Experience with new autotitrating nasal continuous positive airway pressure machines.
Since the introduction of nasal continuous positive airway pressure (nCPAP) in the treatment of sleep apnoea, enormous technical improvements in nCPAP devices have been achieved. nCPAP has become the most effective and widely used standard therapy for obstructive sleep apnoea. Recently, machines that automatically titrate the effective nCPAP pressure have become available. The question now is, whether and how they work and what the benefits and limitations of such devices are. The algorithms that control the machines are quite different and so is their effectiveness. Even in devices that generally work well, there may be some principal limitations. The algorithm may be mislead by artefacts, especially leaks. Apnoeas and arousal may occur because the pressure increase is too slow or breathing disturbances reoccur after a pressure decrease. Autotitrating nasal continuous positive airway pressure may reduce the work required to determine effective pressure. It is a valuable treatment option for patients who need high and variable nasal continuous positive airway pressure. It should not be used as an unattended pressure titration tool because this will lead to a loss of quality in patient care and a reduced acceptance of nasal continuous positive airway pressure, as pressure determination is only a small part of the adaptation of the patient to nasal continuous positive airway pressure.


Proliferation-dependent topoisomerase II content as a determinant of antineoplastic drug action in human, mouse, and Chinese hamster ovary cells.
We have shown previously that quiescent Chinese hamster ovary (CHO) cells are less sensitive than log phase CHO cells to the cytotoxic and DNA cleavage effects of etoposide, a drug which appears to act via DNA topoisomerase II. This loss of sensitivity was associated with a decrease in topoisomerase enzyme activity in nuclear extracts of the quiescent cells. We have now extended our observations by examining the basis for the reduction in enzyme activity during quiescence. DNA topoisomerase II content, as assayed by immunoblotting with a polyclonal rabbit anti-topoisomerase II antiserum, was virtually absent in nuclear extracts of quiescent CHO cells in contrast to logarithmically growing cells. This suggests that the previously demonstrated loss of enzyme activity in CHO cells is a function of reduction in content rather than posttranslational modifications of the enzyme. Quiescent human lymphoblastic CCRF cells also exhibited reduced topoisomerase II content compared to actively proliferating cultures, but the difference was less than that observed in CHO cells. In contrast, log and plateau phase cultures of mouse leukemia L1210 cells exhibited similar topoisomerase II content. Reduction in enzyme content correlated with the ability of these cell lines to accumulate during quiescence with a G0-G1 content of DNA. Sensitivity to the DNA cleavage effects of etoposide in dividing and nondividing cells correlated well with enzyme content. As has been observed with CHO cells, both CCRF and L1210 cells in plateau phase were more resistant to the cytotoxic effects of etoposide than those actively dividing. The result with L1210 cells was surprising, however, in light of the equivalent DNA damage observed under the two growth conditions. Our data indicate that topoisomerase II enzyme content is proliferation dependent in some but not all cells and suggest that while enzyme content may be important in drug resistance in some cell types, other factors can decrease the sensitivity of the cell to cleavable complex formation as well.


Bradykinin-stimulated arachidonic acid release from MDCK cells is not protein kinase C dependent.
Bradykinin (BK)-induced release of arachidonic acid (AA) from Madin-Darby canine kidney (MDCK) D1 cells was investigated. Phorbol 12-myristate 13-acetate (PMA) caused a synergistic increase in BK- and A-23187-induced release of AA but alone had no effect on this release. Inhibition of protein kinase C (PKC) with bisindolmaleimide I (BIS) abolished the synergistic effects of PMA but did not affect AA release caused by BK or A-23187 alone. Downregulation of PKC with 100 nM PMA resulted in a reduction of AA release induced by BK or A-23187 addition, which corresponded to a decrease in cytoplasmic phospholipase A2 (cPLA2) activity as measured in cell extracts. Although Western blotting revealed no differences in cPLA2 expression as a result of PMA treatment, phosphorylation of the enzyme, as assessed by phosphoserine content, was significantly reduced in PKC-depleted cells. These results imply that, with PKC downregulation, subsequent BK stimulation results in a Ca(2+)-dependent translocation of a less phosphorylated, less active form of cPLA2. Any stimulation of PKC by BK addition did not appear as a significant event in onset responses leading to AA release. On the other hand, inhibition of the mitogen-activated protein kinase (MAPK) cascade with the MAPK kinase inhibitor, PD-98059, significantly decreased BK-induced release of AA, a finding that, with our other results, points to the existence of a PKC-independent route for stimulation of MAPK and the propagation of onset responses.


Distribution and frequency of endocrine cells in the pancreas of the ddY mouse: an immunohistochemical study.
The regional distribution and frequency of pancreatic endocrine cells in ddY mice were studied by an immunohistochemical (peroxidase anti-peroxidase; PAP) method using four types of specific antisera against insulin, glucagon, somatostatin and human pancreatic polypeptide (hPP). In the pancreatic islets, most of insulin-immunoreactive (IR) cells were located in the central portion. Most of glucagon- and somatostatin-IR cells were observed in peripheral regions although a somewhat smaller number of cells were also located in the central regions. HPP-IR cells were randomly distributed throughout the entire islets. In the exocrine pancreas, insulin-, glucagon-, somatostatin- and hPP-IR cells were detected; they occurred mainly among the exocrine parenchyma as solitary cells. Cell clusters consisted of only insulin- or only glucagon-IR cells and were distributed in the pancreas parenchyma as small islets. In addition, insulin- and glucagon-IR cells were also demonstrated in the pancreatic duct regions. Insulin-IR cells were located in the epithelium and sub-epithelial connective tissue regions as solitary cells and/or clusters (3-4 cells), and glucagon-IR cells were mainly located in the epithelium as solitary cells. Overall, there were 63.89+/-5.39% insulin-, 26.52+/-3.55% glucagon-, 7.25+/-2.83% somatostatin- and 1.90+/-0.58% hPP-IR cells. In conclusion, some strain-dependent characteristic distributional patterns of pancreatic endocrine cells were found in the ddY mouse.


Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin.
Matrix metalloproteinases (MMPs) classically have been implicated in basement membrane destruction associated with late-stage tumor cell invasion and metastasis. However, recent studies have demonstrated that one MMP family member, matrilysin, is expressed in a high percentage of early-stage human colorectal tumors. We analyzed matrilysin expression in benign intestinal tumors from mice heterozygous for the ApcMin allele (Min/+) and found that the mRNA was induced in the majority (88%) of these adenomas. Protein was detected in the tumor cells, where, surprisingly, it was predominantly immunolocalized to the lumenal surface of dysplastic glands rather than the basement membrane or extracellular matrix. To address the role of matrilysin in Min intestinal tumorigenesis, we generated Min/+ mice deficient in this MMP by gene targeting and homologous recombination. The absence of matrilysin resulted in a reduction in mean tumor multiplicity in Min/+ animals of approximately 60% and a significant decrease in the average tumor diameter. Based on these findings, we conclude that matrilysin is a suppressor of the Min phenotype, possibly by functioning in a capacity independent of matrix degradation. These results argue for the use of MMP inhibitors in the treatment and prevention of early-stage colon cancer.


Chromosomal aberrations involving telomeres and interstitial telomeric sequences.
Telomeres are specialised nucleoproteic complexes localised at the physical ends of linear eukaryotic chromosomes that maintain their stability and integrity. In vertebrate chromosomes, the DNA component of telomeres is constituted by (TTAGGG)n repeats, which can be localised at the terminal regions of chromosomes (true telomeres) or at intrachromosomal sites (interstitial telomeric sequences or ITSs, located at the centromeric region or between the centromere and the telomere). In the past two decades, the use of molecular cytogenetic techniques has led to a new spectrum of spontaneous and clastogen-induced chromosomal aberrations being identified, involving telomeres and ITSs. Some aberrations involve the chromosome ends and, indirectly, the telomeric repeats located at the terminal regions of chromosomes (true telomeres). A second type of aberrations directly involves the telomeric sequences located at the chromosome ends. Finally, there is a third class of aberrations that specifically involves the ITSs. The aims of this review are to provide a detailed description of these aberrations and to summarise the available data regarding their induction by physical and chemical mutagens.


Emerging issues and future needs in humanitarian assistance.
During the past two decades, there has been tremendous investment in the ability to intervene in disaster settings, and significant barriers remain to providing appropriate services to populations affected by natural and man-made calamities. Many of the barriers to providing effective assistance exist within the NGO community, and illustrate emerging needs for international agencies. These emerging needs include improving methods of recipient participation to promote the local health system, developing improved methods for quality assurance, enhancing options for personnel development, and addressing long-term needs of reconstruction and rehabilitation. Relief agencies face challenges on all levels to develop sound practices in providing humanitarian assistance that can lead to long-term benefits to populations affected by disaster.


Disposition of morphine in rat brain: relationship to biological activity.
The levels of morphine in plasma and brain subcortex of rats were determined by gas-liquid chromatography and radioimmunoassay at various time intervals after a single i.v. injection of graded doses of morphine (0.44, 1.04 and 2.25 mg/kg). The disappearance curve of morphine plasma levels appeared to be composed of at least two exponential terms: a rapid disappearance during the 1st hr, which was dependent on the unit dose of morphine injected and a slower disappearance rate after the 1st hr. The highest morphine levels in the brain were measured already 5 min after its injection and these levels only slightly decreased over the next 2 hr. Thereafter a more rapid disappearance of brain morphine was observed. The brain/plasma ratio gradually increased from 0.18 at 5 min after injection to about 1.0 at 60 and 120 min and decreased to approximately 0.4 at 4 hr after injection. This may suggest that morphine is retained in the brain during the 1st hr after injection and that it might be removed from the brain between 2 and 4 hr, possibly by an active process. The relationship between brain morphine levels and the degree of antinociception as assessed with the hot plate procedure appeared to be rather complicated. Shortly after morphine injection, but also at 60 and 120 min after injection, the antinociceptive effect was much lower than might be expected from the levels of morphine in the brain. Several possible explanations for this phenomenon are discussed. A high dose of naltrexone, which completely blocked the antinociceptive effect of morphine, did not affect brain and plasma levels of morphine. Rifampicin, which attenuates development of morphine tolerance, increased brain levels of morphine but did not change plasma levels. Pretreatment with the tripeptide prolyl-leucyl-glycinamide, which facilitates development of morphine tolerance, decreased brain morphine levels and increased plasma levels at 3 hr after morphine injection. This suggests that tolerance development and the rate with which morphine is removed from the brain may have at least some common underlying mechanisms.


Cardiopulmonary exercise testing in evaluation of patients of chronic obstructive pulmonary disease.
Objective assessment of severity in patients with chronic obstructive pulmonary disease (COPD) is mainly limited to pulmonary function testing performed at rest. But, accurate assessment of exercise capacity in patients with COPD may be possible with cardiopulmonary exercise testing (CPET). Forty-three patients with stable COPD were included and were divided into three groups based upon the spirometry data as per the Global Initiative for Obstructive Lung Disease (GOLD) guidelines as follows: Group A: mild COPD, Group B: moderately severe COPD and Group C: severe COPD. Symptom-limited CPET was performed using treadmill on incremental continuous ramp protocol in all of them. Five patients (11.6%) had mild COPD; 16 (37.2%) had moderately severe COPD and the remaining 22 (51.6%) patients had severe COPD. Anaerobic threshold was attained in all the 43 patients. The dominant symptom at peak exercise were dyspnoea (n = 19) and both dyspnoea and leg fatigue (n = 7). The other causes of exercise limitation included dyspnoea with significant oxygen desaturation (n = 6); and dyspnoea with severe oxygen desaturation (n = 2). Six patients complained only of leg fatigue at peak exercise. A significant correlation between forced expiratory volume in the first second (FEV1) percent predicted and the predicted maximum oxygen uptake (VO2 max % predicted) was observed in all the three groups (r = 0.39, p = 0.011) but with marked variability of peak VO2 for a given degree of airflow obstruction. Twenty-three (53.5%) patients with low anaerobic threshold (< 30%) were identified as potential group likely to benefit from exercise training for pulmonary rehabilitation. Cardiopulmonary exercise testing is useful to determine the causes of exercise limitation and to assess the maximal exercise capacity of patients with COPD.


Pre- and undiagnosed-hypertension in urban Chinese adults: a population-based cross-sectional study.
Hypertension is common in adults and often undiagnosed, and the prevalence of pre- and undiagnosed-hypertension remains unclear. We aimed to investigate the prevalence of pre- and undiagnosed-hypertension and their correlates among urban Chinese adults. A total of 7435 participants aged 20-79 were included in this study. Data on demographics, lifestyle and medical history were collected through a structured interview. Pre- and undiagnosed-hypertension was defined as systolic blood pressure/ diastolic blood pressure (SBP/DBP) of 120-139/80-89 mm Hg and SBP⩾140 mm Hg and/or DBP⩾90 mm Hg, respectively, in participants without a history of hypertension and use of antihypertensive medication. Prevalence rates were calculated and standardized using local age- and gender-specific census data. Data were analysed using multinomial logistic regression with adjustment for potential confounders. Of all the participants, 2726 (36.7%) were diagnosed with pre-hypertension and 919 (12.3%) with undiagnosed-hypertension. Undiagnosed-hypertension accounted for 37.3% of all participants with hypertension. The prevalence of pre-hypertension gradually decreased with age, while undiagnosed-hypertension increased, although presenting different changing patterns among men and women. In a fully adjusted multinomial logistic regression, age, male sex, low socio-economic status (SES), abdominal obesity, alcohol drinking, physical inactivity and type 2 diabetes mellitus (T2DM) were significantly associated with increased odds of pre- and undiagnosed-hypertension. In conclusions, the prevalence of pre- and undiagnosed-hypertension was ~50% among urban Chinese adults. Abdominal obesity, low SES, alcohol drinking, physical inactivity and T2DM may be indicators for pre- and undiagnosed-hypertension.


Sampling strategies for accurate computational inferences of gametic phase across highly polymorphic major histocompatibility complex loci.
Genes of the Major Histocompatibility Complex (MHC) are very popular genetic markers among evolutionary biologists because of their potential role in pathogen confrontation and sexual selection. However, MHC genotyping still remains challenging and time-consuming in spite of substantial methodological advances. Although computational haplotype inference has brought into focus interesting alternatives, high heterozygosity, extensive genetic variation and population admixture are known to cause inaccuracies. We have investigated the role of sample size, genetic polymorphism and genetic structuring on the performance of the popular Bayesian PHASE algorithm. To cover this aim, we took advantage of a large database of known genotypes (using traditional laboratory-based techniques) at single MHC class I (N = 56 individuals and 50 alleles) and MHC class II B (N = 103 individuals and 62 alleles) loci in the lesser kestrel Falco naumanni. Analyses carried out over real MHC genotypes showed that the accuracy of gametic phase reconstruction improved with sample size as a result of the reduction in the allele to individual ratio. We then simulated different data sets introducing variations in this parameter to define an optimal ratio. Our results demonstrate a critical influence of the allele to individual ratio on PHASE performance. We found that a minimum allele to individual ratio (1:2) yielded 100% accuracy for both MHC loci. Sampling effort is therefore a crucial step to obtain reliable MHC haplotype reconstructions and must be accomplished accordingly to the degree of MHC polymorphism. We expect our findings provide a foothold into the design of straightforward and cost-effective genotyping strategies of those MHC loci from which locus-specific primers are available.


Optimizing data collection for public health decisions: a data mining approach.
Collecting data can be cumbersome and expensive. Lack of relevant, accurate and timely data for research to inform policy may negatively impact public health. The aim of this study was to test if the careful removal of items from two community nutrition surveys guided by a data mining technique called feature selection, can (a) identify a reduced dataset, while (b) not damaging the signal inside that data. The Nutrition Environment Measures Surveys for stores (NEMS-S) and restaurants (NEMS-R) were completed on 885 retail food outlets in two counties in West Virginia between May and November of 2011. A reduced dataset was identified for each outlet type using feature selection. Coefficients from linear regression modeling were used to weight items in the reduced datasets. Weighted item values were summed with the error term to compute reduced item survey scores. Scores produced by the full survey were compared to the reduced item scores using a Wilcoxon rank-sum test. Feature selection identified 9 store and 16 restaurant survey items as significant predictors of the score produced from the full survey. The linear regression models built from the reduced feature sets had R2 values of 92% and 94% for restaurant and grocery store data, respectively. While there are many potentially important variables in any domain, the most useful set may only be a small subset. The use of feature selection in the initial phase of data collection to identify the most influential variables may be a useful tool to greatly reduce the amount of data needed thereby reducing cost.


Differential expression of thyroid hormone receptor isoforms is strikingly related to cardiac and skeletal muscle phenotype during postnatal development.
The genomic actions of thyroid hormones (THs) are mediated by receptors (TRs) that are encoded by two protooncogenes, c-erbA-alpha and c-erbA-beta. The precise functions of the TR isoforms are unclear and this study focuses on the potential roles of the TRalpha and TRbeta isoforms in mammalian striated muscles postnatally. The porcine TRalpha1, TRalpha2 and TRbeta1 cDNAs were first cloned, sequenced and characterised by Northern blotting. A quantitative analysis of TR isoform expression was then undertaken, using RNase protection analysis with novel riboprobes designed to detect relative expression levels of TRalpha1, TRalpha2, TRbeta1 and TRbeta2, in functionally distinct muscles from 7-week-old pigs kept under controlled conditions of nutrition and thermal environment. We found a striking muscle-specific pattern of TRalpha isoform distribution: in heart the mRNA level of TRalpha2 (non-TH binding) was markedly greater (P<0.01) than that of TRalpha1 (TH binding); in longissimus dorsi the opposite pattern of expression occurred (TRalpha1>TRalpha2, P<0.001); in soleus, diaphragm and rhomboideus there were no differences between the two isoforms. The overall abundance of TRbeta was very much lower than that of TRalpha, and TRbeta1 was expressed at a higher level than TRbeta2 in all muscles. Together with recent data from TR gene inactivation studies and the established role of TH in determining myosin heavy chain isoform expression and muscle phenotype, these results suggest a role for differential expression of TR isoforms in acquisition and maintenance of optimal cardiac and skeletal muscle function.


Tunable Self-Assembled Nanostructures of Electroactive PEGylated Tetra(Aniline) Based ABA Triblock Structures in Aqueous Medium.
PEGylated tetra(aniline) ABA triblock structure PEG-TANI-PEG (2) consisting of tetra(aniline) (TANI) and polyethylene glycol (PEG) was synthesized by coupling the tosylated-PEG to boc-protected NH2/NH2 TANI (1) through a simple nucleophilic substitution reaction. Deprotection of 2 resulted in a leucoemeraldine base state of TANI (2-LEB), which was oxidized to stable emeraldine base (2-EB) state. 2-EB was doped with 1 M HCl to emeraldine salt (2-ES) state. FTIR, 1H and 13C NMR and UV-Vis-NIR spectroscopy, and MS (ESI) was used for structural characterization. The synthesized triblock structure exhibited good electroactivity as confirmed by CV and UV-Vis-NIR spectroscopy. Self-assembling of the triblock structure in aqueous medium was assessed by DLS, TEM, and SEM. Spherical aggregates were observed with variable sizes depicting the effect of concentration and oxidation of 2-LEB. Further, the aggregates showed acid/base sensitivity as evaluated by doping and dedoping of 2-EB with 1 M HCl and 1 M NH4OH, respectively. Future applications in drug delivery and sensors are envisaged for such tunable self-assembled nanostructures in aqueous media.


Personality trait changes among young Finns: the role of life events and transitions.
Recent research has shown that personality traits continue to develop throughout the life span, but most profound changes are typically found during young adulthood. Increasing evidence suggests that life events play a significant role in many of these changes. The present longitudinal study examined the role of work, education, social, and health-related life events in the development of the Big Five traits among young Finns. Participants were originally recruited in 2004 through elementary schools in a middle-sized Finnish city. Participants' Big Five traits and life events were measured via self-reports at ages 20 and 23 (Ns = 597 and 588, respectively). Entering work life, beginning a relationship, and studying in university predicted increases in Conscientiousness, trying drugs predicted increases in Neuroticism, and onset of a chronic disease predicted increases in Neuroticism and Conscientiousness between ages 20 and 23. The results suggest that mature life transitions relate to stronger increases in Conscientiousness in young adulthood, and that non-normative life choices and events may predict increases in Neuroticism.


Single-vesicle detection and analysis of peptide-induced membrane permeabilization.
The capability of membrane-active peptides to disrupt phospholipid membranes is often studied by investigating peptide-induced leakage of quenched fluorescent molecules from large unilamellar lipid vesicles. In this article, we explore two fluorescence microscopy-based single-vesicle detection methods as alternatives to the quenching-based assays for studying peptide-induced leakage from large unilamellar lipid vesicles. Specifically, we use fluorescence correlation spectroscopy (FCS) to study the leakage of fluorescent molecules of different sizes from large unilamellar lipid vesicles dispersed in aqueous solution, and we use confocal imaging of surface-immobilized large unilamellar lipid vesicles to investigate whether there are heterogeneities in leakage between individual vesicles. Of importance, we design an experimental protocol that allows us to quantitatively correlate the results of the two methods; accordingly, it can be assumed that the two methods provide complementary information about the same leakage process. We use the two methods to investigate the membrane-permeabilizing activities of three well-studied cationic membrane-active peptides: mastoparan X, melittin, and magainin 2. The FCS results show that leakage induced by magainin 2 is less dependent on the size of the encapsulated fluorescent molecules than leakage induced by mastoparan X and melittin. The confocal imaging results show that all three peptides induce leakage by a heterogeneous process in which one portion of the vesicles are completely emptied of their contents but another portion of the vesicles are only partially emptied. These pieces of information regarding leakage induced by mastoparan X, melittin, and magainin 2 could not readily have been obtained by the established assays for studying peptide-induced leakage from lipid vesicles.


Organ distributions and clearance studies of 99mtechnetium-labeled Corynebacterium parvum in patients with leukemia.
The clearance, metabolism and localization of Corynebacterium parvum (C. parvum) labeled with 99mtechnetium (99mTc) given intravenously was studied in various leukemia patients to develop the method and to evaluate reticuloendothelial systems (RES) function. A computer program was utilized to characterize the clearance. C. parvum 0.05 mg was labeled aseptically with 10 mCi of 99mTc with a reducing agent. It was injected intravenously over 5 s and clearance was characterized over the next 60 min. The low dose of C. parvum did not cause any symptoms. The blood or plasma clearance time (t 1/2) was in the range of 0.65 to 1.96 min, in eight patients. By whole body imaging, the distribution of C. parvum was found mainly in the liver, and to a much lesser extent in the spleen, lungs, and bone marrow. Nonparticulate 99mTc (which was not sedimented by centrifugation of blood samples at 3000 rpm for 30 min) appeared rapidly in the blood after i.v. injection accounting for more than half of the radioactivity in a few minutes. In vitro incubation of 99mTc labeled C. parvum with saline, whole blood, serum or leukocytes revealed that the release of free 99mTc resulted from the combined action of serum and leukocytes. The rapid clearance will limit the utility of this preparation in characterizing RES function in man and its modification by disease or therapy.


Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis.
Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure.


A Three-Compartment Pharmacokinetic Model to Predict the Interstitial Concentration of Talaporfin Sodium in the Myocardium for Photodynamic Therapy: A Method Combining Measured Fluorescence and Analysis of the Compartmental Origin of the Fluorescence.
To evaluate the effectiveness of photodynamic therapy occurring in the interstitial space of the myocardium, we estimated the interstitial concentration of talaporfin sodium in the canine myocardium by constructing a three-compartment pharmacokinetic model based on measured changes in talaporfin sodium plasma concentration and myocardial fluorescence. Differential rate equations of talaporfin sodium concentration in the plasma, interstitial space, and cell compartment were developed with individual compartment volume, concentration, and rate constants. Using measured volume ratios based on histological examinations, we defined that the myocardial fluorescence consisted of the linear addition of fluorescence generated from these three compartments. The rate constants were obtained by fitting to minimize the sum of the squared errors between the measured talaporfin sodium concentrations and the calculated concentrations divided by the number of data points using the conjugate gradient method in MATLAB. We confirmed that this fitting operation may be appropriate, because a coefficient of determination between the measured talaporfin sodium changes and the calculated concentrations using our equations was 0.99. Consequently, to estimate the interstitial concentration in the canine myocardium, we propose a three-compartment pharmacokinetic model construction methodology using measured changes in talaporfin sodium plasma concentration and changes in myocardial fluorescence.


Amino acid substitutions in the pore affect the anomalous mole fraction effect of CaV1.2 channels.
The anomalous mole fraction effect (AMFE) is an important indicator of ion-ion interactions in the pore of voltage-gated Ca2+ channels (VGCCs). The residues at position 1144 that differ in several classes of VGCCs are important to the permeation of the pore. Phe-1144 (F, CaV1) was substituted with glycine (G, CaV2) and lysine (K, CaV3) and the effects of mutation on the voltage and concentration dependency of AMFE were observed. Whole-cell currents were recorded in external solutions with Ca2+ and Ba2+ at the indicated ratios with a total divalent cation concentration of 2, 10 or 20 mM, at holding potentials from -80 to -20 mV. Results showed the ratio of Ba2+ to Ca2+ currents determined at 2 mM to be different from that determined under higher concentrations for wild-type channels but this ratio was not different when tail currents were evoked at different potentials. AMFE was greatest at relatively positive potentials (-20 mV) and when the total divalent cation concentrations were kept low (2 mM). AMFE was attenuated for F/G while it was accentuated for F/K compared with wild-type, respectively. The results demonstrated that glycine and lysine substitutions of Phe-1144 affect AMFE through different mechanisms. Additionally, residues at position 1144 were shown to be major determinates of channel permeation of several classes of VGCCs.


[Age-related clinical and laboratory features of patients with occluded main arteries of lower extremities].
The study of clinical and laboratory features of patients with occluded main arteries of lower extremities included morphological characteristics of peripheral blood platelets in patients of different age in the acute period of the disease and after surgical treatment. The results were subjected to correlation analysis versus standard hemostatic parameters. Mean cell volume and enhanced anisocytosis proved the most informative morphological indicators. The mean platelet volume was increased in all patients before and after surgery especially in the elder age group. It reflected persistent activation of thrombocytopoiesis as confirmed by the studies of hemostasis. Therefore, these parameters may be used for additional testing in diagnostics of the risk of ischemic complications and repeated thrombosis. The timely prescription of auxiliary corrective therapy increases effectiveness of the treatment and the quality of life in the patients with occluded main arteries of lower extremities.


Return-to-work programs following occupational hand injuries.
Return-to-work programs are no longer luxuries that only the major industries can afford to provide. Direct cost savings can be documented with the use of such programs, but just as important is the message that the company cares and looks out for the employee's best interest. The occupational medicine team's responsibility to the patient and the employer no longer ends with the provision of quality medical treatment. The ultimate goal is to return the patient to his or her job. Return-to-work programs successfully facilitate that process.


The comparative utility of fluorescence in situ hybridization and reverse transcription-polymerase chain reaction in the diagnosis of alveolar rhabdomyosarcoma.
Fluorescence in situ hybridization (FISH) for FOXO1 gene rearrangement and reverse transcription-polymerase chain reaction (PCR) for PAX3/7-FOXO1 fusion transcripts have become routine ancillary tools for the diagnosis of alveolar rhabdomyosarcomas (ARMS). Here we summarize our experience of these adjunct diagnostic modalities at a tertiary center, presenting the largest comparative series of FISH and PCR for suspected or possible ARMS to date. All suspected or possible ARMS tested by FISH or PCR for FOXO1 rearrangement or PAX3/7-FOXO1 fusion transcripts over a 7-year period were included. FISH and PCR results were correlated with clinical and histologic findings. One hundred samples from 95 patients had FISH and/or PCR performed. FISH had higher rates of technical success (96.8 %) compared with PCR (88 %). Where both tests were utilized successfully, there was high concordance rate between them (94.9 %). In 24 histologic ARMS tested for FISH or PCR, 83.3 % were translocation-positive (all for PAX3-FOXO1 by PCR) and included 3 histologic solid variants. In 76 cases where ARMS was excluded, there were 3 potential false-positive cases with FISH but none with PCR. PCR had similar sensitivity (85.7 %) and better specificity (100 %) in aiding the diagnosis of ARMS, compared with FISH (85 and 95.8 %, respectively). All solid variant ARMS harbored FOXO1 gene rearrangements and PAX3-FOXO1 ARMS were detected to the exclusion of PAX7-FOXO1. In comparative analysis, both FISH and PCR are useful in aiding the diagnosis of ARMS and excluding its sarcomatous mimics. FISH is more reliable technically but has less specificity than PCR. In cases where ARMS is in the differential diagnosis, it is optimal to perform both PCR and FISH: both have similar sensitivities for detecting ARMS, but FISH may confirm or exclude cases that are technically unsuccessful with PCR, while PCR can detect specific fusion transcripts that may be useful prognostically.


Ambient temperature below which pigs should not be continuously showered in lairage.
Showering pigs with cold water during preslaughter lairage is thought to be useful in reducing the body temperature of hot, easily stressed animals. However, showering when the ambient temperature is too low could chill them too severely. To assess the effects of showering and to determine a temperature below which pigs should not be showered, pigs from one source, passing through a commercial slaughterhouse lairage, were split into two groups of approximately 50 each, showered and unshowered, on 10 days with a range of ambient temperatures. The pigs' behaviour and any damage to their skin were recorded, various measures of body temperature were taken before and after showering, and blood taken at slaughter was analysed for plasma creatine kinase, cortisol and lactate. Showering prevented the usual reduction in activity observed in pigs in lairage at high ambient temperatures. On the basis of the reduction in their flank temperature during showering, it is recommended that pigs should not be showered continuously if the temperature inside or outside the lairage falls below 5 degrees C, and showering should cease if they are seen to be shivering.


Toward Accurate Thermal Modeling of Phase Change Material-Based Photonic Devices.
Reconfigurable or programmable photonic devices are rapidly growing and have become an integral part of many optical systems. The ability to selectively modulate electromagnetic waves through electrical stimuli is crucial in the advancement of a variety of applications from data communication and computing devices to environmental science and space explorations. Chalcogenide-based phase-change materials (PCMs) are one of the most promising material candidates for reconfigurable photonics due to their large optical contrast between their different solid-state structural phases. Although significant efforts have been devoted to accurate simulation of PCM-based devices, in this paper, three important aspects which have often evaded prior models yet having significant impacts on the thermal and phase transition behavior of these devices are highlighted: the enthalpy of fusion, the heat capacity change upon glass transition, as well as the thermal conductivity of liquid-phase PCMs. The important topic of switching energy scaling in PCM devices, which also helps explain why the three above-mentioned effects have long been overlooked in electronic PCM memories but only become important in photonics, is further investigated. These findings offer insight to facilitate accurate modeling of PCM-based photonic devices and can inform the development of more efficient reconfigurable optics.


Antiepileptic drugs: evolution of our knowledge and changes in drug trials.
Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938-1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970-1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology. The last period (1989-2019) was dominated by the introduction of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials. The expansion of the pharmacological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inadequate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second-generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies.


Abdominal multi-organ segmentation with organ-attention networks and statistical fusion.
Accurate and robust segmentation of abdominal organs on CT is essential for many clinical applications such as computer-aided diagnosis and computer-aided surgery. But this task is challenging due to the weak boundaries of organs, the complexity of the background, and the variable sizes of different organs. To address these challenges, we introduce a novel framework for multi-organ segmentation of abdominal regions by using organ-attention networks with reverse connections (OAN-RCs) which are applied to 2D views, of the 3D CT volume, and output estimates which are combined by statistical fusion exploiting structural similarity. More specifically, OAN is a two-stage deep convolutional network, where deep network features from the first stage are combined with the original image, in a second stage, to reduce the complex background and enhance the discriminative information for the target organs. Intuitively, OAN reduces the effect of the complex background by focusing attention so that each organ only needs to be discriminated from its local background. RCs are added to the first stage to give the lower layers more semantic information thereby enabling them to adapt to the sizes of different organs. Our networks are trained on 2D views (slices) enabling us to use holistic information and allowing efficient computation (compared to using 3D patches). To compensate for the limited cross-sectional information of the original 3D volumetric CT, e.g., the connectivity between neighbor slices, multi-sectional images are reconstructed from the three different 2D view directions. Then we combine the segmentation results from the different views using statistical fusion, with a novel term relating the structural similarity of the 2D views to the original 3D structure. To train the network and evaluate results, 13 structures were manually annotated by four human raters and confirmed by a senior expert on 236 normal cases. We tested our algorithm by 4-fold cross-validation and computed Dice-Sørensen similarity coefficients (DSC) and surface distances for evaluating our estimates of the 13 structures. Our experiments show that the proposed approach gives strong results and outperforms 2D- and 3D-patch based state-of-the-art methods in terms of DSC and mean surface distances.


ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels.
The authors have previously shown that individuals heterozygous for ABCA1 mutations have decreased high density lipoprotein cholesterol, increased triglycerides and an increased frequency of coronary artery disease (CAD), and that single nucleotide polymorphisms (SNPs) in the coding region of the ABCA1 gene significantly impact plasma lipid levels and the severity of CAD in the general population. They have now identified several SNPs in non-coding regions of ABCA1 which may be important for the appropriate regulation of ABCA1 expression (i.e. in the promoter, intron 1 and the 5' untranslated region), and have examined the phenotypic effects of these SNPs in the REGRESS population. Out of 12 SNPs, four were associated with a clinical outcome. A threefold increase in coronary events with an increased family history of CAD was evident for the G-191C variant. Similarly, the C69T SNP was associated with a twofold increase in events. In contrast, the C-17G was associated with a decrease in coronary events and the InsG319 was associated with less atherosclerosis. For all these SNPs, the changes in atherosclerosis and CAD occurred without detectable changes in plasma lipid levels. These data suggest that common variation in non-coding regions of ABCA1 may significantly alter the severity of atherosclerosis, without necessarily influencing plasma lipid levels.


Neonatal intracranial hemorrhage in premature infants.
Since the advent of modern methods of neonatal care, intracranial hemorrhage in premature infants, which is usually intraventricular, is probably not as uniformly fatal as generally admitted and the survivors are likely to develop post-hemorrhagic hydrocephalus. This paper is a retrospective study of 11 premature babies born between 1968 and 1972 and diagnosed as having hydrocephalus secondary to neonatal intracranial hemorrhage. Nine of these are still alive and two have died, one at 3 and one at 17 months of age. Eight underwent permanant surgical drainage of hydrocephalus. The perinatal history, laboratory data, clinical evolution, and neurological outcome were studied. Two groups of infants were identified; those with signs of acute neurological deterioration in the neonatal period who had the most severe neurological sequellae (in four cases, periventricular lesions in addition to hydrocephalus were seen on the air study and in one case confirmed at autopsy) and those showing no obvious neurological signs in the neonatal period. Of this latter group, two appear to be developing normally. The therapeutic implications of the findings are discussed.


Heparin-binding epidermal growth factor and its receptors mediate decidualization and potentiate survival of human endometrial stromal cells.
Heparin-binding epidermal growth factor (HB-EGF) has pleiotropic biological functions in many tissues, including those of the female reproductive tract. It facilitates embryo development and mediates implantation and is thought to have a function in endometrial receptivity and maturation. The mature HB-EGF molecule manifests its activity as either a soluble factor (sol-HB-EGF) or a transmembrane precursor (tm-HB-EGF) and can bind two receptors, EGFR and ErbB4/HER4. In this study, we identify factors that modulate expression of HB-EGF, EGFR, and ErbB4 in endometrial stromal cells in vitro. We demonstrate that levels of sol- and tm-HB-EGF, EGFR, and ErbB4 are increased by cAMP, a potent inducer of decidualization of the endometrial stroma. We also show that production of sol- and tm-HB-EGF is differentially modulated by TNF alpha and TGF beta. Our data suggest that HB-EGF has a function in endometrial maturation in mediating decidualization and attenuating TNF alpha- and TGF beta-induced apoptosis of endometrial stromal cells.


Clinical features associated with REM sleep behavior disorder symptoms in the early stages of Parkinson's disease.
We aimed to characterize the clinical features associated with REM sleep behaviour disorder (RBD) in early stage Parkinson's disease (PD). Presence of clinical RBD was determined according to ICSD minimal clinical criteria and a validated RBD questionnaire. We registered time of appearance of RBD symptoms in relation to PD onset and the occurrence of RBD symptoms in the past in non-RBD patients. RBD and non-RBD groups were compared in terms of motor and cognitive dysfunction. The same comparisons were made between patients who reported RBD symptoms at some point in time (including those non-RBD patients that reported occurrence of RBD symptoms in the past) and those who did not (RBDS and non-RBDS, respectively). We assessed 75 patients. Forty-one (55%) patients presented with RBD, 19 beginning before PD onset. Five non-RBD patients reported having had RBD symptoms in the past. There were no significant differences between RBD and non-RBD patients. RBDS group presented a significantly higher proportion of non-tremor motor sub-type compared to non-RBDS patients. Our results suggest that RBD is very frequent in the early stages of PD. In some patients, RBD symptoms could have disappeared before or in the first years after motor disturbance onset. Non-tremor motor sub-type was related to RBD symptoms history, rather than to the presence of RBD clinical criteria at time of evaluation, suggesting that the physiopathological changes that cause the association with motor status could remain, in spite of symptom fluctuation.


Selenium fertilizers and foliar application, Danish experiments.
In 1963 Se-deficiency was observed for the first time in Denmark in a few sheep in West Jutland. The sheep were cured by injection of "Tokosel", and a survey of the Se-status of Danish fodder crops was initiated. A comprehensive set of data was produced during the early 70's, using the fluorometric method. The survey showed a general Se-deficiency in the whole country, and series of experiments were carried out to elucidate the possibility of raising the selenium level in plants from the native 0.02-0.04 ppm to more than the desired minimum of 0.05 ppm. Three different methods of application were tested: seed pretreatment, fertilizer enrichment, and foliar application. Seed pre-treatment has some disadvantages while the two other methods proved to be efficient and safe in a series of experiments and in tests on a large number of farms all over Denmark. These experiments and tests are discussed in detail. It is concluded that about 120 g Se/ha as sodium selenite, 10 g Se/ha as sodium selenate - both added through PK- or NPK-fertilizers, or foliar application of about 5 g Se/ha are sufficient yearly treatments to raise the native Se content of the Danish crops to levels of 0.05-0.1 ppm.


Celastrol Suppresses Glioma Vasculogenic Mimicry Formation and Angiogenesis by Blocking the PI3K/Akt/mTOR Signaling Pathway.
Angiogenesis and vasculogenic mimicry (VM) are thought to be the predominant processes ensuring tumor blood supply during the growth and metastasis of glioblastoma (GBM). Celastrol has potential anti-glioma effects, however the mechanisms underlying these effects remain unclarified. Recent studies have shown that the PI3K/Akt/mTOR signaling pathway is closely related to angiogenesis and VM formation. In the present study, we have demonstrated, for the first time, that celastrol eliminated VM formation by blocking this signaling pathway in glioma cells. By the treatment of celastrol, tumor growth was suppressed, tight junction and basal lamina structures in tumor microvasculature were disarranged in U87 glioma orthotopic xenografts in nude mice. Periodic acid Schiff (PAS)-CD31 staining revealed that celastrol inhibited both VM and angiogenesis in tumor tissues. Additionally, celastrol reduced the expression levels of the angiogenesis-related proteins CD31, vascular endothelial growth factor receptor (VEGFR) 2, angiopoietin (Ang) 2 and VEGFA, VM-related proteins ephrin type-A receptor (EphA) 2, and vascular endothelial (VE)-cadherin. Hypoxia inducible factor (HIF)-1α, phosphorylated PI3K, Akt, and mTOR were also downregulated by treatment with celastrol. In vitro, we further demonstrated that celastrol inhibited the growth, migration, and invasion of U87 and U251 cells, disrupted VM formation, and blocked the activity of PI3K, Akt, and mTOR. Collectively, our data suggest that celastrol inhibits VM formation and angiogenesis likely by regulating the PI3K/Akt/mTOR signaling pathway.


Development of a competitive immunoassay for the determination of N-(2-hydroxyethyl)valine adducts in human haemoglobin and its application in biological monitoring.
Ethylene oxide (EO) is an important industrial compound and a directly acting mutagen. Human exposure to it can be monitored by the determination of haemoglobin (Hb) adducts. An immunoassay that quantifies the N-terminal adduct N-(2-hydroxyethyl)valine in whole blood was developed, and its potential usefulness as a tool for biologically monitoring occupational exposure demonstrated. Analytical reliability was confirmed in a comparative study with gas chromatography-mass spectrometry (range 0.040-589 nmol g(-1) Hb, correlation coefficient 0.98, n=10). The assay was configured as a competitive enzyme-linked immunosorbent assay to facilitate the rapid throughput of samples. The assay uses a whole blood matrix and has a working range of 10-10000 pmol N-(2-hydroxyethyl)valine g(-1) hB. The assay does not appear to be affected by structurally similar metabolites and has been used to determine adducts in human blood samples. The first results from potentially exposed workers indicate the assay might be a powerful tool for the routine occupational biomonitoring of EO exposure.


Bronchial asthma and acid reflux into the distal and proximal oesophagus.
The prevalence of pathological gastro-oesophageal reflux in children and adolescents with asthma was studied by 24 hour two level oesophageal pH monitoring in 42 subjects aged 9-20 years with moderate or severe bronchial asthma. The importance of oesophagobronchial nerve reflexes and of aspiration of gastric acid as triggers in asthma was assessed by studying whether episodes of reflux into the distal and into the proximal oesophagus were followed by asthma attacks. Twenty-one subjects (50%) had a pathological total reflux time in the distal oesophagus and six (16%) in the proximal oesophagus. Nine patients had pathological gastro-oesophageal reflux into the distal oesophagus together with symptoms of asthma during the day on which the recording took place. In three of them the episodes of asthma symptoms were significantly correlated with preceding episodes of reflux into the distal oesophagus, and in one subject to reflux into the proximal oesophagus. We conclude that pathological gastro-oesophageal reflux is common in children and adolescents with asthma, but it seems to provoke symptoms of asthma in only a few. Symptoms of asthma were more often elicited by exposure of the distal oesophagus to gastric acid, possibly by a vagal reflex, than by aspiration of gastric juice.


Persistent pain is common 1 year after ankle and wrist fracture surgery: a register-based questionnaire study.
Substantial literature documents that persistent postsurgical pain is a possible outcome of many common surgical procedures. As fracture-related surgery implies a risk of developing neuropathic pain and complex regional pain syndrome (CRPS), further studies investigating the prevalence and pain characteristics are required. All patients undergoing primary surgery because of ankle or wrist fracture at Hvidovre and Odense University Hospitals, Denmark, between April 15, 2013 and April 15, 2014, were identified from the Danish Fracture Database. A questionnaire regarding pain characteristics was sent to patients 1 yr after primary surgery. Replies were received from 328 patients, of whom 18.9% experienced persistent postsurgical pain defined as pain daily or constantly at a level that interfered much or very much with daily activities, 42.8% reported symptoms suggestive of neuropathic pain, and 4.0% fulfilled the diagnostic patient-reported research criteria for CRPS. Persistent postsurgical pain 1 yr after wrist and ankle fracture surgery is frequent, and a large proportion of patients experience symptoms suggestive of neuropathic pain and CRPS. Patients should be informed about the substantial risk of developing persistent postsurgical pain. Future studies investigating risk factors for persistent postsurgical pain that include both surgically and conservatively treated fractures are required.


Quantitative diffusion tensor tractography of the motor and sensory tract in children with cerebral palsy.
the aim of this study was to compare the findings of quantitative diffusion tensor tractography of the motor and sensory tracts in children with cerebral palsy (CP) and typically developed comparison individuals, and also to evaluate the correlation with gross motor function. thirty-four children with CP (mean age 2y 2.mo, SD 2y 0mo; 19 with spastic diplegia, eight with hemiplegia, six with spastic quadriplegia, and one with spastic triplegia) and 21 healthy comparison children (mean 2y 1.68mo, SD 2y 8.64mo) were evaluated. The distribution of Gross Motor Function Classification System (GMFCS) levels in the CP group was as follows: level I, 7; level II, 14; level III, 5; level IV, 3; and level V, 5. The following three diffusion tensor imaging (DTI) parameters including tractography were evaluated for each tract (corticospinal tract [CST] and posterior thalamic radiation [PTR]): number of fibres, tract-based fractional anisotropy, and region of interest (ROI)-based fractional anisotropy. We compared each value between the two groups, and correlated each value with the GMFCS level. the number of fibres and ROI-based fractional anisotropy values of both tracts were significantly lower in children with CP than in the comparison group (p<0.05-0.001). Additionally, there was significant negative correlation between GMFCS level and motor-sensory parameters (p<0.001-0.05). DTI parameters of the CST and PTR in children with CP were significantly lower than in comparison children. In addition, these parameters were significantly correlated with GMFCS level.


uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies.
Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease involved in cancer invasion and metastasis, interacting with plasminogen activator inhibitor-1 (PAI-1), which was originally identified as a blood-derived endogenous fast-acting inhibitor of uPA. At concentrations found in tumor tissue, however, both PAI-1 and uPA promote tumor progression and metastasis. Consistent with the causative role of uPA and PAI-1 in cancer dissemination, several retrospective and prospective studies have shown that elevated levels of uPA and PAI-1 in breast tumor tissue are statistically independent and potent predictors of poor patient outcome, including adverse outcome in the subset of breast cancer patients with lymph node-negative disease. In addition to being prognostic, high levels of uPA and PAI-1 have been shown to predict benefit from adjuvant chemotherapy in patients with early breast cancer. The unique clinical utility of uPA/PAI-1 as prognostic biomarkers in lymph node-negative breast cancer has been confirmed in two independent level-of-evidence-1 studies (that is, in a randomized prospective clinical trial in which the biomarker evaluation was the primary purpose of the trial and in a pooled analysis of individual data from retrospective and prospective studies). Thus, uPA and PAI-1 are among the best validated prognostic biomarkers currently available for lymph node-negative breast cancer, their main utility being the identification of lymph node-negative patients who have HER-2-negative tumors and who can be safely spared the toxicity and costs of adjuvant chemotherapy. Recently, a phase II clinical trial using the low-molecular-weight uPA inhibitor WX-671 reported activity in metastatic breast cancer.


Neural population coding of multiple stimuli.
In natural scenes, objects generally appear together with other objects. Yet, theoretical studies of neural population coding typically focus on the encoding of single objects in isolation. Experimental studies suggest that neural responses to multiple objects are well described by linear or nonlinear combinations of the responses to constituent objects, a phenomenon we call stimulus mixing. Here, we present a theoretical analysis of the consequences of common forms of stimulus mixing observed in cortical responses. We show that some of these mixing rules can severely compromise the brain's ability to decode the individual objects. This cost is usually greater than the cost incurred by even large reductions in the gain or large increases in neural variability, explaining why the benefits of attention can be understood primarily in terms of a stimulus selection, or demixing, mechanism rather than purely as a gain increase or noise reduction mechanism. The cost of stimulus mixing becomes even higher when the number of encoded objects increases, suggesting a novel mechanism that might contribute to set size effects observed in myriad psychophysical tasks. We further show that a specific form of neural correlation and heterogeneity in stimulus mixing among the neurons can partially alleviate the harmful effects of stimulus mixing. Finally, we derive simple conditions that must be satisfied for unharmful mixing of stimuli.


Challenges to Transforming Unconventional Social Media Data into Actionable Knowledge for Public Health Systems During Disasters.
Every year, there are larger and more severe disasters and health organizations are struggling to respond with services to keep public health systems running. Making decisions with limited health information can negatively affect response activities and impact morbidity and mortality. An overarching challenge is getting the right health information to the right health service personnel at the right time. As responding agencies engage in social media (eg, Twitter, Facebook) to communicate with the public, new opportunities emerge to leverage this non-traditional information for improved situational awareness. Transforming these big data is dependent on computers to process and filter content for health information categories relevant to health responders. To enable a more health-focused approach to social media analysis during disasters, 2 major research challenges should be addressed: (1) advancing methodologies to extract relevant information for health services and creating dynamic knowledge bases that address both the global and US disaster contexts, and (2) expanding social media research for disaster informatics to focus on health response activities. There is a lack of attention on health-focused social media research beyond epidemiologic surveillance. Future research will require approaches that address challenges of domain-aware, including multilingual language understanding in artificial intelligence for disaster health information extraction. New research will need to focus on the primary goal of health providers, whose priority is to get the right health information to the right medical and public health service personnel at the right time.


Increased carotid intima thickness and decreased media thickness in premenopausal women with systemic lupus erythematosus: an investigation by non-invasive high-frequency ultrasound.
To determine whether high-frequency ultrasound (US) yielding separate assessments of intima and media thickness gives additional information about the vascular morphology compared with the total common carotid artery intima-media thickness (CCA-IMT). Using a 22 MHz US instrument, we determined the near-wall CCA-IMT, the intima and media layers, and the intima/media (I/M) ratio in 47 premenopausal women with systemic lupus erythematosus (SLE), 20 healthy women, and 17 postmenopausal women (mean ages 37, 40, and 69 years, respectively). In SLE, the carotid intima was thicker (0.19 ± 0.04 vs. 0.12 ± 0.02 mm), the media thinner (0.45 ± 0.12 vs. 0.68 ± 0.24 mm), the I/M ratio higher (0.45 ± 0.17 vs. 0.20 ± 0.07) (all p < 0.0001), and the CCA-IMT lower (0.64 ± 0.13 vs. 0.80 ± 0.25 mm, p < 0.01) compared to age-matched controls. The SLE patients had a thicker carotid intima compared to the postmenopausal women (0.19 ± 0.04 vs. 0.14 ± 0.03 mm, p < 0.0001) and a similar I/M ratio. Separate assessment of carotid artery wall layers demonstrated a thicker intima, thinner media, and a higher I/M ratio in women with SLE compared to healthy controls and indicated an artery wall status in SLE comparable to 30-years-older healthy women. Separate estimates of carotid intima and media layers may be preferable to CCA-IMT in SLE patients.


Resistance to virus infection conferred by the interferon-induced promyelocytic leukemia protein.
The interferon (IFN)-induced promyelocytic leukemia (PML) protein is specifically associated with nuclear bodies (NBs) whose functions are yet unknown. Two of the NB-associated proteins, PML and Sp100, are induced by IFN. Here we show that overexpression of PML and not Sp100 induces resistance to infections by vesicular stomatitis virus (VSV) (a rhabdovirus) and influenza A virus (an orthomyxovirus) but not by encephalomyocarditis virus (a picornavirus). Inhibition of viral multiplication was dependent on both the level of PML expression and the multiplicity of infection and reached 100-fold. PML was shown to interfere with VSV mRNA and protein synthesis. Compared to the IFN mediator MxA protein, PML had less powerful antiviral activity. While nuclear body localization of PML did not seem to be required for the antiviral effect, deletion of the PML coiled-coil domain completely abolished it. Taken together, these results suggest that PML can contribute to the antiviral state induced in IFN-treated cells.


Potential of HIV Self-Sampling to Increase Testing Frequency Among Gay, Bisexual, and Other Men Who Have Sex With Men, and the Role of Online Result Communication: Online Cross-Sectional Study.
Late HIV diagnosis remains frequent among the gay, bisexual, and other men who have sex with men (GBMSM) population across Europe. HIV self-sampling could help remove barriers and facilitate access to testing for this high-risk population. We assessed the capacity of HIV self-sampling to increase the testing frequency among GBMSM living in Denmark, Germany, Greece, Portugal, Romania, and Spain, and evaluated the role of new technologies in the result communication phase. We analyzed a convenience sample of 5019 GBMSM with prior HIV testing experience who were recruited during 2016 through gay dating websites. We estimated the proportion of GBMSM who reported that the availability of self-sampling would result in an increase of their current testing frequency. We constructed a Poisson regression model for each country to calculate prevalence ratios and 95% CIs of factors associated with an increase of testing frequency as a result of self-sampling availability. Overall, 59% (between country range 54.2%-77.2%) of the participants considered that they would test more frequently for HIV if self-sampling was available in their country. In the multivariate analysis, the increase of testing frequency as a result of self-sampling availability was independently associated with reporting a higher number of unprotected anal intercourse events in all countries except for Greece. Independent associations were also observed among GBMSM who were not open about their sex life in Germany, Greece, Portugal, and Spain; those with a lower number of previous HIV tests in Denmark, Greece, Portugal, and Spain; and for those that took their last test more than 3 months previously in Germany, Portugal, Romania, and Spain. In addition, 58.4% (range 40.5%-73.6%) of the participants indicated a preference for learning their result through one-way interaction methods, mainly via email (25.6%, range 16.8%-35.2%) and through a secure website (20.3%, range 7.3%-23.7%). Almost two thirds (65%) of GBMSM indicated preferring one of these methods even if the result was reactive. Availability of HIV self-sampling kits as an additional testing methodology would lead to a much-needed increase of testing frequency, especially for the hidden, high-risk, and undertested GBMSM population. Online-based technologies without any personal interaction were preferred for the communication of the results, even for reactive results.


Foot Strike Angle Prediction and Pattern Classification Using LoadsolTM Wearable Sensors: A Comparison of Machine Learning Techniques.
The foot strike pattern performed during running is an important variable for runners, performance practitioners, and industry specialists. Versatile, wearable sensors may provide foot strike information while encouraging the collection of diverse information during ecological running. The purpose of the current study was to predict foot strike angle and classify foot strike pattern from LoadsolTM wearable pressure insoles using three machine learning techniques (multiple linear regression-MR, conditional inference tree-TREE, and random forest-FRST). Model performance was assessed using three-dimensional kinematics as a ground-truth measure. The prediction-model accuracy was similar for the regression, inference tree, and random forest models (RMSE: MR = 5.16°, TREE = 4.85°, FRST = 3.65°; MAPE: MR = 0.32°, TREE = 0.45°, FRST = 0.33°), though the regression and random forest models boasted lower maximum precision (13.75° and 14.3°, respectively) than the inference tree (19.02°). The classification performance was above 90% for all models (MR = 90.4%, TREE = 93.9%, and FRST = 94.1%). There was an increased tendency to misclassify mid foot strike patterns in all models, which may be improved with the inclusion of more mid foot steps during model training. Ultimately, wearable pressure insoles in combination with simple machine learning techniques can be used to predict and classify a runner's foot strike with sufficient accuracy.


A computational analysis of bone formation in the cranial vault in the mouse.
Bones of the cranial vault are formed by the differentiation of mesenchymal cells into osteoblasts on a surface that surrounds the brain, eventually forming mineralized bone. Signaling pathways causative for cell differentiation include the actions of extracellular proteins driven by information from genes. We assume that the interaction of cells and extracellular molecules, which are associated with cell differentiation, can be modeled using Turing's reaction-diffusion model, a mathematical model for pattern formation controlled by two interacting molecules (activator and inhibitor). In this study, we hypothesize that regions of high concentration of an activator develop into primary centers of ossification, the earliest sites of cranial vault bone. In addition to the Turing model, we use another diffusion equation to model a morphogen (potentially the same as the morphogen associated with formation of ossification centers) associated with bone growth. These mathematical models were solved using the finite volume method. The computational domain and model parameters are determined using a large collection of experimental data showing skull bone formation in mouse at different embryonic days in mice carrying disease causing mutations and their unaffected littermates. The results show that the relative locations of the five ossification centers that form in our model occur at the same position as those identified in experimental data. As bone grows from these ossification centers, sutures form between the bones.


[Chromosome anomalies in acute lymphoblastic leukemia].
Detectable karyotypic changes have been observed in more than 50% of patients with ALL. Distinct nonrandom chromosome abnormalities have been found. Some of these can be correlated with particular parameters such as age, morphology of the blasts, lymphocyte surface markers, prognosis. Karyotype is an important independent prognostic factor in ALL, even when other well-known risk factors are considered but an abnormal clone is not always associated with a poor prognosis. Burkitt leukemia and lymphomas have been shown to present characteristic and specific translocations t(8;14) and variants t (2;8) and t(8;22). It appears that the structural change of chromosome n degree 8 involving band q24 is a consistent chromosome feature in these malignancies, and that this peculiar region on chromosome n degree 8 probably plays an important biological role in the development of these malignant proliferations. The association of cytogenetic and molecular biology techniques would allow in the near future a better understanding of the genesis and significance of chromosome anomalies in malignant blood diseases.


Role of trans fatty acids in health and challenges to their reduction in Indian foods.
Evidence indicates that dietary trans fatty acids (TFA) obtained from partially hydrogenated vegetable oils (PHVO) increase the risk of coronary heart disease (CHD). Studies have implicated TFA in increasing the risk and incidence of diabetes. Furthermore, TFA may compromise fetal and early infant growth and development. In rats, partial substitution of either linoleic acid (18:2 n-6) with saturated fatty acids (SFA, 6 en %) or SFA with TFA (3 en % from vanaspati) decreased peripheral insulin sensitivity, but these effects were greater in TFA group. Since a large proportion of Indian population is insulin resistant, the TFA content in Indian edible fats/oils and foods should be reduced. Vanaspati (PHVO) provides up to 40% TFA, is used in Indian cooking and in the preparation of commercially fried, processed, bakery, ready-to-eat and street foods. TFA in biscuits and sweets range 30-40 and 6-26% of total fatty acids respectively. There is no regulation on TFA content in vanaspati, bakery fats and shortenings. Reduction in Indian edible fats/ oils and foods can be achieved by: a) specifying limits of TFA in vanaspati, bakery fats and shortenings by upgrading technology; b) advocating the substitution of natural plant oils containing lower percent of polyunsaturated fatty acids for PHVO. Indian edible oil industry needs to develop and adopt alternative technologies to produce zero TFA. Consumer education about negative health effects of TFA and providing food based guidelines to reduce TFA consumption in the entire population need to be actively pursued.


[The energy utilization of alfalfa leaf by adult swine].
By means of the respiration test technique the energy metabolism of adult pigs fed with a basic ration plus alfalfa leaves with 110-200 g crude fibre/kg DM was measured in 3 test periods. The digestibility of the energy of the alfalfa leave ranks amounted to--decreasing with increasing crude fibre content--66, 60 and 59%; the respective energy retention values were 7.5, 6.9 and 6.9 MJ NEFs or 510, 470 and 470 EFs/kg DM. According to the measured values there were no significant differences in the digestibility of the energy and in the energy concentration of NEFs between fresh and dried alfalfa leaves of largely equal chemical composition.


Mixed spermatogenic germ cell nuclear extracts exhibit high base excision repair activity.
Spermatogenic cells exhibit a lower spontaneous mutation frequency than somatic tissues in a lacI transgene and many base excision repair (BER) genes display the highest observed level of expression in the testis. In this study, uracil-DNA glycosylase-initiated BER activity was measured in nuclear extracts prepared from tissues obtained from each of three mouse strains. Extracts from mixed spermatogenic germ cells displayed the greatest activity followed by liver then brain for all three strains, and the activity for a given tissue was consistent among the three strains. Levels of various BER proteins were examined by western blot analyses and found to be consistent with activity levels. Nuclear extracts prepared from purified Sertoli cells, a somatic component of the seminiferous epithelium, exhibited significantly lower activity than mixed spermatogenic cell-type nuclear extracts, thereby suggesting that the high BER activity observed in mixed germ cell nuclear extracts was not a characteristic of all testicular cell types. Nuclear extracts from thymocytes and small intestines were assayed to assess activity in a mitotically active cell type and tissue. Overall, the order of tissues/cells exhibiting the greatest to lowest activity was mixed germ cells > Sertoli cells > thymocytes > small intestine > liver > brain.


Oriented bacterial cellulose microfibers with tunable mechanical performance fabricated via green reassembly avenue.
Bacterial cellulose has garnered remarkable interest from researchers, particularly those working in the biomedical field. In this work, BC microfibers were fabricated via green dissolution (ZnCl2) and regeneration (ethanol). The orientation of cellulose chains was investigated during extrusion and simple post-processing via polarized optical microscopy and small-angle X-ray scattering. The results implied that the mechanical properties of BC microfibers can be tuned by rational pre-stretching. The BC microfibers can be programmable, and be used to suture hard or soft tissues. The as-designed paralleled BC microfibers have good biocompatibility and can regulate the directional growth of cells on their surface. The as-obtained BC microfiber with a high tensile strength of up to ∼115 MPa is suitable for surgical sutures. The tunable BC microfibers may be utilized as an adequate fiber-derived biomedical material product.


Raves, psychosis, and spirit healing.
This paper reflects the intersection of three cultures: the rave (all night dance party and use of the drug, Ecstasy) culture; the ward culture of an inpatient psychiatric program for First Episode Psychosis; the spirit healing culture of the Philippines. All three intersected in Toronto, Canada in the mid 1990s, as illustrated by the clinical case of a 19-year-old university student who was hospitalized with symptoms of drug-induced psychosis. Her initial treatment was not successful and presented dilemmas for the treating staff. Transfer to a second psychiatric facility that permitted attendance at a traditional Filipino healing ceremony resulted in a cure, with no recurrence 10 years later. According to James Dow's 1986 formulation, the components of the key spiritual healing session paralleled the very elements the young woman had sought by participating in raves, an activity that was problematic because it led to family displeasure. Whereas attendance at a rave triggered illness, the healing session, sanctioned by her family and taking place in their midst, resulted in healing.


The impact of relaxing interventions on human contact patterns and SARS-CoV-2 transmission in China.
Nonpharmaceutical interventions to control SARS-CoV-2 spread have been implemented with different intensity, timing, and impact on transmission. As a result, post-lockdown COVID-19 dynamics are heterogeneous and difficult to interpret. We describe a set of contact surveys performed in four Chinese cities (Wuhan, Shanghai, Shenzhen, and Changsha) during the pre-pandemic, lockdown and post-lockdown periods to quantify changes in contact patterns. In the post-lockdown period, the mean number of contacts increased by 5 to 17% as compared to the lockdown period. However, it remains three to seven times lower than its pre-pandemic level sufficient to control SARS-CoV-2 transmission. We find that the impact of school interventions depends nonlinearly on the intensity of other activities. When most community activities are halted, school closure leads to a 77% decrease in the reproduction number; in contrast, when social mixing outside of schools is at pre-pandemic level, school closure leads to a 5% reduction in transmission.


An online survey of Irish general practitioner experience of and attitude toward managing problem alcohol use.
In the general practice setting screening, brief intervention and counselling have been shown to be effective in the reduction of problem alcohol use. This study aimed to explore Irish general practitioners' (GPs) current practice of and attitudes towards the management of problem alcohol use. An online survey was emailed, with one email reminder, to 1750 general/family practitioners who were members of the Irish College of General Practitioners (ICGP) and for whom an active email address was available. Overall, 476 completed questionnaires were received representing a 27.2% response rate. Two-thirds of the respondents reported that they have managed patients for problem alcohol use and related issues in the past year. The majority, 96%, of respondents indicated that they initiate conversations around alcohol even when the patient does not do so. Almost two thirds of GPs stated that they use structured brief intervention when talking to patients about their alcohol intake and circa 85% reported that they provide some form of counselling in relation to reducing alcohol consumption. While more than two out of three GPs felt prepared when counselling patients in relation to alcohol consumption, almost half considered they are ineffective in helping patients to reduce alcohol consumption. One third of GPs advised that they did not have access to an addiction counsellor. GPs in this survey reported widespread experience of screening and intervention, however, many still felt ineffective. In order to maximise the potential impact of GPs, a clearer understanding is required of what interventions are effective in different scenarios. Furthermore, GPs are only part of the solution in terms of addressing alcohol consumption. The services available in the broader health care system and Government alcohol related policy needs to further support GPs and patients.


Inhibition of human natural killer cell activity by influenza virions and hemagglutinin.
Natural killer (NK) cells keep viral infections under control at the early phase by directly killing infected cells. Influenza is an acute contagious respiratory viral disease transmitted from host-to-host in the first few days of infection. The evasion of host innate immune defenses including NK cells is important for its success as a viral pathogen of humans and animals. NK cells encounter influenza virus within the microenvironment of infected cells. It therefore is important to investigate the direct effects of influenza virus on NK cell activity. Recently we demonstrated that influenza virus directly infects human NK cells and induces cell apoptosis to counter their function (H. Mao, W. Tu, G. Qin, H. K. W. Law, S. F. Sia, P.-L. Chan, Y. Liu, K.-T. Lam, J. Zheng, M. Peiris, and Y.-L. Lau, J. Virol. 83:9215-9222, 2009). Here, we further demonstrated that both the intact influenza virion and free hemagglutinin protein inhibited the cytotoxicity of fresh and interleukin-2 (IL-2)-activated primary human NK cells. Hemagglutinin bound and internalized into NK cells via the sialic acids. This interaction did not decrease NKp46 expression but caused the downregulation of the zeta chain through the lysosomal pathway, which caused the decrease of NK cell cytotoxicity mediated by NKp46 and NKp30. The underlying dysregulation of the signaling pathway involved zeta chain downregulation, leading to decreased Syk and ERK activation and granule exocytosis upon target cell stimulation, finally causing reduced cytotoxicity. These findings suggest that influenza virus developed a novel strategy to evade NK cell innate immune defense that is likely to facilitate viral transmission and also contribute to virus pathogenesis.


Factors determining cognitive, motor and language scores in low birth weight infants from North India.
Children born with low birth weight (LBW) tend to have lower neurodevelopmental scores compared to term normal birth weight children. It is important to determine factors that influence neurodevelopment in these low birth weight children especially in the first 2-3 years of life that represents a period of substantial brain development. This secondary data analysis was conducted using data from LBW infants enrolled soon after birth in an individually randomized controlled trial (RCT) and followed up till end of 1st year. Neurodevelopmental assessment was done at 12 months of corrected age by trained psychologists using Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-III). Factors influencing cognitive, motor and language scores were determined using multivariable linear regression model. Linear growth (i.e., length for age z score, LAZ) [cognitive: Standardized ẞ-coefficient = 2.19, 95% CI; 1.29, 3.10; motor: 2.41, 95% CI; 1.59, 3.23; language: 1.37, 95% CI; 0.70, 2.04], stimulation at home [cognitive: 0.21, 95% CI; 0.15, 0.27; motor: 0.12, 95% CI; 0.07, 0.17; language: 0.21, 95% CI; 0.16, 0.25] and number of diarrhoeal episodes [cognitive: -2.87, 95% CI; -4.34, -1.39; motor: -2.62, 95% CI; -3.93, -1.29; language: -2.25, 95% CI; -3.32, -1.17] influenced the composite scores in all three domains i.e., cognitive, language and motor. While increase in LAZ score and stimulation led to increase in composite scores; an increase in number of diarrhoeal episodes was associated with decrease in scores. Weight for height z scores (WHZ) were associated with motor and language but not with cognitive scores. Additionally, a negative association of birth order with cognitive and language scores was noted. The findings indicate the possible importance of promoting nutrition and preventing diarrhoea as well as ensuring optimal stimulation and nurturance at home for enhancing child development in LBW infants.


Trichophyton indotineae and other terbinafine-resistant dermatophytes in North America.
Dermatophyte infections (a.k.a. ringworm, tinea) affect an estimated 20%-25% of the world's population. In North America, most dermatophytoses are caused by Trichophyton rubrum or Trichophyton mentagrophytes species complexes. Severe and antifungal-resistant dermatophytoses are a growing global public health problem. A new species of the T. mentagrophytes species complex, Trichophyton indotineae, has recently emerged and is notable for the severe infections it causes, its propensity for antifungal resistance, and its global spread. In this issue of the Journal of Clinical Microbiology, C. F. Cañete-Gibas, J. Mele, H. P. Patterson, et al. (J Clin Microbiol 61:e00562-23, 2023, https://doi.org/10.1128/JCM.00562-23) summarize the results of speciation and AFST performed on North American dermatophyte isolates received at a fungal diagnostic reference laboratory. Within their collection, 18.6% of isolates were resistant to terbinafine (a first-line oral antifungal for dermatophytoses), and similar proportions of T. rubrum and T. indotineae demonstrated terbinafine resistance. The authors also found that T. indotineae has been present in North America since at least 2017. These findings highlight the importance of increased surveillance efforts to monitor trends in severe and antifungal-resistant dermatophytoses and the need for antifungal stewardship efforts, the success of which is contingent upon improving laboratory capacity for dermatophyte speciation and AFST.


Reticulocyte hemoglobin equivalent as a marker to assess iron deficiency: A large pediatric tertiary care hospital study.
Detection of iron deficiency (ID) remains challenging. We aimed to evaluate the performance of reticulocyte hemoglobin equivalent (Ret-He) as a potential diagnostic marker to assess ID and iron deficiency anemia (IDA) in a large pediatric cohort. A total of 3158 patients (aged 15 days to 19 years with a median age of 8.5 years; 60.2% female) were retrospectively studied. Statistical analysis was performed (a) to evaluate relationship of Ret-He with other relevant complete blood count and iron panel parameters; (b) to compare the levels of Ret-He in ID and IDA groups to a control group; and (c) to assess sensitivity and specificity of Ret-He in ID, IDA, and anemia without ID groups. Ret-He values were significantly positively correlated to ferritin and transferrin saturation (TSAT). The median Ret-He was significantly lower in ID. A Ret-He cutoff of ≤30.0 pg distinguished cases of ID from the control group with a sensitivity of 90.2%, specificity of 59.5%, and area under curve (AUC) of 0.88. Ret-He showed better diagnostic performance in the IDA group and acceptable performance for ID without anemia. The sensitivity, specificity, and AUC were 90.1%, 80.9%, and 0.93 for IDA at cutoff value of ≤27.4 pg, and 80.8%, 51.1%, and 0.70 for ID without anemia at cutoff value of ≤30.8 pg, respectively. Our large pediatric tertiary care hospital study demonstrates that Ret-He is a reliable marker to help confirm IDA in pediatric population. However, further studies are needed for its use to capture the early stages of ID.


Weaker Connectivity of the Cortical Networks Is Linked with the Uncharacteristic Gait in Youth with Cerebral Palsy.
Cerebral palsy (CP) is the most prevalent pediatric neurologic impairment and is associated with major mobility deficiencies. This has led to extensive investigations of the sensorimotor network, with far less research focusing on other major networks. The aim of this study was to investigate the functional connectivity (FC) of the main sensory networks (i.e., visual and auditory) and the sensorimotor network, and to link FC to the gait biomechanics of youth with CP. Using resting-state functional magnetic resonance imaging, we first identified the sensorimotor, visual and auditory networks in youth with CP and neurotypical controls. Our analysis revealed reduced FC among the networks in the youth with CP relative to the controls. Notably, the visual network showed lower FC with both the sensorimotor and auditory networks. Furthermore, higher FC between the visual and sensorimotor cortices was associated with larger step length (r = 0.74, pFDR = 0.04) in youth with CP. These results confirm that CP is associated with functional brain abnormalities beyond the sensorimotor network, suggesting abnormal functional integration of the brain's motor and primary sensory systems. The significant association between abnormal visuo-motor FC and gait could indicate a link with visuomotor disorders in this patient population.


The effects of stretching on strength performance.
Strength and flexibility are common components of exercise programmes; however, it is not clear how best to include both of these elements in a single training programme. It is common practice among athletes, coaches and recreational exercisers to perform a stretching routine before a strength training session. Stretching exercises are regularly recommended, even in many textbooks, with the claimed purpose of preventing injury and muscle soreness, or even enhancing performance. However, as highlighted in recent review articles, this recommendation lacks scientific evidence. Thus, the purpose of the present review is to determine the acute and chronic effects of stretching on strength performance, together with the underlying mechanisms. Although most studies have found acute decreases in strength following stretching, and that such decreases seem to be more prominent the longer the stretching protocol, the number of exercises and sets, and the duration of each set have, in general, exceeded the ranges normally recommended in the literature. Consequently, the duration of the stimuli were excessively long compared with common practice, thus making evident the need for further studies. In addition, when recommending flexibility exercises, one should consider other underlying issues, such as the safety of the participants, possible increases in injury risks and the unnecessary time expenditure. Many mechanisms underlying stretching exercises still demand investigation so that links between the observed effects, their causes and the consequences may be constructed.


From methodology to data analysis: Prospects for the n = 1 intrasubject design.
The target article is important not only for black-box studies, but also for those interested in tracing cognitive processing and/or subjective experience (via systematic self-observation). I provide two examples taken from my own research. I then proceed to discuss how best to analyze data from the n = 1 study, which has a factorial design.


Rapid changes in the electrical state of the 1999 Izmit earthquake rupture zone.
Crustal fluids exist near fault zones, but their relation to the processes that generate earthquakes, including slow-slip events, is unclear. Fault-zone fluids are characterized by low electrical resistivity. Here we investigate the time-dependent crustal resistivity in the rupture area of the 1999 Mw 7.6 Izmit earthquake using electromagnetic data acquired at four sites before and after the earthquake. Most estimates of apparent resistivity in the frequency range of 0.05 to 2.0 Hz show abrupt co-seismic decreases on the order of tens of per cent. Data acquired at two sites 1 month after the Izmit earthquake indicate that the resistivity had already returned to pre-seismic levels. We interpret such changes as the pressure-induced transition between isolated and interconnected fluids. Some data show pre-seismic changes and this suggests that the transition is associated with foreshocks and slow-slip events before large earthquakes.


Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy.
To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy. This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries. The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001). Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population. This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.


An Innovative Simulation-based Community-engaged Intervention for Training Research Assistants in Culturally Appropriate Informed Consent.
Enrolling under-represented groups in biomedical research remains challenging owing to limited health literacy, historic medical abuses, and mistrust. Addressing such barriers requires scrutiny of informed consent processes and training of research assistants (RAs). Applying simulation methods that are well-established in medical education, Simulation-based Community-engaged Research Intervention for Informed Consent Protocol Testing and Training (SCRIIPTT) engages community members as community advisors (CAs) to train RAs in implementing culturally appropriate approaches, such as addressing difficult issues related to race and power dynamics, into the informed consent training process. To present SCRIIPTT's development, implementation, and preliminary findings. Over 12 months, our community-academic partnership 1) introduced SCRIIPTT to the greater community using the Truth & Reconciliation Model, which acknowledges the wrongs of research and offers an apology; 2) deepened understanding of community concerns; 3) developed the intervention; 4) conducted a pilot; and 5) disseminated findings. SCRIIPTT included a comprehensive training manual, scenarios for simulated informed consent encounters, and a 37-item checklist to measure performance. Outcomes include CA and RA satisfaction surveys, and RA performance rating. The checklist adequately measured observable behaviors. RAs reported important gains in knowledge, self-confidence, and cultural competence in conducting informed consent. CAs reported positive experiences, being fully engaged and valued as members of the research team and participants during simulation encounters. This pilot study demonstrated the feasibility of SCRIIPTT, with preliminary evidence of effectiveness and acceptability. SCRIIPTT offers an innovative approach for community engagement in research training and advancing the skills of RAs in culturally appropriate informed consent.


Association of antibiotic treatment-resistant Lyme arthritis with T cell responses to dominant epitopes of outer surface protein A of Borrelia burgdorferi.
To explore further the association of antibiotic treatment-resistant Lyme arthritis and T cell reactivity with outer surface protein A (OspA) of Borrelia burgdorferi, including the identification of T cell epitopes associated with this treatment-resistant course. The responses of peripheral blood and, if available, synovial fluid lymphocytes to B burgdorferi proteins, fragments, and synthetic peptides, as determined by proliferation assay and interferon-gamma production, were compared in 16 patients with treatment-responsive and 16 with treatment-resistant Lyme arthritis. The maximum severity of joint swelling correlated directly with the response to OspA. Moreover, the only significant difference between patients with treatment-resistant and treatment-responsive arthritis was in reactivity with N-terminal and C-terminal fragments of OspA, OspA1 (amino acids [aa] 16-106), and OspA3 (aa 168-273). Epitope mapping showed that 14 of the 16 patients with treatment-resistant arthritis had responses to OspA peptides (usually 4 or 5 epitopes), whereas only 5 of the 16 patients with treatment-responsive arthritis had reactivity with these peptides (usually 1 or 2 epitopes) (P = 0.003). Patients with HLA-DRB1 alleles associated with treatment-resistant arthritis were more likely to react with peptide 15 (aa 154-173) and, to a lesser degree, with peptide 21 (aa 214-233) than patients with other alleles, whereas the responses to other epitopes were similar in both groups. The maximum severity of joint swelling and the duration of Lyme arthritis after antibiotic treatment are associated with T cell responses to specific epitopes of OspA.