Protective behaviours of near work and time outdoors in myopia prevalence and progression in myopic children: a 2-year prospective population study.
To investigate the protective behaviours of longer near work distance, discontinuing near work and more time outdoors in recess from parent self-report in the myopia prevalence and progression among myopic children aged 9-11 years. Myopia Investigation study in Taipei is a longitudinal population-based study that enrolled elementary school students in Taipei. We provided vision and refraction examination every 6 months. Spherical equivalent (SE) of cycloplegic refraction ≤-0.50 Diopter (D) is defined as myopia. Total 10 743 (70.4%) students completed 2-year refraction data and questionnaire. The myopia prevalence and progression (difference of SE) in baseline, 6, 12, 18 and 24 months were compared by generalised estimating equations. Children with persistent protective behaviour had significant lower prevalence of myopia. The protective impact was statistically significant from 6 to 24 months. In 2 years follow-up, risk ratio after adjusting the background variables and the other two behaviours in near work distance, near work time and outdoor time were 0.71, 0.89 and 0.77. In SE analysis, after adjusting the other two behaviours, near work distance >30 cm (-0.7 vs -1.04 D; p<0.001), discontinuing near work every 30 min (-0.77 vs -0.96 D, p=0.005) and more time outdoors in recess from parent self-report (-0.75 vs -0.98 D; p=0.012) revealed protective impacts on diminishing myopia progression from 6 to 24 months. In myopic children aged around 10 years in Taipei, longer distance in near work, discontinuing near work every 30 min and more outdoor time from parent self-report are protective behaviours in myopia prevalence and progression in 6-24 months.


Mixed monolayers involving DPPC, DODAB and oleic acid and their interaction with nicotinic acid at the air-water interface.
The behaviour of binary mixtures involving dipalmitoylphosphatidylcholine (DPPC), dioctadecyldimethylammonium bromide (DODAB) and oleic acid (OA) was investigated at the air-water interface by surface pressure-area (pi-A) measurements and by Brewster angle microscopy (BAM). Thermodynamic analysis indicates for the system DPPC/DODAB miscibility with strong negative deviations from the ideal behaviour, from low to high surface pressures over all the composition range. For systems DODAB/OA and DPPC/OA, thermodynamic analysis and BAM observation indicate miscibility from low to intermediate surface pressures, and phase separation in a limited range of composition at high surface pressures. The interaction of nicotinic acid (NA) with pure lipids and with selected compositions of mixed systems was investigated. Significant positive deviations of pi-A isotherms in the presence of NA indicate attractive interactions between NA and the polar groups of DPPC and DODAB. NA easily penetrates in expanded regimes while it tends to be segregated from condensed regimes in mixed monolayers.


Evaluation of the chick wing territory as an equipotential self-differentiating system.
Harrison (1918: J. Exp. Zool. 25: 413-461) described a developmental field as an "equipotential self-differentiating system." The present study was undertaken to address the question: To what extent can be pre-limb territory of a chick embryo be considered a developmental field? To what extent is the chick pre-limb territory an equipotential self-differentiating system? Two sets of experiments were undertaken to address these questions: (1) Whole and half limb territories were explanted to the celoma of host embryos, and (2) portions of the wing territories were extirpated. The wing exhibited the quality of self-differentiation after stage 12, in that the isolated wing territory, grafted to a host celom, could form limbs beginning at stage 12 (however, complete wings formed only from wing territories of stage 16 and older). On the other hand, the chick wing territory did not appear to exhibit equipotentiality. No posterior half limb graft formed normal limbs, and only in two exceptional cases did anterior half limb grafts form limbs. If part or all of the wing territory was removed from chick embryos, normal limbs formed in less than 15% of the cases after stage 15, in about 30% of the cases at stages 13 and 14, but in over half the cases at stages 10-12. Wound healing and reinitiation of limb potential may be responsible for the higher incidence of limb formation at the younger ages.


Estimation of age-related vulnerability to air pollution: assessment of respiratory health at local scale.
This paper demonstrates association of short-term variation in pollution and health outcomes within the same geographical area for a typical urban setting in the northern part of the UK from time series analysis. It utilises publicly available datasets for regulated air pollutants (PM₁₀, NO₂, SO₂, CO and O₃), meteorology and respiratory hospital admissions (and mortality) between April 2002 and December 2005 to estimate the respiratory health effect of pollution exposure, mainly in the elderly. Our results show that PM₁₀ and O₃ are positively associated with respiratory hospital admissions in the elderly, specifically in the age group 70-79. CO effects seem to be concentrated on the most elderly age group (80+) whereas NO₂ seems to have the opposite age-related effect, with lower effects on the more elderly.


Gain-of-function factor H-related 5 protein impairs glomerular complement regulation resulting in kidney damage.
Genetic variation within the factor H-related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury.


Acute ischemic stroke: imaging-guided tenecteplase treatment in an extended time window.
Tenecteplase is a modified tissue plasminogen activator with a longer half-life and higher fibrin specificity than alteplase. We conducted a prospective, nonrandomized, pilot study of 0.1 mg/kg IV tenecteplase given 3 to 6 hours after ischemic stroke onset. For a control group, we used patients contemporaneously treated with sub-3-hour 0.9 mg/kg IV alteplase following standard selection criteria. All patients underwent pretreatment and 24-hour perfusion/angiographic imaging with CT or MRI. Eligibility criteria for tenecteplase (but not alteplase) treatment included a perfusion lesion at least 20% greater than the infarct core, with an associated vessel occlusion. Primary outcomes, assessed blind to treatment group, were reperfusion (reduction in baseline-24-hour mean transit time lesion) and major vessel recanalization. Fifteen patients received tenecteplase, and 35 patients received alteplase. The tenecteplase group had greater reperfusion (mean 74% vs 44% in the alteplase group, p = 0.01) and major vessel recanalization (10/15 tenecteplase vs 7/29 alteplase, p = 0.01). Despite later time to treatment, more tenecteplase patients (10/15 vs 7/35 alteplase, p = 0.001) had major neurologic improvement at 24 hours (NIH Stroke Scale reduction > or = 8). Four of the alteplase patients and none of the tenecteplase patients had parenchymal hematoma at 24 hours. Tenecteplase 0.1 mg/kg, using advanced imaging guidance in an extended time window, may have significant biologic efficacy in acute ischemic stroke. The imaging selection differences between the tenecteplase and alteplase groups prevent a conclusive efficacy comparison. Nonetheless, these results lend support for randomized trials comparing tenecteplase with alteplase, preferably incorporating penumbral/angiographic imaging selection.


[Improved procedure of the search for poly(ADP-ribose) polymerase-1 potential inhibitors with use of molecular docking approach].
A search for poly(ADP-ribose) polymerase-1 inhibitors by virtual screening of a chemical compound database and a subsequent experimental verification of their activities have been done. It was shown that the most efficient method to predict inhibitory properties implies a combinatorial approach joining molecular docking capabilities with structural filtration. Among more than 300000 database chemicals 9 PARP1 inhibitors were revealed; the most active ones, namely: STK031481, STK056130, and STK265022,--displayed biological effect at a micro-molar concentration (IC50 = 2.0 microM, 1.0 microM and 2.6 microM, respectively).


Light-enhanced Hypoxia-responsive Gene Editing for Hypoxia-resistant Photodynamic And Immunotherapy.
Hypoxia is a key hallmark of solid tumors and can cause resistance to various treatments such as photodynamic and immunotherapy. Microenvironment-responsive gene editing provides a powerful tool to overcome hypoxia resistance and remodel hypoxic microenvironments for enhanced tumor therapy. Here, we develop a light-enhanced hypoxia-responsive multifunctional nanocarrier to perform spatiotemporal specific dual gene editing for enhanced photodynamic and immunotherapy in breast cancer. As a gated molecule of nanocarrier, the degradation of azobenzene moieties under hypoxic conditions triggers controllable release of Cas9 ribonucleoprotein in hypoxic site of the tumor. Hyaluronic acid was conjugated with chloramine e6 to coat mesoporous silica nanoparticles for targeted delivery in tumor and generation of high levels of reactive oxygen species, which could result in increased hypoxia levels for effective cleavage of azobenzene bonds to improve gene editing efficiency and reduce toxic side effects with light irradiation. Moreover, dual targeting HIF-1α and PD-L1 in the anoxic microenvironments could overcome hypoxia resistance and remodel immune microenvironments, which reduced tumor plasticity and resistance to photodynamic and immunotherapy. In summary, we develop a light-enhanced hypoxia responsive nanocomposite for controllable gene editing which holds great promise for synergistic hypoxia-resistant photodynamic and immunotherapy. This article is protected by copyright. All rights reserved.


Prognostic significance of karyotype in a twelve-year follow-up in childhood acute lymphoblastic leukemia.
We report a follow-up of 49 children with acute lymphoblastic leukemia (ALL) diagnosed between 1972 and 1978 (follow-up 12-18 years). This series allowed us to analyze the predictive value of karyotype in a long-term follow-up. Karyotypes were abnormal in 33 cases (67.3%): pseudodiploidy in 11 (22.4%), hyperdiploidy > 50 chromosomes in 8 (16.3%), hyperdiploidy 47-50 chromosomes in 11 (22.4%), and hypodiploidy in 3 cases (6.1%). Event-free survival (EFS) and survival studies showed that the outcome of patients was determined only by treatment and karyotype. Eleven patients have survived, nine in first remission (6 years 5 months to 15 years 2 months), and two are in second remission (3 years 8 months and 8 years 2 months). All ploidy groups are represented in these patients. Late relapses can occur in the hyperdiploid > 50 group, thus accounting for shorter EFS than expected, but because of the unusually long second remission of one patient, the rate of surviving patients was higher for this ploidy group than for all other ploidy groups together. Conversely, patients with only numerical abnormalities (no matter which ploidy group they belonged to), had a better outcome than did patients with structural changes or normal karyotypes and no discrepancy between EFS and survival curves was observed in this chromosomal group. Thus, our results suggest that numerical changes only should be considered an indicator of low risk factor, but our results, based on partially banded karyotypes, need to be verified by a current method and therapy.


Evaluation of the functional effects of genetic variants‒missense and nonsense SNPs, indels and copy number variations‒in the gene encoding human deoxyribonuclease I potentially implicated in autoimmunity.
Genetic variants, such as single nucleotide polymorphisms (SNPs), in the deoxyribonuclease I (DNase I) gene which remarkably reduce or abolish the activity are assumed to be substantially responsible for the genetic backgrounds determining susceptibility to autoimmune dysfunction. Here, we evaluated many genetic variants, including missense and nonsense SNPs, and indel (inframe) variants in the gene, potentially implicated in autoimmune diseases as functional variants resulting in altered activity levels. Eighteen missense and 7 nonsense SNPs, and 9 indel (inframe) variants were found to result in loss of function and disappearance of DNase I activity. Furthermore, considering the positions in the DNase I protein corresponding to the various nonsense SNPs, all of the other nonsense SNPs and frameshift variants registered in the Ensembl database ( https://asia.ensembl.org ) appear likely to exert a pathogenetic effect through loss of the activity. Accordingly, a total of 60 genetic variants in the DNase 1 gene (DNASE1) inducing abolishment or marked reduction of the DNase I activity could be identified as genetic risk factors for autoimmunity, irrespective of how sparsely they were distributed in the population. It was noteworthy that SNP p.Gln244Arg, reportedly associated with autoimmunity and reducing the activity to about half of that of the wild type, and SNP p.Arg107Gly, abolishing the activity completely, were distributed worldwide and in African populations at the polymorphic level, respectively. On the other hand, with regard to copy number variations in DNASE1 where loss of copy leads to a reduction of the in vivo enzyme activity, only 2 diploid copy numbers were distributed in Japanese and German populations, demonstrating no loss of copy. These exhaustive data for genetic variants in DNASE1 resulting in loss or marked reduction of the DNase I activity are highly informative when considering genetic predisposition leading to autoimmune dysfunction.


The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia.
Febuxostat is tolerable in chronic kidney disease (CKD) patients with hyperuricemia. However, the long-term effect of lowering uric acid with febuxostat on renal function and blood pressure has not been elucidated. This was a 2 years retrospective observational study. 86 CKD patients with hyperuricemia who continued with allopurinol (allopurinol group, n = 30), switched from allopurinol to febuxostat (switched group, n = 25), or were newly prescribed febuxostat (febuxostat group, n = 31) were included in this study. Serum uric acid, estimated glomerular filtration rate (eGFR), blood pressure, and urinary protein were analyzed. Moreover, the impact of serum uric acid reduction on renal function and blood pressure was assessed. Serum uric acid in the switched and febuxostat groups was significantly reduced at 6 months (switched group; 8.49 ± 1.32-7.19 ± 1.14 mg/dL, p < 0.0001, febuxostat group; 9.43 ± 1.63-6.31 ± 0.90 mg/dL, p < 0.0001). In the allopurinol group, serum uric acid was increased (6.86 ± 0.87-7.10 ± 0.85 mg/dL, p = 0.0213). eGFR was significantly increased (35.2 ± 12.8-37.3 ± 13.9 mL/min/1.73 m2, p = 0.0232), while mean arterial pressure (93.1 ± 10.8-88.2 ± 9.5 mmHg, p = 0.0039) was significantly decreased at 6 months in the febuxostat group, resulting in the retention of eGFR for 2 years. The impact of serum uric acid reduction might have beneficial effects on CKD progression and blood pressure. However, a large prospective study is needed to determine the long-term efficacy of febuxostat therapy in CKD patients with hyperuricemia.


Viral Modulation of the DNA Damage Response and Innate Immunity: Two Sides of the Same Coin.
The DDR consists of multiple pathways that sense, signal, and respond to anomalous DNA. To promote efficient replication, viruses have evolved to engage and even modulate the DDR. In this review, we will discuss a select set of diverse viruses and the range of mechanisms they evolved to interact with the DDR and some of the subsequent cellular consequences. There is a dichotomy in that the DDR can be both beneficial for viruses yet antiviral. We will also review the connection between the DDR and innate immunity. Previously believed to be disparate cellular functions, more recent research is emerging that links these processes. Furthermore, we will discuss some discrepancies in the literature that we propose can be remedied by utilizing more consistent DDR-focused assays. By doing so, we hope to obtain a much clearer understanding of how broadly these mechanisms and phenotypes are conserved among all viruses. This is crucial for human health since understanding how viruses manipulate the DDR presents an important and tractable target for antiviral therapies.


Comparable progression of spinocerebellar ataxias between Caucasians and Chinese.
The aim of this study is to reappraise the progression of the five most common spinocerebellar ataxias (SCAs) in the Chinese population and to establish a much-needed critical comparison with that in other ethnic groups. There are very few longitudinal cohort studies of SCAs in Asian populations. An intriguing finding in an earlier study demonstrated a faster progression of SCA among Chinese than that among Caucasians. Patients with SCA1, SCA2, SCA3, SCA6 or SCA17 were consecutively assessed using the scale for the assessment and rating of ataxia (SARA) for five years. A linear mixed model was used to compare the annual progression rates measured using the SARA among patients with different SCA subtypes. Predictors of the progression rates were analyzed. A total of 199 patients with SCA (10 with SCA1, 37 with SCA2, 118 with SCA3, 25 with SCA6 and 9 with SCA17) were enrolled. The mean annual increase in SARA scores was 1.23 points for SCA1, 1.52 points for SCA2, 1.60 points for SCA3, 0.99 points for SCA6 and 3.26 points for SCA17. A larger CAG repeat length (≥74) was associated with faster progression in SCA3, whereas a lower total SARA score at the first visit (<12) was associated with faster clinical progression in SCA6. The results of this study confirm that the annual progression rates of SCA2 and SCA3 are comparable between Han Chinese and other ethnic populations. More studies are warranted to confirm the rapid progression of SCA17 observed in our cohort.


F-18 Fluorodeoxyglucose Positron Emission Tomography Metabolic Phenotype in Myelin Oligodendrocyte Glycoprotein Antibody-Positive Autoimmune Epilepsy.
We describe the metabolic phenotype on F-18 fluorodeoxyglucose positron emission tomography (PET) in a 13-year-old female with myelin oligodendrocyte glycoprotein (MOG) antibody-positive encephalitis. Unilateral hemispheric hypometabolism on PET may be the metabolic phenotype of autoimmune epilepsy associated with MOG antibody.


Efficient breast cancer mammograms diagnosis using three deep neural networks and term variance.
Breast cancer (BC) is spreading more and more every day. Therefore, a patient's life can be saved by its early discovery. Mammography is frequently used to diagnose BC. The classification of mammography region of interest (ROI) patches (i.e., normal, malignant, or benign) is the most crucial phase in this process since it helps medical professionals to identify BC. In this paper, a hybrid technique that carries out a quick and precise classification that is appropriate for the BC diagnosis system is proposed and tested. Three different Deep Learning (DL) Convolution Neural Network (CNN) models-namely, Inception-V3, ResNet50, and AlexNet-are used in the current study as feature extractors. To extract useful features from each CNN model, our suggested method uses the Term Variance (TV) feature selection algorithm. The TV-selected features from each CNN model are combined and a further selection is performed to obtain the most useful features which are sent later to the multiclass support vector machine (MSVM) classifier. The Mammographic Image Analysis Society (MIAS) image database was used to test the effectiveness of the suggested method for classification. The mammogram's ROI is retrieved, and image patches are assigned to it. Based on the results of testing several TV feature subsets, the 600-feature subset with the highest classification performance was discovered. Higher classification accuracy (CA) is attained when compared to previously published work. The average CA for 70% of training is 97.81%, for 80% of training, it is 98%, and for 90% of training, it reaches its optimal value. Finally, the ablation analysis is performed to emphasize the role of the proposed network's key parameters.


Magnetic-field induced melting of long-range magnetic order akin to Kitaev insulators in the metallic compound Tb5Si3.
There have been constant efforts to find 'exotic' quantum spin-liquid (QSL) materials. Some of the transition metal insulators dominated by the direction-dependent anisotropic exchange interaction ('Kitaev model' for honeycomb network of magnetic ions) are considered to be promising cases for the same. In such Kitaev insulators, QSL is achieved from the zero-field antiferromagnetic state by the application of magnetic-field, suppressing other exchange interactions responsible for magnetic order. Here, we show that the features attributable to long-range magnetic ordering of the intermetallic compound, Tb5Si3, (TN= 69 K), containing honey-comb network of Tb ions, are completely suppressed by a critical applied field,Hcr, in heat-capacity and magnetization data, mimicking the behavior of Kitaev physics candidates. The neutron diffraction patterns as a function ofHreveal that it is an incommensurate magnetic structure that gets suppressed, showing peaks arising from multiple wave vectors beyondHcr. Increasing magnetic entropy as a function ofHwith a peak in the magnetically ordered state is in support of some kind of magnetic disorder in a narrow field range afterHcr. Such a high-field behavior for a metallic heavy rare-earth system to our knowledge has not been reported in the past and therefore is intriguing.


Assessment of dispersive liquid-liquid microextraction conditions for gas chromatography time-of-flight mass spectrometry identification of organic compounds in honey.
The suitability of the dispersive liquid-liquid microextraction (DLLME) technique for gas chromatography (GC) characterization of minor organic compounds in honey samples is evaluated. Under optimized conditions, samples were pre-treated by liquid-liquid extraction with acetonitrile followed by DLLME using carbon tetrachloride (CCl4, 0.075 mL) as extractant. The yielded settled phase was analyzed by GC using high resolution time-of-flight (TOF) mass spectrometry (MS). The whole sample preparation process is completed in approximately 10 min, with a total consumption of organic solvents below 4 mL, relative standard deviations lower than 12% and with more than 70 organic compounds, displaying linear retention index in the range from 990 to 2900, identified in the obtained extracts. In comparison with HS SPME extraction, higher peak intensities were attained for most volatile and semi-volatile compounds amenable to both extraction techniques. Furthermore, other species such as highly polar and water soluble benzene acids, long chain fatty acids, esters and flavonoids, which are difficult to concentrate by HS SPME, could be identified in DLLME extracts. Some of the compounds identified in DLLME extracts have been proposed as useful for samples classification and/or they are recognized as markers of honeys from certain geographic areas.


Perinatal death in a term fetal growth restriction randomized controlled trial: the paradox of prior risk and consent.
The disproportionate intrauterine growth intervention trial at term was an intention to treat analysis and compared labor induction with expectant monitoring in pregnancies complicated by fetal growth restriction at term and showed equivalence for neonatal outcomes. To evaluate trial participation bias and to examine the generalizability of the results of an obstetrical randomized trial. We used data from participants and nonparticipants of a randomized controlled trial-the disproportionate intrauterine growth intervention trial at term (n=1116) -to perform a secondary analysis. This study compared induction of labor and expectant management in women with term growth restriction. Data were collected in the same manner for both groups. Baseline characteristics and neonatal and maternal outcomes were compared. The primary outcome was a composite measure of adverse neonatal outcome. Secondary outcomes were delivery by cesarean delivery and instrumental vaginal delivery; length of stay in the neonatal intensive care, neonatal ward, and the maternal hospital; and maternal morbidity. Nonparticipants were older, had a lower body mass index, had a higher level of education, smoked less, and preferred expectant management. The time between study inclusion and labor onset was shorter in participants than in nonparticipants. Notably, 4 perinatal deaths occurred among nonparticipants and none among participants. Among nonparticipants, there were more children born with a birthweight below the third centile. The nonparticipants who had expectant management were monitored less frequently than the participants in both the intervention and the expectant arm. We found less favorable outcomes and more perinatal deaths in nonparticipants. Protocol-driven management, differences between participants and nonparticipants, or the fact that nonparticipants had a preference for expectant management might explain the findings.


Striatal dopamine level increases in the urinary storage phase in cats: an in vivo microdialysis study.
Parkinson's disease is a common neurodegenerative disease that shows not only movement disorder, but also profound urinary dysfunction. Bladder hyperactivity is the major urodynamic abnormality. Therefore, the basal ganglia have been thought to modulate the micturition reflex. In six male adult cats under ketamine anesthesia, in which spontaneous isovolumetric micturition reflexes had been generated, we measured levels of striatal dopamine, in micturition and storage phases, using in vivo microdialysis. The striatal dopamine level significantly increased in the storage phase as compared with that in the micturition phase. It is suggested that striatal dopamine may inhibit the micturition reflex via the dopamine D1 receptor-GABAergic direct striatal output pathway, and that disruption of this pathway may be what leads to bladder hyperactivity in patients with Parkinson's disease.


Uptake of breast screening and associated factors among Hong Kong women aged ≥50 years: a population-based survey.
To examine the uptake of breast screening and its associated factors among Hong Kong Chinese women aged ≥50 years. Cross-sectional population-based survey. A sample of Hong Kong Chinese women was recruited through telephone random-digit dialling. The survey consisted of six sections: perceived health status, use of complementary medicine, uptake of breast screening, perceived susceptibility to cancer, family history of cancer and demographic data. The factors associated with uptake of breast screening were analysed using logistic regression analysis. In total, 1002 women completed the (anonymous) telephone survey. The mean age was 63.5 (standard deviation 10.6) years. The uptake rate of breast screening among Hong Kong Chinese women aged ≥50 years was 34%. The primary reasons for undertaking breast screening were as part of a regular medical check-up (74%), prompted by local signs and symptoms (11%) and a physician's recommendation (7%). Higher educational level, married or cohabiting, family history of cancer, frequent use of complementary therapies, regular visits to a doctor or Chinese herbalist, and the recommendation of a health professional were all independently and significantly associated with increased odds of having had a mammogram. This study provides community-based evidence of the need for public health policy to promote broader use of mammography services among this target population, with emphasis on the active involvement of health care professionals, through the development and implementation of appropriate evidence-based and resource-sensitive strategies.


Development of selected bacterial groups of the rectal microbiota of healthy calves during the first week postpartum.
The intestinal microbiota of newborn calves is largely unexplored even if it is of great significance for their future health. Therefore, the aim of the study was to gain a better insight into the development dynamics of certain bacterial groups during the first week of life. Faecal samples of healthy Simmental calves (dual-purpose breed; n = 80), bottle fed and raised in a dairy farm were taken immediately after birth and at 6/12/24/48/72/168 h (h) after birth. Samples were analysed using cultural, biochemical and molecular-biological methods. The aerobe, anaerobe, Enterobacteriaceae and Enterococcus counts of healthy calves increased significantly between 6 and 24 h postpartum (P <0·05). Apart from the anaerobes, bacterial counts decreased after reaching a plateau at 24-48 h. Enterococcus faecalis was detected in significantly higher counts compared to E. faecium (P <0·05). Lactobacilli developed more slowly and increased until day 7 after birth to a mean value of 6·8 × 107 CFU per g. MALDI-TOF analysis of 2338 lactobacilli isolates resulted in 36 different species. Lactobacillus reuteri became the most common Lactobacillus sp. during the first week of life. This fact seems to be very important for the calf's intestinal health because L. reuteri is known to show in vitro bactericidal effects against bacterial pathogens and anti-infective activities against rotaviruses and Cryptosporidium parvum.


Role of MMP3 and fibroblast-MMP14 in skin homeostasis and repair.
Early lethality of mice with complete deletion of the matrix metalloproteinase MMP14 emphasized the proteases' pleiotropic functions. MMP14 deletion in adult dermal fibroblasts (MMP14Sf-/-) caused collagen type I accumulation and upregulation of MMP3 expression. To identify the compensatory role of MMP3, mice were generated with MMP3 deletion in addition to MMP14 loss in fibroblasts. These double deficient mice displayed a fibrotic phenotype in skin and tendons as detected in MMP14Sf-/- mice, but no additional obvious defects were detected. However, challenging the mice with full thickness excision wounds resulted in delayed closure of early wounds in the double deficient mice compared to wildtype and MMP14 single knockout controls. Over time wounds closed and epidermal integrity was restored. Interestingly, on day seven, post-wounding myofibroblast density was lower in the wounds of all knockout than in controls, they were higher on day 14. The delayed resolution of myofibroblasts from the granulation tissue is paralleled by reduced apoptosis of these cells, although proliferation of myofibroblasts is induced in the double deficient mice. Further analysis showed comparable TGFβ1 and TGFβR1 expression among all genotypes. In addition, in vitro, fibroblasts lacking MMP3 and MMP14 retained their ability to differentiate into myofibroblasts in response to TGFβ1 treatment and mechanical stress. However, in vivo, p-Smad2 was reduced in myofibroblasts at day 5 post-wounding, in double, but most significant in single knockout, indicating their involvement in TGFβ1 activation. Thus, although MMP3 does not compensate for the lack of fibroblast-MMP14 in tissue homeostasis, simultaneous deletion of both proteases in fibroblasts delays wound closure during skin repair. Notably, single and double deficiency of these proteases modulates myofibroblast formation and resolution in wounds.


C-type lectins and phagocytosis.
To recognise and respond to pathogens, germ-line encoded pattern recognition receptors (PRRs) bind to conserved microbial structures and activate host defence systems, including microbial uptake by phagocytosis. Phagocytosis is a complex process that is instrumental in the control of extracellular pathogens, and this activity is mediated by several PRRs, including a number of C-type lectins. While some of these receptors have clearly been shown to mediate or regulate the uptake of pathogens, others are more contentious and are less well understood in terms of their phagocytic potential. Furthermore, very little is known about the underlying phagocytic mechanisms. Here, we review the phagocytic roles of the mannose receptor, Dectin-1, dendritic cell-specific ICAM grabbing non-integrin (DC-SIGN), DCL-1, mannose binding lectin and surfactant proteins A and D.


Hydration and clinical warning signs of dengue fever in primary care: An observational prospective study.
Dengue fever is an arbovirosis expanding worldwide, for which hydration has been reported to reduce the risk of hospitalization. Our objective was to estimate the volume of hydration in Reunionese patients with dengue. A prospective observational study included patients presenting with a 'dengue-like' syndrome in ambulatory care. General practitioners recruited patients during consultation, and beverage consumption over the previous 24 hours was reported at two different times. Warning signs were defined according to the 2009 WHO guidelines. GPs included 174 patients from April to July 2019. Average oral hydration volume was 1863 mL and 1944 mL, at the 1st and 2nd medical consultations, respectively. Water was the most wide consumed liquid. Drinking at least 5 glasses of liquid was significantly associated with fewer clinical warning signs at the 1st medical consultation (p = 0.044). Sufficient hydration volume could prevent dengue warning signs. Further studies with standardized measurement of hydration would be needed.


A systematic review of patient-reported outcome measures used to assess sleep in postpartum women using Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines.
We performed a systematic review to identify the best patient-reported outcome measure (PROM) of postpartum sleep in women. We searched four databases for validated PROMs used to assess postpartum sleep. Studies were considered if they evaluated at least one psychometric measurement property of a PROM. An overall performance rating was assigned for each psychometric measurement property of each PROM based upon COSMIN criteria. A modified GRADE approach was used to assess the level of evidence and recommendations were then made for each PROM. We identified 15 validation studies of eight PROMs, in 9,070 postpartum women. An adequate number of sleep domains was assessed by five PROMs: Bergen Insomnia Scale (BIS), Pittsburgh Sleep Quality Index (PSQI), General Sleep Disturbance Scale (GSDS), Athens Insomnia Scale (AIS), and the Sleep Symptom Checklist (SSC). BIS and GSDS were the only PROMs to demonstrate adequate content validity and at least a low level of evidence of sufficient internal consistency, resulting in Class A recommendations. The BIS was the only PROM, which is easily accessible and free to use for noncommercial research, that achieved a Class A recommendation. The BIS is the best currently available PROM of postpartum sleep. However, this PROM fails to assess several important domains such as sleep duration (and efficiency), chronotype, sleep-disordered breathing and medication usage. Future studies should focus on evaluating the psychometric measurement properties of BIS in the North American setting and in different cultural groups, or to develop a more specific PROM of postpartum sleep.


Mercury and selenium content in Otolithes ruber and Psettodes erumei from Khuzestan Shore, Iran.
In this paper the level of selenium and mercury is analyzed in edible part and liver of Psettodes erumei and Otolithes ruber two commercial fish in Persian Gulf. The average concentration of Hg and Se in edible parts of P. erumei was 0.077 ± 0.062 and 0.044 ± 0.018 (μg g(-1)ww), and in liver was 0.127 ± 0.122 and 0.132 ± 0.610 (μg g(-1)ww) respectively. In O. ruber, the average concentration of Hg and Se in edible parts was 0.348-0.27 and 0.06 ± 0.021 (μg g(-1)ww) and in liver was 0.176 ± 0.174 and 0.093 ± 0.022 (μg g(-1)ww), respectively. P. erumei has higher mean molar ratio Se/Hg (1.98) compared to O. ruber (0.88).


Facile fabrication of ternary NiTiFe-LDH ultrathin nanosheets for efficient conversion of amines into imines under visible light.
Ternary NiTiFe-LDH with an ultrathin nanosheet morphology was successfully fabricated via a facile co-precipitation method, followed by refluxing, and was used as a catalyst for oxidative coupling of amines to produce imines under visible light. The obvious superior activity observed in NiTiFe-LDH ultrathin nanosheets compared with binary NiTi-LDH and bulk NiTiFe-LDH can be ascribed to an enhanced light absorption capability caused by the introduction of Fe3+ ions as well as the ultrathin nanosheets which can minimize the recombination of the photogenerated charge carriers and provide more catalytically active sites for the reaction. As a result, more catalytically active O2˙- radicals are generated over NiTiFe-LDH ultrathin nanosheets, which leads to their superior activity. This study not only shows the possibility of using LDHs in photocatalytic organic transformations but also demonstrates an effective strategy to promote the activity of LDH-based photocatalysts via simultaneous composition and morphology modulation of LDHs.


Anesthesia Considerations in Neurological Emergencies.
Airway obstruction and respiratory failure are common complications of neurological emergencies. Anesthesia is often employed for airway management, surgical and endovascular interventions or in the intensive care units in patients with altered mental status or those requiring burst suppression. This article provides a summary of the unique airway management and anesthesia considerations and controversies for neurologic emergencies in general, as well as for specific commonly encountered conditions: elevated intracranial pressure, neuromuscular respiratory failure, acute ischemic stroke, and acute cervical spinal cord injury.


Studies on the maturation of thymus stem cells. The effects of catecholamines, histamine and peptide hormones on the expression of T cell alloantigens.
Studies have been performed in order to investigate the effects of catecholamines. histamine, peptide hormones and various other agents known to increase cellular adenosine 3':5'-cyclic monophosphate (cAMP) levels on the expression of Thy-1 and TL antigens on 14-day fetal thymic stem cells. It has been shown that the proportions of Thy-1 and TL positive cells, as detected by dye exclusion cytotoxicity tests, can be significantly increased by some of these agents and that these effects may be inhibited by beta adrenergic and H2 antagonists. The value of these tests as a means for studying normal thymic stem cell maturation and for investigating T cell deficiency is discussed.


Mechanism of TATA-binding protein recruitment to a TATA-less class III promoter.
The TATA-binding protein (TBP) is required for transcription by RNA polymerase III (pol III), even though many pol III templates, such as the adenovirus VA1 gene, lack a consensus TATA box. We show that TBP alone does not form a stable, productive interaction with VA1 DNA. However, it can be incorporated into an initiation complex if the other class III basal factors, TFIIIB and TFIIIC, are also present. TFIIIB can associate with the evolutionarily conserved C-terminal domain of TBP in the absence of DNA or TFIIIC, suggesting that TFIIIB exists in solution as a complex with TBP. The stable association of TBP with an essential component of the pol III transcription apparatus may account for the ability of TATA-less class III genes to recruit TBP.


Intrauterine devices and endometrial cancer risk: a pooled analysis of the Epidemiology of Endometrial Cancer Consortium.
Intrauterine devices (IUDs), long-acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual-level data from 4 cohort and 14 case-control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled-ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled-OR = 0.81, 95% CI = 0.74-0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled-OR = 0.69, 95% CI = 0.58-0.82), older age at first use (≥ 35 years pooled-OR = 0.53, 95% CI = 0.43-0.67), older age at last use (≥ 45 years pooled-OR = 0.60, 95% CI = 0.50-0.72), longer duration of use (≥ 10 years pooled-OR = 0.61, 95% CI = 0.52-0.71) and recent use (within 1 year of study entry pooled-OR = 0.39, 95% CI = 0.30-0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes.


Peripheral blood white cell responses during concurrent copper deficiency and gastro-intestinal nematodiasis in sheep.
Sheep experimentally depleted of copper (Cu) and infected with Trichostrongylus axei and Trichostrongylus colubriformis were studied for changes in white blood cell (WBC) populations, anti-parasite antibody responses and in vitro proliferative response to phytohaemagglutinin (PHA), lipopolysaccharide (LPS) and Trichostrongylus spp. antigens. Increases in circulating total WBC, lymphocyte, monocyte and neutrophil leucocyte numbers had a bimodal distribution which was related to the different developmental stages of the nematode. Eosinophil leucocyte numbers were generally lower than those of uninfected control sheep and could be associated with parasite-induced selective unresponsiveness of PHA responsive cells. The in vitro blastogenic responses of lymphocytes to PHA stimulation increased rapidly soon after infection, reaching a peak at 2 weeks, but then declined rapidly and from 5 weeks after infection responses to PHA were barely detectable. The patterns of proliferative response against LPS and Trichostrongylus spp. antigens were identical and correlated with the appearance of anti-parasite antibodies in the serum. These last three responses reached their maxima 5 weeks after infection and then stabilized at a plateau around peak levels. It was concluded that, although the changes in the host immune response could not be consistently associated with interactions between Cu deficiency and infection, the results nevertheless suggest that Cu, as a micro-nutrient, has a role in the mechanism of cell-mediated immunity in sheep infected with Trichostrongylus spp.


Isolation of Arcobacter butzleri and A. cryaerophilus in samples of meats and from meat-processing plants by a culture technique and detection by PCR.
A pilot survey of sources of contamination with arcobacters (representing a potential risk for humans) was done in a wide range of samples involved various kinds of meat (beef, pork, meat products, chilled chickens, etc.) from a retail level and domestic farming. Sanitary practices in slaughterhouses and production lines were checked in two different plants (a beef and pork production and a chicken processing plant). The method is based on a selective enrichment to isolate suspect strains, in combination with a PCR technique specific for arcobacters. The choice of a suitable enrichment broth and a plating agar was made with the use of pure bacterial strains and by means of real meat samples seeded with Arcobacter butzleri. The PCR technique was optimized to allow differentiation of a 1223 bp product, typical of the genus Arcobacter, and a product of 686 bp, specific for A. butzleri a total number of 198 samples were tested, of that 33 (17%) were found to be positive for the genus Arcobacter but only 22 (11%) for A. butzleri.


Angiotensin-converting enzyme insertion/deletion (rs106180) and angiotensin type 1 receptor A1166 C (rs106165) genotypes and psoriasis: Correlation with cellular immunity, lipid profile, and oxidative stress markers.
Psoriasis is a chronic inflammatory skin condition and angiotensin-converting enzyme (ACE) is a key circulating enzyme converting angiotensin (Ang) I to the vasoactive peptide Ang II. The exact role of ACE insertion (I)/deletion (D) polymorphism (rs106180) in psoriasis is not clear. We aimed to examine whether the ACE I/D and Ang II type 1 receptor (AT1R) A1166 C-polymorphisms (rs106165), lipid profile, and stress oxidative are associated with susceptibility to psoriasis. One hundred patients with psoriasis and 100 sex- and age-matched unrelated healthy controls were recruited for this case-control study. ACE I/D and AT1R A1166 C polymorphisms were identified by the polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively, malondialdehyde (MDA) was detected by the high-performance liquid chromatography, serum arylesterase (ARE) activity of paraoxonase and catalase activities were detected by the spectrophotometry, superoxide dismutase (SOD) activity and vascular adhesion protein (VAP)-1 were measured by ELISA. The presence of C allele of AT1R A1166 C and I allele of ACE considerably increased the risk of psoriasis by 6.42-fold (P < 0.001). The distribution of II-genotype of ACE was significantly higher in psoriasis patients than in control group and increased the risk of disease by 3.11-times (P = 0.023). The higher levels of MDA in patients and the higher activity of SOD, ARE, and CAT was observed in healthy controls with I/D+I/I-genotype of ACE I/D. This study for the first time demonstrated that the ACE I/D and AT1R A 1166 C genes polymorphisms robustly increases the risk of developing psoriasis in population from west of Iran. In addition, these individuals had significantly higher VAP-1 and MDA concentration and lower enzymatic and nonenzymatic antioxidant-status, suggesting that psoriatic patients carrying C allele of AT1R1166 polymorphism may be more susceptible to cardiovascular disease and myocardial infarction compared with A allele.


[Methods to predict the percentage of degradation of fluorescence induced by laser impulses in the immunofluorescence FTA-ABS technic].
The force, diameter, and pulse time of laser rays in the FTA-ABS immunofluorescence technique permit us to calculate and to predict what the percentage of degradation of the emitted fluorescence will be for the operating conditions in which this degradation is produced.


Decay of infectious SARS-CoV-2 and surrogates in aquatic environments.
The introduction of SARS-CoV-2 containing human stool and sewage into water bodies may raise public health concerns. However, assessment of public health risks by faecally contaminated water is limited by a lack of knowledge regarding the persistence of infectious SARS-CoV-2 in water. In the present study the decay rates of viable infectious SARS-CoV-2 and SARS-CoV-2 RNA were determined in river and seawater at 4 and 20°C. These decay rates were compared to S. typhimurium bacteriophage MS2 and pepper mild mottle virus (PMMoV). Persistence of viable SARS-CoV-2 was temperature dependent, remaining infectious for significantly longer periods of time in both freshwater and seawater at 4°C than at 20°C. T90 for infectious SARS-CoV-2 in river water was 2.3 days and 3.8 days at 20°C and 4°C, respectively. The T90 values were 1.1 days and 2.2 days in seawater at 20°C and 4°C, respectively. In contrast to the rapid inactivation of infectious SARS-CoV-2 in river and sea water, viral RNA was relatively stable. The RNA decay rates were increased in non-sterilised river and seawater, presumably due to the presence of microbiota. The decay rates of infectious MS2, MS2 RNA and PMMoV RNA differed significantly from the decay rate of SARS-CoV-2 RNA, suggesting that their use as surrogate markers for the persistence of SARS-CoV-2 in the environment is limited.


Accelerated reversal of atracurium blockade with divided doses of neostigmine.
The hypothesis that administration of neostigmine in divided doses might accelerate the antagonism of neuromuscular blockade was investigated. Neostigmine 0.05 mg X kg-1 was administered either in a single bolus dose (Group I, n = 16) or in an initial dose of 0.01 mg X kg-1 followed three minutes later by 0.04 mg X kg-1 (Group II, n = 16) for antagonism of atracurium-induced blockade. Reversal was attempted at 10 per cent spontaneous recovery of twitch height. The mean time (+/- SD) from the first injection of the drug until the train-of-four (TOF) ratio value had reached 0.75 was significantly shorter in Group II (p less than 0.05) than in Group I (391.8 +/- 83.3 and 468.6 +/- 150.3 seconds respectively). The rate of TOF ratio recovery was 2.5 times faster after neostigmine administration in divided doses. It is concluded that administration of neostigmine in divided doses, as described in this study, produced a significantly faster reversal of residual atracurium-induced neuromuscular blockade as compared to a single bolus administration.


Urinary excretion of vascular endothelial growth factor is increased in children with reflux nephropathy.
We determined the urinary levels of vascular endothelial growth factor (VEGF) in patients with reflux nephropathy to elucidate its clinical significance as a predictor of the development of renal damage. Seventy-two patients (47 boys and 25 girls) aged 10-18 years with reflux nephropathy were studied. Vesicoureteral reflux was resolved surgically in all cases at least 2 years before enrollment. Urinary VEGF, alpha1-microglobulin and albumin levels were determined using morning spot urine samples. Plasma VEGF, serum creatinine and beta2-microglobulin levels were measured simultaneously. The severity of renal scarring and right and left kidney function were assessed by 99mTc dimercaptosuccinic acid renal scan. No significant correlation was found between the plasma and urinary VEGF levels. Urinary VEGF increased significantly with the increase in severity of renal scarring (p < 0.0001). Urinary VEGF levels correlated significantly with serum beta2-microglobulin (p < 0.002) and urinary alpha1-microglobulin (p < 0.03). No significant correlation of urinary VEGF levels with serum creatinine and urinary albumin levels was found. Nearly 60% of the patients with elevated urinary VEGF had normal levels of serum beta2-microglobulin and/or urinary alpha1-miocroglobulin. Urinary VEGF level appears to reflect its production in the kidney. Since urinary VEGF shows a propensity to elevate before the increase in serum beta2-microglobulin and/or urinary alpha1-microglobulin, urinary VEGF may serve as an early indicator of the development of reflux nephropathy.


Oscillatory rheology of carboxymethyl cellulose gels: Influence of concentration and pH.
The flow properties of ionic polysaccharides are determined by the interplay of electrostatic and hydrophobic interactions, which depend on the ionic strength and pH of the solvent. We explore the LVE and LAOS rheology of carboxymethyl cellulose (CMC) in aqueous media, focusing on its gelling behaviour. We find that addition of HCl promotes gel formation and addition of NaOH suppresses it. The former effect is interpreted as being caused by a decrease of the charge density of the polymer, which facilitates interchain associations and the later effect can be assigned to solubilisation of cellulose backbone by NaOH. Our results along with a review of the literature allow us to establish the concentration regimes and associated properties of physical gels of carboxymethyl cellulose. At neutral pH, the storage modulus of NaCMC gels of varying molecular weight and DS at a given concentration does not vary by more than a factor 5.


alpha(9)beta(1) integrin engagement inhibits neutrophil spontaneous apoptosis: involvement of Bcl-2 family members.
Integrin signaling is comprised of well-characterized pathways generally involved in cell survival. alpha(9)beta(1) integrin has recently become a target of study and has been shown to present pro-survival effects on neutrophils. However, there are no detailed studies on how alpha(9)beta(1) integrin-coupled signaling pathways interact and how they converge to finally modulate spontaneous apoptosis in neutrophils. In this regard we sought to investigate the main signaling events triggered by alpha(9)beta(1) integrin engagement and how these signaling pathways modulate the apoptotic program of human neutrophils. Using VLO5, a snake venom disintegrin shown to bind to alpha(9)beta(1) integrin in neutrophils, we demonstrate that alpha(9)beta(1) integrin engagement leads to the activation of integrin signaling pathways and potently reduces neutrophil spontaneous apoptosis. These effects are dependent on the activation of PI3K and MAPK pathways, since both LY294002 (PI3K inhibitor) or PD95059 (MEK inhibitor) reverted the effects of VLO5/alpha(9)beta(1) interaction. Moreover we show that VLO5/alpha(9)beta(1) engagement induces NF-kappaB nuclear translocation and increases the ratio between anti- and pro-apoptotic proteins by inducing the degradation of pro-apoptotic protein Bad and increasing the expression of anti-apoptotic protein Bcl-x(L). VLO5 also inhibited the early steps of neutrophil spontaneous apoptosis by preventing Bax translocation to the outer mitochondrial membrane and consequent cytochrome c release. In conclusion, as the mechanistic details of alpha(9)beta(1) integrin signaling pathways in human neutrophils becomes clearer, it should become possible to develop new therapeutic agents for human diseases where neutrophils play a prominent role.


ppGpp cycle in Escherichia coli.
Kinetics of accumulation and degradation of ppGpp and pppGpp were analysed in spoT+ and spoT strains of Escherichia coli. The experimental data in this paper indicate that on degradation ppGpp is not converted to pppGpp but instead is converted to GDP which is in turn phosphorylated to GTP. In addition the data are consistent with the idea the pppGpp is a direct precursor of ppGpp. We propose that ppGpp is metabolised according to the following pathway: GTP-pppGpp--ppGpp--GDP--GTP, which we call the ppGpp cycle. Coupled with the observations in spot strains we assume that ppGpp blocks its own synthesis by inhibiting the synthesis of pppGpp but not the interconversion of the two nucleotides.


Role of metals in oxygen radical reactions.
Partially-reduced forms of dioxygen or "oxy-radicals" (superoxide, O2-/HO2; hydrogen peroxide, H2O2; hydroxyl radical X OH) and oxidants of comparable reactivity are implicated in an increasing number of physiological, toxicological, and pathological states. Transition metal catalysis is recognized as being integral to the generation and the reactions of these activated oxygen species. Factors such as pH and chelation govern the reactivity of the transition metals with dioxygen and "oxy-radicals" and therefore influence the apparent mechanisms by which oxidative damage to phospholipids, DNA, and other biomolecules is initiated. In biological systems the concentrations of redox-active transition metals capable of catalyzing these reactions appears to be relatively low. However, under certain conditions metal storage and transport proteins (ferritin, transferrin, ceruloplasmin, etc.) may furnish additional redox active metals.


The roles of reactive gliosis and mitosis on tropic factor production in traumatized nervous system tissue.
Proximal stumps of rat sciatic nerves were attached to inlet ends of Y-shaped silastic implants and offered a 'choice' of growing toward an Elvax pellet containing homogenate from previously crushed optic nerve which had been exposed to saline or cytosine arabinofuranoside (AraC). Previous studies indicate that AraC administration inhibits reactive gliosis in crushed optic nerve. Preferential or exclusive growth of axons occurred in implant forks attached to pellets containing saline- (vs drug-) exposed optic nerve homogenates. In contrast, inhibition of Schwann cell mitosis had no discernible effect on tropic factor production in distal stumps of transected sciatic nerves. Tropic activity of homogenates from cultures containing reactive-like astrocytes was nearly 4 times higher than homogenates not containing these cells. Results suggest a possible link between formation of hypertrophic reactive astrocytes and production of neurotropic factor.


A cost of illness comparison for toxigenic Clostridioides difficile diagnosis algorithms in developing countries.
Availability of several commercial tests with different Clostridioides difficile targets contributes to uncertainty and controversies around the optimal diagnostic algorithm. While numerous studies have estimated the financial impact of C. difficile infection, models to guide testing strategies decisions in developing countries, where economic value significantly impacts clinical practice, are currently not available. To determine the cost of illness of different C. difficile infection (CDI) diagnostic strategies in developing countries. Cost-comparison analysis was performed to compare eleven different algorithms of CDI diagnosis. The basis of calculation was a hypothetical cohort of 1000 adult inpatients suspected of CDI. We analyzed turnaround time of test results (i.e., time from taking sample to results emission), test performance (i.e., sensitivity and specificity) and testing costs. Patients were divided in true positive, false positive, true negative and false negative in order to integrate test performance and economics effects. Additional medical costs were calculated: costs of hygiene, medication, length of stay and intensive care unit costs, based on a Brazilian University Hospital costs. CDI prevalence was considered 22.64%. From laboratory-assisted tests, simultaneous glutamate dehydrogenase (GDH) and toxin A/B rapid immunoassay arbitrated by nucleic acid amplification test (NAAT) presented the lowest cost of illness (450,038.70 USD), whereas standalone NAAT had the highest (523,709.55 USD). Empirical diagnosis only presented the highest overall cost (809,605.44 USD). The two-step algorithm with simultaneous GDH and toxin A/B rapid immunoassay arbitrated by NAAT seems to be the best strategy for CDI diagnosis in developing countries.


Transient forebrain ischemia impact on lymphocyte DNA damage, glutamic acid level, and SOD activity in blood.
Brain ischemia-reperfusion injury remains incompletely understood but appears to involve a complex series of interrelated biochemical pathways caused mainly by a burst of reactive oxygen species (ROS). In the present work we studied the impact of postischemic condition in the early phase of reperfusion on plasma and blood cells. Transient forebrain ischemia was induced in Wistar rats by four-vessel occlusion model. Blood samples collected during postischemic reperfusion 20, 40, 60, 90, and 120 min after ischemia were used for assessing breaks of lymphocyte DNA, fluorimetric measurement of whole blood glutamate concentration, and spectrophotometrical determination of SOD activity in plasma and blood cells. Our results showed the most interesting changes of all observed parameters mainly at 40 and 120 min of reperfusion, when we observed peak DNA damage of lymphocytes and highest glutamate level and total and Cu/Zn SOD activity. At those time points, Mn SOD activity was low in plasma, as well as in blood cells. On the contrary, at 60 and 90 min, all studied parameters were approximately at the level of control. Ischemia/reperfusion injury has influence on blood cells and has at least two waves of impact on DNA damage of peripheral lymphocytes, affects activity of major antioxidant enzymes SODs, as well as blood glutamic acid level. Elevation of Mn SOD activity probably plays an important role in the processes of elimination of postischemic damage in blood cells.


Serine proteinase inhibitors on chromosome 14 and the genetics of familial chronic obstructive airways disease.
Environmental and genetic factors contribute to familial chronic obstructive airways disease. The genetic component could be polygenic or in some families be associated with one or two major genes. It is assumed that most cases of familial chronic obstructive airways disease are polygenic, but this conclusion is based on insufficient data. The use of linkage analysis using DNA probes for specific genes that may have a direct role in the disease process should facilitate our understanding of the genetics. Genetic deficiency of alpha1-antitrypsin is associated with predisposition to pulmonary emphysema. In the absence of alpha 1-antitrypsin deficiency I suggest that a study of serine-proteinase inhibitors on chromosome 14 may identify a significant proportion of families where only one major gene is important.


Progestogen-only contraception in women at high risk of venous thromboembolism.
The objective of the study was to evaluate the venous impact of a progestogen-only contraception on women at high risk of venous thromboembolism (VTE). In this retrospective cohort study, 204 consecutive women at high risk of VTE were recruited between January 1992 and June 1997 and were prospectively followed. Women using chlormadinone acetate (CMA) at antigonadotropic doses (n=102) were matched by age and date of referral and history of venous thrombosis with women who had no hormonal contraception (n=102). During follow-up (mean of 33 months), nine episodes of VTE were observed: three in women receiving CMA and six in nontreated women. Using the Cox model to adjust for confounding variables such as age, thrombophilia and body mass index, the relative risk of VTE associated with the use of CMA was not significant [relative risk: 0.8 (0.2-3.9)]. These reassuring results need to be confirmed in other prospective studies.


Dataset for the assessment of metallic pollution in the Saint-Charles River sediments (Québec City, QC, Canada).
This Data in Brief article presents sedimentological and geochemical parameters from a set of sedimentary samples collected in the Saint-Charles River, a tributary of the Saint-Lawrence River flowing in Québec City (QC, Canada). It details the experimental design, methods, materials and results of destructive analyses related to a multi-proxy study of polymetallic contamination in sediments collected within an urban reservoir (Spatial and temporal patterns of metallic pollution in Québec City, Canada: Sources and hazard assessment from reservoir sediment records, https://doi.org/10.1016/j.scitotenv.2019.04.021, (Chassiot et al., 2019)). The present article summarizes the results of relevant parameters on a set of 68 samples: total organic carbon (TOC), sulfur content, grain-size, and concentrations of heavy and trace metals. It also presents the calculation of enrichment factors, geoaccumulation indexes, and metallic pollution index.


Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2.
Hepatic insulin resistance is a key contributor to the pathogenesis of obesity and type 2 diabetes (T2D). Paradoxically, the development of insulin resistance in the liver is not universal, but pathway selective, such that insulin fails to suppress gluconeogenesis but promotes lipogenesis, contributing to the hyperglycemia, steatosis, and hypertriglyceridemia that underpin the deteriorating glucose control and microvascular complications in T2D. The molecular basis for the pathway-specific insulin resistance remains unknown. Here we report that oxidative stress accompanying obesity inactivates protein-tyrosine phosphatases (PTPs) in the liver to activate select signaling pathways that exacerbate disease progression. In obese mice, hepatic PTPN2 (TCPTP) inactivation promoted lipogenesis and steatosis and insulin-STAT-5 signaling. The enhanced STAT-5 signaling increased hepatic IGF-1 production, which suppressed central growth hormone release and exacerbated the development of obesity and T2D. Our studies define a mechanism for the development of selective insulin resistance with wide-ranging implications for diseases characterized by oxidative stress.


Prediction of true circulatory decompensation in chronic heart failure for optimal timing of mechanical circulatory support: non-invasive arterial-ventricular coupling.
Prospective comparative studies to predict the risk of hemodynamic deterioration in patients referred for transplantation were performed on the basis of standard invasive and non-invasive data and new wave intensity (WI) parameters. Study Group 1 consisted of 151 consecutive outpatients (age 48.7 ± 12 years; 110 men) with end-stage dilative cardiomyopathy. Group 2, consisting of 11 consecutive patients (age 50 ± 11 years; 6 men) with sinus rhythm and "true" decompensation, was used to create "critical values" of WI. There were no demographic or somatic (weight and height) differences between the groups. The follow-up period of ambulatory patients was 31 ± 8 months. Non-invasive WI was studied in the common carotid artery. Complete invasive and non-invasive data were also recorded on the day of investigation. During follow-up 44 pts were lost; there were 15 cardiac deaths (10%), life-saving ventricular assist device implantation in 10 (6.6%) and transplantation in 19 (12.7%). For statistical purposes this group was named the "events" Group B (n = 44). A predisposing factor for events (death, "true" decompensation and "urgent" transplantation in ambulatory patients) was low first peak ("cut-off value" assessed in Group 2 < 4100 mmHg*s³) (OR 45.6, CI 14.5-143.3, p < 0.001). Less powerful predictors of the risk of deterioration were pulmonary capillary pressure (PCP), diastolic pulmonary artery pressure (PAP) and E/A mitral wave relation (p = 0.05). The new ventricular-arterial coupling parameter 1st peak of WI can potentially be used to distinguish patients at high risk for true deterioration and death. This parameter can be used to predict the need for assist device implantation.


Microelectronics mounted on a piezoelectric transducer: method, simulations, and measurements.
This paper describes the design of a highly integrated ultrasound sensor where the piezoelectric ceramic transducer is used as the carrier for the driver electronics. Intended as one part in a complete portable, battery operated ultrasound sensor system, focus has been to achieve small size and low power consumption. An optimized ASIC driver stage is mounted directly on the piezoelectric transducer and connected using wire bond technology. The absence of wiring between driver and transducer provides excellent pulse control possibilities and eliminates the need for broad band matching networks. Estimates of the sensor power consumption are made based on the capacitive behavior of the piezoelectric transducer. System behavior and power consumption are simulated using SPICE models of the ultrasound transducer together with transistor level modelling of the driver stage. Measurements and simulations are presented of system power consumption and echo energy in a pulse echo setup. It is shown that the power consumption varies with the excitation pulse width, which also affects the received ultrasound energy in a pulse echo setup. The measured power consumption for a 16 mm diameter 4.4 MHz piezoelectric transducer varies between 95 microW and 130 microW at a repetition frequency of 1 kHz. As a lower repetition frequency gives a linearly lower power consumption, very long battery operating times can be achieved. The measured results come very close to simulations as well as estimated ideal minimum power consumption.


Effects of oxidative stress on the expression of limbic-specific protease neuropsin and avoidance learning in mice.
We evaluated the effects of oxidative stress in mouse brain induced by the intraperitoneal injection of diethyldithiocarbamate (DDC) on gene expression of the novel serine protease, neuropsin, and on shock-avoidance learning. The level of neuropsin mRNA in the hippocampal pyramidal neurons increased at 2 h after DDC treatment and decreased thereafter. At 7 days neuropsin mRNA significantly decreased to 60% of the pretreated control level and then returned to the control level at 30 days. Genes for tissue plasminogen activator, manganese superoxide dismutase, and heat shock protein did not differ in DDC-treated mice vs. the control group at 7 and 30 days. The shuttle-box avoidance learning was retarded at 7 days after DDC administration. However, it recovered to the control level at 30 days after DDC administration. The results suggest that generation of reactive oxygen species has an important role in neuropsin transcript in the limbic areas which might be related to the disturbance in avoidance learning.


The effect of ultrasound-guided intraperitoneal injection of ulinastatin on lung development in intrauterine growth-restricted fetal rabbits.
To investigate the effect and mechanism of ulinastatin (UTI) on development of lungs in fetal rabbits with intrauterine growth retardation (IUGR). Twenty pregnant rabbits were equally divided into normal, IUGR, UTI, and LY groups. The normal group was only injected with saline and marked with tattoo ink. IUGR models were established by injecting N-nitro-L-arginine methyl ester in the rabbits of IUGR, UTI, and LY groups. The three groups were injected with saline, UTI, or UTI + LY294002 (PI3K inhibitor) respectively, and then marked with tattoo ink. After cesarean section, neonatal weights, and levels of dipalmitoyl phosphatidylcholine (DPPC), nitric oxide (NO), P-Akt, P-eNOS, and pulmonary surfactant-associated protein A (SP-A) were determined in tissues of the lungs. Radial alveoli count (RAC), pulmonary interstitial ratio, and ultrastructural changes in type II alveolar epithelial cells (AEC II) were also determined through light and electron microscopy. Compared with control, the IUGR group showed significantly decreased weight, RAC, lamellar bodies in AEC II, and levels of P-Akt, P-eNOS, DPPC, NO, and SP-A, and increased pulmonary interstitial ratio (p < .05). The UTI treatment did not affect the weight; however, all other parameters were opposite to those observed in the IUGR group (p < .05). Furthermore, these UTI-mediated changes were inhibited by LY294002. Intraperitoneal UTI injection can promote the development of lungs and increase pulmonary surfactant production in IUGR fetal rabbits, potentially by activating PI3K/Akt/eNOS/NO signaling.


Improved accuracy and reproducibility of a novel CT-free robotic surgical assistant for medial unicompartmental knee arthroplasty compared to conventional instrumentation: a cadaveric study.
Alignment errors in medial unicompartmental knee arthroplasty (UKA) predispose to premature implant loosening and polyethylene wear. The purpose of this study was to determine whether a novel CT-free robotic surgical assistant improves the accuracy and reproducibility of bone resections in UKA compared to conventional manual instrumentation. Sixty matched cadaveric limbs received medial UKA with either the ROSA® Partial Knee System or conventional instrumentation. Fifteen board-certified orthopaedic surgeons with no prior experience with this robotic application performed the procedures with the same implant system. Bone resection angles in the coronal, sagittal and transverse planes were determined using optical navigation while resection depth was obtained using calliper measurements. Group comparison was performed using Student's t test (mean absolute error), F test (variance) and Fisher's exact test (% within a value), with significance at p < 0.05. Compared to conventional instrumentation, the accuracy of bone resections with CT-free robotic assistance was significantly improved for all bone resection parameters (p < 0.05), other than distal femoral resection depth, which did not differ significantly. Moreover, the variance was significantly lower (i.e. fewer chances of outliers) for five of seven parameters in the robotic group (p < 0.05). All values in the robotic group had a higher percentage of cases within 2° and 3° of the intraoperative plan. No re-cuts of the proximal tibia were required in the robotic group compared with 40% of cases in the conventional group. The ROSA® Partial Knee System was significantly more accurate, with fewer outliers, compared to conventional instrumentation. The data reported in our current study are comparable to other semiautonomous robotic devices and support the use of this robotic technology for medial UKA. Cadaveric study, Level V.


The Vps33a gene regulates behavior and cerebellar Purkinje cell number.
A mutation in the Vps33a gene causes Hermansky-Pudlak Syndrome (HPS)-like-symptoms in the buff (bf) mouse mutant. The encoded product, Vps33a, is a member of the Sec1 and Class C multi-protein complex that regulates vesicle trafficking to specialized lysosome-related organelles. As Sec1 signaling pathways have been implicated in pre-synaptic function, we examined brain size, cerebellar cell number and the behavioral phenotype of bf mutants. Standardized behavioral tests (SHIRPA protocols) demonstrated significant motor deficits (e.g., grip strength, righting reflex and touch escape) in bf mutants, worsening with age. Histological examination of brain revealed significant Purkinje cell loss that was confirmed with staining for calbindin, a calcium binding protein enriched in Purkinje cells. This pathologic finding was progressive, as older bf mutants (13-14 months) showed a greater attrition of neurons, with their cerebella appearing to be particularly reduced (approximately 30%) in size relative to those of age-matched-control cohorts. These studies suggest that loss of Purkinje neurons is the most obvious neurological atrophy in the bf mutant, a structural change that generates motor coordination deficits and impaired postural phenotypes. It is conceivable therefore that death of cerebellar cells may also be a clinical feature of HPS patients, a pathological event which has not been reported in the literature. In general, the bf mutant may be a potentially new and useful model for understanding Purkinje cell development and function.


The procoagulant activity of human granulocytes, lymphocytes and monocytes stimulated by endotoxin. Coagulation and electron microscopic studies.
Leukocytes from donor blood were separated by ficoll/Urovison density centrifugation into granulocytes, lymphocytes and monocytes. The cell fractions were suspended in a culture medium to which endotoxin of Salmonella enteritidis was added at a final concentration of 10 microgram/ml. Endotoxin-stimulated monocytes developed a very high tissue factor (thromboplastin) activity while in granulocytes an only negligible amount of tissue factor activity was detectable. The tissue factor activity measured in the preparation of the lymphocytes can be explained by contamination with monocytes. Eelectron microscopic studies showed the lysosomes of all monocytes to be enlarged and activated. Only a fraction of the granulocytes appeared degranulated with prominent vacuoles containing inclusion bodies. Possibly the high tissue factor activity of the monocytes triggers the development of the disseminated intravascular coagulation in the Shwartzman phenomenon.


A dihydropyridine-sensitive voltage-dependent calcium channel in the sarcolemmal membrane of crustacean muscle.
Single-channel currents through calcium channels in muscle of a marine crustacean, the isopod Idotea baltica, were investigated in cell-attached patches. Inward barium currents were strongly voltage-dependent, and the channels were closed at the cell's resting membrane potential. The open probability (Po) increased e-fold for an 8.2 mV (+/- 2.4, n = 13) depolarization. Channel opening were mainly brief (< 0.3 ms) and evenly distributed throughout 100-ms pulses. Averaged, quasimacroscopic currents showed fast activation and deactivation and did not inactivate during 100-ms test pulses. Similarly, channel activity persisted at steadily depolarized holding potentials. With 200 mM Ba2+ as charge carrier, the average slope conductance from the unitary currents between +30 and +80 mV, was 20 pS (+/- 2.6, n = 12). The proportion of long openings, which were very infrequent under control conditions, was greatly increased by preincubation of the muscle fibers with the calcium channel agonist, the dihydropyridine Bay K8644 (10-100 microM). Properties of these currents resemble those through the L-type calcium channels of mammalian nerve, smooth muscle, and cardiac muscle cells.


Rutin protects against H2O2-triggered impaired relaxation of placental arterioles and induces Nrf2-mediated adaptation in Human Umbilical Vein Endothelial Cells exposed to oxidative stress.
Rutin intake is associated with a reduced risk of cardiovascular disease (CVD). The exact mechanism by which rutin can protect against CVD development is still enigmatic. Since, rutin is a compound with a relatively short half-life, the direct antioxidant effect of rutin cannot explain the long-lasting effect on human health. We hypothesized that rutin next to its direct antioxidant effect that improves endothelial function, may also induce an adaptive response in endogenous antioxidant systems. In Human Umbilical Vein Endothelial Cells (HUVECs), the direct antioxidant effect was confirmed. During scavenging of Reactive Oxygen Species (ROS), rutin is oxidized into a quinone derivative. HUVECs pretreated with rutin quinone became better protected against a second challenge with oxidative stress 3h later. LC-MS/MS analysis indicated that rutin quinone targets cysteine 151 of Keap1. Moreover, we found that the quinone is an inhibitor of the selenoprotein thioredoxin reductase 1. These properties correlated with an activation of Nrf2 and upregulation of Glutamate Cysteine Ligase, the rate-limiting enzyme of glutathione synthesis, while NF-κB and HIF activation became blunted by rutin treatment. Furthermore, rutin was found to prevent hydrogen peroxide from impairing relaxation of human chorionic plate placental vessels, which may help to protect endothelial function. Rutin functions as an antioxidant and is oxidized into a quinone that upregulates the Nrf2-mediated endogenous antioxidant response. This mechanism suggests that rutin selectively exerts its protective effects in regions with increased oxidative stress, and explains how rutin reduces the risk of developing CVD. The newly found mechanism behind the long-term protection of rutin against cardiovascular disease, the selective upregulation of endogenous antioxidant systems, contributes to the further understanding why rutin can reduce the risk on developing cardiovascular disease.


Carbon stocks of tree plantations in a Western Ghats landscape, India: influencing factors and management implications.
Biomass and carbon stock assessments in data-deficient plantations and identifying the factors influencing tree growth, distribution, and carbon stocks are extremely important for implementing sound silvicultural management and monitoring practices to achieve REDD+ goals. We conducted carbon stock assessments in five major plantation types in a regional landscape in the central Western Ghats, India, by establishing fifty 0.1-ha plots across the landscape. We quantified the overall carbon stocks by summing the carbon pools across mature trees, deadwood, and soil (0 -15 cm) components. Allometric equations were compared to address the uncertainty in the tree biomass carbon. The tree biomass carbon and soil organic carbon varied significantly across the plantation types (F = 55.23, p < 0.00). The present study yielded the highest carbon stocks in Pinus plantation (201.91 ± 9.52 Mg ha-1) and the least in Eucalyptus (122.63 ± 9.73 Mg ha-1). The correlation analysis displayed a strong influence of mean annual precipitation and edaphic factors on soil organic carbon, while basal area and elevation were good predictors of tree biomass carbon. The principal component analysis revealed an association of predictor variables in the distribution of plantation types. We found a strong association between mean annual precipitation on Pinus plantation and mean annual temperature on Eucalyptus and Acacia plantations. On the other hand, teak pure plantation was associated with structural and topographic variables, while edaphic factors mainly influenced the distribution of teak mixed plantations. The findings of the present study conclude substantial carbon storage ability of the plantations in the studied landscape which can play a significant role in mitigating the effects of climate change and reaching carbon neutrality.


Regulatory and associated political issues with respect to Bt transgenic maize in the European union.
Legislation at the national level in Europe as well as that developed by the European Union (EU) generally permits release and commercialization of genetically modified organisms (GMOs). However, only 10 plant/event combinations were registered as of 2002: three maize events (Bt176, Mon810, and Bt11), with the other seven divided among carnation (3), oil-seed rape (2), tobacco (1), and raddiccio (1). Of these, only one maize event (Bt176) has been registered as a legal variety, and this was in Spain, where 22,000ha have been planted annually since 1998. In this paper, we first provide an overview on the complexity of EU GMO legislation. Then we discuss the minor role that results of EU-funded biosafety research have had on governmental policy. Finally, we provide information about initiatives for post-commercialization monitoring plans of Bt maize in Europe. As a result of the slow progress to date, we conclude that commercialization of GMOs will be seriously delayed in the EU for the next several years.


Altered dopamine modulation of LTD-like plasticity in Alzheimer's disease patients.
Mechanisms of synaptic plasticity like long term depression (LTD) are altered in experimental models of Alzheimer's disease (AD). LTD-like plasticity mechanisms has not been yet fully investigated in AD patients. Here we studied the effects of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex in a group of patients with a diagnosis of probable AD, compared to healthy age-matched controls (HS). Moreover, we tested the effects of a single dose of orally administered L-dopa, one of the key neurotransmitters in modulating synaptic plasticity mechanisms, on rTMS induced plasticity. We found that in AD patients the 1 Hz rTMS protocol did not induce the expected inhibitory effect, while a long lasting inhibition of MEP was observed in HS. In addition, L-dopa induced a clear form of reversal of the direction of plasticity in HS that was not evident in AD. Dopamine modulation of LTD-like plasticity is impaired when tested in AD patients. These findings provide evidence of possible dysfunction of dopaminergic transmission in AD patients.


Microstructure and corrosion properties of as sub-rapid solidification Mg-Zn-Y-Nd alloy in dynamic simulated body fluid for vascular stent application.
Magnesium alloy stent has been employed in animal and clinical experiment in recent years. It has been verified to be biocompatible and degradable due to corrosion after being implanted into blood vessel. Mg-Y-Gd-Nd alloy is usually used to construct an absorbable magnesium alloy stent. However, the corrosion resistant of as cast Mg-Y-Gd-Nd alloy is poor relatively and the control of corrosion rate is difficult. Aiming at the requirement of endovascular stent in clinic, a new biomedical Mg-Zn-Y-Nd alloy with low Zn and Y content (Zn/Y atom ratio 6) was designed, which exists quasicrystals to improve its corrosion resistance. Additionally, sub-rapid solidification processing was applied for preparation of corrosion-resisting Mg-Zn-Y-Nd and Mg-Y-Gd-Nd alloys. Compared with the as cast sample, the corrosion behavior of alloys in dynamic simulated body fluid (SBF) (the speed of body fluid: 16 ml/800 ml min(-1)) was investigated. The results show that as sub-rapid solidification Mg-Zn-Y-Nd alloy has the better corrosion resistance in dynamic SBF due to grain refinement and fine dispersion distribution of the quasicrystals and intermetallic compounds in alpha-Mg matrix. In the as cast sample, both Mg-Zn-Y-Nd and Mg-Y-Gd-Nd alloys exhibit poor corrosion resistance. Mg-Zn-Y-Nd alloy by sub-rapid solidification processing provides excellent corrosion resistance in dynamic SBF, which open a new window for biomedical materials design, especially for vascular stent application.


Historical Ethnobotany: Interpreting the Old Records.
For centuries, knowledge about the use of plants has been collected, published, or simply left in archives [...].


Patient-Reported Outcomes and Risk of Hospitalization and Readmission in Patients with Inflammatory Bowel Diseases.
Patient-reported outcome measures (PROMs) provide a wholesome view of patient well-being. We conducted a retrospective cohort study to evaluate whether PROMs inform risk of unplanned healthcare utilization in patients with IBD. We identified adult patients with IBD who completed at least two surveys in a large Internet-based cohort within 1 year. We evaluated the association between baseline patient characteristics, disease activity indices, medication use, and PROMs, assessed using NIH Patient-Reported Outcome Measurement Information System (PROMIS) and subsequent risk of incident hospitalization (at time of first follow-up) within 1 year, and readmission within 1 year (in patients with hospitalization at first follow-up), using multivariable logistic regression. Of 7902 patients with IBD (45.5 year, 72% females, 63% Crohn's disease), 1377 (17.4%) were hospitalized within 1 year. Among PROMs, pain interference (adjusted OR per 5-point increase in PROMIS, 1.09; 95% CI 1.05-1.14), but not depression, anxiety, fatigue or sleep disturbance, was predictive of higher risk of hospitalization. Prior surgery or hospitalization, symptomatic disease, biologic, and corticosteroid use were also associated with higher risk of hospitalization. Of 521 patients hospitalized with IBD, 133 (25.5%) were readmitted within 1 year. Anxiety and pain interference were predictive of higher risk of readmission, whereas depression was associated with lower risk of readmission. In a large Internet-based cohort study, PROMs may have a modest effect on modifying risk of unplanned healthcare utilization in patients with IBD, with pain interference being most consistently associated with increased risk of hospitalization and readmission.


A system-approach method for the adjustment of time-varying continuous drug infusion in individual patients: a simulation study.
The aim of this simulation study was to present a system-approach method for adjustment of continuous drug infusions at time-varying rates, aimed at achieving and then maintaining required drug concentration-time profiles in patients. The method presented can be used for safe and cost-effective individualization of drug dosing by computer-controlled infusion pumps. Utilization of this method is exemplified by simulation experiments, aimed at adjusting continuous infusions of Factor VIII (FVIII) at time-varying rates, which would theoretically yield required concentration-time profiles of FVIII in hemophilia A patients over several days.


Establishment of a database of metformin plasma concentrations and erythrocyte levels in normal and emergency situations.
Knowledge of blood metformin concentrations may be crucial for adapting the dose to the patient's kidney function and investigating a putative link between this drug and lactic acidosis. We therefore established the first database of blood metformin concentrations. In order to provide cross-sectional data from clinical practice in a university medical centre, the authors retrospectively reviewed all available metformin plasma concentrations and erythrocyte level results (all of which were measured using the same assay technique). The assays had been requested for either dose adjustment in relation to the patient's renal status or screening for potential metformin accumulation, metformin overdose or lactic acidosis. A total of 798 metformin assays were performed in 467 patients. The mean ± SD (range) plasma concentrations and erythrocyte levels were 2.7 ± 7.3 (0-113) mg/L and 2.0 ± 4.4 (0-61) mg/L, respectively (published therapeutic values: 0.5 ± 0.4 mg/L and 0.8 ± 0.4 mg/L, respectively). Four plasma concentration categories were defined on a pragmatic basis: undetectable (9.7%), therapeutic range (40.6%), slight-to-moderate elevation (42.6%) and marked elevation (7.1%). Greater knowledge of blood metformin concentrations is required to adjust treatment and avoid wrongly incriminating the drug in lactic acidosis. Establishment of the first database of blood metformin concentrations may help physicians to better evaluate metformin use and dosage levels (particularly in elderly patients and those with poor kidney function), determine the presence and intensity of metformin accumulation and, ultimately, establish the prognosis of the latter condition.


Lateral patellofemoral ligament reconstruction.
Abstract Medial dislocation of the patella is a disabling condition; there are several reports in the literature describing this condition and its association with failed lateral retinacular release. The diagnosis and treatment of medial subluxation of the patella may be difficult. Direct repair or imbrication of the lateral retinaculum provides initial stability but a noticeable increase in medial excursion usually reappears. In this article, we describe a simple and reproducible technique to reconstruct the lateral patellofemoral ligament with autogenous tissue that is based on the basic principles of all ligament reconstruction. Reconstruction of the lateral patellofemoral ligament is useful in eliminating the symptoms related to medial instability of the patella after failed lateral retinacular release; however, it must be considered a salvage procedure because it does not address the pathomechanics that led to the initial patellofemoral symptoms.


Correlation between early changes of serum lipids and clinical severity in patients with wasp stings.
Wasp stings are a serious problem worldwide, and patients in severe cases may experience multi-organ failure. However, the mechanism of hypolipidemia in patients with wasp stings is unknown. To investigate the relationship between early changes in lipid levels and clinical severity and the possible underlying mechanisms. A retrospective analysis of 212 patients (mild: 77; moderate: 50; severe: 85) with wasp stings was conducted. Clinical data, including lipid test results within 24 h of admission, were analysed. A total of 1060 healthy age- and gender-matched controls were used. Patients with wasp stings had lower lipid levels than healthy controls (P<0.01). Lipid levels decreased with disease severity, except for triglycerides (P<0.05). The number of stings, degree of organ failure, need for mechanical ventilation and extracorporeal blood purification, and mortality were higher in the severe group than in the mild and moderate groups (P<0.01). A decrease in lipid levels was accompanied by an increase in inflammatory indicators. In the severe group, a reduction in lipid levels was associated with ventilator application and blood purification, independent of survival status. Patients with wasp stings experience a reduction in lipid levels, which is related to the severity of clinical manifestations. Early lipid levels may serve as a simple indicator for the severity of wasp stings, and targeting lipid metabolism may be a novel treatment.


Spatial relationships between the pulmonary veins and sites of complex fractionated atrial electrograms during atrial fibrillation.
Pulmonary vein (PV) isolation is used for the treatment of atrial fibrillation (AF). Complex fractionated atrial electrogram (CFAE) mapping has been introduced to guide AF ablation. However, the spatial relationship between PV and CFAE is not well defined. The study included 21 patients (mean age 57 +/- 11 years, 17 men, 14 paroxysmal, two persistent, and five long-standing persistent AF) referred for PV isolation. Electrograms were sampled for 8 seconds at each site during stable AF (13 induced). High-frequency was defined as <80 ms of CFAE value. The distance between CFAE and the nearest PV ostium was measured. The PV ostia and antra were demarcated by fluoroscopy guidance and endocardial reconstruction. Among 82 PV mapped (left common four, superior 17, inferior 17; right superior 21, inferior 21, middle 2), 52.4% and 25.6% of high-frequency CFAE were located on the anterior and posterior walls, respectively, inside the PV or at the ostium. No high-frequency CFAE was observed in two out of 60 and one out of 20 PV anteriorly, versus seven out of 60 and 11 out of 20 PV (P < 0.001) posteriorly, in paroxysmal and persistent AF, respectively. In the PV with high-frequency CFAE, the mean shortest distances to the PV ostia in paroxysmal versus persistent AF were 2.7 +/- 5.1 versus 7.4 +/- 5.4 mm anteriorly (P < 0.01), and 6.5 +/- 6.4 versus 9.4 +/- 8.4 mm posteriorly (ns). During PV isolation, extending the ablation lesions by up to 10 mm from the PV ostia might cover most high-frequency CFAE around the PV antra. High-frequency CFAE were more often located in the PV ostia in paroxysmal than in persistent AF.


Evaluation of BAYESIL for automated annotation of 1H NMR data using limited sample volumes: application to African elephant serum.
Technological advancements enabled the analyses of limited sample volumes on 1H NMR. Manual spectral profiling of the data is, however, complex, and timely. To evaluate the performance of BAYESIL for automated identification and quantification of 1H NMR spectra of limited volume samples. Aliquots of a pooled African elephant serum sample were analyzed using standard and reduced volumes. Performance was evaluated on confidence scores, non-detects and laboratory CV. Of the 47 compounds detected, 28 had favorable performances. The approach could differentiate samples based on biological variation. BAYESIL is valuable for limited sample 1H NMR data analyses.


The roles of diet and exercise in the management of patients with insulin-dependent diabetes mellitus.
Current dietary recommendations for patients with diabetes are similar to those for the US population in general, including a moderate intake of sucrose. Awareness of the carbohydrate content of meals will allow adjustments of the dose of meal-related short-acting insulin when the size of the meal is altered; thus, meal planning can be flexible without sacrificing glycemic control. Although exercise may have potential benefits for patients with diabetes, it is also associated with greater risk in these persons than in their nondiabetic counterparts and frequently complicates the management of their disease. If there are no contraindications to regular, vigorous exercise and the patient desires to participate, careful self-monitoring of blood glucose, combined with snacks and insulin dose adjustment, should enable the intensively treated patient to exercise safely.


Mutations of early neurogenesis inDrosophila.
Embryonic lethal mutations at the Notch locus are known to produce a conspicuous central nervous system hypertrophy accompanied by a hypotrophy of the epidermal sheath. We have studied several zygotic mutants belonging to four different autosomal complementation groups which produce the same phenotype. The embryonic development of the new mutants, as well as that of Notch, consists of an initial enlargement of the neurogenic region at the expenses of epidermal cell precursors. The possibility is discussed that these five loci are involved in the determination of neural and epidermal cell precursors.