDH mutations at the pre- and post-alloHCT timepoints by digital droplet PCR or error-corrected next generation sequencing. The cohort included patients who had been treated with IDH inhibitors pre- and post-transplant (20% and 17% for IDH1 and 38% and 28% for IDH2). Overall, 55% of patients analyzed had detectable IDH mutations during complete remission prior to alloHCT. However, there were no statistically significant differences in overall survival (OS), relapse-free survival (RFS), and cumulative incidence of relapse (CIR) at 3 years between patients who tested positive or negative for a persistent IDH mutation during remission (OS: IDH1 p=1, IDH2 p=0.87; RFS: IDH1 p=0.71, IDH2 p= 0.78; CIR: IDH1 p=0.92, IDH2 p=0.97). There was also no difference in the prevalence of persistent IDH mutation between patients who did and did not receive an IDH inhibitor (p=0.59). Mutational profiling of available relapse samples showed that 8 out of 9 patients still exhibited the original IDH mutation, indicating that the IDH mutations remained stable through the course of the disease. This study demonstrates that persistent IDH mutations during remission is not associated with inferior clinical outcomes after alloHCT in patients with AML.


Factors associated with fertility outcomes in cows treated with protocols to synchronize estrus and ovulation in seasonal-calving, pasture-based dairy production systems.
Logistic regression was used to identify factors associated with fertility outcomes in cows treated with protocols to synchronize estrus and ovulation. Lactating dairy cows (n=1,538) were enrolled in a completely randomized block design study to evaluate synchronization treatments. Within each herd (n=8), cows were divided into 3 calving groups: early [≥ 42 d in milk (DIM) at mating start date (MSD); n=1,244], mid (21 to 41 DIM at MSD; n=179), and late (0 to 20 DIM at MSD; n=115), based on DIM at MSD. Cows in the early-, mid-, and late-calving groups were synchronized to facilitate estrus or timed artificial insemination (TAI) at MSD (planned breeding 1; PB1), 21 d (PB2), and 42 d (PB3) after MSD, respectively. For each PB, cows in the relevant calving group were stratified by parity and calving date and randomly assigned to (1) d -10 GnRH (10 μg i.m. of buserelin) and CIDR [controlled internal drug release insert, 1.38 g of progesterone (P4)]; d -3 PGF(2α) (25mg i.m. of dinoprost); d -2 CIDR out and AI at observed estrus (CIDR_OBS); (2) same as CIDR_OBS, but GnRH 36 h after CIDR out and TAI 18 h later (CIDR_TAI); (3) same as CIDR_TAI, but no CIDR (i.e., Ovsynch); or (4) untreated controls (CTRL). Use of a CIDR-based ovulation synchronization protocol (i.e., CIDR_TAI) increased synchronization rates in anovular cows. Both CIDR_OBS and CIDR_TAI animals without a corpus luteum (CL) had increased likelihood of conception at first service compared with Ovsynch animals without a CL. Animals with low body condition score (BCS) treated with CIDR_OBS had an increased likelihood of conceiving at first service compared with low-BCS animals treated with CIDR_TAI, Ovsynch, or CTRL. Animals <60 d in milk (DIM) treated with CIDR_OBS and CIDR_TAI had increased likelihood of conceiving at first service compared with animals treated with Ovsynch. Treatment with CIDR_TAI increased synchronization rate in cows categorized as low BCS, anovulatory, and <60 DIM compared with both CIDR_OBS and Ovsynch, and increased submission rate compared with CIDR_OBS. Conception rate in cows within these categories, however, was greatest for CIDR_OBS, resulting in minimal differences in actual pregnancy rates between CIDR_OBS and CIDR_TAI treatments, both of which were superior to Ovsynch. Treatment differences in the response variables investigated were minimal in cows categorized as medium or high BCS, ovulatory, and >60 DIM, indicating that CIDR-based protocols could be targeted at particular cows, and all other cows could be synchronized using Ovsynch.


[Ductal hyperplasia and ductal carcinoma in situ. Definition--classification--differential diagnosis].
This review emphasizes the pathology of premalignant ductal breast diseases and its practical relevance to the patients management. The histological criteria for recognizing Ductal Hyperplasia (DH) are now well established. These include an intraluminal heterogeneous proliferation of glandular cells positive for keratins 8/18/19 and epithelial cells with expression of keratins 5/6/14. As a hyperplastic process the epithelial cells disclose an haphazard irregular growth with slit like irregular lumina (fenestrated growth pattern). The florid DH indicates a slight subsequent increased risk for cancer development. Our knowledge of the nature of noninvasive ductal neoplasia continues to evolve. Recent molecular genetic and immunohistochemical efforts have disclosed that atypical ductal hyperplasia (ADH) constituted a clonal neoplastic proliferation of an epithelial cell. Histological hallmarks of ADH are their cytologic features of uniformity and monotony of proliferation of cells and its micropapillary, cibriform or solid growth pattern. So from histology ADH simulates the highly differentiated DCIS, but can be distinguished from the latter quantitatively by the aggregate cross sectional diameter or the number of ducts that are completely involved by the atypical proliferation. ADH indicates a few fold subsequent increased risk for developing carcinoma. So this lesion requires a close follow up with 3 to 4 examinations per year and annual mammograms. Ductal carcinoma in situ (DCIS) consists of cytologically malignant cells in the parenchyma that have not invaded into the stroma. Recent studies have shown that DCIS is a heterogeneous group of tumors. Attempts have been made to classify it into histologic patterns, nuclear grades, tumors with or without comedo-necroses etc. We can draw the conclusion from several studies that the most important histologic feature is the nuclear grade. Holland et al. have suggested a very useful classification scheme that includes nuclear grade and histological features. The modifiers of treatment are as follows: 1. nuclear grade or differentiation of the DCIS 2. extension of the lesion 3. excision with clear margins So efforts to classify DCIS underscore the central role of pathology in determining the grade of the DCIS, its size and the adequacy of the surgical excision in terms of free margins. All three parameters are included in a score system of the Van Nuys Prognostic Index.


Extended rotational diffusion and orientational relaxation of symmetric top molecules in a strong dc electric field: second-rank orientational correlation functions.
Second-rank orientational correlation functions (pertaining to Kerr effect relaxation and Raman scattering) are obtained using the extended rotational diffusion (J-diffusion) model of symmetric top polar molecules in a strong constant external field. It is shown that the shape of the molecule noticeably affects all second-rank correlation functions and relaxation times in the rare collision limit. In the opposite limit of frequent collisions, the quantities of interest are shown to be shape independent as a consequence of vanishingly small inertial effects. An interpolation formula for the orientation relaxation times in the intermediate regime between the rare and frequent collision limits is also given.


Identification and validation of reference genes for gene expression analysis using quantitative PCR in Spodoptera litura (Lepidoptera: Noctuidae).
Reverse transcription quantitative polymerase chain reaction (qRT-PCR) has rapidly become the most sensitive and accurate method for the quantification of gene expression. To facilitate gene expression studies and obtain more accurate qRT-PCR data, normalization relative to stable housekeeping genes is required. These housekeeping genes need to show stable expression under the given experimental conditions for the qRT-PCR results to be accurate. Unfortunately, there are no studies on the stability of housekeeping genes used in Spodoptera litura. In this study, eight candidate reference genes, elongation factor 1 alpha (EF1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ribosomal protein L10 (RPL10), ribosomal protein S3 (RPS3), beta actin (ACTB), beta FTZ-F1 (FTZF1), ubiquinol-cytochrome c reductase (UCCR), and arginine kinase (AK), were evaluated for their suitability as normalization genes under different experimental conditions using the statistical software programs, BestKeeper, geNorm and Normfinder, and the comparative ΔCt method. We determined the expression levels of the candidate reference genes for three biotic factors (developmental stage, tissue and population), and four abiotic treatments (temperature, insecticide, food and starvation). The results indicated that the best sets of candidates as reference genes were as follows: GAPDH and UCCR for developmental stages; RPL10, AK and EF1 for different tissues; RPL10 and EF1 for different populations in China; GAPDH and EF1 for temperature-stressed larvae; AK and ACTB for larvae treated with different insecticides; RPL10, GAPDH and UCCR for larvae fed different diets; RPS3 and ACTB for starved larvae. We believe that these results make an important contribution to gene analysis studies in S. litura and form the basis of further research on stable reference genes in S. litura and other organisms.


Pomegranate polyphenolics reduce inflammation and ulceration in intestinal colitis-involvement of the miR-145/p70S6K1/HIF1α axis in vivo and in vitro.
This study investigated the potential role of the p70S6K1/HIF1α axis in the anti-inflammatory activities of pomegranate (Punica granatum L.) polyphenolics in dextran sodium sulfate (DSS)-induced colitis in Sprague-Dawley rats and in lipopolysaccharide (LPS)-treated CCD-18Co colon-myofibroblastic cells. Rats were administered either control (CT) or pomegranate beverage (PG), containing ellagic acid and ellagitannins, then exposed to three cycles of 3% DSS followed by a 2-week recovery period. PG protected against DSS-induced colon inflammation and ulceration (50% and 66.7%, P=.05 and .045, respectively), and decreased the Ki-67 proliferative index in the central and basal regions compared to the control. PG also significantly reduced the expression of proinflammatory cytokines (TNF-α and IL-1β), COX-2, and iNOS at mRNA and protein levels. In addition, the expression of p70S6K1 and HIF1α was reduced, while the tumor suppressor miR-145 was induced by PG. The intestinal microbiota of rats treated with PG showed a significant increase in Ruminococcaceae that include several butyrate producing bacteria (P=.03). In vitro, PG reduced the expression of p70S6K1 and HIF1α and induced miR-145 in a dose-dependent manner. The involvement of miR-145/p70S6K1 was confirmed by treating LPS-treated CCD-18Co cells with miR-145 antagomiR, where the pomegranate polyphenolics reversed the effects of the antagomiR for p70S6K1 mRNA and protein levels. These results suggest that pomegranate polyphenols attenuated DSS-induced colitis by modulating the miR-145/p70S6K/HIF1α axis, indicating potential use in therapeutic treatment of ulcerative colitis.


[Performance evaluation of Real-Q Enterovirus Quantification kit for enterovirus by real-time PCR].
Molecular methods have enabled rapid diagnosis of aseptic meningitis and have reduced both unnecessary therapeutic interventions and medical costs. In this study, we evaluated the analytical performance of the recently developed Real-Q Enterovirus Quantification kit (BioSewoom Inc., Korea). We evaluated the detection limit, precision, linearity, and cross-reactivity of the Real-Q Enterovirus Quantification kit and compared it with the conventional PCR method. From March to September 2009, we tested 91 CSF specimens from patients who visited the pediatrics department of the university hospital with symptoms of aseptic meningitis or infantile sepsis, and we also tested 48 CSF specimens from patients with febrile convulsion for differential diagnosis. The Real-Q Enterovirus Quantification kit showed good linearity (r=0.997) within a range from 3 × 10(2) to 3 × 10(10) copies/mL, and the detection limit of the kit was 83 copies/mL. The within-run, between-run, and between-day CVs were 5.3-7.6%, 9.5-12.3%, and 11.4-13.4%, respectively. There was no cross reactivity between enteroviruses and various microorganisms. Positive results were obtained for 39.1% (25/64) of the patients suspected of aseptic meningitis and 44.4% (12/27) of the patients suspected of infantile sepsis. However, among the 48 children with febrile conversion, only 4 were positive for enterovirus. Further, the concordance with conventional PCR was high (73/74). The Real-Q Enterovirus Quantification kit showed excellent linearity and high reliability with a broad reportable range. It showed good detection rate when used with clinical specimens and also showed a high concordance with the conventional method. Therefore, this assay would be clinically useful not only in diagnosis of aseptic meningitis but also in differential diagnosis of infantile sepsis.


Development of an anthropometric database for Hong Kong Chinese CAD operators.
With the increasing popularity of using computer-aided design (CAD) in Hong Kong, it is time to look into the design of a suitable workplace for the CAD operators working in the industries. This can be achieved by applying anthropometric data into the design for enhancing performance and reducing musculoskeletal problems. In order to avoid any mismatches in anthropometric dimensions, which is believed to be one of the main causes of fatigue and occupational illness among workers, in the workplace design for them, eleven relevant body dimensions from a group of 150 Hong Kong male adults with ages ranging from 18 to 28 years were collected and analyzed to develop a computerized anthropometric database for Hong Kong CAD operators. The eleven anthropometric dimensions measured were: shoulder rest height, elbow-fingertip length, shoulder breadth, hip breadth, sitting eye height, elbow rest height, third lumbar disc-pan length, thigh clearance height, popliteal height, buttock-popliteal length, and stature. The computerized database can provide some useful statistics such as mean, standard deviation and relevant percentiles of all the measured dimensions. With the aid of these statistics, a new workplace for CAD operators was designed which improved performance substantially.


Folinic acid protection against hematopoietic depression induced by nitrous oxide in rats.
We studied the degree of hematopoietic depression and spontaneous recovery of depressed hematopoietic cells with 50% nitrous oxide-oxygen inhalation for 6 or 12 h in 120 Sprague-Dawley rats. Bone marrow and blood were sampled serially immediately after, 1 day, 3 days, and 1 wk following nitrous oxide inhalation. After 1 wk of culturing of hematopoietic stem cells, the number of the colony-forming units of granulocytes and monocytes and the colony-forming units of T lymphocytes grown from bone marrow and blood were counted. There was no change in the number of colonies immediately after inhalation compared with the control group, but there was a significant decrease in the number of colonies 1 and 3 days after inhalation (P < 0.001), and 1 wk after inhalation, there was spontaneous recovery without any treatment. Nitrous oxide may depress the early phase of differentiation of hematopoietic stem cells such as granulocytes, monocytes, and lymphocytes as well as erythrocytes. Also, the degree of suppression was more intense after 12 h than after 6 h of inhalation. That is, the length of inhalation time corresponds to the intensity and rapidity of suppression. To evaluate the protective effect of folinic acid against hematopoietic depression, folinic acid (0.1 mg/0.3 mL) was injected intraperitoneally before or after nitrous oxide inhalation. The groups injected with folinic acid showed significant increase in the number of colonies, especially in the group receiving folinic acid 12 h and 1 h before nitrous oxide inhalation (P < 0.001). Pretreatment with folinic acid may prevent the hematopoietic depression caused by the prolonged and repeated use of nitrous oxide.


Modulation of B lymphocyte signalling by the B subunit of Escherichia coli heat-labile enterotoxin.
The non-toxic B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent mucosal adjuvant and immunomodulator capable of blocking autoimmune disease. These effects are linked with its ability to modulate lymphocyte populations--a feature that is dependent on binding to ubiquitously expressed cell surface receptors. Here, we demonstrate that EtxB can trigger up-regulated expression of class II MHC and CD25 on purified populations of B lymphocytes, suggesting that EtxB can directly activate biochemical signalling pathways in these cells. The nature of the intracellular signalling events was investigated. B cells cultured with EtxB, but not a non-receptor binding mutant protein, EtxB(G33D), caused the activation of the extracellular signal-regulated kinase (Erk) forms of mitogen-activated protein (MAP) kinase in a process that was dependent on MAPK/Erk kinase (MEK), phosphoinositide 3-kinase (PI3-kinase) and protein kinase C (PKC), as determined by the use of specific inhibitors. PI3-kinase was critical not only in the activation of MAP kinase but also in the up-regulation of both class II and CD25. However, MEK inhibition only partially abrogated the EtxB-mediated up-regulation of MHC class II expression and did not affect CD25 expression--findings suggesting that additional pathways downstream of PI3-kinase are involved. A role for PKC in these processes was suggested by the finding that inhibitors of PKC completely blocked EtxB-mediated CD25 up-regulation. Thus, we have shown that receptor binding by EtxB triggers multiple signalling pathways in B cells that regulate the expression of key cell surface molecules.


Naturally occurring parainfluenza virus 3 infection in adults induces mild exacerbation of asthma associated with increased sputum concentrations of cysteinyl leukotrienes.
Viral respiratory tract infections represent the most frequent cause of asthma exacerbation in both children and adults, but the precise mechanism of such exacerbation remains unknown. To determine the critical mediator of naturally occurring parainfluenza virus (PIV) 3-induced mild asthma exacerbations in adults. The study subjects were 19 adult asthmatics with mild asthma exacerbation (peak expiratory flow = 60-80% of predicted before bronchodilator use and >80% of predicted after initial bronchodilator treatment). Differential cell counts and concentrations of inflammatory markers including eosinophil cationic protein (ECP), cysteinyl leukotrienes (cysLTs), interleukin (IL)-5, IL-10 and IL-12 were measured in the induced sputum obtained from adults with PIV3- (n = 9) and non-cold-induced (n = 10) exacerbation of asthma during both acute and convalescent phases. PIV3 infection was confirmed by the presence of viral RNA in nasopharyngeal aspirates. Mild exacerbation of asthma was not associated with significant changes in sputum differential cell counts. Concentrations of sputum ECP and cytokines were comparable between PIV3 and non-cold-induced patients. In contrast, PIV3 infection was associated with a significant increase in sputum cysLTs during the acute phase of mild asthma exacerbation. Our results identified cysLTs as a critical mediator of PIV3-induced acute asthma exacerbation.


Nickel Foam Promotes Syntrophic Metabolism of Propionate and Butyrate in Anaerobic Digestion.
Enhanced interspecies electron transfer (IET) among symbiotic microorganisms is an effective method to increase the rate of methane (CH4) production in anaerobic digestion. Direct interspecies electron transfer (DIET), which does not involve dissolved redox media, is considered an alternative and superior method to enhance methane production by interspecific hydrogen (H2) transfer (IHT). In this study, nickel foam was built into a semicontinuous anaerobic reactor to investigate its effect on the metabolism of propionate and butyrate. Both increased the average yield of CH4 in anaerobic digestion by 18.1 and 15.9%, respectively. Analysis of bacterial and archaeal communities showed that the addition of nickel foam could increase the relative abundance of microbial communities involved in DIET and could increase the diversity of microorganisms in the reactor. Moreover, the anaerobic digestion performance of the nickel foam reactor was good at high hydrogen partial pressure.


Timing of Adjuvant Radiotherapy in Glioblastoma Patients: A Single-Institution Experience With More Than 400 Patients.
The standard of care for patients with newly diagnosed glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy (RT) and temozolomide (TMZ). To investigate whether the timing of adjuvant RT after surgery affected outcome in patients with GBM. We retrospectively reviewed all patients with a diagnosis of GBM at our institution. A total of 447 patients were included in our analysis. Patients were divided into 3 equal groups based on the interval between surgery and RT. The primary outcome was overall survival (OS). Patients who began RT less than 21 days after surgery tended to be older, have a lower a Karnofsky Performance Status score, and higher recursive partitioning analysis class. These patients were more likely to have undergone biopsy only and received 3-dimensional conformal RT or 2-dimensional RT. The median OS for patients who started RT less than 21 days after surgery, between 21 and 32 days after surgery, and more than 32 days after surgery was 374, 465, and 478 days, respectively (P = .004). On multivariate Cox regression analysis, Karnofsky Performance Status score lower than 70, undergoing biopsy only, recursive partitioning analysis classes IV and V/VI, use of less than 36 Gy RT, and lack of TMZ chemotherapy were predictors of worse OS. The interval between surgery and RT was not significantly associated with OS on multivariate analysis. Patients who begin RT less than 21 days after surgery tend to have worse prognostic factors than those who begin RT later. When accounting for significant covariates, the effect of timing between surgery and RT is not significant.


The Experience of Empathy in Everyday Life.
We used experience sampling to examine perceptions of empathy in the everyday lives of a group of 246 U.S. adults who were quota sampled to represent the population on key demographics. Participants reported an average of about nine opportunities to empathize per day; these experiences were positively associated with prosocial behavior, a relationship not found with trait measures. Although much of the literature focuses on the distress of strangers, in everyday life, people mostly empathize with very close others, and they empathize with positive emotions 3 times as frequently as with negative emotions. Although trait empathy was negatively associated only with well-being, empathy in daily life was generally associated with increased well-being. Theoretically distinct components of empathy-emotion sharing, perspective taking, and compassion-typically co-occur in everyday empathy experiences. Finally, empathy in everyday life was higher for women and the religious but not significantly lower for conservatives and the wealthy.