Alterations of plasma cytokine biomarkers for identifying age at onset of schizophrenia with neurological soft signs.
Several studies have been suggested that immunity plays a part in neurodevelopment and schizophrenia pathogenesis. Early age of onset in schizophrenia is associated with genetic factors which affect neurodevelopment. This study aims to identify immune abnormalities associated with neurodevelopmental impairments in early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) patients. We determined the plasma levels of six cytokines (IL-1β, IL-4, IL-6, IL-10, IL-12 and TNF-α) in schizophrenia patients and healthy controls. Measurements included neurological soft signs (NSS) to distinguish and subgroup those with neurodevelopmental impairments. The study included 210 schizophrenia patients, which were divided into 84 EOS and 126 AOS patients, as well as 122 healthy controls. We observed significant differences in levels of IL-4, IL-6 and IL-10 between EOS and AOS patients. The results demonstrated the area under ROC curve (AUC) of the IL-4 in EOS and healthy controls was 0.81. Moreover, these results indicated that AUC of the IL-4 and the combination of IL-4, IL-6 and IL-12 in EOS with NSS and healthy controls were 0.91 and 0.95. These cytokines are altered in EOS and schizophrenia patients with neurodevelopmental impairments and demonstrated good classification abilities. These findings manifested that both pro- and anti-inflammatory cytokines are contributed to the clinical and pathophysiological features of schizophrenia. Future works are expected to explore potential genetic effectors and predictors as well as therapeutic directions in personalized medicine for early-onset schizophrenia.


Variants in estrogen receptor alpha gene are associated with phenotypical expression of obsessive-compulsive disorder.
Compelling data from animal and clinical studies suggest that sex steroids may play a role in the etiopathology of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in estrogen receptor genes ESR1 and ESR2 may contribute to the genetic susceptibility to OCD, through a case-control association study using an extensive linkage disequilibrium-mapping approach. Twenty tag single-nucleotide polymorphisms (tagSNPs) covering the ESR2 region and nine tagSNPS from regions of ESR1 reported to be related to transcriptional control were genotyped in 229 OCD patients and 279 controls. SNP association and haplotype analysis were performed. The association of these genes and OCD subphenotypes was tested, considering early-onset OCD, comorbid tic and affective disorders, and OCD symptom dimensions. No significant difference in the distribution of alleles or genotypes was detected between controls and OCD subjects. Nevertheless, on analyzing OCD subphenotypes, SNP rs34535804 in ESR1 and a five SNPs haplotype, located at the 5' end of intron 1 of ESR1, were associated with the presence of contamination obsessions and cleaning compulsions. Specifically, carriers of the ACCCG haplotype, a combination of functional alleles related to higher ER alpha expression, showed a reduced risk of suffering from these symptoms. Our results suggest that the ESR1 gene may contribute to the genetic vulnerability to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may well help to identify susceptibility genes for the disorder.


Aphid effector Me10 interacts with tomato TFT7, a 14-3-3 isoform involved in aphid resistance.
We demonstrated previously that expression of Macrosiphum euphorbiae salivary protein Me10 enhanced aphid reproduction on its host tomato (Solanum lycopersicum). However, the mechanism of action of Me10 remained elusive. To confirm the secretion of Me10 by the aphid into plant tissues, we produced Me10 polyclonal antibodies. To identify the plant targets of Me10, we developed a tomato immune induced complementary DNA yeast two-hybrid library and screened it with Me10 as bait. Immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays were performed to validate one of the interactions in planta, and virus-induced gene silencing was used for functional characterization in tomato. We demonstrated that Me10 is secreted into the plant tissues and interacts with tomato 14-3-3 isoform 7 (TFT7) in yeast. Immunoprecipitation assays confirmed that Me10 and its homologue in Aphis gossypii, Ag10k, interact with TFT7 in planta. Further, BiFC revealed that Me10 interaction with TFT7 occurs in the plant cell cytoplasm. While silencing of TFT7 in tomato leaves did not affect tomato susceptibility to M. euphorbiae, it enhanced longevity and fecundity of A. gossypii, the non-host aphid. Our results suggest the model whereby TFT7 plays a role in aphid resistance in tomato and effectors of the Me10/Ag10k family interfere with TFT7 function during aphid infestation.


Safety criteria to start early mobilization in intensive care units. Systematic review.
Mobilization of critically ill patients admitted to intensive care units should be performed based on safety criteria. The aim of the present review was to establish which safety criteria are most often used to start early mobilization for patients under mechanical ventilation admitted to intensive care units. Articles were searched in the PubMed, PEDro, LILACS, Cochrane and CINAHL databases; randomized and quasi-randomized clinical trials, cohort studies, comparative studies with or without simultaneous controls, case series with 10 or more consecutive cases and descriptive studies were included. The same was performed regarding prospective, retrospective or cross-sectional studies where safety criteria to start early mobilization should be described in the Methods section. Two reviewers independently selected potentially eligible studies according to the established inclusion criteria, extracted data and assessed the studies' methodological quality. Narrative description was employed in data analysis to summarize the characteristics and results of the included studies; safety criteria were categorized as follows: cardiovascular, respiratory, neurological, orthopedic and other. A total of 37 articles were considered eligible. Cardiovascular safety criteria exhibited the largest number of variables. However, respiratory safety criteria exhibited higher concordance among studies. There was greater divergence among the authors regarding neurological criteria. There is a need to reinforce the recognition of the safety criteria used to start early mobilization for critically ill patients; the parameters and variables found might contribute to inclusion into service routines so as to start, make progress and guide clinical practice.


Differential response of the natriuretic peptide system to weight loss and exercise in overweight or obese patients.
Relative atrial natriuretic peptide (ANP) deficiency has been implicated in the pathogenesis of obesity-associated cardiovascular and metabolic disease. We tested the hypothesis that more than 5% body weight reduction through 6 months hypocaloric dieting alters ANP release at rest and more so during exercise in overweight or obese patients. Venous mid-regional pro-ANP concentration was assessed at rest and after incremental exhaustive exercise testing before and after weight reduction. We also measured natriuretic peptide receptor A and C mRNA expression in subcutaneous adipose tissue to gauge both ANP responsiveness and clearance mechanisms. The average weight reduction of 9.1 ± 3.8 kg was associated with reductions in visceral and subcutaneous abdominal fat mass, liver fat content, insulin resistance, and ambulatory blood pressure. However, mid-regional pro-ANP plasma concentrations were unchanged with weight loss (51 ± 24 vs. 53 ± 24 pmol/l). Exercise elicited similar acute mid-regional pro-ANP increases before and after weight loss. Adipose tissue natriuretic peptide receptor type A mRNA expression remained unchanged, whereas natriuretic peptide receptor type C mRNA decreased with weight loss. We conclude that physical exercise acutely increases ANP release in obese patients, whereas modest diet-induced weight loss primarily affects ANP clearance mechanisms. Interventions combining weight loss and regular physical exercise may be particularly efficacious in reversing obesity-associated relative natriuretic peptide deficiency.


[Hygiene requirements for the level of intellectual intensivity loads in foreign language learning].
The material of this article provides information about the basics of hygiene conditions and nature of intellectual loads of students of secondary schools in the perception of information in a foreign language. Are the most favorable conditions for the successful training of perception and assimilation of information supplied in the course of the learning process in one foreign language or some more different ones? It was found that the process of perception and assimilation of educational information in foreign languages is associated with some degree of mental and emotional stress of students. At the same time, the effectiveness of the learning process depends on the degree of stress. Certain parameters of the psychological and emotional stress students usually have a stimulating effect on their central nervous system. Another level, the psychological and emotional stress of students on the contrary, causes a braking effect of functional activity of the relevant structures of the central nervous system of students and reduces the effectiveness of training.


A comprehensive review on beneficial dietary phytochemicals in common traditional Southern African leafy vegetables.
Regular intake of sufficient amounts of certain dietary phytochemicals was proven to reduce the incidence of noncommunicable chronic diseases and certain infectious diseases. In addition, dietary phytochemicals were also reported to reduce the incidence of metabolic disorders such as obesity in children and adults. However, limited information is available, especially on dietary phytochemicals in the commonly available traditional leafy vegetables. Primarily, the review summarizes information on the major phytochemicals and the impact of geographical location, genotype, agronomy practices, postharvest storage, and processing of common traditional leafy vegetables. The review also briefly discusses the bioavailability and accessibility of major phytochemicals, common antinutritive compounds of the selected vegetables, and recently developed traditional leafy vegetable-based food products for dietary diversification to improve the balanced diet for the consumers. The potential exists for better use of traditional leafy vegetables to sustain food security and to improve the health and well-being of humans.


Scar revision via resurfacing.
Numerous techniques exist to treat noticeable facial scars. Techniques range from surgical excision to resurfacing. In this review of dermabrasion and laser resurfacing, we address the clinical considerations, techniques, adjuncts, and peri-operative management of scar resurfacing. Dermabrasion offers the advantage of being a tried-and-true technique familiar to surgeons. Recent advances in laser technology have resulted in the increased use of pulsed-dye lasers (PDLs), erbium:yttrium-aluminum-garnet (YAG) lasers, and CO(2) lasers. PDLs are effective for hypertrophic scars and show lower rates of recurrence compared with erbium:YAG and CO2 lasers. In contrast, erbium:YAG and CO(2) lasers are well suited to treating atrophic and acne scars. Chemical peels play a minor role in scar resurfacing and function primarily as an adjunct. Scar resurfacing is an integral part of scar camouflage and is often used in conjunction with excision and irregularization techniques.


Redox cycling behavior of individual and binary mixtures of catecholamines at gold microband electrode arrays.
The electrochemical redox cycling (RC) behavior of individual and binary mixtures of three catecholamines are investigated using gold microelectrode arrays in vitro. Catecholamines showed reversible or irreversible responses during RC depending on their oxidation products' cyclization rate. The RC behavior of the binary mixtures supports the disproportionation reaction of catecholamines, which has been previously reported, but not under RC conditions or with mixtures. This fundamental study provides insights on the effects of complicated mechanisms and kinetics on RC and sets the foundation for future applications of RC for in vivo multi-neurotransmitter analysis.


C-kit protein expression in uterine and ovarian mesenchymal tumours.
The protooncogene c-kit encoding transmembrane tyrosine kinase receptor protein plays an important role in the signal transduction pathway that regulates cellular growth and repair. Gene product KIT overexpression has been shown in a number of different neoplasms, particularly in mastocytosis and gastrointestinal stromal tumours (GIST). The morphologic similarity of uterine mesenchymal tumours and GIST, and the presence of KIT protein in normal uterine tissue, suggests that uterine sarcomas may have the same c-kit overexpression. The purpose of this study was to determine the overexpression of c-kit protein in uterine and ovarian sarcomas. Immunohistochemical staining using a polyclonal anti-c-kit antibody was performed on tissue blocks from 12 carsinosarcomas, 14 leiomyosarcomas, 8 endometrial stromal sarcomas, 2 adenosarcomas, 1 atypical leiomyoma, 1 leiomyoma with limited experience, and 10 leiomyomas. The slides were evaluated by a semiquantitative method. C-kit was positive in 10 of 12 (83%) carcinosarcomas, 10 of 14 (71%) leiomyosarcomas, 6 of 8 75(%) endometrial stromal sarcomas, 1 of 2 (50%) adenosarcomas, 1 leiomyoma with limited experience, and 1 of 10 (10%) leiomyomas. The uterine sarcomas express c-kit, like GISTs. It seems that KIT may have a significant role in the oncogenesis of mesenchymal tumours of the uterus and ovary.


Leprosy--a case for mental health care.
One hundred twenty institutionalized cases of leprosy were tested for anxiety and depression on standard scales before and after psychiatric treatment. The latter seems to be effective in reducing both anxiety and depression after a course of treatment of three months. This appears to be a sound justification to advocate mental health care in institutions of leprosy in conjunction with physical care. Leprosy is a chronic and disabling disease entity. With the social stigma associated to the disease the psychiatric hazards of the disease are as bad as its physical manifestations. However, usually, only the latter attract attention. Ignorance about the disease and social values about the disease can at once land a person in depression on utterance of the diagnosis. Further, anxiety about the outcome of the disease in particular and future in general are known to exist in sufferers of leprosy.


Morphological and molecular confirmation of the validity of Trichuris rhinopiptheroxella in the endangered golden snub-nosed monkey (Rhinopithecus roxellana).
The golden snub-nosed monkey (Rhinopithecus roxellana) is an endangered species endemic to China. Relatively little is known about the taxonomic status of soil-transmitted helminths (STH) in these monkeys. Trichuris spp. (syn. Trichocephalus) are among the most important STHs, causing significant socio-economic losses and public health concerns. To date, five Trichuris species have been reported in golden monkeys, including a novel species, T. rhinopiptheroxella, based on morphology. In the present study, molecular and morphological analysis was conducted on adult Trichuris worms obtained from a dead golden snub-nosed monkey, to better understand their taxonomic status. Morphology indicated that the adult Trichuris worms were similar to T. rhinopiptheroxella. To further ascertain their phylogenetic position, the complete mitochondrial (mt) genome of these worms was sequenced and characterized. The mt genome of T. rhinopiptheroxella is 14,186 bp, encoding 37 genes. Phylogenetic analysis based on the concatenated amino acids of 12 protein-coding genes (with the exception of atp8) indicated that T. rhinopiptheroxella was genetically distinct and exhibited 27.5-27.8% genetic distance between T. rhinopiptheroxella and other Trichuris spp. Our results support T. rhinopiptheroxella as a valid Trichuris species and suggest that mt DNA could serve as a marker for future studies on the classification, evolution and molecular epidemiology of Trichuris spp. from golden snub-nosed monkeys.


Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma.
Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL. Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis. The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category. The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL.


Polymorphisms of the dopamine D4 receptor gene (DRD4 VNTR) and cannabinoid CB1 receptor gene (CNR1) are not strongly related to cue-reactivity after alcohol exposure.
Polymorphisms in the D4 dopamine receptor gene (DRD4) and the CB1 cannabinoid receptor gene (CNR1) have been associated with a differential response to alcohol after consumption. The goal of the present study was to investigate whether heavy drinkers with these polymorphisms would respond with enhanced cue-reactivity after alcohol exposure. Eighty-eight male heavy drinkers were genotyped for the DRD4 variable number of tandem repeats (VNTR) [either DRD4 long (L) or short (S)] and the CNR1 rs2023239 polymorphism (either CT/CC or TT). Participants were exposed to water and beer in 3-minute trials. Dependent variables of main interest were subjective craving for alcohol, subjective arousal and salivary reactivity. Overall, no strong evidence was found for stronger cue-reactivity (= outcome difference between beer and water trial) in the DRD4 L and CNR1 C allele groups. The DRD4 VNTR polymorphism tended to moderate salivary reactivity such that DRD4 L participants showed a larger beverage effect than the DRD4 S participants. Unexpectedly, the DRD4 L participants reported, on average, less craving for alcohol and more subjective arousal during cue exposure, compared with the DRD4 S participants. As weekly alcohol consumption increased, the CNR1 C allele group tended to report more craving for alcohol during the alcohol exposure than the T allele group. The DRD4 and CNR1 polymorphisms do not appear to strongly moderate cue-reactivity after alcohol cue exposure, in male heavy drinkers.


Evaluation of the Effectiveness of Fermented Soybean-Lettuce Powder for Improving Menopausal Symptoms.
Menopause syndrome causes a decline in the quality of life of postmenopausal women. Hormone therapy is recommended for the treatment of menopausal syndromes. However, it has several side effects. Soybean has been safely used to relieve the symptoms of menopause. Lettuce has antidiabetic and anti-inflammatory effects and improves sleep quality. Natural nitric oxide metabolites are produced through fermentation, which increases the effectiveness of the functional substances. This study assessed the alleviation of menopausal syndrome symptoms by natural nitric oxide-containing soybean lettuce extract using the Kupperman index. This study included adult women with menopausal syndrome and a Kupperman index of ≥15. After a four-week study with 40 participants, the final analysis included 39 participants in the experimental group (n = 19) and the placebo group (n = 20). Body mass index, waist circumference, and the total cholesterol, low-density and high-density lipoprotein cholesterol, and triglyceride levels were not altered before and after treatment in both groups. There was a significant decrease in the Kupperman index after treatment in the experimental group, but no significant change was observed in the placebo group. Soybean lettuce extract alleviates menopause syndrome without any special side effects.


Variational bayesian blind deconvolution using a total variation prior.
In this paper, we present novel algorithms for total variation (TV) based blind deconvolution and parameter estimation utilizing a variational framework. Using a hierarchical Bayesian model, the unknown image, blur, and hyperparameters for the image, blur, and noise priors are estimated simultaneously. A variational inference approach is utilized so that approximations of the posterior distributions of the unknowns are obtained, thus providing a measure of the uncertainty of the estimates. Experimental results demonstrate that the proposed approaches provide higher restoration performance than non-TV-based methods without any assumptions about the unknown hyperparameters.


Fibroblast growth factor 23 in untreated nephrotic syndrome.
Despite its importance in bone and cardiovascular disease in subjects with kidney disease, there are no data on fibroblast growth factor 23 (FGF23) perturbations in nephrotic syndrome. We evaluated FGF23 and markers of mineral bone metabolism in subjects with untreated NS. In this cross-sectional study, we measured circulating levels of FGF23, 25-hydroxy vitamin D [25(OH)D], 1,25 di-hydroxy vitamin D [1,25(OH)2 D], serum albumin, serum calcium, phosphorus, creatinine and intact parathyroid hormone (iPTH) in 101 patients with adults onset NS and 40 healthy controls. We examined the correlation between FGF23 and markers of mineral bone metabolism. Compared to healthy controls, subjects with NS showed reduced levels of 25(OH)D (21.76 ± 10.18 vs 35.74 ± 40.27 nmol/L, P = 0.001), 1,25(OH)2 D (median; 37.80 vs 73.13 pmol/L, P = 0.0001) and FGF23 (37.81 ± 20.42 vs 48.20 ± 11.60 pg/mL, P = 0.004) levels. Serum phosphorus levels were marginally, but significantly higher in subjects with nephrotic syndrome compared to healthy controls (P = 0.004). Serum iPTH levels were significantly higher in subjects with NS compared to healthy controls (52.24 ± 39.58 vs 37.90 ± 14.60 pg/mL, P = 0.028). We conclude that FGF23 is reduced in subjects with NS compared to healthy controls. The reduced levels of Vitamin D, and urinary losses may contribute to lower levels of FGF23 in NS.


Hypothesis Learning in Automated Experiment: Application to Combinatorial Materials Libraries.
Machine learning is rapidly becoming an integral part of experimental physical discovery via automated and high-throughput synthesis, and active experiments in scattering and electron/probe microscopy. This, in turn, necessitates the development of active learning methods capable of exploring relevant parameter spaces with the smallest number of steps. Here, an active learning approach based on conavigation of the hypothesis and experimental spaces is introduced. This is realized by combining the structured Gaussian processes containing probabilistic models of the possible system's behaviors (hypotheses) with reinforcement learning policy refinement (discovery). This approach closely resembles classical human-driven physical discovery, when several alternative hypotheses realized via models with adjustable parameters are tested during an experiment. This approach is demonstrated for exploring concentration-induced phase transitions in combinatorial libraries of Sm-doped BiFeO3 using piezoresponse force microscopy, but it is straightforward to extend it to higher-dimensional parameter spaces and more complex physical problems once the experimental workflow and hypothesis generation are available.


Regulation of rat hepatic L-pyruvate kinase promoter composition and activity by glucose, n-3 polyunsaturated fatty acids, and peroxisome proliferator-activated receptor-alpha agonist.
Carbohydrate regulatory element-binding protein (ChREBP), MAX-like factor X (MLX), and hepatic nuclear factor-4alpha (HNF-4alpha) are key transcription factors involved in the glucose-mediated induction of hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3 polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome proliferator-activated receptor alpha (PPARalpha) agonist) interfere with glucose-stimulated L-PK gene transcription in vivo and in rat primary hepatocytes. Feeding rats a diet containing n-3 PUFA or WY14643 suppressed hepatic mRNA(L-PK) but did not suppress hepatic ChREBP or HNF-4alpha nuclear abundance. Hepatic MLX nuclear abundance, however, was suppressed by n-3 PUFA but not WY14643. In rat primary hepatocytes, glucose-stimulated accumulation of mRNA(LPK) and L-PK promoter activity correlated with increased ChREBP nuclear abundance. This treatment also increased L-PK promoter occupancy by RNA polymerase II (RNA pol II), acetylated histone H3 (Ac-H3), and acetylated histone H4 (Ac-H4) but did not significantly impact L-PK promoter occupancy by ChREBP or HNF-4alpha. Inhibition of L-PK promoter activity by n-3 PUFA correlated with suppressed RNA pol II, Ac-H3, and Ac-H4 occupancy on the L-PK promoter. Although n-3 PUFA transiently suppressed ChREBP and MLX nuclear abundance, this treatment did not impact ChREBP-LPK promoter interaction. HNF4alpha-LPK promoter interaction was transiently suppressed by n-3 PUFA. Inhibition of L-PK promoter activity by WY14643 correlated with a transient decline in ChREBP nuclear abundance and decreased Ac-H4 interaction with the L-PK promoter. WY14643, however, had no impact on MLX nuclear abundance or HNF4alpha-LPK promoter interaction. Although overexpressed ChREBP or HNF-4alpha did not relieve n-3 PUFA suppression of L-PK gene expression, overexpressed MLX fully abrogated n-3 PUFA suppression of L-PK promoter activity and mRNA(L-PK) abundance. Overexpressed ChREBP, but not MLX, relieved the WY14643 inhibition of L-PK. In conclusion, n-3 PUFA and WY14643/PPARalpha target different transcription factors to control L-PK gene transcription. MLX, the heterodimer partner for ChREBP, has emerged as a novel target for n-3 PUFA regulation.


Attomolar analyte sensing techniques (AttoSens): a review on a decade of progress on chemical and biosensing nanoplatforms.
Detecting the ultra-low abundance of analytes in real-life samples, such as biological fluids, water, soil, and food, requires the design and development of high-performance biosensing modalities. The breakthrough efforts from the scientific community have led to the realization of sensing technologies that measure the analyte's ultra-trace level, with relevant sensitivity, selectivity, response time, and sampling efficiency, referred to as Attomolar Analyte Sensing Techniques (AttoSens) in this review. In an AttoSens platform, 1 aM detection corresponds to the quantification of 60 target analyte molecules in 100 μL of sample volume. Herein, we review the approaches listed for various sensor probe design, and their sensing strategies that paved the way for the detection of attomolar (aM: 10-18 M) concentration of analytes. A summary of the technological advances made by the diverse AttoSens trends from the past decade is presented.


Endemic systemic mycoses: coccidioidomycosis, histoplasmosis, paracoccidioidomycosis and blastomycosis.
Endemic deep or systemic mycoses are common in specific geographical areas of the world. Coccidioidomycosis is present in semi-desert areas, histoplasmosis and paracoccidioidomycosis in tropical regions and blastomycosis belongs to temperate climates. The two former are widely distributed in the American continent and some tropical regions of the world; the third is limited to Central and South America, and the last to North America and Central and East Africa. These mycoses all have a similar pathogenesis, as the inoculum enters the host through the respiratory tract. Cutaneous manifestations are secondary to lymphatic and hematogenous dissemination. These deep mycoses are exceptional in Europe. Most cases are observed in returning travelers from endemic areas, aid workers, archaeologists, speleologist and immigrants. However, there have been some autochthonous cases of histoplasmosis due to Histoplasma capsulatum var. capsulatum reported in European countries such as Italy and Germany. In this article, we provide up-to-date epidemiological, clinical, diagnostic and therapeutic data on the four most important imported systemic mycoses in Europe.


Validation of diet composition for the Dietary Approaches to Stop Hypertension trial. DASH Collaborative Research Group.
The Dietary Approaches to Stop Hypertension trial involved 4 clinical sites at which 459 participants (in 5 cohorts) were fed 3 dietary patterns over 11 weeks per cohort. The 3 patterns were a control diet, a fruits and vegetables diet, and a combination diet. Before the intervention, key nutrient levels in each diet were validated at 2 energy levels (2,100 and 3,100 kcal) by chemical analysis of the prepared menus. During intervention, diets were sampled across all cohorts, sites, and energy levels, and 7-day menu cycle composites were assayed. In general, sodium, potassium, calcium, and magnesium in the validated menus for each diet/energy level met the nutrient targets, though moderate variability was evident among individual menus, particularly for potassium, calcium, and magnesium. However, as intended, there was clear separation and no overlap in mineral levels in individual menus of diets that were designed to differ. During intervention, macronutrient contents met nutrient goals. Sodium, potassium, calcium, and magnesium in the diets generally met target levels, though potassium in the fruits and vegetables diet was 11% to 23% below target. There were no consistent differences in nutrient levels between sites. The mean nutrient levels in the validated menus and diets sampled during intervention were in excellent agreement with each other, though sodium was somewhat higher (approximately 6%) in the diets from intervention vs validation. These results indicate the success of the quality control measures implemented and suggested consistent overall diet composition throughout the 28 months during which the study was conducted.


Diagnostic power of the noninvasive condom catheter method in patients eligible for transurethral resection of the prostate.
The aim of this study was to determine the accuracy of the non-invasive condom catheter method for diagnosing B(ladder) O(utlet) O(bstruction) in patients eligible for T(rans)U(rethral) R(esection) of the P(rostate). A group of 71 patients eligible for TURP on clinical grounds were invasively and non-invasively studied. On the basis of invasive pressure-flow studies they were stratified into obstructed, equivocal or unobstructed, according to the International Continence Society standard. Subsequently they were diagnosed non-invasively on the basis of a free flowrate measurement, or on the basis of the free flowrate measurement plus the isovolumetric bladder pressure measured with the condom catheter method. R(eceiver) O(perating) C(haracteristic)s were calculated. The A(rea) U(nder) the (RO)C for discriminating unobstructed/equivocal patients from obstructed patients was 0.68 in our population. This improved to 0.84 for the 50 patients in whom the isovolumetric bladder pressure was not underestimated by the non-invasive method. In our population of TURP patients, the low flowrates affected the accuracy of the condom method to a degree that it did not perform better than a free flowrate measurement, which performed remarkably well. By excluding measurements in which the condom pressure underestimated the isovolumetric bladder pressure this method may contribute to a more accurate, patient friendly diagnosis of BOO in these patients. In the present study this exclusion was done by comparison with an invasive pressure measurement. A practical non-invasive test would necessitate a non-invasive exclusion criterion, which might be based on the risetime of the condom pressure.


Isolation and amino acid sequence of corticotropin-releasing factor from pig hypothalami.
A polypeptide was isolated from acid extracts of porcine hypothalami on the basis of its high ability to stimulate the release of corticotropin from superfused rat pituitary cells. After an initial separation by gel filtration on Sephadex G-25, further purification was carried out by reversed-phase HPLC. The isolated material was homogeneous chromatographically and by N-terminal sequencing. Based on automated gas-phase sequencing of the intact and CNBr-cleaved peptide and on carboxypeptidase Y digestion, the primary structure of this 41-residue polypeptide was determined to be Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val -Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys -Leu-Met-Glu-Asn-Phe-NH2. Porcine corticotropin-releasing factor (CRF) shares a common amino acid sequence (residues 1-39) with rat and human CRF and differs from these only in positions 40 and 41. However, isoleucine was also present at position 40 in porcine CRF, but in a smaller percentage than asparagine. The sequence of porcine CRF shows 83% homology with ovine CRF. Porcine CRF markedly stimulated the release of corticotropin from superfused rat and pig pituitary cells. The biological activity and close structural relationship to CRFs of other species indicate that the peptide isolated represents porcine CRF.


Genome-Wide Loss of Heterozygosity and DNA Copy Number Aberration in HPV-Negative Oral Squamous Cell Carcinoma and Their Associations with Disease-Specific Survival.
Oral squamous cell cancer of the oral cavity and oropharynx (OSCC) is associated with high case-fatality. For reasons that are largely unknown, patients with the same clinical and pathologic staging have heterogeneous response to treatment and different probability of recurrence and survival, with patients with Human Papillomavirus (HPV)-positive oropharyngeal tumors having the most favorable survival. To gain insight into the complexity of OSCC and to identify potential chromosomal changes that may be associated with OSCC mortality, we used Affymtrix 6.0 SNP arrays to examine paired DNA from peripheral blood and tumor cell populations isolated by laser capture microdissection to assess genome-wide loss of heterozygosity (LOH) and DNA copy number aberration (CNA) and their associations with risk factors, tumor characteristics, and oral cancer-specific mortality among 75 patients with HPV-negative OSCC. We found a highly heterogeneous and complex genomic landscape of HPV-negative tumors, and identified regions in 4q, 8p, 9p and 11q that seem to play an important role in oral cancer biology and survival from this disease. If confirmed, these findings could assist in designing personalized treatment or in the creation of models to predict survival in patients with HPV-negative OSCC.


Swarna Bhasma Induces Antigen-Presenting Abilities of Macrophages and Helps Antigen Experienced CD4+ T Cells to Acquire Th1 Phenotypes Against Leishmania donovani Antigens.
In leishmaniasis, the protective immunity is largely mediated by proinflammatory cytokine producing abilities of T cells and an efficient parasite killing by phagocytic cells. Notwithstanding a substantial progress that has been made during last decades, the mechanisms or factors involved in establishing protective immunity against Leishmania are not identified. In ancient Indian literature, metallic "bhasma," particularly that of "swarna" or gold (fine gold particles), is indicated as one of the most prominent metal-based therapeutic medicine, which is known to impart protective and curative properties in various health issues. In this work, we elucidated the potential of swarna bhasma (SB) on the effector properties of phagocytes and antigen-activated CD4+ T cells in augmenting the immunogenicity of L. donovani antigens. The characterization of SB revealing its shape, size, composition, and measurement of cytotoxicity established the physiochemical potential for its utilization as an immunomodulator. The activation of macrophages with SB enhanced their capacity to produce nitric oxide and proinflammatory cytokines, which eventually resulted in reduced uptake of parasites and their proliferation in infected cells. Further, in Leishmania-infected animals, SB administration reduced the generation of IL-10, an anti-inflammatory cytokine, and enhanced pro-inflammatory cytokine generation by antigen activated CD4+ T cells with increased frequency of double (IFNγ+/TNFα+) and triple (IFNγ+TNFα+IL-2+) positive cells and abrogated disease pathogeneses at the early days of infection. Our results also suggested that cow-ghee (A2) emulsified preparation of SB, either alone or with yashtimadhu, a known natural immune modulator which enhances the SB's potential in enhancing the immunogenicity of parasitic antigens. These findings suggested a definite potential of SB in enhancing the effector functions of phagocytes and CD4+ T cells against L. donovani antigens. Therefore, more studies are needed to elucidate the mechanistic details of SB and its potential in enhancing vaccine-induced immunity.


HDACs in skeletal muscle remodeling and neuromuscular disease.
Skeletal muscle is made of heterogeneous myofibers with different contractile and metabolic properties. The diverse functionality of myofibers enables skeletal muscle to carry out different tasks from maintaining body posture to performing active movements. In addition to motility, skeletal muscle, which constitutes 40% of body mass, is also a key target of insulin action and performs an essential function in glucose metabolism. Adult skeletal muscle is a highly adaptive organ system and can undergo specific changes in contractile and metabolic properties to meet different functional demands. This plasticity of myofibers reflects a highly coordinated change in gene expression program that is controlled by neural activity. The capacity for on-demand remodeling confers skeletal muscle the remarkable adaptability important for animal survival; its dysregulation, however, could contribute to muscle and metabolic diseases. How neural activity dictates transcriptional programming to modify muscle functionality and diversity is a fundamental issue. Recent studies have identified members of class IIa HDACs as important effectors in both physiological and pathological muscle remodeling. By way of modifying myofiber properties, pharmacological manipulation of IIa HDACs activity could have potential therapeutic utility in the treatment of muscle disorders.


In vivo X-ray fluorescence of lead in bone using K X-ray excitation with 109Cd sources: radiation dosimetry studies.
Independent experiments have been performed at two centers, to evaluate the dosimetric properties of their respective 109Cd K X-ray fluorescence (XRF) bone lead measurement systems. Measurements were made of the dose to several points on the skin on the lower leg, at the surface of the tibia, in the red marrow tibia cavity, at the midcalf, and in the abdominal region occupied by the conceptus. Overall agreement between the two data sets was found. Similarities and differences are discussed. The effective dose values for an in vivo measurement of tibia lead concentration in 1-, 5-, and 10-year-old and adult subjects were calculated from one data set to be 1100, 420, 190, and 34/38 (male/female) nSv, respectively, for an in vivo median precision (one standard deviation) of 4.9 micrograms Pb (g bone mineral)-1 for a 30-min adult measurement.


Growth cone macropinocytosis of neurotrophin receptor and neuritogenesis are regulated by neuron navigator 1.
Neuron navigator 1 (Nav1) is a cytoskeleton-associated protein expressed during brain development that is necessary for proper neuritogenesis, but the underlying mechanisms are poorly understood. Here we show that Nav1 is present in elongating axon tracts during mouse brain embryogenesis. We found that depletion of Nav1 in cultured neurons disrupts growth cone morphology and neurotrophin-stimulated neuritogenesis. In addition to regulating both F-actin and microtubule properties, Nav1 promotes actin-rich membrane ruffles in the growth cone and promotes macropinocytosis at those membrane ruffles, including internalization of the TrkB receptor for the neurotrophin brain-derived neurotropic factor (BDNF). Growth cone macropinocytosis is important for downstream signaling, neurite targeting, and membrane recycling, implicating Nav1 in one or more of these processes. Depletion of Nav1 also induces transient membrane blebbing via disruption of signaling in the Rho GTPase signaling pathway, supporting the novel role of Nav1 in dynamic actin-based membrane regulation at the cell periphery. These data demonstrate that Nav1 works at the interface of microtubules, actin, and plasma membrane to organize the cell periphery and promote uptake of growth and guidance cues to facilitate neural morphogenesis during development.


Novel amplitude and frequency demodulation algorithm for a virtual dynamic atomic force microscope.
Frequency-modulated atomic force microscopy (FM-AFM; also called non-contact atomic force microscopy) is the prevailing operation mode in (sub-)atomic resolution vacuum applications. A major obstacle that prohibits a wider application range is the low frame capture rate. The speed of FM-AFM is limited by the low bandwidth of the automatic gain control (AGC) and frequency demodulation loops. In this work we describe a novel algorithm that can be used to overcome these weaknesses. We analysed the settling times of the proposed loops and that of the complete system, and we found that an approximately 70-fold improvement can be achieved over the existing real and virtual atomic force microscopes. We show that proportional-integral-differential controllers perform better in the frequency demodulation loop than conventional proportional-integral controllers. We demonstrate that the signal to noise ratio of the proposed system is 5.7 × 10(-5), which agrees with that of the conventional systems; thus, the new algorithm would improve the performance of FM-AFMs without compromising the resolution.


Registered nurse leadership style and confidence in delegation.
Leadership and confidence in delegation are two important explanatory constructs of nursing practice. The relationship between these constructs, however, is not clearly understood. To be successful in their roles as leaders, regardless of their experience, registered nurses (RNs) need to understand how to best delegate. The present study explored and described the relationship between RN leadership styles, demographic variables and confidence in delegation in a community teaching hospital. Utilizing a cross-sectional survey design, RNs employed in one acute care hospital completed questionnaires that measured leadership style [Path-Goal Leadership Questionnaire (PGLQ)] and confidence in delegating patient care tasks [Confidence and Intent to Delegate Scale (CIDS)]. Contrary to expectations, the data did not confirm a relationship between confidence in delegating tasks to unlicensed assistive personnel (UAPs) and leadership style. Nurses who were diploma or associate degree prepared were initially less confident in delegating tasks to UAPs as compared with RNs holding a bachelor's degree or higher. Further, after 5 years of clinical nursing experience, nurses with less educational experience reported more confidence in delegating tasks as compared with RNs with more educational experience. The lack of a relationship between leadership style and confidence in delegating patient care tasks were discussed in terms of the PGLQ classification criteria and hospital unit differences. As suggested by the significant two-way interaction between educational preparation and clinical nursing experience, changes in the nurse's confidence in delegating patient care tasks to UAPs was a dynamic changing variable that resulted from the interplay between amount of educational preparation and years of clinical nursing experience in this population of nurses. Clearly, generalizability of these findings to nurses outside the US is questionable, thus nurse managers must be familiar with the Nurse Practice Act in their country in order to ensure proper delegation of tasks to appropriate assistive personnel. It is imperative that nurse managers provide nurses with the educational opportunities necessary to develop delegation and supervision strategies to adapt to the changing RN role while adhering to differences in scope of practice. Globally, RNs are caring for increasing numbers of acutely ill patients with scarce resources ensuring an adequately trained RN/UAP team can help support optimal patient care.


No Obvious Role for Suspicious Oral Pathogens in Arthritis Development.
A particular role for Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa) has been suggested in periodontitis and rheumatoid arthritis (RA), as these bacteria could initiate the formation of rheumatoid factor (RF) and anticitrullinated protein autoantibodies (ACPA). We assessed whether serum antibodies against Pg and Aa in RA patients and non-RA controls reflect the subgingival presence of Pg and Aa, and evaluated the relationship of these antibodies to the severity of periodontal inflammation and RA-specific serum autoantibodies. In 70 Indonesian RA patients and 70 non-RA controls, the subgingival presence of Pg and Aa was assessed by bacterial 16S rRNA gene sequencing, and serum IgG levels specific for Pg and Aa were determined. In parallel, serum levels of ACPA (ACPA:IgG,IgA) and RF (RF:IgM,IgA) were measured. The extent of periodontal inflammation was assessed by the periodontal inflamed surface area. In both RA patients and the controls, the presence of subgingival Pg and Aa was comparable, anti-Pg and anti-Aa antibody levels were associated with the subgingival presence of Pg and Aa, and anti-Pg did not correlate with ACPA or RF levels. The subgingival Pg and Aa were not related to RA. No noteworthy correlation was detected between the antibodies against Pg and Aa, and RA-specific autoantibodies.


Increased expression diversity buffers the loss of adaptive potential caused by reduction of genetic diversity in new unfavourable environments.
Mechanisms underlying adaptation to rapid environmental change are issues in evolutionary biology. It is widely accepted that reduction in genetic diversity when suddenly exposed to an unfavourable environment limits the adaptive potential of populations. With growing empirical evidence that expression diversity is likely to increase in the new environment, the role that expression diversity plays in adaptation needs to be theorized. Here, we first established a negative exponential relationship between expression diversity and genetic diversity using a phenomenological differential equation. We then derived a complex trade-off relationship between the changes of expression and genetic diversity, which followed a combination of exponential functions. Furthermore, we found the increase in expression diversity could buffer the loss of adaptive potential as genetic diversity decreased to a certain extent. These theoretical deductions were validated by transcriptomic data of Miscanthus lutarioriparius grown in two experimental fields and supported by good fit and random simulation. These results suggest that increased expression diversity may compensate the loss of genetic diversity and allow the populations to maintain a certain level of phenotypic variation to cope with sudden environmental change. This may buffer the quick diminishing of adaptive potential and consequently increases the change of adaptation to the new environment.


Supplementation of oat (Avena sativa L.) extract abates alcohol-induced acute liver injury in a mouse model.
Dietary supplementation of oats has been associated with reduced risk of cardiovascular disease, diabetes, and gastrointestinal disorders. The role of oat extract as prophylactic in treating acute liver injury is not thoroughly established. We, therefore, hypothesized that oat extract would exert protective effect against alcohol-induced acute liver injury in a mouse model. To test this hypothesis, male C57BL/6 mice were pretreated with phenolic-enriched ethyl acetate (EA) fraction of oats (prepared by fractionating aqueous ethanolic extract with solvents of increasing polarity) at dosages of 125 and 250 mg kg-1 d-1 for 12 consecutive days. Acute liver injury was induced by administering 5 doses of 50% ethanol intragastrically (10 g/kg body weight) to mice at an interval of 12 hours. The alcohol-induced liver injury was evaluated by measuring serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, antioxidant parameters, mitochondrial function, and histology of liver tissue. Our results demonstrated that pretreatment with EA fraction at 250 mg kg-1 d-1 significantly (P < .001 for aspartate aminotransferase, alanine aminotransferase, and thiobarbituric acid-reactive species and P < .01 for lactate dehydrogenase and nitrites) reduced the levels of liver injury markers and significantly (P < .001 for glutathione reductase and glutathione S-transferase; P < .01 for catalase, superoxide dismustase, and vitamin C; P < .05 for reduced glutathione and NAD(P)H quinone dehydrogenase 1) increased the levels of antioxidant defenses. Furthermore, EA-pretreated mice showed mechanistic inhibition of nuclear factor κB signaling pathway through decreased phosphorylation and degradation of IκBα. We conclude that phenolic-enriched EA fraction of oats has immense potential to serve as dietary intervention against alcohol-induced liver damage.


Blood electrolytes exhibit a strong influence on the mobility of artificial catalytic microengines.
The developments in biomedical sciences foresee the inclusion of self-propelled catalytic micromotors for in vivo therapeutic strategies in the near future. We show here that blood electrolytes, such as Na(+), K(+), Ca(2+), Cl(-), SO4(2-) and phosphates, decrease the mobility of the Pt catalyzed tubular microjets. This effect is significant and in many cases, the microjets are completely disabled at physiologically relevant concentrations of the ions. A strategy to counterbalance this negative influence is suggested. These findings have a strong influence in the field of bubble-propelled artificial micromotors, where applications in blood are often envisioned.


Tendomers - force sensitive bis-rotaxanes with jump-like deformation behavior.
We consider tendomers, which are formed by pairs of rotaxane molecules where each one consists of a linear chain with N Kuhn segments that are threaded through m + 1 small rings. These rings can slide freely along the chains but cannot pass through each other or detach from the chain. By crosslinking the first slide rings of the two rotaxanes a slip-link between the two polymer backbones is formed. The remaining m slide rings form a one-dimensional real gas confined between the slip-link and the other chain end. When pulling the two ends of the chains which are next to the slip-link, an applied external force causes a compression of the slide rings. We consider the exact partition function of this model taking into account the repulsion between the slide rings and the finite extensibility of the polymer chains which is compared with Monte-Carlo simulation data for the tendomer under external force. To understand the underlying physics of the tendomer, we discuss also a simplified thermodynamic approach by taking into account the interplay between chain deformation and compression of the gas of slide rings. We show that tendomers exhibit a jump like mechanical response at a critical pulling force ∝ (m/N)1/2, where the compression of the gas of slide rings sets is. While the tendomer deforms at low forces similar to a short chain of about 2(N - m)/(m + 2) segments, it displays a jump-like decrease in elasticity beyond the critical force and deforms then like a chain of about 2(N - m) segments, before the finite extensibility of the chains sets in. This results in a strong peak of the mechanical susceptibility of the tendomer as a function of the applied force. Thus, tendomers are molecular-elastic elements with a jump-like strain-softening behavior. Our results are generalized to asymmetric tendomers that differ in the number of slide rings per rotaxane, which allows to design multi-step force extension curves with defined critical forces. Finally, we discuss some aspects of gels formed by tendomers, which are promising candidates for tailor-made stress sensitive elastomers.


MIF Inhibitor ISO-1 Protects Photoreceptors and Reduces Gliosis in Experimental Retinal Detachment.
Photoreceptor death and retinal gliosis underlie the majority of vision threatening retinal diseases including retinal detachment (RD). Although the underlying pathobiology of vision limiting processes in RD is not fully understood, inflammation is known to play a critical role. We conducted an iTRAQ proteomic screen of up- and down-regulated proteins in a murine model of RD to identify potential targetable candidates. Macrophage migration inhibitory factor (MIF) was identified and evaluated for neurotoxic and pro-gliotic effects during RD. Systemic administration of the MIF inhibitor ISO-1 significantly blocked photoreceptor apoptosis, outer nuclear layer (ONL) thinning, and retinal gliosis. ISO-1 and MIF knockout (MIFKO) had greater accumulation of Müller glia pERK expression in the detached retina, suggesting that Müller survival pathways might underlie the neuroprotective response. Our data show the feasibility of the MIF-inhibitor ISO-1 to block pathological damage responses in retinal detachment and provide a rationale to explore MIF inhibition as a potential therapeutic option for RD.


Improving cascade outcomes for active TB: A global systematic review and meta-analysis of TB interventions.
To inform policy and implementation that can enhance prevention and improve tuberculosis (TB) care cascade outcomes, this review aimed to summarize the impact of various interventions on care cascade outcomes for active TB. In this systematic review and meta-analysis, we retrieved English articles with comparator arms (like randomized controlled trials (RCTs) and before and after intervention studies) that evaluated TB interventions published from January 1970 to September 30, 2022, from Embase, CINAHL, PubMed, and the Cochrane library. Commentaries, qualitative studies, conference abstracts, studies without standard of care comparator arms, and studies that did not report quantitative results for TB care cascade outcomes were excluded. Data from studies with similar comparator arms were pooled in a random effects model, and outcomes were reported as odds ratio (OR) with 95% confidence interval (CI) and number of studies (k). The quality of evidence was appraised using GRADE, and the study was registered on PROSPERO (CRD42018103331). Of 21,548 deduplicated studies, 144 eligible studies were included. Of 144 studies, 128 were from low/middle-income countries, 84 were RCTs, and 25 integrated TB and HIV care. Counselling and education was significantly associated with testing (OR = 8.82, 95% CI:1.71 to 45.43; I2 = 99.9%, k = 7), diagnosis (OR = 1.44, 95% CI:1.08 to 1.92; I2 = 97.6%, k = 9), linkage to care (OR = 3.10, 95% CI = 1.97 to 4.86; I2 = 0%, k = 1), cure (OR = 2.08, 95% CI:1.11 to 3.88; I2 = 76.7%, k = 4), treatment completion (OR = 1.48, 95% CI: 1.07 to 2.03; I2 = 73.1%, k = 8), and treatment success (OR = 3.24, 95% CI: 1.88 to 5.55; I2 = 75.9%, k = 5) outcomes compared to standard-of-care. Incentives, multisector collaborations, and community-based interventions were associated with at least three TB care cascade outcomes; digital interventions and mixed interventions were associated with an increased likelihood of two cascade outcomes each. These findings remained salient when studies were limited to RCTs only. Also, our study does not cover the entire care cascade as we did not measure gaps in pre-testing, pretreatment, and post-treatment outcomes (like loss to follow-up and TB recurrence). Among TB interventions, education and counseling, incentives, community-based interventions, and mixed interventions were associated with multiple active TB care cascade outcomes. However, cost-effectiveness and local-setting contexts should be considered when choosing such strategies due to their high heterogeneity.


Evidence for an inequality in the forces that generate principal and reverse bends in sperm flagella.
The response of the mechanism initiating flagellar bends to imposed mechanical transients has been studied by holding the head of a sea urchin sperm in the tip of a sinusoidally vibrating micropipet and then displacing the micropipet laterally at a speed of up to 1.15 micron ms-1 for 1.5 beat cycle, without vibration, before resuming sinusoidal vibration with the initial phase, frequency and amplitude at the new location of the pipet. This transient displacement of the micropipet delays the initiation of the bend that was due to initiate 0.5 beat cycle after onset of the displacement. The amount of this delay increases with the speed of the displacement, for speeds up to 1 micron ms-1. Analysis of the flagellar waveforms during the transient showed that with imposed displacements at speeds of equal magnitude, the initiation of a principal bend was delayed to a longer extent than that of a reverse bend. At a micropipet speed of 0.75 micron ms-1, there was an average delay of 0.21 beat cycle in the initiation time of a principal bend as compared to a delay of only about 0.04 beat cycle in the initiation time of a reverse bend during displacements in the opposite direction. For both principal and reverse bends, the second bend due to initiate during the transient displacement initiated in most of the cases with no delay, regardless of the micropipet speed. Our results suggest that the force generated by microtubule sliding to initiated a new reverse bend is greater than that generated to initiate a principal bend.


Tunable physical properties in BiAl1-x Mn x O3 thin films with novel layered supercell structures.
Morphological control in oxide nanocomposites presents enormous opportunities for tailoring the physical properties. Here, we demonstrate the strong tunability of the magnetic and optical properties of Bi-based layered supercell (LSC) multiferroic structures, i.e., BiAl1-x Mn x O3, by varying the Al : Mn molar ratio. The microstructure of the LSC structure evolves from a supercell structure to Al-rich pillars in the supercell structure as the Al molar ratio increases. The LSC structures present excellent multiferroic properties with preferred in-plane magnetic anisotropy, a tunable band gap and anisotropic dielectric permittivity, all attributed to the microstructure evolution and their anisotropic microstructure. Three different strain relaxation mechanisms are identified that are active during thin film growth. This study provides opportunities for microstructure and physical property tuning which can also be explored in other Bi-based LSC materials with tailorable multiferroic and optical properties.


Body mass index of married Bangladeshi women: trends and association with socio-demographic factors.
Body mass index (BMI) is a good indicator of nutritional status in a population. In underdeveloped countries like Bangladesh, this indicator provides a method that can assist intervention to help eradicate many preventable diseases. This study aimed to report on changes in the BMI of married Bangladeshi women who were born in the past three decades and its association with socio-demographic factors. Data for 10,115 married and currently non-pregnant Bangladeshi women were extracted from the 2007 Bangladesh Demographic and Health Survey (BDHS). The age range of the sample was 15-49 years. The mean BMI was 20.85 ± 3.66 kg/m(2), and a decreasing tendency in BMI was found among birth year cohorts from 1972 to 1992. It was found that the proportion of underweight females has been increasing in those born during the last 20 years of the study period (1972 to 1992). Body mass index increased with increasing age, education level of the woman and her husband, wealth index, age at first marriage and age at first delivery, and decreased with increasing number of ever-born children. Lower BMI was especially pronounced among women who were living in rural areas, non-Muslims, employed women, women not living with their husbands (separated) or those who had delivered at home or non-Caesarean delivery.


Decision making for the critically ill neonate near the end of life.
Our purpose was to review the medical records of 122 infants who died in our neonatal intensive care unit (NICU) to characterize decision making for the critically ill neonate near the end of life. The majority of deaths (72%) were related to some complication of prematurity. Families participated in the decision-making process in 75% of the instances. A decision was made to limit, withdraw, or withhold life-sustaining treatment for 82% of the infants. At the time of decision making, prognosis was judged to be poor or hopeless and the burdens of treatment unacceptable for 90% of the infants. This study confirms that health care providers and families together can confront the ethical decision of whether to continue or forego life-sustaining treatment for the critically ill neonate near the end of life and, in the majority of cases, will choose to limit, withdraw, or withhold such support.


Competition, cooperation, and mutation: improving a synthetic replicator by light irradiation.
Replication and mutation are necessary elements of evolution, and some properties of self-replicating molecules (replicators) can be explored with synthetic structures. Selection and evolution at the molecular level require systems capable of competition and inheritable change. These phenomena have now been observed with synthetic molecules. Two such molecules were prepared having sufficient structural similarity that they catalyzed each other's formation as well as their own. One of the replicators bears a photochemically active function that is cleaved on irradiation. The resulting species is more effective at replication than the original and rapidly takes over the system's resources.


Variants of the 3' region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases.
The CagA protein of Helicobacter pylori is an immunogenic antigen of variable size and unknown function that has been associated with increased virulence as well as two mutually exclusive diseases, duodenal ulcer and gastric carcinoma. The 3' region of the cagA gene contains repeated sequences. To determine whether there are structural changes in the 3' region of cagA that predict outcome of H. pylori infection, we examined 155 cagA gene-positive H. pylori isolates from Japanese patients including 50 patients with simple gastritis, 40 with gastric ulcer, 35 with duodenal ulcer, and 30 with gastric cancer. The 3' region of the cagA gene was amplified by PCR followed by sequencing. CagA proteins were detected by immunoblotting using a polyclonal antibody against recombinant CagA. One hundred forty-five strains yielded PCR products of 642 to 651 bp; 10 strains had products of 756 to 813 bp. The sequence of the 3' region of the cagA gene in Japan differs markedly from the primary sequence of cagA genes from Western isolates. Sequence analysis of the PCR products showed four types of primary gene structure (designated types A, B, C, and D) depending on the type and number of repeats. Six of the seven type C strains were found in patients with gastric cancer (P < 0.01 in comparison to noncancer patients). Comparison of type A and type C strains from patients with gastric cancer showed that type C was associated with higher levels of CagA antibody and more severe degrees of atrophy. Differences in cagA genotype may be useful for molecular epidemiology and may provide a marker for differences in virulence among cagA-positive H. pylori strains.


Genetic- and Lifestyle-dependent Dental Caries Defined by the Acidic Proline-rich Protein Genes PRH1 and PRH2.
Dental caries is a chronic infectious disease that affects billions of people with large individual differences in activity. We investigated whether PRH1 and PRH2 polymorphisms in saliva acidic proline-rich protein (PRP) receptors for indigenous bacteria match and predict individual differences in the development of caries. PRH1 and PRH2 variation and adhesion of indigenous and cariogenic (Streptococcus mutans) model bacteria were measured in 452 12-year-old Swedish children along with traditional risk factors and related to caries at baseline and after 5-years. The children grouped into low-to-moderate and high susceptibility phenotypes for caries based on allelic PRH1, PRH2 variation. The low-to-moderate susceptibility children (P1 and P4a-) experienced caries from eating sugar or bad oral hygiene or infection by S. mutans. The high susceptibility P4a (Db, PIF, PRP12) children had more caries despite receiving extra prevention and irrespective of eating sugar or bad oral hygiene or S. mutans-infection. They instead developed 3.9-fold more caries than P1 children from plaque accumulation in general when treated with orthodontic multibrackets; and had basic PRP polymorphisms and low DMBT1-mediated S. mutans adhesion as additional susceptibility traits. The present findings thus suggest genetic autoimmune-like (P4a) and traditional life style (P1) caries, providing a rationale for individualized oral care.


Qualitative analysis of adhesive interface nanoleakage using FE-SEM/EDS.
The purpose of this study was to evaluate the quality of short term sealing of current adhesives. Five adhesive systems were used and evaluated in this study; two kinds of two-step adhesives (Single Bond and Clearfil SE Bond) and three one-step adhesives (Clearfil S3 Bond, G Bond and One-Up Bond F-plus). Flat occlusal superficial dentin surfaces from extracted human third molars were finished with wet 600-grit silicon-carbide paper and bonded with one of the adhesives. After 24h storage at 37 degrees C in water, the bonded assemblies were sectioned into approximately 1mm thick slabs. Two central slabs from each tooth were chosen and immersed into 50% (w/v) solution of silver ammoniacal nitrate for 18 h and exposed to photodeveloping solution for 6h. The specimens were then slightly polished, argon ion-etched. In order to examine the nanoleakage within the resin/dentin interface, penetration of silver was observed in a field emission (FE)-SEM using yttrium-aluminium-garnet (YAG) backscattered electron mode. EDS analysis was also carried out in parallel to identify the existence of metallic silver particles. The penetration pattern of silver depended on the adhesive used, indicating different nanoleakage in different adhesive systems. Single Bond, One-Up Bond F-plus and G Bond showed clear silver uptake in both the adhesive and hybrid layer. Clearfil SE Bond showed less silver penetration and slight silver peak on the elemental energy spectroscopy of EDS. Clearfil S3 Bond did not display clear silver penetration under 2000x magnification by FE-SEM, and no existence of metallic silver of the Clearfil S3 Bond group by EDS, could be detected. The nanoleakage, as well as its location depends on the adhesives. Different nanoleakage expressions were revealed between two-step and one-step adhesives and also among one-step adhesives themselves.


The first eight months of Sweden's COVID-19 strategy and the key actions and actors that were involved.
COVID-19 has affected millions of people worldwide. This paper reviews the Swedish pandemic response. A narrative review was carried out and a timeline constructed. By September 1, 2020, 0.8% of Swedish residents had tested positive for the virus and 0.06% of the population had died, which was higher than neighbouring Nordic countries, but lower than some European countries with general lockdowns. The main actors were the Public Health Agency, the National Board of Health and Welfare, the Civil Contingencies Agency and the Government. County councils and regions implemented policies, in conjunction with the Department of Education and county administrative boards. Sweden's response was less invasive than many other countries, with no general lockdown. It focused on mitigation: slowing, but not stopping, the pandemic. Physical distancing was recommended in public spaces, but mandatory in bars, restaurants and at events. Visits to nursing facilities were banned. Kindergartens and schools for children up to 16 stayed open, but closed for older children for three months. There were no enforced quarantines for infected households or geographical regions, and facemasks were not recommended outside health care. Sweden chose a different pandemic strategy to its peer nations. This paper examines the first eight months.


Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Chronic Leukemia Working Party. European Bone Marrow Transplantation Group.
We studied the clinical course of 130 chronic myeloid leukemia (CML) patients (89 males and 41 females) in the European Bone Marrow Transplantation Group (EBMT) registry who received transplants before January 1, 1988 and who subsequently had evidence of recurrent leukemia. All patients had received a pretransplant conditioning regimen including total body irradiation (TBI). The first evidence of relapse was cytogenetic only in 74 (57%) patients and hematologic in 56 (43%). The overall actuarial survival from relapse was 36% at 6 years, with a significantly higher proportion of survivors among female patients (53% v 30%; P < .002). In univariate analysis, the 6-year probability of survival was 52% for patients with cytogenetic relapse and 30% for patients relapsing in chronic phase (CP), while no patient who relapsed in advanced phase (AP or BC) survived more than 3.5 years from relapse (P < .0001). The actuarial survival of patients relapsing before 6 months, between 6 and 12 months, and later than 12 months after transplant was 27%, 26%, and 45%, respectively (P < .002). Among patients with cytogenetic relapse, partial or complete disappearance of Ph-positive cells occurred in 40% of untreated patients and in 42% of those treated with interferon (IFN). However, IFN therapy significantly delayed progression toward hematologic disease. Cytogenetic responses were observed in 25% of patients who received IFN for relapse into CP, while only one minor cytogenetic response was reported in patients on conventional chemotherapy. For patients presenting with cytogenetic relapse as well as for those in hematologic relapse, IFN therapy significantly improved the 2-year probability of survival. However, long-term survival for IFN-treated patients in either group was not different from long-term survival in comparable patients not receiving IFN therapy. Twenty-nine patients of this series underwent a second bone marrow transplant (BMT) and the projected survival at 4 years after the second transplant is 28%. In multivariate Cox regression analysis, four factors remained significantly associated with survival: disease phase at relapse (P < .0001), duration of time interval from BMT to relapse (P = .0001), interferon therapy at relapse (P = .0024), and patient sex (P = .0032). This retrospective study provides evidence that some patients who relapse after BMT may benefit from treatment with IFN; a second BMT may offer the chance of cure. Data from this analysis may be useful in designing future prospective trials on posttransplant CML relapse.


Holmium Laser Enucleation vs Bipolar Plasmakinetic Enucleation of a Large Volume Benign Prostatic Hyperplasia: A Randomized Controlled Trial.
Objectives: To compare safety and efficacy of bipolar plasmakinetic enucleation of prostate (BPEP) vs holmium laser enucleation of prostate (HoLEP) for management of large benign prostatic hyperplasia (BPH) (>80 g). Patients and Methods: Patients with failed medical treatment, International Prostate Symptom Score (IPSS) >13, peak urinary flow rate (Qmax)<15 mL/s and prostate size ≥80 g were enrolled in this randomized controlled trial from November 2016 to February 2018 and managed by HoLEP (Group A; 33 patients) or BPEP (Group B; 31 patients). Patients on anticoagulants (AC) were not excluded. Patients were followed up for 12 months. Perioperative data were compared between both groups using Student's-t, Mann-Whitney, Paired-t, Wilcoxon signed rank, chi-square, or Fisher-exact tests as appropriate. Results: There was no significant difference between both groups in age, rate of presentation with urinary retention, recurrent hematuria, frequency of patients on ACs/antiplatelets, prostate size, prostate specific antigen (PSA), Qmax, IPSS, quality of life (QoL), and post-void residual urine (PVRU). Operative time was significantly longer in BPEP (p = 0.003) and catheterization duration (p = 0.019). Other perioperative parameters including level of Na+ and hemoglobin, resected tissue weight, hospital stay, and complications were not significantly different between both groups. There was no need for blood transfusion in all patients. There was significant postoperative improvement in IPSS, PVRU, QoL, PSA, and Qmax in each group. However, there was no significant difference between both groups in these parameters. Conclusion: HoLEP and BPEP are comparable regarding safety and efficacy for treatment of BPH (>80 g) including patients on ACs. However, BPEP required a longer catheterization duration and operative time. ClinicalTrials.gov Identifier: NCT03998150.


Terminal care of the very old. Changes in the way we die.
This study examines the use of advance directives, limitations of treatment, and medical interventions during the terminal hospitalization of the old-old. Study periods before and after the implementation of the Patient Self-Determination Act of 1990 were chosen to determine if there has been a change in terminal care. Chart review was performed for all patients 85 years and older who died in the hospital during 1988 and 1993. Patient characteristics, presence of advance directives, do-not-resuscitate orders, and other treatment limitations were noted as were interventions listed in the Medical Directive. Less than 12% of the 167 study patients had an advance directive. Length of stay for these terminal admissions decreased from 18.5 to 9.6 days. Ninety-five percent of the patients were "do not resuscitate" by time of death, but orders were written sooner in 1993--75% within 24 hours of admission. Patients with early do-not-resuscitate orders had fewer high-intensity interventions. More patients had "comfort measures only" during the study period. An overall decrease in high-intensity interventions and a specific decrease in the use of transfusions, invasive tests, minor surgery, and cardiopulmonary resuscitation was seen. Patients 85 years and older are receiving fewer high-intensity interventions during their terminal hospitalizations. More attention is being paid to comfort and few are receiving cardiopulmonary resuscitation. There is little reference to formal advance directives in decision making for these patients.


Controlled-release fertilizer (CRF): a green fertilizer for controlling non-point contamination in agriculture.
Fertilizers contribute greatly to high yields but also result in environmental non-point contamination, including the emission of greenhouse gas (N2O) and eutrophication of water bodies. How to solve this problem has become a serious challenge, especially for China as its high ecological pressure. Controlled-release fertilizer(CRF) has been developed to minimize the contamination while keeping high yield and has become a green fertilizer for agriculture. Several CRFs made with special coating technology were used for testing the fertilizer effects in yield and environment through pot experiment and field trial. The result indicated that the CRFs had higher N use efficiency, thus reducing N loss through leaching and volatilization while keeping higher yields. Comparing with imported standard CRFs, the test on CRFs showed similar fertilizer effect but with much lower cost. CRFs application is becoming a new approach for minimizing non-point contamination in agriculture.


Human teratogens update 2011: can we ensure safety during pregnancy?
Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer-generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is "safe" for use during pregnancy. In the absence of adequate, well-controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus.


Immunoreactions for P53 isoforms are associated with ultrastructural proliferative profiles in benign thyroid nodules.
P53 isoforms originate from the alternative initiation of P53 gene translation through usage of an internal promoter located in intron 4. All P53 isoforms are spliced in intron 9 and may modulate cell proliferation and cell fate outcome in response to DNA damage. To examine immunoexpression of P53 isoforms in benign proliferative lesions occurring in multinodular thyroids and to assess the ultrastructural phenotype of P53 distribution in the thyrocytes of those lesions by electron microscopy. By immunohistochemistry and transmission electron microscopy (TEM), we evaluated 38 multinodular thyroids containing a total of 102 benign lesions: 38 nodular goiters (NG; colloid=20, parenchymatous=18), 52 follicular adenomas (FA) and 12 Hashimoto's thyroditis (HT). FA were classified into 10 normo-follicular, 9 macro-follicular, 28 micro-follicular and 5 solid variants. Immunoreaction for P53 isoforms was observed in approximately 50% of all lesions, except macrofollicular variant FA (33%). At TEM analysis, immunoreactive NG, FA and TH lesions showed signs of proliferation by simultaneous appearance of dispersed chromatin, increased amounts of cytoplasmic organelles and dilation of the rough endoplasmic reticulum. TEM signs of apoptosis and proliferation were also detected in FA, but with different rates compared to NG. The immunohistochemical expression of P53 isoforms in NG, FA and HT suggests their role in the development of these lesions. Ultrastructural findings support the hypothesis that P53 immunoexpression correlates with reactive proliferative changes in thyrocytes.


Suicide rate, prevalence of diagnosed depression and prevalence of working physicians in Hungary.
Based on the well-known relationship between depression and suicide, we investigated the regional distribution of the suicide rate, rate of diagnosed depression and prevalence of working physicians in Hungary. A strong significant positive correlation was found between the rate of working physicians and rate of diagnosed depression, and both parameters showed a strong significant negative correlation with the suicide rate. The more physicians per 100,000 inhabitants, the better is the recognition of depression and the lower is the suicide rate in the given region. The rate of working doctors was significantly higher in the counties located in western Hungary, which may have a role in the lower suicide mortality in this area of the country.


Inwardly rectifying potassium channel Kir4.1 is responsible for the native inward potassium conductance of satellite glial cells in sensory ganglia.
Satellite glial cells (SGCs) surround primary afferent neurons in sensory ganglia, and increasing evidence has implicated the K(+) channels of SGCs in affecting or regulating sensory ganglion excitability. The inwardly rectifying K(+) (Kir) channel Kir4.1 is highly expressed in several types of glial cells in the central nervous system (CNS) where it has been implicated in extracellular K(+) concentration buffering. Upon neuronal activity, the extracellular K(+) concentration increases, and if not corrected, causes neuronal depolarization and uncontrolled changes in neuronal excitability. Recently, it has been demonstrated that knockdown of Kir4.1 expression in trigeminal ganglia leads to neuronal hyperexcitability in this ganglia and heightened nociception. Thus, we investigated the contribution of Kir4.1 to the membrane K(+) conductance of SGCs in neonatal and adult mouse trigeminal and dorsal root ganglia. Whole cell patch clamp recordings were performed in conjunction with immunocytochemistry and quantitative transcript analysis in various mouse lines. We found that in wild-type mice, the inward K(+) conductance of SGCs is blocked almost completely with extracellular barium, cesium and desipramine, consistent with a conductance mediated by Kir channels. We then utilized mouse lines in which genetic ablation led to partial or complete loss of Kir4.1 expression to assess the role of this channel subunit in SGCs. The inward K(+) currents of SGCs in Kir4.1+/- mice were decreased by about half while these currents were almost completely absent in Kir4.1-/- mice. These findings in combination with previous reports support the notion that Kir4.1 is the principal Kir channel type in SGCs. Therefore Kir4.1 emerges as a key regulator of SGC function and possibly neuronal excitability in sensory ganglia.


Elevated plasma levels of IgE in Plasmodium falciparum-primed individuals reflect an increased ratio of IL-4 to interferon-gamma (IFN-gamma)-producing cells.
People living in Plasmodium falciparum-endemic areas frequently have elevated levels of total as well as P. falciparum-specific serum IgE. This study aimed at investigating whether the elevated serum IgE levels reflect a shift in the balance between CD4+ T helper 1 (Th1) and T helper 2 (Th2) cells in individuals naturally exposed to the P. falciparum parasite. To investigate the role of Th1 and Th2 cells in the human P. falciparum system we used the ELISPOT assay to determine the ratio of IFN-gamma- and IL-4-producing cells after specific antigen or mitogen activation in vitro. The donors were individuals who had acquired immunity through natural exposure to the parasite. In response to the specific malaria antigens, very few IL-4-producing cells were seen. However, in the response of individual donors to the polyclonal T cell activator, leucoagglutinin (La), the anti-malarial IgE levels in plasma were correlated with an increased ratio of IL-4/IFN-gamma producing cells. Thus, donors with ratios of IL-4/IFN-gamma > 1 exhibited mean plasma anti-malarial IgE levels significantly greater than those with ratios < 1. In individuals not living in P. falciparum-endemic areas the ratio of IL-4/IFN-gamma was always < 1. Taken together, our data suggest a shift in the balance between Th1 and Th2 cells in naturally P. falciparum-primed individuals, associated with elevated anti-P. falciparum plasma IgE levels. The role and biological significance of IgE (Th2-type immune response) for protection against P. falciparum and/or pathogenesis of malaria require further study.


Substance Use and Recidivism Outcomes for Prison-Based Drug and Alcohol Interventions.
We conducted a systematic review to examine the substance use and recidivism outcomes of prison-based substance use interventions. We searched public health, criminology, and psychology databases, and conducted forward and backward snowballing methods to identify additional studies. Studies were included if they were published between January 1, 2000 and June 30, 2017; were published in English; and reported substance use and/or recidivism outcomes of prison-based substance use interventions. Studies were reviewed for methodological rigor using the Effective Public Health Practice Project's Quality Assessment Tool for Quantitative Studies. Our search returned 49 studies: 6 were methodologically strong, 20 were moderate, and 23 were weak. Results suggest therapeutic communities are effective in reducing recidivism and, to a lesser extent substance use after release. There is also evidence to suggest that opioid maintenance treatment is effective in reducing the risk of drug use after release from prison for opioid users. Furthermore, care after release from prison appears to enhance treatment effects for both types of interventions. Results provide evidence that policymakers can use to make informed decisions on best-practice approaches when addressing prisoner substance dependence and improving long-term outcomes. This comprehensive review highlights the difficulties of conducting quality research in the prison setting and suggests innovative study design for future research.


Osseointegration of implants in irradiated bone with and without hyperbaric oxygen treatment: an experimental study in rat Tibiae.
Hyperbaric oxygen (HBO) has been recommended to enhance implant osseointegration in irradiated bone. The aim of this study was to further investigate the effects of HBO on implant integration in irradiated bone tissue. The present study was an experimental intraindividual study in 16 rats. A single fraction of 20 Gy external irradiation was applied to one rat hind leg, while the other served as a nonirradiated control. Three days after radiation, two implants were inserted in each tibial tuberosity. The rats were divided into two groups: non-HBO treated (group 1) and HBO treated (group 2). Five weeks after radiation, removal torque tests were performed. Implants with surrounding tissue were processed to undecalcified cut and ground sections for histomorphometric evaluations of bone-to-implant contact and bone area. Retrieved bones were also investigated with dual-energy x-ray absorptiometry. The non-HBO treated rats (group 1) demonstrated higher, but not statistically significantly higher, values in the nonirradiated leg for all investigated parameters compared to the HBO-treated rats (group 2). However, the mean value for bone area was significantly higher in the irradiated sides compared to the nonirradiated control sides. In the present study, HBO treatment did not have a significant impact on osseointegration of implants in irradiated bone.


A time for every purpose: using time-dependent sensitivity analysis to help understand and manage dynamic ecological systems.
Sensitivity analysis is often used to help understand and manage ecological systems, by assessing how a constant change in vital rates or other model parameters might affect the management outcome. This allows the manager to identify the most favorable course of action. However, realistic changes are often localized in time-for example, a short period of culling leads to a temporary increase in the mortality rate over the period. Hence, knowing when to act may be just as important as knowing what to act upon. In this article, we introduce the method of time-dependent sensitivity analysis (TDSA) that simultaneously addresses both questions. We illustrate TDSA using three case studies: transient dynamics in static disease transmission networks, disease dynamics in a reservoir species with seasonal life-history events, and endogenously-driven population cycles in herbivorous invertebrate forest pests. We demonstrate how TDSA often provides useful biological insights, which are understandable on hindsight but would not have been easily discovered without the help of TDSA. However, as a caution, we also show how TDSA can produce results that mainly reflect uncertain modeling choices and are therefore potentially misleading. We provide guidelines to help users maximize the utility of TDSA while avoiding pitfalls.


[Treatment of choroidal hemangioma].
Eight (8) cases of choroidal hemangioma, comprising 6 of the solitary type and 2 of the diffuse type, were treated with Argon laser, including 2 cases in combination with cryotherapy. The success rate was 76.5%, with visual acuity improved in 75% of them during an average follow-up of 11.7 months. Tumors with much subretinal fluid were first given cryosurgery before Argon laser treatment for good synergic therapeutic effects.


A novel photodynamic therapy targeting cancer cells and tumor-associated macrophages.
Tumor-associated macrophages (TAM) in cancer stroma play important roles for cancer cell growth, invasion, angiogenesis, and metastases. We synthesized a novel photosensitizer, mannose-conjugated chlorin (M-chlorin), designed to bind mannose receptors highly expressed on TAMs. We evaluated the newly available photodynamic therapy (PDT) with M-chlorin against gastric and colon cancer. We evaluated PDT with M-chlorin for in vitro cytotoxicity and apoptosis induction in cancer cells compared with chlorin alone and glucose-conjugated chlorin (G-chlorin). The subcellular localization of M-chlorin was observed by confocal microscopy, and the M-chlorin PDT effects against TAMs including THP-1-induced M2-polarized macrophages were evaluated. Anticancer effects were also investigated in an allograft model where cytotoxic effects against TAMs in the cancer cell stroma were analyzed by immunohistochemistry. M-chlorin PDT strongly induced cell death in cancer cells to almost the same extent as G-chlorin PDT by inducing apoptosis. M-chlorin was incorporated into cancer cells where it localized mainly in lysosomes and endoplasmic reticula. M-chlorin PDT revealed strong cytotoxicity for M2 macrophages induced from THP-1 cell lines, and it induced stronger cytotoxicity than G-chlorin PDT in the allograft model through killing both cancer cells and TAMs in the cancer stroma. The M-chlorin PDT produced strong cytotoxicity against cancer tissue by inducing apoptosis of both cancer cells and TAMs in the cancer stroma. This novel PDT thus stands as a new candidate for very effective, next-generation PDT.


The alpha-isoform of caveolin-1 is a marker of vasculogenesis in early lung development.
Caveolin-1 is a scaffolding protein component of caveolae, membrane invaginations involved in endocytosis, signal transduction, trans- and intracellular trafficking, and protein sorting. In adult lung, caveolae and caveolin-1 are present in alveolar endothelium and Type I epithelial cells but rarely in Type II cells. We have analyzed patterns of caveolin-1 expression during mouse lung development. Two caveolin-1 mRNAs, full-length and a 5' variant that will translate mainly into caveolin-1alpha and -beta isoforms, are detected by RT-PCR at embryonic day 12 (E12) and afterwards in the developing and adult lung. Immunostaining analysis, starting at E10, shows caveolin-1alpha localized in primitive blood vessels of the forming lung, in an overlapping pattern to the endothelial marker PECAM-1, and later in all blood vessels. Caveolin-1alpha is not detected in fetal or neonatal lung epithelium but is detected in adult epithelial Type I cells. Caveolin-1 was previously shown to be expressed in alveolar Type I cells. These data suggest that expression of caveolin-1 isoforms is differentially regulated in endothelial and epithelial cells during lung development. Caveolin-1alpha is an early marker for lung vasculogenesis, primarily expressed in developing blood vessels. When the lung is fully differentiated postnatally, caveolin-1alpha is also expressed in alveolar Type I cells.


Mycolicibacterium nivoides sp. nov isolated from a peat bog.
A fast-growing, non-chromogenic, acid-fast-staining bacterium (DL90T) was isolated from a peat bog in northern Minnesota. On the basis of 16S rRNA gene sequence similarity (99.8 % identity with Mycolicibacterium septicum and 98 % with Mycolicibacterium peregrinum) and chemotaxonomic data (fatty acid content), strain DL90T represents a member of the genus Mycolicibacterium. Physiological tests (growth curves, biofilm formation, antibiotic sensitivity, colony morphologies and heat tolerance) and biochemical analysis (arylsulfatase activity and fatty acid profiles) distinguish DL90T from its closest relative M. septicum. Phylogenomic reconstruction of the 'Fortuitium-Vaccae' clade, digital DNA-DNA hybridization (DDH) values of 61 %, and average nucleotide identity (ANI) values of approximately 95 % indicate that DL90T is likely to be diverged from M. septicum. Thus, we propose that DL90T represents a novel species, given the name Mycolicibacterium nivoides with the type strain being isolate DL90T (=JCM 32796T=NCCB 100660T).


The significance of meeting Dawes-Redman criteria in computerised antenatal fetal heart rate assessment.
To investigate the significance of not meeting Dawes-Redman criteria on computerised cardiotocography in high-risk pregnancies. Retrospective observational study. UK university hospital. High-risk pregnancies undergoing antenatal assessment. We interrogated the database for records of computerised fetal heart rate assessment and pregnancy outcomes. Neonatal outcome and stillbirths. Excluding duplicate assessment in the same pregnancy, 14 025 records with complete information on the criteria of normality having been met and the outcome of the pregnancy were available. Criteria were not met for 907 records (6.46%). The gestational age of assessment was lower in the group not meeting criteria of normality. Overall, 32 stillbirths occurred in normally formed fetuses (2.28/1000). Stillbirths were more frequent in the group not meeting criteria (odds ratio [OR] 8.78, 95% CI 4.28-18.02). This finding persisted even after records with abnormally low short-term variation (STV) were excluded. The confidence intervals around the rate of stillbirth in the two groups overlapped beyond an STV of 8 ms. Approximately 1:16 pregnancies do not meet the criteria of normality. The criteria are not met more often at preterm gestation than at term. The risk of stillbirth was higher in the group not meeting criteria of normality, even if cases with low STV are excluded. Cases not meeting criteria should be followed up closely, unless the STV is ≥8 ms. Stillbirths still occurred in the group meeting criteria, but the rate was lower than in the general population.


Association of Prolactin, Oxytocin, and Homocysteine With the Clinical and Cognitive Features of a First Episode of Psychosis Over a 1-Year Follow-Up.
The clinical debut of schizophrenia is frequently a first episode of psychosis (FEP). As such, there is considerable interest in identifying associations between biological markers and clinical or cognitive characteristics that help predict the progression and outcome of FEP patients. Previous studies showed that high prolactin, low oxytocin, and high homocysteine are factors associated with FEP 6 months after diagnosis, at which point plasma levels were correlated with some clinical and cognitive characteristics. We reexamined 75 patients at 12 months after diagnosis to measure the evolution of these molecules and assess their association with clinical features. At follow-up, FEP patients had lower prolactin levels than at baseline, and patients treated with risperidone or paliperidone had higher prolactin levels than patients who received other antipsychotic agents. By contrast, no changes in oxytocin and homocysteine plasma levels were observed between the baseline and follow-up. In terms of clinical features, we found that plasma prolactin and homocysteine levels were correlated with the severity of the psychotic symptoms in male FEP patients, suggesting that they might be factors associated with psychotic symptomatology but only in men. Together with oxytocin, these molecules may also be related to sustained attention, verbal ability, and working memory cognitive domains in FEP patients. This study suggests that focusing on prolactin, oxytocin, and homocysteine at a FEP may help select adequate pharmacological treatments and develop new tools to improve the outcome of these patients, where sex should also be borne in mind.