Correction of remounting errors by masking reference points in small footprint polishing process.
The remounting accuracy of optical components between measurement and polishing affects the polishing results, especially for small polishing footprint processes such as magnetorheological jet polishing (MJP). In this paper, two important remounting errors (translation and rotation errors) are discussed, and a masking method is proposed to correct these errors. A mathematical model that describes the relationship between remounting errors and reference points is constructed. A mask is created to provide reference points on a sample because such points are important for identifying remounting errors. The remounting errors are then used as bases in correcting the parameters used for actual polishing. Experiments are conducted on a K9 optical sample to validate the proposed approach. After the reference points are obtained by measuring the mask on the sample, the remounting errors are derived. The translation errors are 5.61 mm in the X direction and 6.08 mm in the Y direction; the rotation error is 4.1°. Deviations from the desired positions are eliminated and the desired surface smoothness is obtained after parameter correction. Results indicate that the proposed method is suitable for high-precision polishing.


A subcellular analysis of genetic modulation of PINK1 on mitochondrial alterations, autophagy and cell death.
Mutations in the PTEN-induced putative kinase1 (PINK1) represent the second most frequent cause of autosomal recessive Parkinson's disease. The PINK1 protein mainly localizes to mitochondria and interacts with a variety of proteins, including the pro-autophagy protein beclin1 and the ubiquitin-ligase parkin. Upon stress conditions, PINK1 is known to recruit parkin at the surface of dysfunctional mitochondria and to activate the mitophagy cascade. Aim of this study was to use a simple and highly reproducible catecholamine cell model and transmission electron microscopy to characterize whether PINK1 could affect mitochondrial homeostasis, the recruitment of specific proteins at mitochondria, mitophagy and apoptosis. Samples were analyzed both in baseline conditions and following treatment with methamphetamine (METH), a neurotoxic compound which strongly activates autophagy and produces mitochondrial damage. Our data provide robust sub-cellular evidence that the modulation of PINK1 levels dramatically affects the morphology and number of mitochondria and the amount of cell death. In particular, especially upon METH exposure, PINK1 is able to increase the total number of mitochondria, concurrently recruit beclin1, parkin and ubiquitin and enhance the clearance of damaged mitochondria. In the absence of functional PINK1 and upon autophagy stress, we observe a failure of the autophagy system at large, with marked accumulation of dysfunctional mitochondria and dramatic increase of apoptotic cell death. These findings highlight the strong neuroprotective role of PINK1 as a key protein in the surveillance and regulation of mitochondrial homeostasis.


Evidence that NiNi acetyl-CoA synthase is active and that the CuNi enzyme is not.
The bifunctional CO dehydrogenase/acetyl-CoA synthase (CODH/ACS) plays a central role in the Wood-Ljungdahl pathway of autotrophic CO(2) fixation. One structure of the Moorella thermoacetica enzyme revealed that the active site of ACS (the A-cluster) consists of a [4Fe-4S] cluster bridged to a binuclear CuNi center with Cu at the proximal metal site (M(p)) and Ni at the distal metal site (M(d)). In another structure of the same enzyme, Ni or Zn was present at M(p). On the basis of a positive correlation between ACS activity and Cu content, we had proposed that the Cu-containing enzyme is active [Seravalli, J., et al. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 3689-3694]. Here we have reexamined this proposal. Enzyme preparations with a wider range of Ni (1.6-2.8) and Cu (0.2-1.1) stoichiometries per dimer were studied to reexamine the correlation, if any, between the Ni and Cu content and ACS activity. In addition, the effects of o-phenanthroline (which removes Ni but not Cu) and neocuproine (which removes Cu but not Ni) on ACS activity were determined. EXAFS results indicate that these chelators selectively remove M(p). Multifrequency EPR spectra (3-130 GHz) of the paramagnetic NiFeC state of the A-cluster were examined to investigate the electronic state of this proposed intermediate in the ACS reaction mechanism. The combined results strongly indicate that the CuNi enzyme is inactive, that the NiNi enzyme is active, and that the NiNi enzyme is responsible for the NiFeC EPR signal. The results also support an electronic structure of the NiFeC-eliciting species as a [4Fe-4S](2+) (net S = 0) cluster bridged to a Ni(1+) (S = (1)/(2)) at M(p) that is bridged to planar four-coordinate Ni(2+) (S = 0) at M(d), with the spin predominantly on the Ni(1+). Furthermore, these studies suggest that M(p) is inserted during cell growth. The apparent vulnerability of the proximal metal site in the A-cluster to substitution with different metals appears to underlie the heterogeneity observed in samples that has confounded studies of CODH/ACS for many years. On the basis of this principle, a protocol to generate nearly homogeneous preparations of the active NiNi form of ACS was achieved with NiFeC signals of approximately 0.8 spin/mol.


Breast Cancer Malignant Processes are Regulated by Pax-5 Through the Disruption of FAK Signaling Pathways.
The study of genetic factors regulating breast cancer malignancy is a top priority to mitigate the morbidity and mortality associated with this disease. One of these factors, Pax-5, modulates cancer aggressiveness through the regulation of various components of the epithelial to mesenchymal transitioning (EMT) process. We have previously reported that Pax-5 expression profiles in cancer tissues inversely correlate with those of the Focal Adhesion Kinase (FAK), a potent activator of breast cancer malignancy. In this study, we set out to elucidate the molecular and regulatory relationship between Pax-5 and FAK in breast cancer processes. Interestingly, we found that Pax-5 mediated suppression of breast cancer cell migration is dependent of FAK activity. Our mechanistic examination revealed that Pax-5 inhibits FAK expression and activation. We also demonstrate that Pax-5 is a potent modulator of FAK repressors (p53 and miR-135b) and activator (NFκB) which results in the overall suppression of FAK-mediated signaling cascades. Altogether, our findings bring more insight to the molecular triggers regulating phenotypic transitioning process and signaling cascades leading to breast cancer progression.


Presence of fruits decreases probability of retaining flowers in a sequentially flowering plant.
Both intrinsic and extrinsic plant processes affect the fate of flowers along an inflorescence in sequentially flowering plants. We investigated whether the intrinsic process of competition for limited resource between fruits and flowers owing to resource preemption or sink strength of basal fruits, or architectural effects due to positional differences in the probability of retaining flowers, explains a lower probability of retaining distal flowers in Yucca glauca. Further, we investigated how the extrinsic process of seed herbivory interacts with the plant's intrinsic processes of flower retention. We carried out a field experiment to compare flower retention among nine combinations of three inflorescence treatments (basal flowers only, distal flowers only, distal flowers with presence of basal fruits) and three ovule damage treatments (no, low and high) that serve as a cue for potential future seed herbivory. Also, we quantified flower retention in naturally pollinated inflorescences. Experimental results showed that the probabilities of retaining basal and distal flowers in the absence of basal fruits were similar, thus rejecting the architectural effects hypothesis. Further, in the presence of basal fruits that were in their initial stages of growth, the probability of retaining distal flowers decreased, which supports the sink strength hypothesis. We did not see an effect of ovule damage. In naturally pollinated inflorescences, the probability of retaining distal flowers decreased with increasing number of basal fruits. Results suggest that basal fruits constitute strong resource sinks reducing the probability of retaining distal flowers. Previous studies have tested this mechanism in cultivated plants. Our study shows evidence for this mechanism in a wild flower population.


The structure of Aip1p, a WD repeat protein that regulates Cofilin-mediated actin depolymerization.
Actin-interacting protein 1 (Aip1p) is a 67-kDa WD repeat protein known to regulate the depolymerization of actin filaments by cofilin and is conserved in organisms ranging from yeast to mammals. The crystal structure of Aip1p from Saccharomyces cerevisiae was determined to a 2.3-A resolution and a final crystallographic R-factor of 0.204. The structure reveals that the overall fold is formed by two connected seven-bladed beta-propellers and has important implications for the structure of Aip1 from other organisms and WD repeat-containing proteins in general. These results were unexpected because a maximum of 10 WD repeats had been reported in the literature for this protein using sequence data. The surfaces of the beta-propellers formed by the D-A and B-C loops are positioned adjacent to one another, giving Aip1p a shape that resembles an open "clamshell." The mapping of conserved residues to the structure of Aip1p reveals dense patches of conserved residues on the surface of one beta-propeller and at the interface of the two beta-propellers. These two patches of conserved residues suggest a potential binding site for F-actin on Aip1p and that the orientation of the beta-propellers with respect to one another plays a role in binding an actin-cofilin complex. In addition, the conserved interface between the domains is mediated by a number of interactions that appear to impart rigidity between the two domains of Aip1p and may make a large substrate-induced conformational change difficult.


Evolution of robustness in digital organisms.
We study the evolution of robustness in digital organisms adapting to a high mutation rate. As genomes adjust to the harsh mutational environment, the mean effect of single mutations decreases, up until the point where a sizable fraction (up to 30% in many cases) of the mutations are neutral. We correlate the changes in robustness along the line of descent to changes in directional epistasis, and find that increased robustness is achieved by moving from antagonistic epistasis between mutations towards codes where mutations are, on average, independent. We interpret this recoding as a breakup of linkage between vital sections of the genome, up to the point where instructions are maximally independent of each other. While such a recoding often requires sacrificing some replication speed, it is the best strategy for withstanding high rates of mutation.


Validity of screening tests for Sjögren's syndrome in ambulatory patients with chronic diseases.
To determine the validity of screening tests for Sjogren's syndrome (SS) in ambulatory patients with chronic diseases. Three hundred randomly selected patients from the rheumatology and internal medicine clinics of a tertiary care center were assessed for SS according to the American-European Consensus Group criteria. During the screening phase, an interview, the European questionnaire for sicca symptoms, Schirmer-I test, and the wafer test were carried out in all patients. Patients with positive screening had confirmatory tests including fluorescein staining test, nonstimulated whole salivary flow, and autoantibody testing. Confirmatory tests were also done in 13 patients with negative screening. During the last phase, lip biopsy was proposed to patients who met preestablished criteria. Women made up 79% of the study population. Mean age of subjects was 42.8+/-15.7 years. Two hundred twenty patients (73%) had positive screening. The distribution of positive test results was: xerophthalmia 118 (39%), xerostomia 103 (34%), Schirmer-I test 101 (34%), and wafer test 187 (62%) patients. Forty (13%) patients met criteria for SS. All screening tests were useful for identifying patients with SS; however, the model composed of at least one positive response to the European questionnaire (EQ1), Schirmer-I test, and wafer test showed the best performance. Use of the European questionnaire, Schirmer-I test, and wafer test in parallel was useful for identifying patients with SS among ambulatory patients with chronic diseases.


Aesthetics Assessment and Patient Reported Outcome of Nasolabial Aesthetics in 18-Year-Old Patients With Unilateral Cleft Lip.
To determine if there is a correlation between objective nasolabial aesthetics assessment using the Cleft Aesthetic Rating Scale (CARS) and patient satisfaction. Retrospective analysis of a generic satisfaction questionnaire and independent assessment by three cleft surgeons of the nasolabial area of these patients on 2D frontal photographs, using the CARS. The Vrije Universiteit Medical Center and The Academic Center for Dentistry Amsterdam. Thirty-nine 18-year old patients with a repaired complete or incomplete unilateral cleft lip, with or without a cleft palate, and a completed satisfaction questionnaire. Exclusion criteria were an incomplete questionnaire; a history of facial trauma; and congenital syndromes affecting facial appearance. The correlation between surgeon evaluation (on a 5-point Likert scale) and patient satisfaction (not, moderately or very satisfied) on nasolabial appearance was assessed using Spearman rho (ρ). There was a negligible correlation between surgeon evaluation and patient satisfaction on nose assessment (ρ = 0.20) and a moderate correlation on lip assessment (ρ = 0.32). Most literature supports this discrepancy between different objective aesthetics evaluation methods and subjective patient-reported outcome measures, suggesting there are factors playing a role in patient satisfaction that are impossible to objectify with assessment methods. Therefore, a strong emphasis should remain on clear communication between the physician and patient regarding their expectations, perception, and satisfaction of surgery results.


Glycogen resynthesis in leg muscles of rats during exercise.
This study was undertaken to determine whether glycogen resynthesis can occur in glycogen-depleted muscles in response to glucose feeding during prolonged exercise. Rats were exercised for 40 min with a treadmill running program designed to deplete muscle glycogen. One group was studied immediately after the glycogen-depletion exercise. A second group was given 1 g glucose by stomach tube and exercised for an additional 90 min at a running speed of 22 m/min on a treadmill set at an 8 degree incline; they were given additional 1-g glucose feedings after 30 and 60 min of running. The initial 40-min run resulted in liver glycogen depletion, large decreases in plasma glucose and insulin concentrations, and a marked lowering of muscle glycogen. The glucose feedings resulted in greater than twofold increases in the concentrations of glucose and insulin in plasma, and of glycogen in leg muscles, during the 90 min of running. No repletion of liver glycogen occurred. These results provide evidence that glycogen resynthesis can occur in glycogen-depleted muscle despite continued moderate intensity exercise if sufficient glucose is made available.


Prefrontal-temporal gray matter deficits in bipolar disorder patients with persecutory delusions.
Although brain structural deficits have been repeatedly associated with bipolar disorder (BD), inconsistency in morphometric results has been a feature of neuroimaging studies. We hypothesize that this discrepancy is related to the heterogeneity of BD, and examine the question of whether or not more homogeneous clinical subgroups display a more coherent pattern of morphometric abnormalities. In a case-control design, we examined differences in gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) concentration in 42 BD patients and 42 healthy matched controls using optimized voxel-based morphometry (VBM). Subgroup analyses of patients with a lifetime history of psychotic symptoms (BDP, n=30) and patients with mood-incongruent psychotic symptoms in the form of persecutory delusions (BDPD, n=15) were performed to accord with previous genetic findings. Analysis of the total BD sample was largely inconclusive, but the BDPD patient subgroup displayed a widespread pattern of significant decreases in GM concentration in the dorsolateral prefrontal (DLPFC), temporal and cingulate cortices, and a significant CSF increase in the adjacent outer ventricular sulci. Comparison of BDPD patients versus BD and BDP patients without persecutory delusions revealed a significant GM decrease in the left DLPFC for the former group. BDPD show pronounced structural abnormalities of the prefrontal and temporal lobes which are similar to the deficits previously reported for schizophrenia (SCZ). Our findings suggest that stratification based solely on psychotic symptoms is insufficient for the differentiation of BD into biologically meaningful subgroups, but also question the pathophysiological validity of the dichotomy in classification between schizophrenia and BD.


An atomic model of the thin filament in the relaxed and Ca2+-activated states.
Contraction of striated muscles is regulated by tropomyosin strands that run continuously along actin-containing thin filaments. Tropomyosin blocks myosin-binding sites on actin in resting muscle and unblocks them during Ca2+-activation. This steric effect controls myosin-crossbridge cycling on actin that drives contraction. Troponin, bound to the thin filaments, couples Ca2+-concentration changes to the movement of tropomyosin. Ca2+-free troponin is thought to trap tropomyosin in the myosin-blocking position, while this constraint is released after Ca2+-binding. Although the location and movements of tropomyosin are well known, the structural organization of troponin on thin filaments is not. Its mechanism of action therefore remains uncertain. To determine the organization of troponin on the thin filament, we have constructed atomic models of low and high-Ca2+ states based on crystal structures of actin, tropomyosin and the "core domain" of troponin, and constrained by distances between filament components and by their location in electron microscopy (EM) reconstructions. Alternative models were also built where troponin was systematically repositioned or reoriented on actin. The accuracy of the different models was evaluated by determining how well they corresponded to EM images. While the initial low and high-Ca2+ models fitted the data precisely, the alternatives did not, suggesting that the starting models best represented the correct structures. Thin filament reconstructions were generated from the EM data using these starting models as references. In addition to showing the core domain of troponin, the reconstructions showed additional detail not present in the starting models. We attribute this to an extension of TnI linking the troponin core domain to actin at low (but not at high) Ca2+, thereby trapping tropomyosin in the OFF-state. The bulk of the core domain of troponin appears not to move significantly on actin, regardless of Ca2+ level. Our observations suggest a simple model for muscle regulation in which troponin affects the charge balance on actin and hence tropomyosin position.


Biology and treatment of adult acute lymphoblastic leukemia.
The molecular analysis of acute lymphoblastic leukemia (ALL) has provided exciting insights into the pathogenesis of this disease. This disease is heterogenous and can be subtyped based on chromosomal, immunophenotypic, and structural criteria. The varying prognostic implications of different ALL subtypes markedly influence the treatment decisions in adults. Many patients with T-cell ALL can be cured with chemotherapy alone. In contrast, patients with early B-lineage ALL with certain chromosomal abnormalities, especially the Philadelphia chromosome, do not have durable responses to chemotherapy and should receive a bone marrow transplantation if an HLA-matched donor is available. Recent reports have shown improved results for adults with B-cell ALL (Burkitt's) after intensive alternating cycles of chemotherapy containing high doses of methotrexate and cyclophosphamide. Future clinical and laboratory investigation should lead to the development of novel and possibly more effective treatments specifically tailored for different subsets of ALL.


Evolution of the Role of RA and FGF Signals in the Control of Somitogenesis in Chordates.
During vertebrate development, the paraxial mesoderm becomes segmented, forming somites that will give rise to dermis, axial skeleton and skeletal muscles. Although recently challenged, the "clock and wavefront" model for somitogenesis explains how interactions between several cell-cell communication pathways, including the FGF, RA, Wnt and Notch signals, control the formation of these bilateral symmetric blocks. In the cephalochordate amphioxus, which belongs to the chordate phylum together with tunicates and vertebrates, the dorsal paraxial mesendoderm also periodically forms somites, although this process is asymmetric and extends along the whole body. It has been previously shown that the formation of the most anterior somites in amphioxus is dependent upon FGF signalling. However, the signals controlling somitogenesis during posterior elongation in amphioxus are still unknown. Here we show that, contrary to vertebrates, RA and FGF signals act independently during posterior elongation and that they are not mandatory for posterior somites to form. Moreover, we show that RA is not able to buffer the left/right asymmetry machinery that is controlled through the asymmetric expression of Nodal pathway actors. Our results give new insights into the evolution of the somitogenesis process in chordates. They suggest that RA and FGF pathways have acquired specific functions in the control of somitogenesis in vertebrates. We propose that the "clock and wavefront" system was selected specifically in vertebrates in parallel to the development of more complex somite-derived structures but that it was not required for somitogenesis in the ancestor of chordates.


Screening of Parabens in Natural Water by Salting-out Based Centrifugeless Dispersive Liquid-liquid Microextraction Combined with HPLC-UV.
A simple, efficient and quick salting-out based centrifugeless dispersive liquid-liquid microextraction combined with high-performance liquid chromatography-ultraviolet detection (HPLC-UV) has been successfully developed for the determination of selected parabens in environmental water samples. Herein, following the dispersion of the extracting solvent (1-undecanol) whose melting point is near the room temperature into the sample solution, the cloudy mixture is passed through a test tube filled with sodium chloride, acting as separating agent based on salting-out phenomenon. By immersing the tube inside an ice bath, the fine droplets of the extraction solvent are solidified, easily collected and after returning to the liquid state, injected into HPLC-UV. The values of the detection limit were in the range of 2.5-5.0 µg L-1 while the intra-day (n = 7) and inter-day (n = 9, within three days) precision were below 3.7 and 4.7%, respectively. A satisfactory linearity (0.997 ≥ r2 ≥ 0.996) and quite a broad linear range (5.0-250 µg L-1) were achieved. The relative errors as the accuracy were less than 6.4% in all experiments. The method was eventually employed for the preconcentration and determination of the analytes in various natural water samples and acceptable results were achieved.


Bioluminescence imaging to track bacterial dissemination of Yersinia pestis using different routes of infection in mice.
Plague is caused by Yersinia pestis, a bacterium that disseminates inside of the host at remarkably high rates. Plague bacilli disrupt normal immune responses in the host allowing for systematic spread that is fatal if left untreated. How Y. pestis disseminates from the site of infection to deeper tissues is unknown. Dissemination studies for plague are typically performed in mice by determining the bacterial burden in specific organs at various time points. To follow bacterial dissemination during plague infections in mice we tested the possibility of using bioluminescence imaging (BLI), an alternative non-invasive approach. Fully virulent Y. pestis was transformed with a plasmid containing the luxCDABE genes, making it able to produce light; this lux-expressing strain was used to infect mice by subcutaneous, intradermal or intranasal inoculation. We successfully obtained images from infected animals and were able to follow bacterial dissemination over time for each of the three different routes of inoculation. We also compared the radiance signal from animals infected with a wild type strain and a Δcaf1ΔpsaA mutant that we previously showed to be attenuated in colonization of the lymph node and systemic dissemination. Radiance signals from mice infected with the wild type strain were larger than values obtained from mice infected with the mutant strain (linear regression of normalized values, P<0.05). We demonstrate that BLI is useful for monitoring dissemination from multiple inoculation sites, and for characterization of mutants with defects in colonization or dissemination.


Guardians and research staff experiences and views about the consent process in hospital-based paediatric research studies in urban Malawi: A qualitative study.
Obtaining consent has become a standard way of respecting the patient's rights and autonomy in clinical research. Ethical guidelines recommend that the child's parent/s or authorised legal guardian provides informed consent for their child's participation. However, obtaining informed consent in paediatric research is challenging. Parents become vulnerable because of stress related to their child's illness. Understanding the views held by guardians and researchers about the consent process in Malawi, where there are limitations in health care access and research literacy will assist in developing appropriate consent guidelines. We conducted 20 in-depth interviews with guardians of children and research staff who had participated in paediatric clinical trial and observational studies in acute and non-acute settings in the Southern Region of Malawi. Interviews were audio-recorded, transcribed verbatim, and thematically analysed. Interviews were compared across studies and settings to identify differences and similarities in participants' views about informed consent processes. Data analysis was facilitated by NVIVO 11 software. All participants across study types and settings reported that they associated participating in research with therapeutic benefits. Substantial differences were noted in the decision-making process across study settings. Guardians from acute studies felt that the role of their spouses was neglected during consenting, while staff reported that they had problems obtaining consent from guardians when their partners were not present. Across all study types and settings, research staff reported that they emphasised the benefits more than the risks of the study to participants, due to pressure to recruit. Participants from non-acute settings were more likely to recall information shared during the consent process than participants in the acute setting. The health care context, culture and research process influenced participants' understanding of study information across study types and settings. We advise research managers or principal investigators to define minimum requirements that would not compromise the consent process and conduct study specific training for staff. The use of one size fits all consent process may not be ideal. More guidance is needed on how these differences can be incorporated during the consent process to improve understanding and delivery of consent. Trial registration Not applicable.


Reduced EDSS progression in multiple sclerosis patients treated with modafinil for three years or more compared to matched untreated subjects.
Modafinil is a wakefulness-promoting drug used to treat narcolepsy, obstructive sleep apnoea, and shift-work sleep disorder. Modafinil has also been used for the treatment of fatigue and excessive sleepiness in other neurological disorders including multiple sclerosis, psychiatric disorders, and for cognitive enhancement. Recent preclinical studies suggest a potential neuroprotective effect of modafinil in neurodegenerative diseases. Therefore, we investigated its neuroprotective potential in multiple sclerosis. To retrospectively assess disease progression in a group of MS patients that had received treatment with modafinil, and a matched group that received no treatment with modafinil. We assessed the expanded disability status scale (EDSS) score change, over at least three years, in 30 patients with MS treated with modafinil, and in 90 patients who did not receive modafinil. The two groups were matched for initial EDSS, age, sex, type of disease, disease duration, duration of follow-up, and concomitant disease modifying therapies. Statistical analysis was performed using a general linear regression model. In relapsing-remitting (RR) patients treated with modafinil there was no significant EDSS change over the follow-up period. In RR patients not treated with modafinil, the mean EDSS increased significantly (0.94; p=0.0001) over the follow-up period. Independent of modafinil treatment status, our model indicated an additional mean EDSS increase of 1.1 point (p=0.0002) for progressive patients i.e. mean EDSS change was 1.1 point for modafinil treated, and 1.1+0.94=2.04 points for modafinil-untreated patients. Our results support the hypothesis that modafinil has neuroprotective potential, and may play a role in the treatment of multiple sclerosis. A prospective study will need to confirm this finding.


Role of leukotrienes B4 and C4 in liver allograft rejection.
Previous studies have shown that eicosanoids may act in vitro as immunoregulatory substances. In this study, the concentrations of leukotriene B4 (LTB4) and leukotriene C4 (LTC4) were measured in a model of allograft rejection. Six orthotopic allotransplants of the liver were performed in dogs without the administration of immunosuppressives. LTB4 levels showed an increase coinciding with the start of rejection, significant differences being present between the basal levels and those measured 24 h post-revascularization (P < 0.05), and every day from the 3rd postoperative day (P < 0.01). LTB4 rose before the parameters generally used in evaluating rejection. LTC4 levels increased significantly (P < 0.001) in the first 24 h, and experienced no further variations. LTB4 may play an important role in the mechanisms which bring about the response to the allograft. This substance could be a specific and early marker for rejection.


Coronary endothelial function testing provides superior discrimination compared with standard clinical risk scoring in prediction of cardiovascular events.
Endothelial dysfunction is regarded as the early stage of atherosclerosis and is associated with cardiovascular (CV) events. This study was designed to determine whether assessment of coronary endothelial function (CEF) is safe and can reclassify risk in patients with early coronary artery disease beyond the Framingham risk score (FRS). CEF was evaluated using intracoronary acetylcholine in 470 patients who presented with chest pain and nonobstructive coronary artery disease. CV events were assessed after a median follow-up of 9.7 years. The association between CEF and CV events was examined, and the net reclassification improvement index (NRI) was used to compare the incremental contribution of CEF when added to FRS.The mean age was 53 years, and 68% of the patients were women with a median FRS of 8. Complications (coronary dissection) occurred in three (0.6%) and CV events in 61 (13%) patients. In univariate analysis, microvascular CEF [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.72-0.97, P=0.032] and epicardial CEF (HR 0.73, 95% CI 0.59-0.90, P=0.01) were found to be significant predictors of CV events, whereas FRS was not (HR 1.05, 95% CI 0.85-1.26, P=0.61). When added to FRS, microvascular CEF correctly reclassified 11.3% of patients [NRI 0.11 (95% CI 0.019-0.21)], epicardial CEF correctly reclassified 12.1% of patients [NRI 0.12 (95% CI -0.02 to 0.26)], and the combined microvascular and epicardial CEF correctly reclassified 22.8% of patients [NRI 0.23 (95% CI 0.08-0.37)]. CEF testing is safe and adds value to the FRS, with superior discrimination and risk stratification compared with FRS alone in patients presenting with chest pain or suspected ischemia.


In vitro susceptibility of ceftaroline against clinically important Gram-positive cocci, Haemophilus species and Klebsiella pneumoniae in Taiwan: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) in 2012-2018.
Ceftaroline, with a unique activity against methicillin-resistant Staphylococcus aureus (MRSA), was not launched in Taiwan before 2019. The in vitro susceptibility data of ceftaroline against important Taiwanese pathogens are lacking. The in vitro susceptibility of ceftaroline against important pathogens collected from 2012 through 2018 were extracted from the Antimicrobial Testing Leadership and Surveillance program. Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) to ceftaroline against all isolates. During the study period, the in vitro data regarding isolates of S. aureus (n = 2049), Staphylococcus epidermidis (n = 185), Streptococcus pneumoniae (n = 334), Streptococcus pyogenes (n = 170), Haemophilus influenzae (n = 75), Haemophilus parainfluenzae (n = 10) and Klebsiella pneumoniae (n = 680) regardless of hospital sites of collection were analyzed. Among the S. aureus isolates studied, 19.4% showed MICs of 1 mg/L to ceftaroline, and 4.4% showed in vitro susceptible-dose dependent to ceftaroline (all MICs, 2 mg/L). Most of other Gram-positive cocci, all H. influenzae and H. parainfluenzae isolates were susceptible to ceftaroline. By contrast, about one-third (35.9%) of K. pneumoniae isolates, irrespective of infection sources, exhibited non-susceptibility to ceftaroline (MIC range, 0.015-256 mg/L; MIC50 and MIC90 values, 0.12 and 256 mg/L, respectively). From the pharmacodynamic perspectives, the ceftaroline dosage of 600 mg as a 2-h intravenous infusion every 8 h is effective against all S. aureus and other Gram-positive isolates regardless of acquisition sites in Taiwan. Before ceftaroline is prescribed in treatment of the patient with Gram-negative infection, a cautious evaluation about patient's healthcare-associated factor is warranted.


Transarterial embolization of renal cell carcinoma as an adjunctive therapy prior to cryoablation: a propensity score matching analysis.
We aimed to assess the safety and effectiveness of transarterial embolization (TAE) prior to percutaneous cryoablation (PCA) in the management of renal cell carcinoma (RCC) compared with PCA alone using a propensity score matching analysis to minimize confounding factors. A retrospective review of all PCAs performed for renal masses identified 9 patients who underwent TAE prior to PCA. These patients were matched in a 2:1 ratio with patients who underwent PCA only using age, gender, and tumor size to create the propensity score model for matching. Other demographic, clinical, and outcomes data were collected. The TAE+PCA group included 5 males and 4 females with a mean age of 67.9 years and mean tumor diameter of 51.7 mm. The PCA only group included 11 males and 7 females with a mean age of 66.8 years and mean tumor diameter of 46.2 mm. No significant differences in these propensity score matched characteristics were identified. Further, the groups had no significant differences in tumor geometry (P = 0.831), R.E.N.A.L. nephrometry scores (P = 0.144), or comorbidity indices (P = 0.392). TAE was technically successful and without complication in all cases. PCA was technically successful in 8 of 9 patients in the TAE+PCA group and in 14 of 18 patients in the PCA only group (P = 0.483). No significant differences in the rate of complications (P = 0.483), change in eGFR (P = 0.691), or change in hematocrit (P = 0.152) were identified between the two groups. TAE of RCC prior to PCA is safe and technically feasible; however, no objective benefits over PCA alone were identified by propensity score matching analysis. Due to small sample size and limitations of the study, no definite conclusions should be drawn. Larger, prospective studies of this therapeutic approach are warranted.


Intake of Bifidobacterium longum and Fructo-oligosaccharides prevents Colorectal Carcinogenesis.
We aimed to investigate the effects of intake of yogurt containing Bifidobacterium longum (BB536-y) and fructo-oligosaccharides (FOS) in preventing colorectal carcinogenesis in healthy subjects, and the preventive effects of short-chain fatty acids (SCFA), whose production was enhanced by the intake of BB536-y and FOS, in human colon cancer cell lines. The subjects were 27 healthy persons who were divided into a group taking yogurt containing BB536 (BB536-y group; n = 14) and a group taking yogurt containing BB536 and FOS (BB536-y with FOS group; n = 13) once a day for 5 weeks. The feces were sampled before and after the intake to analyze the amount of SCFA in the feces and the profile of intestinal flora, such as putrefactive bacteria and Bacteroides fragilis enterotoxin (ETBF). Subsequently, human colon cancer cell lines (DLD-1 cells, WirDr cells) were cultured in the presence of SCFA (butyric acid, isobutyric acid, acetic acid) in order to evaluate the cell growth-inhibitory activity of SCFA (WST-8 assay) by calculating the IC50 value from the dose-response curve. Intake of BB536-y increased the total amount of SCFA in the feces and significantly suppressed the detection rate of ETBF and growth of putrefactive bacteria. Intake of BB536-y with FOS was associated with a higher Bifidobacterium detection rate than that of BB536-y alone. The contents of butyric acid, isobutyric acid, and acetic acid, namely, of SCFA, were also decreased. Analysis of the results of culture of DLD-1 cells and WirDr cells in the presence of butyric acid, isobutyric acid, and acetic acid revealed that each of the substances showed significant cell growth-inhibitory activity, with the activity being the highest for butyric acid, followed by that for isobutyric acid and acetic acid. These findings suggest that intake of both BB536-y and BB536-y with FOS prevents colorectal carcinogenesis.How to cite this article: Ohara T, Suzutani T. Intake of Bifidobacterium longum and Fructo-oligosaccharides prevents Colorectal Carcinogenesis. Euroasian J Hepato-Gastroenterol 2018;8(1):11-17.


Microfluidic approach for the fabrication of cell-laden hollow fibers for endothelial barrier research.
This study reports an advanced approach to effectively generate hollow fibers in a triple-flow polydimethylsiloxane (PDMS) microfluidic device based on the gelation of alginate induced with CaCl2 inside a coaxial flow system. Two PDMS replicas with a semi-cylindrical microchannel were assembled to obtain a complete microchannel with a circular cross-section, which allowed the formation of mild and continuous coaxial flows for the fabrication of hollow fibers without employing complex glass microcapillaries. Mineral oil was introduced into the central flow to serve as an inert space inside the Ca-alginate wall. This was used to maintain the consistent formation of the hollow core of the microfiber and to easily transport fluid through the lumen structure in subsequent applications. The hollow fibers exhibited characteristics such as flexibility while showing robust mechanical strength, high permeability, and biocompatibility, and were used as scaffolds for the attachment and proliferation of human umbilical vein endothelial cells (HUVECs) to mimic a blood vessel. The fully covered HUVEC fibers were further integrated into a neurovascular system and co-cultured with astrocytes forming an on-chip blood brain barrier (BBB) platform. The use of this neurovascular model for drug testing will pave the way for developing or synthesizing a new drug that can cross the BBB in the human brain.


Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype.
The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis. Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data (p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix (p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex. The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.


Investigation of sporulation in the Desulfotomaculum genus: a genomic comparison with the genera Bacillus and Clostridium.
The genus Desulfotomaculum, belonging to the Firmicutes, comprises strictly anaerobic and endospore-forming bacteria capable of dissimilatory sulfate reduction. These microorganisms are metabolically versatile and are widely distributed in the environment. Spore formation allows them to survive prolonged environmental stress. Information on the mechanism of sporulation in Desulfotomaculum species is scarce. Herein, this process was probed from a genomic standpoint, using the Bacillus subtilis model system as a reference and clostridial sporulation for comparison. Desulfotomaculum falls somewhere in between the Bacillus and Clostridium in terms of conservation of sporulation proteins. Furthermore, it showcased the conservation of a core regulatory cascade throughout genera, while uncovering variability in the initiation of sporulation and the structural characteristics of spores from different genera. In particular, while in Clostridium species sporulation is not initiated by a phosphorelay, Desulfotomaculum species harbour homologues of the B. subtilis proteins involved in this process. Conversely, both Clostridium and Desulfotomaculum species conserve very few B. subtilis structural proteins, particularly those found in the outer layers of the spore. Desulfotomaculum species seem to share greater similarity to the outer layers of Clostridium difficile.


Discovery of a quorum-sensing inhibitor of drug-resistant staphylococcal infections by structure-based virtual screening.
Staphylococci are a major health threat because of increasing resistance to antibiotics. An alternative to antibiotic treatment is preventing virulence by inhibition of bacterial cell-to-cell communication using the quorum-sensing inhibitor RNAIII-inhibiting peptide (RIP). In this work, we identified 2',5-di-O-galloyl-d-hamamelose (hamamelitannin) as a nonpeptide analog of RIP by virtual screening of a RIP-based pharmacophore against a database of commercially available small-molecule compounds. Hamamelitannin is a natural product found in the bark of Hamamelis virginiana (witch hazel), and it has no effect on staphylococcal growth in vitro; but like RIP, it does inhibit the quorum-sensing regulator RNAIII. In a rat graft model, hamamelitannin prevented device-associated infections in vivo, including infections caused by methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis strains. These findings suggest that hamamelitannin may be used as a suppressor to staphylococcal infections.


Stakeholder analysis for adopting a personal health record standard in Korea.
Interest in health information exchanges (HIEs) is increasing. Several countries have adopted core health data standards with appropriate strategies. This study was conducted to determine the feasibility of a continuity of care record (CCR) as the standard for an electronic version of the official transfer note and the HIE in Korean healthcare. A technical review of the CCR standard and analysis of stakeholders' views were undertaken. Transfer notes were reviewed and matched with CCR standard categories. The standard for the Korean coding system was selected. Stakeholder analysis included an online survey of members of the Korean Society of Medical Informatics, a public hearing to derive opinions of consumers, doctors, vendors, academic societies and policy makers about the policy process, and a focus group meeting with EMR vendors to determine which HIE objects were technically applicable. Data objects in the official transfer note form matched CCR standards. Korean Classification of Diseases, Korean Standard Terminology of Medicine, Electronic Data Interchange code (EDI code), Logical Observation Identifiers Names and Codes, and Korean drug codes (KD code) were recommended as the Korean coding standard.'Social history', 'payers', and 'encounters' were mostly marked as optional or unnecessary sections, and 'allergies', 'alerts', 'medication list', 'problems/diagnoses', 'results',and 'procedures' as mandatory. Unlike the US, 'social history' was considered optional and 'advance directives' mandatory.At the public hearing there was some objection from the Korean Medical Association to the HIE on legal grounds in termsof intellectual property and patients' personal information. Other groups showed positive or neutral responses. Focus group members divided CCR data objects into three phases based onpredicted adoption time in CCR: (i) immediate adoption; (ii) short-term adoption ('alerts', 'family history'); and (iii) long-term adoption ('results', 'advanced directives', 'functional status', 'medical equipment', 'vital signs', 'plan of care', 'social history'). There were no technical problems in generating the CCR standard document from EMRs. Matters of concern that arose from study results should be resolved with time and consultation.


Use of intravaginal microbicides to prevent acquisition of Trichomonas vaginalis infection in Lactobacillus-pretreated, estrogenized young mice.
D2A21, a novel peptide antibiotic has in vitro activity against a wide spectrum of sexually transmitted diseases (STD). In this study we tested the hypothesis that intravaginal D2A21 would interfere with acquisition of Trichomonas vaginalis infection in a modified mouse model. T. vaginalis infections of estrogenized young mice pretreated with Lactobacillus vaginalis or Lactobacillus rhamnosus were more frequent and persistent than those in mice pre-treated with Lactobacillus gasseri or Lactobacillus acidophilus. One hundred percent T. vaginalis infection was achieved for 2-4 days post-challenge when intravaginal L. rhamnosus pre-treatments were given to estrogenized mice 48 hr prior to a single T. vaginalis challenge. Estrogenized mice pre-treated with L. rhamnosus were pre-medicated with intravaginal placebo gel, 0.5% or 2% D2A21 gel, or 500 microg/mL metronidazole gel prior to T. vaginalis challenge. Both 2% D2A21 and metronidazole gels were significantly more efficacious (10% or none infected) than placebo gel (53% infected) in preventing vaginal T. vaginalis infections in mice.


Skeletal hyperostosis and extraosseous calcification in patients receiving long-term etretinate (Tigason).
In an ongoing study of patients on long-term etretinate (Tigason) therapy, 13 patients with a congenital or inherited disorder of keratinization and 10 patients with psoriasis were examined to investigate the incidence of, and the factors associated with, skeletal hyperostosis. Skeletal scintigraphy, plain radiographs, haematological and biochemical analyses were performed. Using all criteria, 7 of 13 patients with a congenital or inherited disorder of keratinization showed evidence of hyperostosis. No single investigation was able to detect all these cases; in particular, skeletal scintigraphy was positive in only nine of the 13 patients who showed hyperostosis. Eleven of the 13 patients with hyperostosis gave a history of musculoskeletal symptoms compared with three of the 10 patients without hyperostosis. There was no clear association with total dose or duration of treatment. Serum chemistry and haematological studies were normal. In two patients the 24-h urinary calcium excretion was significantly elevated, an abnormality which has not been described previously. Annual lateral thoracic spine radiographs with additional views of symptomatic areas are recommended for patients on long-term etretinate therapy.


A physical and genetic map of Cannabis sativa identifies extensive rearrangements at the THC/CBD acid synthase loci.
Cannabis sativa is widely cultivated for medicinal, food, industrial, and recreational use, but much remains unknown regarding its genetics, including the molecular determinants of cannabinoid content. Here, we describe a combined physical and genetic map derived from a cross between the drug-type strain Purple Kush and the hemp variety "Finola." The map reveals that cannabinoid biosynthesis genes are generally unlinked but that aromatic prenyltransferase (AP), which produces the substrate for THCA and CBDA synthases (THCAS and CBDAS), is tightly linked to a known marker for total cannabinoid content. We further identify the gene encoding CBCA synthase (CBCAS) and characterize its catalytic activity, providing insight into how cannabinoid diversity arises in cannabis. THCAS and CBDAS (which determine the drug vs. hemp chemotype) are contained within large (>250 kb) retrotransposon-rich regions that are highly nonhomologous between drug- and hemp-type alleles and are furthermore embedded within ∼40 Mb of minimally recombining repetitive DNA. The chromosome structures are similar to those in grains such as wheat, with recombination focused in gene-rich, repeat-depleted regions near chromosome ends. The physical and genetic map should facilitate further dissection of genetic and molecular mechanisms in this commercially and medically important plant.


Utilization of Outpatient Eye Care Services in Taiwan: A Nationwide Population Study.
A study based on the Taiwanese National Health Insurance Research Database (NHIRD) to reveal the ocular diseases landscape. This study comprised all ophthalmological outpatient patient visits (n = 6,341,266) in the Taiwanese longitudinal NHIRD 2000. Descriptive analytics based on 15 disease categories of ICD-9-CM and 10 tiers of age categories was performed with SAS for Windows 9.3 (SAS Institute, Inc., Cary, NC, U.S.A.). The average frequency of visits was 0.7 visits per year. The mean age was 36.2 years old. Bimodal peak of visits in the first, second, and eighth decade of life was revealed. Conjunctiva is the most dominant disease category throughout life while different categories play major roles in each decade of life. The most frequent disease code of each category was listed. The bimodal peak of visits revealed the age group of the most prominent ocular disease burden. Peak in school age population can be partially explained by the nationwide vision screening program, while aging accounts for the lens disorder and glaucoma of the senile peak. The disease category frequency variation among age categories reflects the development and aging of the eye. The most frequent disease codes of each category highlight disease of importance for primary practitioners and ophthalmologists. Taiwanese longitudinal NHIRD was used to reveal the ophthalmological disease landscape. The epidemiological insight, while limited in clinical presentation and economic impact, enables physicians and policy makers to improve the overall vision health of the population.


Chemoselective N-deacetylation under mild conditions.
A mild and efficient chemoselective N-deacetylation using the Schwartz reagent at room temperature in rapid time is described. The mild and neutral conditions enable orthogonal N-deacetylation in the presence of some of the common protecting groups (viz. Boc, Fmoc, Cbz, Ts). The deprotection conditions did not induce any epimerization at the chiral amino centre.


Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis.
Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults, and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to establish the efficacy and safety of repeated treatment with DP. Following PRISMA guidelines, we searched multiple databases on Sept 1, 2016, with the terms: "human" AND "dihydroartemisinin-piperaquine" OR "DHA-PPQ". Studies were eligible if they were randomised controlled trials (RCTs) or prospective cohort studies involving repeat exposures to standard 3-day courses of DP for either seasonal malaria chemoprevention, mass drug administration, or treatment of clinical malaria, conducted at any time and in any geographic location. Random-effects meta-analysis was used to generate pooled incidence rate ratios and relative risks, or risk differences. 11 studies were included: two repeat treatment studies (one in children younger than 5 years and one in pregnant women), and nine IPT trials (five in children younger than 5 years, one in schoolchildren, one in adults, two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP+amodiaquine, SP+piperaquine, SP+chloroquine, and co-trimoxazole. Of 14 628 participants, 3935 received multiple DP courses (2-18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared with placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily co-trimoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women) with cardiac parameters, all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP. Monthly DP appears well tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing. Bill & Melinda Gates Foundation and NIH.


Cockroach allergy and asthma in a 30-year-old man.
A growing body of evidence has implicated allergens derived from cockroaches as an important environmental factor that may aggravate asthma in sensitized persons. We present the case of a 30-year-old man with asthma and a cockroach allergy. Allergy skin testing confirmed hypersensitivity to cockroach extract, and a home visit revealed visual evidence of infestation and the presence of Bla g 1 German cockroach allergen in vacuumed dust. As is typical of patients with a cockroach allergy and asthma, multiple factors in addition to cockroach allergen appeared to aggravate the patient's asthma. A multimodality therapeutic regimen, which included medications as well as cleaning of the home, integrated pest management, and professional application of chemical controls, resulted in substantial clinical improvement. The pathophysiology, epidemiology, and clinical features of cockroach-allergic asthma are reviewed, and an approach to diagnosis and management is suggested.


Rib biomechanical properties exhibit diagnostic potential for accurate ageing in forensic investigations.
Age estimation remains one of the most challenging tasks in forensic practice when establishing a biological profile of unknown skeletonised remains. Morphological methods based on developmental markers of bones can provide accurate age estimates at a young age, but become highly unreliable for ages over 35 when all developmental markers disappear. This study explores the changes in the biomechanical properties of bone tissue and matrix, which continue to change with age even after skeletal maturity, and their potential value for age estimation. As a proof of concept we investigated the relationship of 28 variables at the macroscopic and microscopic level in rib autopsy samples from 24 individuals. Stepwise regression analysis produced a number of equations one of which with seven variables showed an R2 = 0.949; a mean residual error of 2.13 yrs ±0.4 (SD) and a maximum residual error value of 2.88 yrs. For forensic purposes, by using only bench top machines in tests which can be carried out within 36 hrs, a set of just 3 variables produced an equation with an R2 = 0.902 a mean residual error of 3.38 yrs ±2.6 (SD) and a maximum observed residual error 9.26yrs. This method outstrips all existing age-at-death methods based on ribs, thus providing a novel lab based accurate tool in the forensic investigation of human remains. The present application is optimised for fresh (uncompromised by taphonomic conditions) remains, but the potential of the principle and method is vast once the trends of the biomechanical variables are established for other environmental conditions and circumstances.


Basic exploratory research versus guideline-compliant studies used for hazard evaluation and risk assessment: bisphenol A as a case study.
Myers et al. [Environ Health Perspect 117:309-315 (2009)] argued that Good Laboratory Practices (GLPs) cannot be used as a criterion for selecting data for risk assessment, using bisphenol A (BPA) as a case study. They did not discuss the role(s) of guideline-compliant studies versus basic/exploratory research studies, and they criticized both GLPs and guideline-compliant studies and their roles in formal hazard evaluation and risk assessment. They also specifically criticized our published guideline-compliant dietary studies on BPA in rats and mice and 17beta-estradiol (E(2)) in mice. As the study director/first author of the criticized E(2) and BPA studies, I discuss the uses of basic research versus guideline-compliant studies, how testing guidelines are developed and revised, how new end points are validated, and the role of GLPs. I also provide an overview of the BPA guideline-compliant and exploratory research animal studies and describe BPA pharmacokinetics in rats and humans. I present responses to specific criticisms by Myers et al. Weight-of-evidence evaluations have consistently concluded that low-level BPA oral exposures do not adversely affect human developmental or reproductive health, and I encourage increased validation efforts for "new" end points for inclusion in guideline studies, as well as performance of robust long-term studies to follow early effects (observed in small exploratory studies) to any adverse consequences.


A health system-based critical care program with a novel tele-ICU: implementation, cost, and structure details.
Improving the efficiency of critical care service is needed as the shortfall of intensivists is increasing. Standardizing clinical practice, telemedicine, and organizing critical care service at a health system level improves outcomes. We developed a health system Critical Care Program based at an academic medical center. The main feature of our program is an intensivist who shares on-site and telemedicine clinical responsibilities. Tele-ICU facilitates the standardization of high-quality critical care across the system. A common electronic medical record made the communications among the ICUs feasible. Combining faculty from medical and surgical critical care divisions increased the productivity of intensivists. We retrospectively reviewed the administrative database data from 2011 and 2012, including mean census, number of transfers, age, sex, case mix index, mortality, readmissions, and financial data. The Critical Care program has 106 adult ICU beds; 54 of those beds can be managed remotely using tele-ICU based at the main University hospital. The mean midnight census of the system for 2012 was 69.44 and total patient-days were 34,406. The capital cost of the tele-ICU was $1,186,220. The annual operational cost is $1,250,112 or $23,150 per monitored ICU-bed. Unadjusted mortality was 6.5% before and 4.9% after implementation (p < 0.0002). We describe a novel health system level ICU program built using "off the shelf" technology based on a large University medical center and a tele-ICU with a full degree of treatment authority across the system.


Experimental demonstration of a synthetic aperture compression scheme for multi-Petawatt high-energy lasers.
We present the experimental demonstration of a subaperture compression scheme achieved in the PETAL (PETawatt Aquitaine Laser) facility. We evidence that by dividing the beam into small subapertures fitting the available grating size, the sub-beam can be individually compressed below 1 ps, synchronized below 50 fs and then coherently added thanks to a segmented mirror.


Community engagement interventions for communicable disease control in low- and lower- middle-income countries: evidence from a review of systematic reviews.
Community engagement (CE) interventions include a range of approaches to involve communities in the improvement of their health and wellbeing. Working with communities defined by location or some other shared interest, these interventions may be important in assisting equity and reach of communicable disease control (CDC) in low and lower-middle income countries (LLMIC). We conducted an umbrella review to identify approaches to CE in communicable disease control, effectiveness of these approaches, mechanisms and factors influencing success. We included systematic reviews that: i) focussed on CE interventions; ii) involved adult community members; iii) included outcomes relevant to communicable diseases in LLMIC; iv) were written in English. Quantitative results were extracted and synthesised narratively. A qualitative synthesis process enabled identification of mechanisms of effect and influencing factors. We followed guidance from the Joanna Briggs Institute, assessed quality with the DARE tool and reported according to standard systematic review methodology. Thirteen systematic reviews of medium-to-high quality were identified between June and July 2017. Reviews covered the following outcomes: HIV and STIs (6); malaria (2); TB (1); child and maternal health (3) and mixed (1). Approaches included: CE through peer education and community health workers, community empowerment interventions and more general community participation or mobilisation. Techniques included sensitisation with the community and involvement in the identification of resources, intervention development and delivery. Evidence of effectiveness of CE on health outcomes was mixed and quality of primary studies variable. We found: i) significantly reduced neonatal mortality following women's participatory learning and action groups; ii) significant reductions in HIV and other STIs with empowerment and mobilisation interventions with marginalised groups; iii) significant reductions in malaria incidence or prevalence in a small number of primary studies; iv) significant reductions in infant diarrhoea following community health worker interventions. Mechanisms of impact commonly occurred through social and behavioural processes, particularly: changing social norms, increasing social cohesion and social capacity. Factors influencing effectiveness of CE interventions included extent of population coverage, shared leadership and community control over outcomes. Community engagement interventions may be effective in supporting CDC in LLMIC. Careful design of CE interventions appropriate to context, disease and community is vital.


Single stage bilateral total hip replacement: Is it an option or a risk?
To evaluate safety and feasibility of two-stage total hip arthroplasty and to compare it with single-stage procedure. The retrospective study was conducted at The Aga Khan University Hospital and comprised all cases of total hip replacements between January 2001 and December 2014 that were retrieved from the database using International Classification of Diseases (9th Revision) coding. A standardised questionnaire was completed, including patient demographics, primary diagnosis, peri and postoperative morbidity and mortality. Differences among patients\' data were analysed using chi square test for dichotomous variables and student t-test for continuous variables. Of the 48 cases, 34(71%) had single-stage bilateral total hip replacement and 14(29%) had two-stage procedure. The mean hospital stay in the single-stage group was 8.1±3.2 days compared to 19.6±5 days in the other group. The two-stage group required a significantly greater need for transfusion compared to the single-stage group (P<0.05). There was no statistically significant increase in peri or postoperative complication (p> 0.05). Simultaneous bilateral total hip arthroplasty was found to be a safe and viable option with a decreased transfusion requirement and shorter hospital stay along with no significant increase in morbidity or mortality.


Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies.
Invasion of host erythrocytes is essential to the life cycle of Plasmodium parasites and development of the pathology of malaria. The stages of erythrocyte invasion, including initial contact, apical reorientation, junction formation, and active invagination, are directed by coordinated release of specialized apical organelles and their parasite protein contents. Among these proteins, and central to invasion by all species, are two parasite protein families, the reticulocyte-binding protein homologue (RH) and erythrocyte-binding like proteins, which mediate host-parasite interactions. RH5 from Plasmodium falciparum (PfRH5) is the only member of either family demonstrated to be necessary for erythrocyte invasion in all tested strains, through its interaction with the erythrocyte surface protein basigin (also known as CD147 and EMMPRIN). Antibodies targeting PfRH5 or basigin efficiently block parasite invasion in vitro, making PfRH5 an excellent vaccine candidate. Here we present crystal structures of PfRH5 in complex with basigin and two distinct inhibitory antibodies. PfRH5 adopts a novel fold in which two three-helical bundles come together in a kite-like architecture, presenting binding sites for basigin and inhibitory antibodies at one tip. This provides the first structural insight into erythrocyte binding by the Plasmodium RH protein family and identifies novel inhibitory epitopes to guide design of a new generation of vaccines against the blood-stage parasite.


Automatic prediction of protein function.
Most methods annotating protein function utilise sequence homology to proteins of experimentally known function. Such a homology-based annotation transfer is problematic and limited in scope. Therefore, computational biologists have begun to develop ab initio methods that predict aspects of function, including subcellular localization, post-translational modifications, functional type and protein-protein interactions. For the first two cases, the most accurate approaches rely on identifying short signalling motifs, while the most general methods utilise tools of artificial intelligence. An outstanding new method predicts classes of cellular function directly from sequence. Similarly, promising methods have been developed predicting protein-protein interaction partners at acceptable levels of accuracy for some pairs in entire proteomes. No matter how difficult the task, successes over the last few years have clearly paved the way for ab initio prediction of protein function.


Age at last birth and its components.
This paper examines the ways in which the behavior of twentieth century cohorts of American women changed simultaneously in the three components of fertility that determine age at last birth--age at first birth, spacing between subsequent births, and parity progression ratios of subsequent births--to produce changes in the timing of the completion of childbearing. It decomposes changes in the mean age at last birth among cohorts and between whites and nonwhites to changes in these three components. To perform these analyses, we developed and applied a method to estimate the distributions and means of ages and last births, birth intervals, and parity progression ratios from age- and parity-specific fertility rates available from vital statistics data. Results show that the cohorts increased and decreased their age at first birth, birth intervals, and parity progression ratios of lower and higher birth orders in almost every possible combination so as to achieve a relatively young age at final birth.


Deltamethrin Intranasal administration induces memory, emotional and tyrosine hydroxylase immunoreactivity alterations in rats.
Parkinson's disease (PD) is a neurodegenerative disease related to the dopaminergic system. The etiology is not fully understood, but it is known that PD is a multifactorial disease that involves genetic and environmental factors, including pesticides. One of these, Deltamethrin (DM), has been widely used for vector control in crops, farming, veterinary medicine and domestic pest control. The purpose of the present study was to investigate the effect of DM repeated administration on motor, cognitive and emotional behavior and dopaminergic parameters. Male Wistar rats received 3 intranasal (i.n.) injections of 100 μL (50 μL/nostril) of DM 0.5 μg/μl or Vehicle (saline solution 0.9%), one injection per week. We observed that DM caused memory (novel object recognition task) and emotion (contextual conditioned fear) alterations accompanied by reduction of TH immunoreactivity in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), and increase of TH immunoreactivity in the dorsal striatum. Motor alterations (catalepsy and open field task) were not observed throughout treatment. These findings suggest a possible early disruption of the dopaminergic pathway caused by repeated DM exposure, similar to that observed in early stages of PD.


Localization of p35 (annexin I, lipocortin I) in normal adult rat kidney and during recovery from ischemia.
The 35-kDa protein (p35, lipocortin I, annexin I), originally discovered as a Ca(++)-dependent substrate for the EGF receptor tyrosine kinase, binds Ca++ and phospholipids, is developmentally regulated in embryos and has restricted expression in adults. Immunohistochemistry of normal rat kidney shows that p35 is enriched in epithelia of Bowman's capsule, the macula densa, and medullary/papillary collecting ducts, suggesting that p35 is related to specialized renal functions. Light staining is observed in the thick ascending limb; elsewhere, immunoreactivity is nil. Since renal recovery from ischemia involves both hyperplasia and hypertrophy and reportedly is accelerated by EGF, we examined p35 distribution during this process. After 48 hours of recovery, both the distribution and amount of renal p35 are altered. Immunoblots show p35 levels increased at least threefold in whole-kidney homogenates. The expression of p35 is still highly restricted in recovering kidneys; however, the thick ascending limb now stains heavily. This is the first documentation of alterations in annexin levels during a pathophysiologic response. However, our attempts to discern effects of exogenous EGF on the recovery from ischemia were negative for both mitotic index and renal function assays.


Effects of aging on adult hand function.
The effects that normal aging have on adult hand function and functional performance are not well understood. An empirical study was conducted examining relationships between prehension pattern type and frequency, hand strength, and performance time in functional tasks. Four groups of 10 adults were selected by age and gender, ranging from 24 to 87 years. Subjects were asked to pour milk into a cup and remove money from a wallet while being videotaped. Prehension patterns were identified with a functionally based classification system. Grip and three types of pinch were measured with a dynamometer and a pinch gauge. Prehension pattern selection did not seem to differ with age. Statistically significant differences in age were found for prehension pattern frequency, hand strength, and performance time. Nondysfunctional older subjects were observed resetting identical prehension patterns secondary to lateral pinch weakness, which contributed to increased prehension pattern frequency and performance time. Hand function seemed to remain stable until age 65 years, after which it diminished slowly. After age 75 years, age differences in performance were most apparent.


Identification and Management: Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Eelated to Hematopoietic Stem Cell Transplantation .
Sinusoidal obstruction syndrome (SOS), also called hepatic veno-occlusive disease (VOD), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) that affects about 1 in 7 patients undergoing this procedure. SOS/VOD is caused by the conditioning regimens administered prior to HSCT; in some cases, SOS/VOD results from chemotherapy alone. SOS/VOD usually develops within three weeks following HSCT; however, it can have later onset. . Clearly understanding how SOS/VOD develops may support prompt detection and treatment when the condition arises. . Research on identification and management of SOS/VOD is summarized, and data from clinical trials are reviewed. . This article describes the syndrome, risk factors, signs and symptoms, and appropriate supportive care and treatment. The authors also offer some practical tips for detecting SOS/VOD and providing patient care, as well as the latest information on treating and preventing this condition.


Resonant soft-X-ray emission as a bulk probe of correlated electron behavior in metallic SrxCa1-xVO3.
The evolution of electron correlation in SrxCa1-xVO3 has been studied using a combination of bulk-sensitive resonant soft x-ray emission spectroscopy, surface-sensitive photoemission spectroscopy, and ab initio band structure calculations. We show that the effect of electron correlation is enhanced at the surface. Strong incoherent Hubbard subbands are found to lie ∼20% closer in energy to the coherent quasiparticle features in surface-sensitive photoemission spectroscopy measurements compared with those from bulk-sensitive resonant soft x-ray emission spectroscopy, and a ∼10% narrowing of the overall bandwidth at the surface is also observed.


Mediating role of daily physical activity on quality of life in patients with heart failure.
An understanding of the contribution of daily physical activity and functional status to quality of life in patients with heart failure has the potential to enable patients to achieve better outcomes. Nevertheless, research that examines the relationship between these 3 variables in heart failure patients in Taiwan is lacking. Therefore, the purpose of this study was to close this gap by exploring the relationship among daily physical activity, functional status, and quality of life in this population. This study used a descriptive, cross-sectional, correlational design. A convenience sample of 108 heart failure patients was recruited, from November 2009 to September 2010, from 4 teaching hospitals in Taiwan. The data were collected by demographic questionnaire, New York Heart Association classification (functional status), Daily Physical Activity Status Index (daily physical activity), and Minnesota Living With Heart Failure Questionnaire (quality of life). Pearson correlations, hierarchical logistic regression, and the Sobel test were conducted to determine the relationship between functional status, daily physical activity, and quality of life. Propensity score analysis was used to adjust the inequality of the underlying diseases that the patients had and ensure the mediating effect. A significant mediating effect of daily physical activity on the relationship between functional status and quality of life was found. Multidisciplinary healthcare providers should work together to develop an intervention focused on enhancing daily physical activity and to evaluate the effectiveness of promoting quality of life for patients living with heart failure.


Duodenopancreatectomy versus duodenum-preserving pancreatic head excision for chronic pancreatitis.
The aim of this study was to compare two surgical procedures in the treatment for chronic pancreatitis (CP): pancreatoduodenectomy resection (classical Whipple - PD procedure, or pylorus-preserving - PPPD) to duodenum-preserving pancreatic head excision with longitudinal pancreatojejunoanastomosis (DPPHE/PJA), to define the advantages of each procedure with regard to postoperative complications, pain relief, and the quality of life. 104 consecutive patients were included into this study. Duodenopancreatectomy was chosen when the head pancreatic mass was present or pancreatic cancer could not be ruled out (48 patients); otherwise DPPHE/PJA was performed (56 patients). Quality of life was measured prospectively on two occasions, before the procedure and during follow-up (median 39 months after surgery) using the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-C30). The test was re-evaluated for patients suffering from CP. Pain intensity was quantified using a specially designed pain score. Early postoperative morbidity and mortality were assessed and evaluated in both groups of patients. Total pain score decreased significantly after surgery in both groups of patients. During the follow-up period, the global quality of life improved by 30.4% in the DPPHE/PJA group, and by 23.2% in the PD/PPPD group. Postoperative morbidity and mortality were higher in the resection group, but the differences were not significant. Both surgical procedures led to significant improvement in the quality of life and pain relief after surgery for CP. The EORTC QLQ-C30 was found to be a valid and readily available test for quality-of-life assessment in patients with CP.


Seeing fearful body expressions activates the fusiform cortex and amygdala.
Darwin's evolutionary approach to organisms' emotional states attributes a prominent role to expressions of emotion in whole-body actions. Researchers in social psychology [1,2] and human development [3] have long emphasized the fact that emotional states are expressed through body movement, but cognitive neuroscientists have almost exclusively considered isolated facial expressions (for review, see [4]). Here we used high-field fMRI to determine the underlying neural mechanisms of perception of body expression of emotion. Subjects were presented with short blocks of body expressions of fear alternating with short blocks of emotionally neutral meaningful body gestures. All images had internal facial features blurred out to avoid confounds due to a face or facial expression. We show that exposure to body expressions of fear, as opposed to neutral body postures, activates the fusiform gyrus and the amygdala. The fact that these two areas have previously been associated with the processing of faces and facial expressions [5-8] suggests synergies between facial and body-action expressions of emotion. Our findings open a new area of investigation of the role of body expressions of emotion in adaptive behavior as well as the relation between processes of emotion recognition in the face and in the body.


Evidence for a host role in thermotolerance divergence between populations of the mustard hill coral (Porites astreoides) from different reef environments.
Studying the mechanisms that enable coral populations to inhabit spatially varying thermal environments can help evaluate how they will respond in time to the effects of global climate change and elucidate the evolutionary forces that enable or constrain adaptation. Inshore reefs in the Florida Keys experience higher temperatures than offshore reefs for prolonged periods during the summer. We conducted a common garden experiment with heat stress as our selective agent to test for local thermal adaptation in corals from inshore and offshore reefs. We show that inshore corals are more tolerant of a 6-week temperature stress than offshore corals. Compared with inshore corals, offshore corals in the 31 °C treatment showed significantly elevated bleaching levels concomitant with a tendency towards reduced growth. In addition, dinoflagellate symbionts (Symbiodinium sp.) of offshore corals exhibited reduced photosynthetic efficiency. We did not detect differences in the frequencies of major (>5%) haplotypes comprising Symbiodinium communities hosted by inshore and offshore corals, nor did we observe frequency shifts ('shuffling') in response to thermal stress. Instead, coral host populations showed significant genetic divergence between inshore and offshore reefs, suggesting that in Porites astreoides, the coral host might play a prominent role in holobiont thermotolerance. Our results demonstrate that coral populations inhabiting reefs <10-km apart can exhibit substantial differences in their physiological response to thermal stress, which could impact their population dynamics under climate change.


Cost-effectiveness analysis of dabigatran and anticoagulation monitoring strategies of vitamin K antagonist.
Vitamin K antagonists are commonly used for the prevention of thromboembolic events. Patient self-monitoring of vitamin K antagonists has proved superior to usual care. Dabigatran has been shown, relative to warfarin, to reduce thromboembolic events without increasing bleeding. We constructed a Markov model to compare vitamin K self-monitoring strategies to dabigatran including effectiveness and costs of monitoring and complications (thromboembolism and major bleeding). The model was used to project the incidence of these complications, life years, quality-adjusted life years, and health system costs with anticoagulant treatment throughout life. The analysis was conducted from the health system perspective and from the societal perspective. Low quality evidence suggests that self-monitoring is at least as effective as dabigatran for the outcomes of thrombosis, bleeding and death. Moderate quality evidence that patient self-monitoring is more effective than other forms of monitoring degree of anticoagulation with vitamin K antagonists, reducing the relative risk of thromboembolism by 41% and death by 34%. The cost per quality adjusted year gained relative to other warfarin monitoring strategies is well below 30,000 € in the short term, and is a dominant alternative from the fourth year. In comparison with dabigatran, the lower annual cost and its equivalence in terms of effectiveness made self-monitoring the dominant option. These results were confirmed in the probabilistic sensitivity analysis. We have moderate quality evidence that self-monitoring of vitamin K antagonists is a cost-effective alternative compared with hospital and primary care monitoring, and low quality evidence, compared with dabigatran. Our analyses contrast with the available cost analysis of dabigatran and usual care of anticoagulated patients.


A new frailty syndrome: central obesity and frailty in older adults with the human immunodeficiency virus.
To evaluate the relationships between body composition and physical frailty in community-dwelling older adults with the human immunodeficiency virus (HIV) (HOA). Cross-sectional. Academic hospital-based infectious disease clinic in Rochester, New York. Forty community-dwelling HOA aged 50 and older undergoing antiretroviral therapy who were able to ambulate without assistive devices with a mean age of 58, a mean BMI of 29.0 kg/m(2), mean CD4 count of 569 cells/mL, and a mean duration since HIV diagnosis of 17 years; 28% were female and 57% Caucasian. Subjective and objective measures of functional status were evaluated using the Physical Performance Test (PPT), the graded treadmill test, knee strength, gait speed, balance, and the Functional Status Questionnaire (FSQ). Body composition was evaluated using dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). Sixty percent (25/40) of the participants met standard criteria for physical frailty. Frail (FR) and nonfrail (NF) participants were comparable in age, sex, CD4 count, and viral load. FR HOA had greater impairments in PPT, peak oxygen uptake, FSQ, walking speed, balance, and muscle quality than NF HOA. FR HOA had a greater body mass index (BMI), fat mass, and truncal fat with lipodystrophy. Moreover, PPT score was inversely related to trunk fat (correlation coefficient (r) = -0.34; P = .04) and ratio of intermuscular fat to total fat (r = -0.60; P = .02) after adjusting for covariates. HOA represent an emerging cohort of older adults who frequently experience frailty at a much younger age than the general older population. Central obesity and fat redistribution are important predictors of frailty in community-dwelling HOA. These findings suggest that physical frailty in HOA may be amenable to lifestyle interventions, especially exercise and diet therapy.


White matter integrity as a predictor of response to treatment in first episode psychosis.
The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response.


A variant alkaline phosphatase found in a case of gastric carcinoma with super bone scan.
A rare case of gastric carcinoma associated with increased serum variant alkaline phosphatase activities is presented. A 54 year old man had extremely high serum alkaline phosphatase activity (18,607 U/l) with normal calcium and phosphate concentrations. His bone scintigram showed abnormal findings, 'super bone scan'. He was diagnosed as having Borrmann type 4 gastric carcinoma with diffuse bone metastases by examinations of the upper gastrointestinal tract and iliac bone biopsy. The alkaline phosphatase isozyme of this patient was of the bone type as measured by cellulose acetate membrane electrophoresis and the placenta/bone type by agarose gel electrophoresis, respectively. Immunoelectrophoresis and the immunoprecipitation method using monoclonal antibodies against various alkaline phosphatase isozymes, however, showed that his serum alkaline phosphatase had the liver type antigenicity. Furthermore, it had a larger molecular size and different sugar chains compared with the common liver type alkaline phosphatase. These findings suggest that a unique variant alkaline phosphatase was produced by gastric cancer cells, which is possibly an explanation for the high serum alkaline phosphatase activities in this patient.


Fractal growth of platinum electrodeposits revealed by in situ electron microscopy.
Fractals are commonly observed in nature and elucidating the mechanisms of fractal-related growth is a compelling issue for both fundamental science and technology. Here we report an in situ electron microscopy study of dynamic fractal growth of platinum during electrodeposition in a miniaturized electrochemical cell at varying growth conditions. Highly dendritic growth - either dense branching or ramified islands - are formed at the solid-electrolyte interface. We show how the diffusion length of ions in the electrolyte influences morphology selection and how instability induced by initial surface roughness, combined with local enhancement of electric field, gives rise to non-uniform branched deposition as a result of nucleation/growth at preferred locations. Comparing the growth behavior under these different conditions provides new insight into the fundamental mechanisms of platinum nucleation.


Expedited assessment of terrestrial arthropod diversity by coupling Malaise traps with DNA barcoding 1.
Monitoring changes in terrestrial arthropod communities over space and time requires a dramatic increase in the speed and accuracy of processing samples that cannot be achieved with morphological approaches. The combination of DNA barcoding and Malaise traps allows expedited, comprehensive inventories of species abundance whose cost will rapidly decline as high-throughput sequencing technologies advance. Aside from detailing protocols from specimen sorting to data release, this paper describes their use in a survey of arthropod diversity in a national park that examined 21 194 specimens representing 2255 species. These protocols can support arthropod monitoring programs at regional, national, and continental scales.


A Vital Mediation: The Sanatorium, before and after Antibiotics.
As drug-resistant strains of tuberculosis spread across India, commentators have warned that we are returning to the sanatorium era. Such concerns might be symptomatically read in terms of loss; however, prophecies of return might also signal that there is something to be regained. Rather than lamenting the end of the antibiotic era, I shift the focus to ask about the sanatorium, not simply as a technology of the past, but as a technology of an imminent future. In examining late nineteenth- and early twentieth-century conversations about treating tuberculosis in India, I demonstrate how the the sanatorium was figured as a therapeutic technology that mediated the relationship between the body and its colonial milieu. In this light, I argue that contemporary prophecies of a future past register not simply the loss of antibiotic efficacy, but also a desire to return to a therapeutics that foregrounds issues of vitality, mediation, and environment.


Occlusion training increases muscular strength in division IA football players.
The purpose of this study was to investigate the effectiveness of 4 weeks of low-intensity resistance training with blood-flow occlusion on upper and lower body muscular hypertrophy and muscular strength in National Collegiate Athletic Association Division IA football players. There were 32 subjects (average age 19.2 ± 1.8 years) who were randomized to an occlusion group or control group. The athletes performed 4 sets of bench press and squat in the following manner with or without occlusion: 30 repetitions of 20% predetermined 1 repetition maximum (1RM), followed by 3 sets of 20 repetitions at 20% 1RM. Each set was separated by 45 seconds. The training duration was 3 times per week, after the completion of regular off-season strength training. Data collected included health history, resting blood pressure, pretraining and posttraining bench press and squat 1RM, upper and lower chest girths, upper and lower arm girths, thigh girth, height, and body mass. The increases in bench press and squat 1RM (7.0 and 8.0%, respectively), upper and lower chest girths (3 and 3%, respectively), and left upper arm girth were significantly greater in the experiment group (p < 0.05). Occlusion training could provide additional benefits to traditional strength training to improve muscular hypertrophy and muscular strength in collegiate athletes.


A neural measure of precision in visual working memory.
Recent studies suggest that the temporary storage of visual detail in working memory is mediated by sensory recruitment or sustained patterns of stimulus-specific activation within feature-selective regions of visual cortex. According to a strong version of this hypothesis, the relative "quality" of these patterns should determine the clarity of an individual's memory. Here, we provide a direct test of this claim. We used fMRI and a forward encoding model to characterize population-level orientation-selective responses in visual cortex while human participants held an oriented grating in memory. This analysis, which enables a precise quantitative description of multivoxel, population-level activity measured during working memory storage, revealed graded response profiles whose amplitudes were greatest for the remembered orientation and fell monotonically as the angular distance from this orientation increased. Moreover, interparticipant differences in the dispersion-but not the amplitude-of these response profiles were strongly correlated with performance on a concurrent memory recall task. These findings provide important new evidence linking the precision of sustained population-level responses in visual cortex and memory acuity.


SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1.
Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of PARP1, which is independent of DNA damage. SIRT1 physically binds to and deacetylates PARP1. Increased acetylation of PARP1 was also detected in hearts of SIRT1(-/-) mice, compared to that detected in the hearts of SIRT1(+/+) mice, confirming a role of SIRT1 in regulating the PARP1 acetylation in vivo. SIRT1-dependent deacetylation blocks PARP1 activity, and it protects cells from PARP1-mediated cell death. We also show that SIRT1 negatively regulates the activity of the PARP1 gene promoter, thus suggesting that the deacetylase controls the PARP1 activity at the transcriptional level as well. These data demonstrate that the activity of PARP1 is under the control of SIRT1, which is necessary for survival of cells under stress conditions.


Infection of lymphoid tissues in the macaque upper respiratory tract contributes to the emergence of transmissible measles virus.
Measles virus (MV), a member of the family Paramyxoviridae, remains a major cause of morbidity and mortality in the developing world. MV is spread by aerosols but the mechanism(s) responsible for the high transmissibility of MV are largely unknown. We previously infected macaques with enhanced green fluorescent protein-expressing recombinant MV and euthanized them at a range of time points. In this study a comprehensive pathological analysis has been performed of tissues from the respiratory tract around the peak of virus replication. Isolation of virus from nose and throat swab samples showed that high levels of both cell-associated and cell-free virus were present in the upper respiratory tract. Analysis of tissue sections from lung and primary bronchus revealed localized infection of epithelial cells, concomitant infiltration of MV-infected immune cells into the epithelium and localized shedding of cells or cell debris into the lumen. While high numbers of MV-infected cells were present in the tongue, these were largely encapsulated by intact keratinocyte cell layers that likely limit virus transmission. In contrast, the integrity of tonsillar and adenoidal epithelia was disrupted with high numbers of MV-infected epithelial cells and infiltrating immune cells present throughout epithelial cell layers. Disruption was associated with large numbers of MV-infected cells or cell debris 'spilling' from epithelia into the respiratory tract. The coughing and sneezing response induced by disruption of the ciliated epithelium, leading to the expulsion of MV-infected cells, cell debris and cell-free virus, contributes to the highly infectious nature of MV.