Serum levels of matrix metalloproteinase 3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis.
Matrix metalloproteinase 3 (MMP-3) is expressed in synovial tissues and involved in cartilage destruction in rheumatoid arthritis and osteoarthritis. To study whether measurement of MMP-3 serum concentrations is useful to monitor the activity of rheumatoid synovitis. Levels of MMP-3 in serum and synovial tissue samples obtained from 29 rheumatoid arthritis patients and 20 osteoarthritis patients were measured by the 1-step sandwich enzyme immunoassay system. Levels of MMP-3 in the serum and synovial samples were significantly higher in rheumatoid arthritis than in osteoarthritis (P < .001), and the levels correlated directly with each other (r = 0.712, P < .001; N = 49). Immunohistochemistry demonstrated almost exclusive localization of MMP-3 to the lining cells in rheumatoid synovium. The immunoreactivity correlated directly with the scores of synovial inflammatory cell infiltration (r = 0.606, P < .001; n = 29) and the MMP-3 levels in the synovial tissues (r = 0.564, P = .001; n = 29) and those in the serum samples (r = 0.529, P = .003; n = 29) in rheumatoid arthritis. Levels of MMP-3 in rheumatoid serum samples dropped to low values at 1 and 2 weeks after total knee arthroplasty, while the levels of C-reactive protein increased at 1 week and the erythrocyte sedimentation rate and counts of white blood cells and platelets were unchanged at 1 and 2 weeks postoperative. Our results demonstrate that MMP-3 levels in the serum of rheumatoid arthritis patients correlate with the levels produced by the synovial lining cells and suggest that the activity of rheumatoid synovitis can be monitored by measuring serum levels of MMP-3.


Time sequential prediction of ventricular-vascular interactions.
A new analytical method (sequential convolution) for describing ventricular-vascular interactions was used to predict instantaneous pressure and flow in four isolated canine left ventricles ejecting into a computer-simulated arterial system. Ventricular pumping ability was described by a load-independent elastance, [E*(t)] combined with a ventricular internal resistance. "Arterial" properties were characterized using a time-based impulse response function that is derived from impedance measurements. Sequential convolution was then used to couple these independent descriptions of ventricular and vascular properties. Predicted pressure-volume trajectories, as well as instantaneous pressures and flows, closely matched the experimental data. Stroke volume, peak pressure, and peak flow were typically within 5% of measured values. This method provides a powerful analytical technique for examining ventricular-vascular interactions and has potential application in evaluating the ventricular-loading effects of more complex in vivo vascular properties.


Combining long-lasting insecticidal nets and indoor residual spraying for malaria prevention in Ethiopia: study protocol for a cluster randomized controlled trial.
Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are the main malaria prevention interventions in Ethiopia. There is conflicting evidence that the combined application of both interventions is better than either LLINs or IRS used alone. This trial aims to investigate whether the combination of LLINs (PermaNet 2.0, Vestergaard Frandsen, Lausanne, Switzerland) with IRS using propoxur will enhance the protective benefits and cost-effectiveness of the interventions against malaria and its effect on mosquito behavior, as compared to each intervention alone. This 2 x 2 factorial cluster randomized controlled trial is being carried out in the Adami Tullu district in south-central Ethiopia for about 116 weeks from September 2014 to December 2016. The trial is based on four arms: LLINs + IRS, LLINs alone, IRS alone and control. Villages (or clusters) will be the unit of randomization. The sample size includes 44 clusters per arm, with each cluster comprised of approximately 35 households (about 175 people). Prior to intervention, all households in the LLINs + IRS and LLINs alone arms will be provided with LLINs free of charge. Households in the LLINs + IRS and IRS alone arms will be sprayed with carbamate propoxur once a year just before the main malaria transmission season throughout the investigation. The primary outcome of this trial will be a malaria incidence based on the results of the rapid diagnostic tests in patients with a fever or history of fever attending health posts by passive case detection. Community-based surveys will be conducted each year to assess anemia among children 5-59 months old. In addition, community-based malaria prevalence surveys will be conducted each year on a representative sample of households during the main transmission season. The cost-effectiveness of the interventions and entomological studies will be simultaneously conducted. Analysis will be based on an intention-to-treat principle. This trial aims to provide evidence on the combined use of LLINs and IRS for malaria prevention by answering the following research questions: Can the combined use of LLINs and IRS significantly reduce the incidence of malaria compared with the use of either LLINs or IRS alone? And is the reduced incidence justifiable compared to the added costs? Will the combined use of LLINs and IRS reduce vector density, infection, longevity and the entomological inoculation rate? These data are crucial in order to maximize the impact of vector control interventions on the morbidity and mortality of malaria. PACTR201411000882128 (8 September 2014).


Isolated abducens nerve palsy due to pituitary apoplexy after mild head trauma.
Pituitary apoplexy is a relatively rare condition. Cranial nerve palsies may develop due to compression of the surrounding structures by the rapidly expanding tumor. While the most commonly affected nerve is the oculomotor nerve, abducens nerve palsy may also occur less commonly. A 68-year-old male patient was admitted to the emergency department with complaints of severe headache, nausea, vomiting, and diplopia after head trauma due to falling. His magnetic resonance imaging evaluation demonstrated a large pituitary adenoma and bleeding into the tumor, which was acutely expanding and leading to compression of the abducens nerve laterally. Isolated abducens palsy due to posttraumatic pituitary apoplexy is a rare clinical condition, and as the symptoms and signs are nonspecific, it can commonly remain clinically undiagnosed. In this article, our aim was to draw attention to a clinical condition in which unfavorable complications may develop if the diagnosis is overlooked.


Why Does Joint Attention Look Atypical in Autism?
This essay answers the question of why autistic children are less likely to initiate joint attention (e.g., use their index finger to point to indicate interest in something) and why they are less likely to respond to bids for their joint attention (e.g., turn their heads to look at something to which another person points). It reviews empirical evidence that autistic toddlers, children, adolescents, and adults can attend covertly, even to social stimuli, such as the direction in which another person's eyes are gazing. It also reviews empirical evidence that autistics of various ages understand the intentionality of other persons' actions. The essay suggests that autistics' atypical resistance to distraction, atypical skill at parallel perception, and atypical execution of volitional actions underlie their atypical manifestations of joint attention.


The Modern Diagnostic Approach to Community-Acquired Pneumonia in Adults.
Respiratory tract infections, the majority of which are community acquired, are among the leading causes of death worldwide and a leading indication for hospital admission. The burden of disease demonstrates a "U"-shaped distribution, primarily affecting young children as the immune system matures, and older adults as the process of immunosenescence and accumulation of comorbidities leads to increased susceptibility to infection. Diagnosis of community-acquired pneumonia (CAP) is traditionally based on demonstration of a new infiltrate on a chest radiograph in a patient presenting with an acute respiratory illness or sepsis. Advances in diagnosis have been slow, and although there are increasing data on the value of computed tomography or lung ultrasound as more sensitive diagnostic methodologies, they are not widely used as initial diagnostic tests. There are a wide range of differential diagnoses and pneumonia "mimics" which should be considered in patients presenting with CAP. Once the diagnosis of CAP has been made, identifying the causative microorganism is the next stage in the diagnostic process. Traditional culture-based approaches are relatively insensitive and achieve a positive diagnosis in only 30 to 70% of cases, even when rigorously applied. Urinary antigen tests, polymerase chain reaction assays, and even next-generation sequencing technologies have become available and are increasing the rates of positive diagnosis. In an era of increasing antimicrobial resistance, the accurate diagnosis of CAP and determining the causative pathogen are ever more important. Getting these both right is key in reducing both morbidity and mortality from CAP, and appropriate antimicrobial stewardship which is now an international healthcare priority.


System performance enhancement with pre-distorted OOFDM signal waveforms in DM/DD systems.
In this work we propose a pre-distortion technique for the mitigation of the nonlinear distortion present in directly modulated/detected OOFDM systems and explore the system performance achieved under varying system parameters. Simulation results show that the proposed pre-distortion technique efficiently mitigates the nonlinear distortion, achieving transmission information rates around 40 Gbits/s and 18.5 Gbits/s over 40 km and 100 km of single mode fiber links, respectively, under optimum operating conditions. Moreover, the proposed pre-distortion technique can potentially provide higher system performance to that obtained with nonlinear equalization at the receiver.


An oligonucleotide microarray resource for transcriptional profiling of Bradyrhizobium japonicum.
A DNA microarray, comprising 70-mer oligonucleotides, representing 8,453 open reading frames (ORFs), was constructed based on the Bradyrhizobium japonicum strain USDA110 genomic sequence. New annotation predicted 199 additional genes, which were added to the microarray and were shown to be transcribed. These arrays were used to profile transcription in cells under a variety of conditions, including growth in minimal versus rich medium, osmotic stress, and free-living cells versus bacteroids. Increased expression was seen for genes involved in translation, motility, and cell envelope synthesis in rich medium whereas expression increased in minimal medium for genes involved in vitamin biosynthesis and stress responses. Treatment with 50 mM NaCl activated stress-inducible genes but repressed genes involved in chemotaxis and motility. Strikingly, no known transport systems for accumulation of compatible solutes or osmoprotectants were induced in response to osmotic stress. A number of nif, fix, and hup genes, but not all, were upregulated in bacteroids. The B. japonicum type III secretion system, known to be important in early nodulation, was downregulated in bacteroids. The availability of a reliable, low-cost B. japonicum microarray provides a useful tool for functional genomic studies of one of the most agriculturally important bacteria.


Evaluation of locally manufactured patient-specific custom made implants for cranial defects using a silicone mould.
Cranial vault defects can pose a significant problem for neurosurgeons where autologous bone is no longer available for cranioplasty. Numerous materials exist to create implants which include polymethyl methacrylate (PMMA) and titanium. A technique using 3-dimensional CT scan reconstruction of a cranial defect and creating a silicon mould which can be autoclaved in theatre to create a PMMA implant was developed. The aim of this study is to evaluate the efficacy, cosmetic result, safety and cost-effectiveness of this procedure and compare this to existing techniques. An ambispective study was performed in patients requiring cranioplasty with a custom made implant. Patients were assessed for risk factors and cosmetic outcome, surgical technique was described and complications and cost compared to existing literature between 2010 and 2016. Thirty retrospective and 30 consecutive prospective patients were recruited into the study. Overall sepsis rate was 8.3%. All septic cases had superficial sepsis of which 2 grafts were removed due to cerebrospinal fluid leakage resulting in wound breakdown. A 100% accurate implant to defect ratio was achieved leading to a high satisfaction rate. Average cost was 5 times cheaper than the closest market related product. Patient specific moulds using PMMA to create custom implants are safe, have excellent cosmetic results and are a very cost-effective option to manage cranial defects. Accurate planning strategies for large craniotomies, where bone will potentially be discarded, add to surgical effectiveness and cost-saving to the patient.


Multifunctional Charge Transporting Materials for Perovskite Light-Emitting Diodes.
Despite their low exciton-binding energies, metal halide perovskites are extensively studied as light-emitting materials owing to narrow emission with high color purity, easy/wide color tunability, and high photoluminescence quantum yields. To improve the efficiency of perovskite light-emitting diodes (PeLEDs), much effort has been devoted to controlling the emitting layer morphologies to induce charge confinement and decrease the nonradiative recombination. The interfaces between the emitting layer and charge transporting layer (CTL) are vulnerable to various defects that deteriorate the efficiency and stability of the PeLEDs. Therefore, the establishment of multifunctional CTLs that can improve not only charge transport but also critical factors that influence device performance, such as defect passivation, morphology/phase control, ion migration suppression, and light outcoupling efficiency, are highly required. Herein, the fundamental limitations of perovskites as emitters (i.e., defects, morphological and phase instability, high refractive index with poor outcoupling) and the recent developments with regard to multifunctional CTLs to compensate such limitations are summarized, and their device applications are also reviewed. Finally, based on the importance of multifunctional CTLs, the outlook and research prospects of multifunctional CTLs for the further improvement of PeLEDs are discussed.


Involvement of peripheral vestibular nerve in individuals with auditory neuropathy.
The vestibulocochlear nerve is a sensory nerve that serves the organs of hearing and equilibrium. Neuropathies of the nerve, particularly auditory neuropathy may be caused by primary demyelination or by axonal diseases. In disorders affecting the cochlear nerve, it is probable that the vestibular nerve is involved as well. There are isolated reports of the involvement of the inferior vestibular nerve (using vestibular-evoked myogenic potentials) in individuals with AN. However, there is a dearth of information on the involvement of the superior vestibular nerve and other functions such as optokinetic, saccade and vestibulo-occular reflex. A total of three subjects diagnosed as having auditory neuropathy, underwent an extensive vestibular assessment consisting of clinical tests of stability (Romberg, Fukuda stepping test), administration of dizziness questionnaire developed by Maryland hearing and balance centre, cervical vestibular-evoked myogenic potentials and a standard electronystagmography test battery. In the present study, the entire subject population assessed showed hypofunctional caloric responses and absent VEMPs. Two out of the three subjects were asymptomatic of vestibular dysfunction. On the clinical tests of stability, two subjects showed deviations to the right, while one subject performed normally. Thus, the present study indicates a possible involvement of peripheral vestibular nerve involvement in individuals with auditory neuropathy.


Understanding flucloxacillin prescribing trends and treatment non-response in UK primary care: a Clinical Practice Research Datalink (CPRD) study.
The volume of prescribed antibiotics is associated with antimicrobial resistance and, unlike most other antibiotic classes, flucloxacillin prescribing has increased. We aimed to describe UK primary care flucloxacillin prescribing and factors associated with subsequent antibiotic prescribing as a proxy for non-response. Clinical Practice Research Datalink patients with acute prescriptions for oral flucloxacillin between January 2004 and December 2013, prescription details, associated Read codes and patient demographics were identified. Monthly prescribing rates were plotted and logistic regression identified factors associated with having a subsequent antibiotic prescription within 28 days. 3 031 179 acute prescriptions for 1 667 431 patients were included. Average monthly prescription rates increased from 4.74 prescriptions per 1000 patient-months in 2004 to 5.74 (increase of 21.1%) in 2013. The highest prescribing rates and the largest increases in rates were seen in older adults (70+ years), but the overall increase in prescribing was not accounted for by an ageing population. Prescribing 500 mg tablets/capsules rather than 250 mg became more common. Children were frequently prescribed low doses and small volumes (5 day course) and prescribing declined for children, including for impetigo. Only 4.2% of new prescriptions involved co-prescription of another antibiotic. Age (<5 and ≥60 years), diagnosis of 'cellulitis or abscess' or no associated code, and 500 mg dose were associated with a subsequent antibiotic prescription, which occurred after 17.6% of first prescriptions. There is a need to understand better the reasons for increased prescribing of flucloxacillin in primary care, optimal dosing (and the need to co-prescribe other antibiotics) and the reasons why one in five patients are prescribed a further antibiotic within 4 weeks.


Type IV pilus proteins form an integrated structure extending from the cytoplasm to the outer membrane.
The bacterial type IV pilus (T4P) is the strongest biological motor known to date as its retraction can generate forces well over 100 pN. Myxococcus xanthus, a δ-proteobacterium, provides a good model for T4P investigations because its social (S) gliding motility is powered by T4P. In this study, the interactions among M. xanthus T4P proteins were investigated using genetics and the yeast two-hybrid (Y2H) system. Our genetic analysis suggests that there is an integrated T4P structure that crosses the inner membrane (IM), periplasm and the outer membrane (OM). Moreover, this structure exists in the absence of the pilus filament. A systematic Y2H survey provided evidence for direct interactions among IM and OM proteins exposed to the periplasm. For example, the IM lipoprotein PilP interacted with its cognate OM protein PilQ. In addition, interactions among T4P proteins from the thermophile Thermus thermophilus were investigated by Y2H. The results indicated similar protein-protein interactions in the T4P system of this non-proteobacterium despite significant sequence divergence between T4P proteins in T. thermophilus and M. xanthus. The observations here support the model of an integrated T4P structure in the absence of a pilus in diverse bacterial species.


Generating, Maintaining, and Exploiting Diversity in a Memetic Algorithm for Protein Structure Prediction.
Computational approaches to de novo protein tertiary structure prediction, including those based on the preeminent "fragment-assembly" technique, have failed to scale up fully to larger proteins (on the order of 100 residues and above). A number of limiting factors are thought to contribute to the scaling problem over and above the simple combinatorial explosion, but the key ones relate to the lack of exploration of properly diverse protein folds, and to an acute form of "deception" in the energy function, whereby low-energy conformations do not reliably equate with native structures. In this article, solutions to both of these problems are investigated through a multistage memetic algorithm incorporating the successful Rosetta method as a local search routine. We found that specialised genetic operators significantly add to structural diversity and that this translates well to reaching low energies. The use of a generalised stochastic ranking procedure for selection enables the memetic algorithm to handle and traverse deep energy wells that can be considered deceptive, which further adds to the ability of the algorithm to obtain a much-improved diversity of folds. The results should translate to a tangible improvement in the performance of protein structure prediction algorithms in blind experiments such as CASP, and potentially to a further step towards the more challenging problem of predicting the three-dimensional shape of large proteins.


Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours.
Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [(111)In-DTPA(0)]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate, a survival benefit of several years compared with historical controls has been reported.


Bayesian graphical network analyses reveal complex biological interactions specific to Alzheimer's disease.
With different approaches to finding prognostic or diagnostic biomarkers for Alzheimer's disease (AD), many studies pursue only brief lists of biomarkers or disease specific pathways, potentially dismissing information from groups of correlated biomarkers. Using a novel Bayesian graphical network method, with data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the aim of this study was to assess the biological connectivity between AD associated blood-based proteins. Briefly, three groups of protein markers (18, 37, and 48 proteins, respectively) were assessed for the posterior probability of biological connection both within and between clinical classifications. Clinical classification was defined in four groups: high performance healthy controls (hpHC), healthy controls (HC), participants with mild cognitive impairment (MCI), and participants with AD. Using the smaller group of proteins, posterior probabilities of network similarity between clinical classifications were very high, indicating no difference in biological connections between groups. Increasing the number of proteins increased the capacity to separate both hpHC and HC apart from the AD group (0 for complete separation, 1 for complete similarity), with posterior probabilities shifting from 0.89 for the 18 protein group, through to 0.54 for the 37 protein group, and finally 0.28 for the 48 protein group. Using this approach, we identified beta-2 microglobulin (β2M) as a potential master regulator of multiple proteins across all classifications, demonstrating that this approach can be used across many data sets to identify novel insights into diseases like AD.


Biochemical, radiologic, ultrastructural, and genetic evaluation of iron overload in acute leukemia and iron-chelation therapy.
Iron overload in hereditary hemochromatosis and hematologic malignancy has unfavorable effects on morbidity. Herein, 53 children (age 108.4±58.3 mo, 25 girls and 28 boys) with acute myeloblastic and lymphoblastic leukemia, who received 4 different chemotherapy protocols, were evaluated for iron overload throughout chemotherapy. Iron overload arose: (1) before chemotherapy, which was dependent on neither chemotherapy nor packed red blood cell transfusions and (2) after chemotherapy, which was dependent on the duration and nature of chemotherapy and partially on transfusion of packed red blood cells. Iron overload was documented in 75% of patients with a ferritin level >1000 ng/mL, by liver and heart magnetic resonance imaging, and they were administered iron-chelation therapy with success. Three of 10 radiologically iron-overloaded patients were heterozygous for H63D mutation. Aminolevulinic acid and porphobilinogen levels were normal. Light microscopic examination of the bone marrow revealed increased iron granules in erythroblasts, platelets, and megakaryocytes, iron-laden macrophages, free iron in the matrix, dyshematopoiesis, and apoptotic cells. Electron microscopic examination revealed iron-laden secondary lysosomes and autolysosomes in normoblasts and iron-laden primary granules in promyelocytes, irrelevant to the ferritin level, implying autophagia due to chemotherapy as a source of the excess iron. We think that iron overload, which is an important complication of acute leukemia, should be evaluated separately from "transfusion overload," and the management principles specific to leukemia should be implemented.


Human Milk Cells and Lipids Conserve Numerous Known and Novel miRNAs, Some of Which Are Differentially Expressed during Lactation.
Human milk (HM) is rich in miRNAs, which are thought to contribute to infant protection and development. We used deep sequencing to profile miRNAs in the cell and lipid fractions of HM obtained post-feeding from 10 lactating women in months 2, 4, and 6 postpartum. In both HM fractions, 1,195 mature known miRNAs were identified, which were positively associated with the cell (p = 0.048) and lipid (p = 0.010) content of HM. An additional 5,167 novel miRNA species were predicted, of which 235 were high-confidence miRNAs. HM cells contained more known miRNAs than HM lipids (1,136 and 835 respectively, p<0.001). Although the profile of the novel miRNAs was very different between cells and lipids, with the majority conserved in the cell fraction and being mother-specific, 2/3 of the known miRNAs common between cells and lipids were similarly expressed (p>0.05). Great similarities between the two HM fractions were also found in the profile of the top 20 known miRNAs. These were largely similar also between the three lactation stages examined, as were the total miRNA concentration, and the number and expression of the known miRNAs common between cells and lipids (p>0.05). Yet, approximately a third of all known miRNAs were differentially expressed during the first 6 months of lactation (p<0.05), with more pronounced miRNA upregulation seen in month 4. These findings indicate that although the total miRNA concentration of HM cells and lipids provided to the infant does not change in first 6 months of lactation, the miRNA composition is altered, particularly in month 4 compared to months 2 and 6. This may reflect the remodeling of the gland in response to infant feeding patterns, which usually change after exclusive breastfeeding, suggesting adaptation to the infant's needs.


Empirical evidence of the association between the presence of musculoskeletal pain and physical disability in community-dwelling senior citizens.
The proportion of people 65 years of age and older who report musculoskeletal pain and physical disability is high. The main objective of this study was to determine whether physical disability was associated with the presence of musculoskeletal pain in a sample of senior citizens. Self-administered questionnaires were sent to a sample of 1306 community-dwelling senior citizens in London, Ontario, Canada between August and October 1995. The questionnaire included questions about pain, difficulty performing activities, depressive symptoms, chronic conditions, and demographic information. A total of 887 seniors completed the questionnaire (70.7% response rate, aged 65-94, 41.2% men, 58.8% women). Logistic regression analysis, without controlling for potential confounding variables, revealed that those who reported having musculoskeletal pain were seven times more likely to have some difficulty performing three or more activities listed in the questionnaire (OR = 6.91 95% CI 4.92-9.69). When significant confounding variables were controlled in the analysis, seniors who reported musculoskeletal pain were still three times more likely to have some difficulty with three or more activities (OR = 2.93, 95% CI 1.96-4.38). Although no causal relationship can be inferred, thorough pain assessment and pain management may be important in the maintenance of independent living for adults 65 years of age or older.


Characterization of the enterocyte-like brush border cytoskeleton of the C2BBe clones of the human intestinal cell line, Caco-2.
The brush border (BB) of the enterocyte is a well-studied example of the actin-based cytoskeleton. We describe here a cell culture model that expresses a faithful representation of the in vivo structure. Two clones (C2BBe 1 and 2) isolated from the cell line Caco-2 (derived from a human colonic adenocarcinoma) formed a polarized monolayer with an apical BB morphologically comparable to that of the human colon. BBs could be isolated by standard methods and contained the microvillar proteins villin, fimbrin, sucrase-isomaltase and BB myosin I, and the terminal web proteins fodrin and myosin II. The immunolocalization of these proteins in confluent, filter-grown monolayers was determined by laser scanning confocal microscopy; patterns of distribution comparable to those in human enterocytes were observed. Sedimentation analysis of cell homogenates derived from C2BBe cells and human colonic epithelial cells demonstrated similar patterns of fractionation of BB proteins; the physical association of those proteins, as determined by extraction from the BB, was also comparable between the two cell types. Like enterocytes of the human intestine, C2BBe cells expressed multiple myosin I immunogens reactive with a head domain-specific monoclonal antibody raised against avian BB myosin I, one of which co-migrated with the approximately 110 kilodalton (kDa) heavy chain of human BB myosin I. In addition, the C2BBe cells express a pair of higher molecular mass immunogens (130 and 140 kDa). These myosin I immunogens all exhibit ATP-dependent association with the C2BBe cytoskeleton. Although the higher molecular mass immunogens were detected in several other human intestinal lines examined, including the parent Caco-2 line, none of these other lines expressed detectable levels of the 110 kDa immunogen, which is presumed to be the heavy chain of human BB myosin I.


Shear bond strength of dental porcelains to nickel-chromium alloys.
The continuous technological advance and increasing availability of new base metal alloys and ceramic systems in the market, coupled to the demands of daily clinical practice, have made the constant evaluation of the bond strength of metal/porcelain combinations necessary. This study evaluated the metal/porcelain shear bond strength of three ceramic systems (Duceram, Williams and Noritake) in combination with three nickel-chromium (Ni-Cr) alloys (Durabond, Verabond and Viron). Thirty cast cylinder specimens (15 mm high; 6 mm in diameter) were obtained for each alloy, in a way that 10 specimens of each alloy were tested with each porcelain. Bond strength was measured with an Emic screw-driven mechanical testing machine by applying parallel shear forces to the specimens until fracture. Shear strength was calculated using the ratio of the force applied to a demarcated area of the opaque layer. Mann-Whitney U test was used for statistical analysis of the alloy/ceramic combinations (p<0.05). Viron/Noritake had the highest shear bond sregnth means (32.93 MPa), while Verabond/Duceram (16.31 MPa) presented the lowest means. Viron/Noritake differed statistically from other combinations (p<0.05). Viron/Duceram had statistically significant higher bond strengths than Verabond/Duceram, Verabond/Williams and Durabond/Noritake (p<0.05). It was also found significant difference (p<0.05) between Verabond/Noritake, Verabond/Duceram and Durabond/Noritake. No statistically significant difference (p>0.05) were observed among the other combinations. In conclusion, the Noritake ceramic system used together with Viron alloy presented the highest resistance to shear forces, while Duceram bonded to Verabond presented the lowest bond strength. Viron/Duceram and Verabond/Noritake provided intermediate results. The combinations between the Williams ceramic system and Ni-Cr alloys had similar shear strengths among each other.


Listening to the brainstem: musicianship enhances intelligibility of subcortical representations for speech.
Auditory experiences including musicianship and bilingualism have been shown to enhance subcortical speech encoding operating below conscious awareness. Yet, the behavioral consequence of such enhanced subcortical auditory processing remains undetermined. Exploiting their remarkable fidelity, we examined the intelligibility of auditory playbacks (i.e., "sonifications") of brainstem potentials recorded in human listeners. We found naive listeners' behavioral classification of sonifications was faster and more categorical when evaluating brain responses recorded in individuals with extensive musical training versus those recorded in nonmusicians. These results reveal stronger behaviorally relevant speech cues in musicians' neural representations and demonstrate causal evidence that superior subcortical processing creates a more comprehensible speech signal (i.e., to naive listeners). We infer that neural sonifications of speech-evoked brainstem responses could be used in the early detection of speech-language impairments due to neurodegenerative disorders, or in objectively measuring individual differences in speech reception solely by listening to individuals' brain activity.


Whole Genome Sequencing Reveals Virulence Potentials of Helicobacter pylori Strain KE21 Isolated from a Kenyan Patient with Gastric Signet Ring Cell Carcinoma.
Helicobacter pylori (H.pylori) infection is etiologically associated with severe diseases including gastric cancer; but its pathogenicity is deeply shaped by the exceptional genomic diversification and geographic variation of the species. The clinical relevance of strains colonizing Africa is still debated. This study aimed to explore genomic features and virulence potentials of H. pylori KE21, a typical African strain isolated from a native Kenyan patient diagnosed with a gastric cancer. A high-quality circular genome assembly of 1,648,327 bp (1590 genes) obtained as a hybrid of Illumina Miseq short reads and Oxford Nanopore MinION long reads, clustered within hpAfrica1 population. This genome revealed a virulome and a mobilome encoding more than hundred features potentiating a successful colonization, persistent infection, and enhanced disease pathogenesis. Furthermore, through an experimental infection of gastric epithelial cell lines, strain KE21 showed the ability to promote interleukin-8 production and to induce cellular alterations resulting from the injection of a functional CagA oncogene protein into the cells. This study shows that strain KE21 is potentially virulent and can trigger oncogenic pathways in gastric epithelial cells. Expended genomic and clinical explorations are required to evaluate the epidemiological importance of H. pylori infection and its putative complications in the study population.


Interferon-tau attenuates uptake of nanoparticles and secretion of interleukin-1β in macrophages.
Type I interferons (IFNs), including IFN-alpha (IFNA) and IFN-beta (IFNB), have anti-inflammatory properties and are used to treat patients with autoimmune and inflammatory disorders. However, little is known of the role of IFN-tau (IFNT), a type I IFN produced by ruminant animals for inflammation. Because IFNB has recently been shown to inhibit nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome activation and subsequent secretion of the potent inflammatory cytokine interleukin (IL)-1β, we examined the effects of ruminant IFNT on NLRP3 inflammasome-mediated IL-1β secretion in human THP-1 macrophages. IFNT dose-dependently inhibited IL-1β secretion induced by nano-silica, a well-known activators of NLRP3 inflammasomes, in human macrophages primed with lipopolysaccharide (LPS, TLR4 agonist) and Pam3CSK4 (TLR1/2 agonist). IFNT also suppressed phagocytosis of nano-silica and reactive oxygen species (ROS) generation. Western blot analysis showed that IFNT inhibited both pro-IL-1β and mature IL-1β. In addition, real-time RT-PCR analysis showed that IFNT suppressed IL-1β mRNA expression induced by LPS and Pam3CSK4. Although nano-silica particles did not induce IL-10 secretion, IFNT induced IL-10 secretion in a dose-dependent manner. Furthermore, IFNT-suppressed IL-1β secretion was restored by anti-IL-10 neutralizing antibody. Ruminant IFNT inhibits NLRP3 inflammasome-driven IL-1β secretion in human macrophages via multiple pathways, including the uptake of nano-silica particles, generation of ROS, and IL-10-mediated inhibition of pro-IL-1β induction. It may be a therapeutic alternative to IFNA and IFNB.


Designing a comprehensive behaviour change intervention to promote and monitor exclusive use of liquefied petroleum gas stoves for the Household Air Pollution Intervention Network (HAPIN) trial.
Increasing use of cleaner fuels, such as liquefied petroleum gas (LPG), and abandonment of solid fuels is key to reducing household air pollution and realising potential health improvements in low-income countries. However, achieving exclusive LPG use in households unaccustomed to this type of fuel, used in combination with a new stove technology, requires substantial behaviour change. We conducted theory-grounded formative research to identify contextual factors influencing cooking fuel choice to guide the development of behavioural strategies for the Household Air Pollution Intervention Network (HAPIN) trial. The HAPIN trial will assess the impact of exclusive LPG use on air pollution exposure and health of pregnant women, older adult women, and infants under 1 year of age in Guatemala, India, Peru, and Rwanda. Using the Capability, Opportunity, Motivation-Behaviour (COM-B) framework and Behaviour Change Wheel (BCW) to guide formative research, we conducted in-depth interviews, focus group discussions, observations, key informant interviews and pilot studies to identify key influencers of cooking behaviours in the four countries. We used these findings to develop behavioural strategies likely to achieve exclusive LPG use in the HAPIN trial. We identified nine potential influencers of exclusive LPG use, including perceived disadvantages of solid fuels, family preferences, cookware, traditional foods, non-food-related cooking, heating needs, LPG awareness, safety and cost and availability of fuel. Mapping formative findings onto the theoretical frameworks, behavioural strategies for achieving exclusive LPG use in each research site included free fuel deliveries, locally acceptable stoves and equipment, hands-on training and printed materials and videos emphasising relevant messages. In the HAPIN trial, we will monitor and reinforce exclusive LPG use through temperature data loggers, LPG fuel delivery tracking, in-home observations and behavioural reinforcement visits. Our formative research and behavioural strategies can inform the development, implementation, monitoring and evaluation of theory-informed strategies to promote exclusive LPG use in future stove programmes and research studies. NCT02944682, Pre-results.


Sample length affects the reliability of language sample measures in 3-year-olds: evidence from parent-elicited conversational samples.
The goal of this study was to investigate the extent to which sample length affected the reliability of total number of words (TNW), number of different words (NDW), and mean length of C-units in morphemes (MLCUm) in parent-elicited conversational samples for 3-year-olds. Participants were sixty 3-year-olds. A 22-min language sample was collected from each child during free play with the parent in the laboratory. Samples of 1, 3, 7, and 10 min were extracted from the 22-min samples. TNW, NDW, and MLCUm were computed from each shorter sample and the 22-min sample. TNW and NDW were adjusted by number of minutes for comparisons. The differences and correlations between each shorter sample cut and the 22-min sample on MLCUm and adjusted TNW and NDW were computed. The shorter samples and the 22-min samples significantly differed in adjusted TNW and NDW, but not in MLCUm. TNW reached an acceptable reliability level (i.e., r = .90) in 7-min samples. NDW and MLCUm approached the acceptable reliability level (rs = .88) in 7-min samples and reached it in 10-min samples. For conversational language samples with similar collection procedures, samples of 7 to 10 min are desirable for calculating TNW, NDW, and MLCUm in 3-year-olds.


MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia.
The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy, but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML.


Stiffness tomography of eukaryotic intracellular compartments by atomic force microscopy.
Precise localization and biophysical characterization of cellular structures is a key to the understanding of biological processes happening both inside the cell and at the cell surface. Atomic force microscopy is a powerful tool to study the cell surface - topography, elasticity, viscosity, interactions - and also the viscoelastic behavior of the underlying cytoplasm, cytoskeleton or the nucleus. Here, we demonstrate the ability of atomic force microscopy to also map and characterize organelles and microorganisms inside cells, at the nanoscale, by combining stiffness tomography with super-resolution fluorescence and electron microscopy. By using this correlative approach, we could both identify and characterize intracellular compartments. The validation of this approach was performed by monitoring the stiffening effect according to the metabolic status of the mitochondria in living cells in real-time.


Characterization of the major metabolites of flavone acetic acid and comparison of their disposition in humans and mice.
Flavone acetic acid represents a novel chemical structure currently undergoing clinical investigation. Broad spectrum activity has been observed in preclinical animal screens, but at doses close to toxic in mice. Phase I clinical trials have established that equivalent plasma drug levels can be achieved in humans, but to date Phase II trials have not demonstrated significant activity in a range of tumor types. Little is known about the drug's biotransformation, although metabolites have been implicated in proposed mechanisms of action. In this paper, we have purified the two major human metabolites present in urine (also the only two metabolites detected in plasma) and characterized their structure, chemical properties, activity, and pharmacokinetics. Metabolite 1 (M1) was a glucuronide conjugated to the 8-acetic acid grouping (Mr 456), was chemically labile, and showed a strong tendency to undergo chemical rearrangement at mildly alkaline pH. Metabolite 2 (M2) was also a glucuronide (Mr 456) but appeared to be an unusual isomer of M1. Both were noncytotoxic. In patients, biotransformation represented the predominant mechanism of drug clearance with as much as 80% of a low dose (0.5 g/m2) recovered in urine as M1 and M2 after only 6 h. At high dose (4.8 to 8.6 g/m2, 1- to 6-h infusion) the appearance of peak concentrations of metabolites in plasma and urine was delayed, apparently due to saturation of glucuronidation pathways. This resulted in an overall reduction in drug clearance by 3- to 4-fold. Mice cleared flavone acetic acid much more slowly than patients (289 ml/h/m2 after 600 mg/m2 i.p. versus 2.3 liters/h/m2 after 4.8 g/m2-1-h i.v. infusion) without producing M1 or M2. A different metabolite, exhibiting characteristics of a conjugate, was detected at low concentrations in plasma, tissues, and tumor. Extensive metabolism to inactive products followed by their rapid clearance may contribute to the lack of activity so far seen in humans.


Open labeled, uncontrolled pharmacokinetic study of a single intramuscular hCG dose in healthy male volunteers.
The current study was designed to compare blood and cerebrospinal fluid (CSF) pharmacokinetic characteristics of two forms of human chorionic gonadotropin (hCG): Pregnyl(R), derived from human urine, and Ovitrelle(R) a recombinant form. Two separate groups, each with six older male human subjects, were dosed with either form of the drug at 10,000 IU intramuscularly (IM), and followed over a 36-hour period. No significant difference in the serum level of hCG was observed for either preparation of hCG (Peak serum conc.: 316 +/- 53 vs. 270 +/- 60 at 12 hours, 311 +/- 38 vs. 321 +/- 60 IU/l at 24 hours; AUC: 10,053 +/- 1,268 vs. 8,793 +/- 1,768, Pregnyl and Ovitrelle, mean +/- SD, respectively). Additionally, both forms of circulating hCG distributed to the central nervous system (CNS) as manifest by an increased number of subjects whose CSF samples showed detectable levels of hCG in their CSF over a 36-hour period. Similarly, there was no significant difference between the two forms when distribution to the CSF was compared at 36 hours (2.0 and 1.2 IU/l; range 1.9 - 2.1 and 1 - 1.4 IU/l for Pregnyl and Ovitrelle, resp.). This preliminary study in normal human volunteers suggests that the two forms of hCG tested, Ovitrelle(R) and Pregnyl(R), when administered IM, distribute in a similar fashion into the circulation and CSF. Consequently, we conclude that these two drugs demonstrate no statistical significant difference with respect to the CSF.


Chordin regulates primitive streak development and the stability of induced neural cells, but is not sufficient for neural induction in the chick embryo.
We have investigated the role of Bone Morphogenetic Protein 4 (BMP-4) and a BMP antagonist, chordin, in primitive streak formation and neural induction in amniote embryos. We show that both BMP-4 and chordin are expressed before primitive streak formation, and that BMP-4 expression is downregulated as the streak starts to form. When BMP-4 is misexpressed in the posterior area pellucida, primitive streak formation is inhibited. Misexpression of BMP-4 also arrests further development of Hensen's node and axial structures. In contrast, misexpression of chordin in the anterior area pellucida generates an ectopic primitive streak that expresses mesoderm and organizer markers. We also provide evidence that chordin is not sufficient to induce neural tissue in the chick. Misexpression of chordin in regions outside the future neural plate does not induce the early neural markers L5, Sox-3 or Sox-2. Furthermore, neither BMP-4 nor BMP-7 interfere with neural induction when misexpressed in the presumptive neural plate before or after primitive streak formation. However, chordin can stabilise the expression of early neural markers in cells that have already received neural inducing signals. These results suggest that the regulation of BMP signalling by chordin plays a role in primitive streak formation and that chordin is not sufficient to induce neural tissue.


PeaKDEck: a kernel density estimator-based peak calling program for DNaseI-seq data.
Hypersensitivity to DNaseI digestion is a hallmark of open chromatin, and DNaseI-seq allows the genome-wide identification of regions of open chromatin. Interpreting these data is challenging, largely because of inherent variation in signal-to-noise ratio between datasets. We have developed PeaKDEck, a peak calling program that distinguishes signal from noise by randomly sampling read densities and using kernel density estimation to generate a dataset-specific probability distribution of random background signal. PeaKDEck uses this probability distribution to select an appropriate read density threshold for peak calling in each dataset. We benchmark PeaKDEck using published ENCODE DNaseI-seq data and other peak calling programs, and demonstrate superior performance in low signal-to-noise ratio datasets.


Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans.
Essential hypertension is a proinflammatory, proconstrictor disease coinciding with endothelial dysfunction and inward vessel remodeling. Using the skin circulation, our aim was to determine whether inducible NO synthase (iNOS) upregulation attenuates NO-dependent cutaneous vasodilation in hypertensive humans. We hypothesized that, with hypertension, localized iNOS inhibition would restore vasodilation in response to NO-dependent stimuli, and iNOS expression would be increased and phosphorylated vasodilator-stimulated phosphoprotein would be decreased. For, in vivo protocols, 4 intradermal microdialysis fibers were placed in 9 hypertensive and 10 normotensive men and women (systolic blood pressure: 146±4 versus 113±2 mm Hg; P<0.001). Microdialysis fibers served as control, iNOS inhibited (1400 W), neuronal NO synthase inhibited (N(ω)-propyl-l-arginine), and nonselective NOS inhibited (N(G)-nitro-l-arginine methyl ester). Cutaneous vascular conductance was calculated (percentage of sodium nitroprusside) during standardized local heating (42°C) and acetylcholine dose-response protocols (0.01, 0.10, 1.00, 5.00, 10.00, 50.00, 100.00 mmol/L). The NO-dependent local heating response was attenuated at control (95±2% versus 76±2% cutaneous vascular conductance; P<0.05) and neuronal NO synthase-inhibited sites (94±4% versus 77±3% cutaneous vascular conductance; P<0.01) in hypertensives. iNOS inhibition augmented the NO-dependent local heating response (93±2% versus 89±10% cutaneous vascular conductance). Acetylcholine-induced vasodilation was attenuated in control sites at doses ≥0.1 mmol/L of acetylcholine in hypertensives and was restored with iNOS inhibition (0.1 mmol/L, P<0.05; 1, 5, and 10 mmol/L, P<0.001; 50 and 100 mmol/L, P<0.01). In vitro iNOS expression was increased (P=0.006) and phosphorylated vasodilator-stimulated phosphoprotein was decreased in skin from hypertensive humans (P=0.04). These data suggest that iNOS is upregulated in essential hypertensive humans and contributes to reduced NO-dependent cutaneous vasodilation.


lncRNA GAS5 restrains CCl4-induced hepatic fibrosis by targeting miR-23a through the PTEN/PI3K/Akt signaling pathway.
Hepatic fibrosis is chronic liver damage with many causes that has a relatively high death rate. The current study showed that long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5), microRNA-23a (miR-23a), and phosphatase and tensin homolog (PTEN) play important roles in the pathological process of hepatic fibrosis but have a relatively unclear regulatory mechanism. This study aimed to investigate the roles of lncRNA GAS5, miR-23a, and PTEN in the pathological process of hepatic fibrosis and hepatic stellate cell (HSC) activation. We used carbon tetrachloride (CCl4) intraperitoneal injections to establish a rat hepatic fibrosis model and exogenous transforming growth factor-β1 to establish an HSC activation model. Quantitative RT-PCR, Western blot, dual-luciferase reporter system, and RNA pull-down assays were used to investigate which microRNAs and lncRNAs participate in the process of hepatic fibrosis and HSC activation. miR-23a expression increased significantly in hepatic fibrosis tissues and activated HSCs. miR-23a interaction with and degradation of PTEN further influenced the downstream signaling pathway phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/Snail (PI3K/Akt/mTOR/Snail), causing E-cadherin expression levels to decrease and α-smooth muscle actin and collagen I expression levels to increase. lncRNA GAS5 can be used as a sponge platform for miR-23a to decrease miR-23a expression levels competitively. We revealed the role of the lncRNA GAS5/miR-23a/PTEN/PI3K/Akt/mTOR/Snail signaling pathway in hepatic fibrosis, providing molecular targets for the treatment of hepatic fibrosis. NEW & NOTEWORTHY This is the first study revealing that microRNA-23a (miR-23a) promotes hepatic fibrosis through the phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/Snail signaling pathway, and long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) can act as a sponge platform for miR-23a. Therefore, lncRNA GAS5/miR-23a may bring molecular targets for hepatic fibrosis therapy.


Trend in height of Turkish and Moroccan children living in the Netherlands.
To study trends in height of Turkish and Moroccan immigrant children living in The Netherlands, to investigate the association between height and background characteristics in these children, and to calculate height-for-age-references data for these groups. Nationwide cross-sectional data collection from children aged 0 to 18 years by trained professionals in 1997 and 2009. The study population consisted of 2,822 Turkish 2,779 Moroccan, and 13,705 Dutch origin children in 1997 and 2,548 Turkish, 2,594 Moroccan, and 11,255 Dutch origin children in 2009. Mean height in cm, and mean height standard deviation scores. In 2009, mean height at the age of 18 y was similar for Turkish and Moroccan children: 177 cm for boys and 163 cm for girls, which was 2 to 3 cm taller than in 1997. Still, Turkish and Moroccan adolescents were 5.5 cm (boys) to 7 cm (girls) shorter than their Dutch peers. No significant differences were found in mean height standard deviation scores across the educational level of the parents, geographical region, primary language spoken at home, and immigrant generation. While the secular height increase in Dutch children came to a halt, the trend in Turkish and Moroccan children living in The Netherlands continued. However, large differences in height between Turkish and Moroccan children and Dutch children remain. We found no association with the background characteristics. We recommend the use of the new growth charts for children of Turkish and Moroccan origin who have a height-for-age below -2SD on the growth chart for Dutch children.


Critically ill patients requiring acute renal replacement therapy are at an increased risk of long-term renal dysfunction, but rarely receive specialist nephrology follow-up.
Episodes of acute kidney injury (AKI) have been associated with the development of chronic kidney disease (CKD). However, follow-up pathways for patients who have survived AKI complicating critical illness are not well established. We hypothesised that patients who had AKI requiring renal replacement therapy (RRT) in intensive care are at risk of CKD, but are rarely referred for nephrology follow-up at hospital discharge. We performed a retrospective analysis of all patients who survived AKI requiring renal replacement therapy in intensive care units (ICUs) in the East London region, examining renal function at baseline, hospital discharge and 3-6 months follow-up. We excluded patients who were known to renal services prior to index admission. From 5,544 critical care admissions, we identified 219 patients who survived to be discharged, having undergone RRT for AKI, that were not previously known to renal services. Of these, 124 (57%) had creatinine measured within 3-6 months after discharge, 104 having a pre-morbid baseline for comparison. Only 26 patients (12%) received specialist nephrology follow-up. At 3-6 months follow-up, the estimated glomerular filtration rate was significantly lower than baseline (48 vs. 60 ml/min/1.73 m(2); p < 0.001), with the prevalence of CKD stage III-V rising from 49 to 70% (p < 0.001). Follow-up of patients who required RRT for AKI in ICU is inconsistent despite evidence of a significant increase in the prevalence of CKD. There is strong justification for the development of robust pathways to identify survivors of AKI in order to detect and manage CKD and its complications.


[Experience of the surgical comprehensive treatment on severe acute pancreatitis].
To summary the experience of the surgical comprehensive treatment of severe acute pancreatitis (SAP). From July 1999 to December 2009, a total of 506 patients suffered SAP were admitted with a mean APACHE II score 12.8 ± 4.6. There were 270 male and 236 female, aged from 16 to 89 years, mean age 43 years. SAP patients were treated by the SAP treatment team which consisted of pancreatic specialized and multidisciplinary doctors. Two hundreds and thirty-four cases (46.2%) received non-operative treatment and 272 cases (53.8%) received surgical intervention. In 506 cases, 445 patients were cured and 52 patients died (31 died in early stage, 21 died in later stage), 9 cases discharged automatically. The overall incidence of complication, overall mortality and overall curative rate were 29.4% (149/506), 10.3% (52/506) and 87.9% (445/506), respectively. The incidences of complication in non-operative group and in surgical intervention group were 27.8% (65/234) and 30.9% (84/272), respectively (P > 0.05). The mortality in non-operative group and in surgical intervention group were 9.4% (22/234) and 11.0% (30/272), respectively (P > 0.05). The curative rates in non-operative group and in surgical intervention group were 90.6% (212/234) and 85.7% (233/272), respectively (P > 0.05). Patients should be treated in ICU in the early phase of the disease when APACHE II score > 10. Pancreatic specialized and multidisciplinary team treatment, appropriate choice of timing, indication and procedure of surgical intervention and details of drainage are vital to the prognosis of SAP.


Evaluating the Relevance of the 2013 Tokyo Guidelines for the Diagnosis and Management of Cholecystitis.
The 2013 Tokyo Guidelines (TG13) are used to diagnose, grade severity, and guide management of acute cholecystitis (AC). The aim of our study was to verify the diagnostic criteria, severity assessment, and management protocols based on the TG13. Our prospectively maintained emergency general surgery registry was used to review patients who had a surgical consultation for right upper quadrant pain (from 2013 to 2015). Diagnosis and severity were graded based on TG13 and compared with pathology reports. Our institutional management protocols were compared with TG13. Nine hundred and fifty-two patients were analyzed, of which 857 had biliary diseases. Mean age was 42 ± 18 years and 67% were female. Seven hundred and seventy-nine had a cholecystectomy, 15 underwent cholecystostomy tube placement, and 63 patients were managed conservatively. Only 4% were febrile on presentation and 51% of patients had leukocytosis. Fifty-nine percent of patients did not have any signs of AC on ultrasonography. The TG13 criteria had a sensitivity of 53% for diagnosing AC (definitive 27%, suspected 26%, and undiagnosed 47%) when compared with the final pathology report; 92.5% of patients with grade I, 93% with grade II, and even 64% with grade III, underwent cholecystectomy safely at our institute. There were no differences in complication rates (3.7% vs 4.7%; p = 0.81), return to operating room rates (0.6% vs 0.7%; p = 0.95), or mortality rates (0.3% vs 0%; p = 0.96) between grade I and grade II patients who underwent early cholecystectomy. The TG13 diagnostic criteria lack sensitivity and missed more than half of the patients with AC, as many patients lack clinical signs (fever and leukocytosis). The TG13 recommendations for conservative management and delayed cholecystectomy in grade II and grade III disease are not warranted.


Increase in cruciferous vegetable intake in women previously treated for breast cancer participating in a dietary intervention trial.
Consumption of cruciferous vegetables has been associated with reduced breast cancer risk mechanistically and in population-based studies, although evidence has been inconsistent. This inconsistency may be related to limitations in quantifying and qualifying cruciferous vegetable exposure using standard instruments for dietary assessment (for example, food-frequency questionnaires, FFQs) or due to low levels of intake demonstrated among U.S. population samples. Cruciferous vegetable intake data are presented from a longitudinal study of a high-vegetable dietary intervention to reduce breast cancer recurrence among breast cancer survivors (n=1,156; 536 intervention and 620 comparison group subjects). Intake was assessed using repeat administration of an FFQ and cross-sectional administration of a cruciferous vegetable-specific FFQ (CVFFQ). Mean intake in the intervention group assessed using the standard FFQ was 37.7 g/day at baseline and increased to 57.1 g/day at 12 mo (P=0.0001) and was sustained through 48 mo. Broccoli and cabbage were the most commonly consumed cruciferous vegetables, regardless of the instrument used to assess intake. Differences in intake by group assignment were shown for raw cruciferous vegetables (30.2 g/day vs. 24.6 g/day, assessed using the CVFFQ), suggesting increased exposure to biologically active, cancer-preventive food constituents. These data suggest that this study population will be the first U.S. population sample to provide ample quantity and variety in cruciferous intake to examine whether these vegetables are protective against breast cancer recurrence.


Body composition and health-related quality of life in patients with obstructive airways disease.
This study evaluated the effects of body weight and lean mass abnormalities on health-related quality of life (HRQL) in obstructive airways disease. Body weight, lean mass (using dual-energy X-ray absorptiometry), and HRQL (using the St George's Respiratory Questionnaire (SGRQ)) were measured in 50 patients. Low lean mass was defined as a lean mass index (lean mass/height2) below the fifth percentile of a control population. Dyspnoea was measured by the baseline dyspnoea index. The mean (SD) age was 69+/-9 yrs; the forced expiratory volume in one second (FEV1) was 39+/-19% of predicted. Patients had 2.4+/-4.1 kg less lean mass than predicted. Increased dyspnoea was the most influential predictor of poor HRQL. Compared to normal-weight patients, those who were underweight had significantly greater impairment in activity, impact, and total SGRQ scores, while those who were overweight had greater impairment in impact and total SGRQ scores. Low lean mass was associated with greater impairment in symptoms, activity and impact subscores and the total SGRQ score. When dyspnoea was added to the model as a covariate, neither weight nor lean mass remained significantly related to HRQL. Thus, although body weight and lean mass abnormalities influence health-related quality of life, their effects appear to be mediated through increased levels of dyspnoea.


A cell surfaceome map for immunophenotyping and sorting pluripotent stem cells.
Induction of a pluripotent state in somatic cells through nuclear reprogramming has ushered in a new era of regenerative medicine. Heterogeneity and varied differentiation potentials among induced pluripotent stem cell (iPSC) lines are, however, complicating factors that limit their usefulness for disease modeling, drug discovery, and patient therapies. Thus, there is an urgent need to develop nonmutagenic rapid throughput methods capable of distinguishing among putative iPSC lines of variable quality. To address this issue, we have applied a highly specific chemoproteomic targeting strategy for de novo discovery of cell surface N-glycoproteins to increase the knowledge-base of surface exposed proteins and accessible epitopes of pluripotent stem cells. We report the identification of 500 cell surface proteins on four embryonic stem cell and iPSCs lines and demonstrate the biological significance of this resource on mouse fibroblasts containing an oct4-GFP expression cassette that is active in reprogrammed cells. These results together with immunophenotyping, cell sorting, and functional analyses demonstrate that these newly identified surface marker panels are useful for isolating iPSCs from heterogeneous reprogrammed cultures and for isolating functionally distinct stem cell subpopulations.


Behavioral traits and airport type affect mammal incidents with U.S. civil aircraft.
Wildlife incidents with aircraft cost the United States (U.S.) civil aviation industry >US$1.4 billion in estimated damages and loss of revenue from 1990 to 2009. Although terrestrial mammals represented only 2.3 % of wildlife incidents, damage to aircraft occurred in 59 % of mammal incidents. We examined mammal incidents (excluding bats) at all airports in the Federal Aviation Administration (FAA) National Wildlife Strike Database from 1990 to 2010 to characterize these incidents by airport type: Part-139 certified (certificated) and general aviation (GA). We also calculated relative hazard scores for species most frequently involved in incidents. We found certificated airports had more than twice as many incidents as GA airports. Incidents were most frequent in October (n = 215 of 1,764 total) at certificated airports and November (n = 111 of 741 total) at GA airports. Most (63.2 %) incidents at all airports (n = 1,523) occurred at night but the greatest incident rate occurred at dusk (177.3 incidents/hr). More incidents with damage (n = 1,594) occurred at GA airports (38.6 %) than certificated airports (19.0 %). Artiodactyla (even-toed ungulates) incidents incurred greatest (92.4 %) damage costs (n = 326; US$51.8 million) overall and mule deer (Odocoileus hemionus) was the most hazardous species. Overall, relative hazard score increased with increasing log body mass. Frequency of incidents was influenced by species relative seasonal abundance and behavior. We recommend airport wildlife officials evaluate the risks mammal species pose to aircraft based on the hazard information we provide and consider prioritizing management strategies that emphasize reducing their occurrence on airport property.


Influence of overweight and obesity on the mortality of hospitalized patients with community-acquired pneumonia.
Obesity is associated with a better prognosis in patients with community-acquired pneumonia (the so-called obesity survival paradox), but conflicting results have been found. To investigate the relationship between all-cause mortality and body mass index in patients with community-acquired pneumonia. This retrospective study included patients with community-acquired pneumonia hospitalized in the First Hospital of Qinhuangdao from June 2013 to November 2018. The patients were grouped as underweight (< 18.5 kg/m2), normal weight (18.5-23.9 kg/m2), and overweight/obesity (≥ 24 kg/m2). The primary outcome was all-cause hospital mortality. Among 2327 patients, 297 (12.8%) were underweight, 1013 (43.5%) normal weight, and 1017 (43.7%) overweight/obesity. The all-cause hospital mortality was 4.6% (106/2327). Mortality was lowest in the overweight/obesity group and highest in the underweight group (2.8%, vs 5.0%, vs 9.1%, P < 0.001). All-cause mortality of overweight/obesity patients was lower than normal-weight patients [odds ratio (OR) = 0.535, 95% confidence interval (CI) = 0.334-0.855, P = 0.009], while the all-cause mortality of underweight patients was higher than that of normal-weight patients (OR = 1.886, 95%CI: 1.161-3.066, P = 0.010). Multivariable analysis showed that abnormal neutrophil counts (OR = 2.38, 95%CI: 1.55-3.65, P < 0.001), abnormal albumin levels (OR = 0.20, 95%CI: 0.06-0.72, P = 0.014), high-risk Confusion-Urea-Respiration-Blood pressure-65 score (OR = 2.89, 95%CI: 1.48-5.64, P = 0.002), and intensive care unit admission (OR = 3.11, 95%CI: 1.77-5.49, P < 0.001) were independently associated with mortality. All-cause mortality of normal-weight patients was higher than overweight/ obesity patients, lower than that of underweight patients. Neutrophil counts, albumin levels, Confusion-Urea-Respiration-Blood pressure-65 score, and intensive care unit admission were independently associated with mortality in patients with community-acquired pneumonia.


Hydrothermal synthesis of inorganic-organic hybrid gadolinium hydroxide nanoclusters with controlled size and morphology.
A series of gadolinium hydroxide [Gd(OH)3] nanoclusters having different morphologies was synthesized in the presence of 3,4-dihydroxy hydrocinnamic acid (DHCA), an organic modifier, under subcritical water conditions. These well-shaped Gd(OH)3 clusters are composed of many nanorods in a parallel orientation, rather than a disordered aggregation of nanorods, which are linked together by organic DHCA molecules. Here DHCA works as an inter-linker to form these cluster-like structures through coordination bonds. All samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and SQUID magnetometry. We investigated the effect of the concentrations of DHCA and KOH on the size and morphology of the Gd(OH)3 clusters. Their possible formation mechanism is also briefly discussed.


Effective strategies for weight loss in post-partum women: a systematic review and meta-analysis.
Post-partum weight loss is critical to preventing and managing obesity in women, but the results from lifestyle interventions are variable and the components associated with successful outcomes are not yet clearly identified. This study aimed to identify lifestyle intervention strategies associated with weight loss in post-partum women. MEDLINE, EMBASE, PubMed, CINAHL and four other databases were searched for lifestyle intervention studies (diet or exercise or both) in post-partum women (within 12 months of delivery) published up to July 2014. The primary outcome was weight loss. Subgroup analyses were conducted for self-monitoring, individual or group setting, intervention duration, intervention types, the use of technology as a support, and home- or centre-based interventions. From 12,673 studies, 46 studies were included in systematic review and 32 randomized controlled trials were eligible for meta-analysis (1,892 women, age 24-36 years). Studies with self-monitoring had significantly greater weight lost than those without (-4.61 kg [-7.08, -2.15] vs. -1.34 kg [-1.66, -1.02], P = 0.01 for subgroup differences). Diet and physical activity when combined were significantly more effective on weight loss compared with physical activity alone (-3.24 kg [-4.59, -1.90] vs. -1.63 kg [-2.16, -1.10], P < 0.001 for subgroup differences). Lifestyle interventions that use self-monitoring and take a combined diet-and-exercise approach have significantly greater weight loss in post-partum women.


The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation.
Platelets are considered to have important functions in inflammatory processes and as actors in the innate immunity. Several studies have shown associations between cardiovascular disease and periodontitis, where the oral anaerobic pathogen Porphyromonas gingivalis has a prominent role in modulating the immune response. Porphyromonas gingivalis has been found in atherosclerotic plaques, indicating spreading of the pathogen via the circulation, with an ability to interact with and activate platelets via e.g. Toll-like receptors (TLR) and protease-activated receptors. We aimed to evaluate how the cysteine proteases, gingipains, of P. gingivalis affect platelets in terms of activation and chemokine secretion, and to further investigate the mechanisms of platelet-bacteria interaction. This study shows that primary features of platelet activation, i.e. changes in intracellular free calcium and aggregation, are affected by P. gingivalis and that arg-gingipains are of great importance for the ability of the bacterium to activate platelets. The P. gingivalis induced a release of the chemokine RANTES, however, to a much lower extent compared with the TLR2/1-agonist Pam3 CSK4 , which evoked a time-dependent release of the chemokine. Interestingly, the TLR2/1-evoked response was abolished by a following addition of viable P. gingivalis wild-types and gingipain mutants, showing that both Rgp and Kgp cleave the secreted chemokine. We also demonstrate that Pam3 CSK4 -stimulated platelets release migration inhibitory factor and plasminogen activator inhibitor-1, and that also these responses were antagonized by P. gingivalis. These results supports immune-modulatory activities of P. gingivalis and further clarify platelets as active players in innate immunity and in sensing bacterial infections, and as target cells in inflammatory reactions induced by P. gingivalis infection.


High-dose BCNU and autologous progenitor cell transplantation given with intra-arterial cisplatinum and simultaneous radiotherapy in the treatment of high-grade gliomas: benefit for selected patients.
A phase II study of postoperative high-dose carmustine (HDBCNU), intracarotid cisplatin (CDDP), and radical radiotherapy in patients with high-grade glioma was performed. Patients underwent 4-6 consecutive days of blood hematopoietic progenitor cell (HPC) apheresis without prior mobilization. Chemotherapy included intracarotid CDDP, 60 mg/m2, and BCNU, 900 mg/m2. HPC were infused 48 h after HDBCNU. Whole brain irradiation, up to 50 Gy, was started on the 8th day after HPC infusion. With a median follow-up time of 44 months, median overall survival was 15.5 months. Eight patients (23.5%) are alive free of disease 2-6 years after treatment (seven out of 25 patients with glioblastoma multiforme and one out of nine patients with anaplastic astrocytoma). Survival was influenced by young age, good performance and complete surgical resection. Two patients (5.8%) died of therapy-related complications. Acute hematological toxicity of HDBCNU was moderate, with a full recovery on day 26. No acute pulmonary or hepatic toxicity was found. Late severe neurological toxicity was observed in one third of patients surviving beyond 2 years. We conclude that HDBCNU, 900 mg/m2, intracarotid CDDP and radical radiotherapy appear to benefit some patients with high-grade gliomas, and phase III studies should preferentially select young patients with resectable tumors.


Epoxyeicosatrienoic acids and heme oxygenase-1 interaction attenuates diabetes and metabolic syndrome complications.
MSCs are considered to be the natural precursors to adipocyte development through the process of adipogenesis. A link has been established between decreased protective effects of EETs or HO-1 and their interaction in metabolic syndrome. Decreases in HO-1 or EET were associated with an increase in adipocyte stem cell differentiation and increased levels of inflammatory cytokines. EET agonist (AKR-I-27-28) inhibited MSC-derived adipocytes and decreased the levels of inflammatory cytokines. We further describe the role of CYP-epoxygenase expression, HO expression, and circulating cytokine levels in an obese mouse, ob/ob(-/-) mouse model. Ex vivo measurements of EET expression within MSCs derived from ob/ob(-/-) showed decreased levels of EETs that were increased by HO induction. This review demonstrates that suppression of HO and EET systems exist in MSCs prior to the development of adipocyte dysfunction. Further, adipocyte dysfunction can be ameliorated by induction of HO-1 and CYP-epoxygenase, i.e. EET.


Perceptual Deficit during a Mental Task.
Subjects monitored for a visual signal while engaged in a demanding mental task. The probability of detecting the signal depends on the time of its presentation during the 8 seconds of the task. A similar time course is observed for failures to detect and for changes of pupil size. Momentary variations in the load that the task imposes on the subject are reflected in both indices. Detection failures are not explained by the pupillary changes.


Hypersensitivity reactions to beta-lactam antibiotics.
Clinicians commonly encounter patients with a history of allergy to penicillin and other beta-lactam antibiotics, since about 10% of the population reports such an allergy. At the same time, it is known that about 90% of these patients are not truly allergic and could safely receive beta-lactam antibiotics. Instead, these patients are treated unnecessarily with alternate broad-spectrum antibiotics, which increases costs and contributes to the development and spread of multiple drug-resistant bacteria. In the case of penicillin, relevant allergenic determinants that elicit immune responses are known. Hence, validated diagnostic skin testing to detect the presence of drug-specific IgE antibodies is available. For non-penicillin beta-lactams, the immunogenic determinants that are produced by degradation are unknown, and diagnostic skin testing is of more limited value. Ideally, patients with a history of penicillin allergy should be evaluated when they are well and not in immediate need of antibiotic therapy. Patients who are found to be penicillin skin test-negative may be safely treated with all beta-lactam antibiotics. Penicillin skin test-positive patients should only receive a penicillin-class antibiotic via rapid desensitization, and only in cases when an alternative agent cannot be substituted. Penicillin skin test-positive patients may be safely treated with monobactams. The extent of allergic cross-reactivity between penicillin arid cephalosporins/carbapenems is uncertain; therefore penicillin skin test-positive patients should only receive these antibiotics via cautious graded challenge or desensitization. Identification of patients who erroneously carry a label of beta-lactam allergy leads to improved utilization of antibiotics and slows the spread of multiple drug-resistant bacteria.


The role of ambulatory mechanics in the initiation and progression of knee osteoarthritis.
This review examines recent in-vivo studies of ambulation and discusses the fundamental role of mechanics of ambulation in the initiation and progression of osteoarthritis at the knee. Recent studies have supported earlier findings that a high adduction moment at the knee during ambulation was most frequently reported to influence the progression of medial compartment osteoarthritis. In contrast to previous findings in patients with osteoarthritis, recent work on healthy subjects reports that cartilage thickness increases with high ambulatory loads. Kinematic changes were associated with the initiation of osteoarthritis. Recent studies of subjects with high risk factors for knee osteoarthritis (obesity and anterior cruciate ligament injury) reported a relationship between kinematic changes during ambulation and the initiation of osteoarthritis at the knee. This review also contrasts the relative influence on osteoarthritis of knee mechanics measured during ambulatory and nonambulatory activities. The initiation of osteoarthritis occurs when healthy cartilage experiences some condition (traumatic or chronic) that causes kinematic changes during ambulation at the knee to shift the load-bearing contact location of the joint to a region not conditioned to the new loading. The rate of progression of osteoarthritis is associated with increased load during ambulation.


Effect of insurance and racial disparities on outcomes in traumatic brain injury.
We evaluated outcome and resource utilization disparities between commercially insured, Medicaid, and Medicare patients. We further analyzed racial disparities in a subset cohort. We reviewed the MarketScan database (2000-2009) for adult traumatic brain injury (TBI) patients. Analyses were performed to evaluate outcome differences by insurance type and race. Outpatient service utilization disparities by insurance and race were also evaluated. Our study included 92,159 TBI patients, 44,108 (47.9%) of whom utilized commercial insurance, 19,743 (21.4%) utilized Medicaid, and 28,308 (30.7%) utilized Medicare. In-hospital mortality was lowest for commercially insured (5.0%) versus 7.6% and 8.5% for Medicaid and Medicare patients, respectively (p < 0.0001). Medicaid patients had a longer hospitalization than commercially insured (12 days versus 6 days; p < 0.0001). Medicaid patients were 1.29 and 1.78 times more likely to die and experience complications than the commercially insured. Females had a lower mortality risk (odds ratio [OR]: 0.80, p < 0.0001) and less complications (OR: 0.67; p < 0.0001) than males. Higher comorbidities increased mortality risk (OR: 2.71; p < 0.0001) and complications (OR: 2.96, p < 0.0001). Mild injury patients had lower mortality (OR: 0.01; p < 0.0001) and less complications (OR: 0.07; p < 0.0001). Medicare (OR: 1.33; p < 0.0001) and higher comorbidity (OR: 1.26; p < 0.0001) patients utilized outpatient rehabilitation services more frequently. Medicare patients had twice the emergency department visits as the commercially insured (p < 0.0001). Medicare (16.6%) patients utilized more rehabilitation than commercially insured (13.4%) and Medicaid (9.1%) patients. Racial disparities were analyzed in a subset of 12,847 white and 4,780 African American (AA) patients. Multivariate analysis showed that AAs were more likely to experience a complication than white patients (OR: 1.13; p = 0.0024) and less likely to utilize outpatient rehabilitation services (OR: 0.83; p = 0.0025) than whites. Insurance and racial disparities continue to exist for TBI patients. Insurance status appears to have an impact on short- and long-term outcomes to a greater degree than patient race.


Efficacy and safety of a novel delayed-release risedronate 35 mg once-a-week tablet.
Dosing regimens of oral bisphosphonates are inconvenient and contribute to poor compliance. The bone mineral density response to a once weekly delayed-release formulation of risedronate given before or following breakfast was non-inferior to traditional immediate-release risedronate given daily before breakfast. Delayed-release risedronate is a convenient regimen for oral bisphosphonate therapy. We report the results of a randomized, controlled, clinical study assessing the efficacy and safety of a delayed-release (DR) 35 mg weekly oral formulation of risedronate that allows patients to take their weekly risedronate dose before or immediately after breakfast. Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5 mg immediate-release (IR) daily (n = 307) at least 30 min before breakfast, or risedronate 35 mg DR weekly, either at least 30 min before breakfast (BB, n = 308) or immediately following breakfast (FB, n = 307). Bone mineral density (BMD), bone turnover markers (BTMs), fractures, and adverse events were evaluated. The primary efficacy variable was percent change from baseline in lumbar spine BMD at Endpoint. Two hundred fifty-seven subjects (83.7%) in the IR daily group, 252 subjects (82.1%) in the DR FB weekly group, and 258 subjects (83.8%) in the DR BB weekly group completed 1 year. Both DR weekly groups were determined to be non-inferior to the IR daily regimen. Mean percent changes in hip BMD were similar across groups. The magnitude of BTM response was similar across groups; some statistical differences were seen that were small and deemed by investigators to have no major clinical importance. The incidence of adverse events leading to withdrawal and serious adverse events were similar across treatment groups. All three regimens were well tolerated. Risedronate 35 mg DR weekly is similar in efficacy and safety to risedronate 5 mg IR daily, and will allow patients to take their weekly risedronate dose immediately after breakfast.


Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise.
Malonyl-CoA, an inhibitor of fatty acid oxidation in skeletal muscle mitochondria, decreases in rat skeletal muscle during exercise or in response to electrical stimulation. Regulation of rat skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme that synthesizes malonyl-CoA, was studied in vitro and in vivo. Avidin-Sepharose affinity-purified ACC from hindlimb skeletal muscle was phosphorylated by purified liver AMP-activated protein kinase with a concurrent decrease in ACC activity. AMP-activated protein kinase was quantitated in resuspended ammonium sulfate precipitates of the fast-twitch red (type IIa fibers) region of the quadriceps muscle. Rats running on a treadmill at 21 m/min up a 15% grade show a 2.4-fold activation of AMP-activated protein kinase concurrently with a marked decrease in ACC activity in the resuspended ammonium sulfate precipitates at all citrate concentrations ranging from 0 to 20 mM. Malonyl-CoA decreased from a resting value of 1.85 +/- 0.29 to 0.50 +/- 0.09 nmol/g in red quadriceps muscle after 30 min of treadmill running. The activation of the AMP-activated protein kinase with consequent phosphorylation and inactivation of ACC may be one of the primary events in the control of malonyl-CoA and hence fatty acid oxidation during exercise.


Atlas generation for subcortical and ventricular structures with its applications in shape analysis.
Atlas-driven morphometric analysis has received great attention for studying anatomical shape variation across clinical populations in neuroimaging research as it provides a local coordinate representation for understanding the family of anatomic observations. We present a procedure for generating atlas of subcortical and ventricular structures, including amygdala, hippocampus, caudate, putamen, globus pallidus, thalamus, and lateral ventricles, using the large deformation diffeomorphic metric atlas generation algorithm. The atlas was built based on manually labeled volumes of 41 subjects randomly selected from the database of Open Access Series of Imaging Studies (OASIS, 10 young adults, 10 middle-age adults, 10 healthy elders, and 11 patients with dementia). We show that the estimated atlas is representative of the population in terms of its metric distance to each individual subject in the population. In the application of detecting shape variations, using the estimated atlas may potentially increase statistical power in identifying group shape difference when comparing with using a single subject atlas. In shape-based classification, the metric distances between subjects and each of within-class estimated atlases construct a shape feature space, which allows for performing a variety of classification algorithms to distinguish anatomies.


Constructing Multi-View High-Order Functional Connectivity Networks for Diagnosis of Autism Spectrum Disorder.
Brain functional connectivity network (FCN) based on resting-state functional magnetic resonance imaging (rs-fMRI) has been widely used to identify neuropsychiatric disorders such as autism spectrum disorder (ASD). Most existing FCN-based methods only estimate the correlation between brain regions of interest (ROIs), without exploring more informative higher-level interactions among multiple ROIs which could be beneficial to disease diagnosis. To fully explore the discriminative information provided by different brain networks, a cluster-based multi-view high-order FCN (Ho-FCN) framework is proposed in this paper. Specifically, we first group the functional connectivity (FC) time series into different clusters and compute the multi-order central moment series for the FC time series in each cluster. Then we utilize the correlation of central moment series between different clusters to reveal the high-order FC relationships among multiple ROIs. In addition, to address the phase mismatch issue in conventional FCNs, we also adopt the central moments of the correlation time series as the temporal-invariance features to capture the dynamic characteristics of low-order dynamic FCN (Lo-D-FCN). Experimentalresults on the ABIDE dataset validate that: 1) the proposed multi-view Ho-FCNs is able to explore rich discriminative information for ASD diagnosis; 2) the phase mismatch issue can be well circumvented by using central moments; and 3) the combination of different types of FCNs can significantly improve the diagnostic accuracy of ASD (86.2%).


Relation of koniocellular layers of dorsal lateral geniculate to inferior pulvinar nuclei in common marmosets.
Traditionally, the dorsal lateral geniculate nucleus (LGN) and the inferior pulvinar (IPul) nucleus are considered as anatomically and functionally distinct thalamic nuclei. However, in several primate species it has also been established that the koniocellular (K) layers of LGN and parts of the IPul have a shared pattern of immunoreactivity for the calcium-binding protein calbindin. These calbindin-rich cells constitute a thalamic matrix system which is implicated in thalamocortical synchronisation. Further, the K layers and IPul are both involved in visual processing and have similar connections with retina and superior colliculus. Here, we confirmed the continuity between calbindin-rich cells in LGN K layers and the central lateral division of IPul (IPulCL) in marmoset monkeys. By employing a high-throughput neuronal tracing method, we found that both the K layers and IPulCL form comparable patterns of connections with striate and extrastriate cortices; these connections are largely different to those of the parvocellular and magnocellular laminae of LGN. Retrograde tracer-labelled cells and anterograde tracer-labelled axon terminals merged seamlessly from IPulCL into LGN K layers. These results support continuity between LGN K layers and IPulCL, providing an anatomical basis for functional congruity of this region of the dorsal thalamic matrix and calling into question the traditional segregation between LGN and the inferior pulvinar nucleus.


Response of fluorescence morphs of the mesophotic coral Euphyllia paradivisa to ultra-violet radiation.
Euphyllia paradivisa is a strictly mesophotic coral in the reefs of Eilat that displays a striking color polymorphism, attributed to fluorescent proteins (FPs). FPs, which are used as visual markers in biomedical research, have been suggested to serve as photoprotectors or as facilitators of photosynthesis in corals due to their ability to transform light. Solar radiation that penetrates the sea includes, among others, both vital photosynthetic active radiation (PAR) and ultra-violet radiation (UVR). Both types, at high intensities, are known to have negative effects on corals, ranging from cellular damage to changes in community structure. In the present study, fluorescence morphs of E. paradivisa were used to investigate UVR response in a mesophotic organism and to examine the phenomenon of fluorescence polymorphism. E. paradivisa, although able to survive in high-light environments, displayed several physiological and behavioral responses that indicated severe light and UVR stress. We suggest that high PAR and UVR are potential drivers behind the absence of this coral from shallow reefs. Moreover, we found no significant differences between the different fluorescence morphs' responses and no evidence of either photoprotection or photosynthesis enhancement. We therefore suggest that FPs in mesophotic corals might have a different biological role than that previously hypothesized for shallow corals.


Zero-crossing approach to high-resolution reconstruction in frequency-domain optical-coherence tomography.
We address the problem of high-resolution reconstruction in frequency-domain optical-coherence tomography (FDOCT). The traditional method employed uses the inverse discrete Fourier transform, which is limited in resolution due to the Heisenberg uncertainty principle. We propose a reconstruction technique based on zero-crossing (ZC) interval analysis. The motivation for our approach lies in the observation that, for a multilayered specimen, the backscattered signal may be expressed as a sum of sinusoids, and each sinusoid manifests as a peak in the FDOCT reconstruction. The successive ZC intervals of a sinusoid exhibit high consistency, with the intervals being inversely related to the frequency of the sinusoid. The statistics of the ZC intervals are used for detecting the frequencies present in the input signal. The noise robustness of the proposed technique is improved by using a cosine-modulated filter bank for separating the input into different frequency bands, and the ZC analysis is carried out on each band separately. The design of the filter bank requires the design of a prototype, which we accomplish using a Kaiser window approach. We show that the proposed method gives good results on synthesized and experimental data. The resolution is enhanced, and noise robustness is higher compared with the standard Fourier reconstruction.


Gatekeeper of pluripotency: a common Oct4 transcriptional network operates in mouse eggs and embryonic stem cells.
Oct4 is a key factor of an expanded transcriptional network (Oct4-TN) that governs pluripotency and self-renewal in embryonic stem cells (ESCs) and in the inner cell mass from which ESCs are derived. A pending question is whether the establishment of the Oct4-TN initiates during oogenesis or after fertilisation. To this regard, recent evidence has shown that Oct4 controls a poorly known Oct4-TN central to the acquisition of the mouse egg developmental competence. The aim of this study was to investigate the identity and extension of this maternal Oct4-TN, as much as whether its presence is circumscribed to the egg or maintained beyond fertilisation. By comparing the genome-wide transcriptional profile of developmentally competent eggs that express the OCT4 protein to that of developmentally incompetent eggs in which OCT4 is down-regulated, we unveiled a maternal Oct4-TN of 182 genes. Eighty of these transcripts escape post-fertilisation degradation and represent the maternal Oct4-TN inheritance that is passed on to the 2-cell embryo. Most of these 80 genes are expressed in cancer cells and 37 are notable companions of the Oct4 transcriptome in ESCs. These results provide, for the first time, a developmental link between eggs, early preimplantation embryos and ESCs, indicating that the molecular signature that characterises the ESCs identity is rooted in oogenesis. Also, they contribute a useful resource to further study the mechanisms of Oct4 function and regulation during the maternal-to-embryo transition and to explore the link between the regulation of pluripotency and the acquisition of de-differentiation in cancer cells.


Mec1p associates with functionally compromised telomeres.
In many organisms, telomere DNA consists of simple sequence repeat tracts that are required to protect the chromosome end. In the yeast Saccharomyces cerevisiae, tract maintenance requires two checkpoint kinases of the ATM family, Tel1p and Mec1p. Previous work has shown that Tel1p is recruited to functional telomeres with shorter repeat tracts to promote telomerase-mediated repeat addition, but the role of Mec1p is unknown. We found that Mec1p telomere association was detected as cells senesced when telomere function was compromised by extreme shortening due to either the loss of telomerase or the double-strand break binding protein Ku. Exonuclease I effects the removal of the 5' telomeric strand, and eliminating it prevented both senescence and Mec1p telomere association. Thus, in contrast to Tel1p, Mec1p associates with short, functionally compromised telomeres.