The current and future status of refractive surgery.
Kerato-refractive surgery has developed rapidly over the past decade. Many surgical procedures have been described for the correction of myopia, hyperopia, and aphakia. For the treatment of myopia, radial keratotomy has been utilized extensively. Most investigators agree that radial keratotomy results seem to be better in patients with 3 diopters or less of myopia. Keratomileusis is a complicated procedure which can correct high degrees of myopia, however, this technically difficult procedure is performed by very few surgeons in North America. Epikeratophakia for the treatment of aphakia is promising especially in the treatment of pediatric patients. The Excimer laser is evolving from a research tool to clinical reality with the coupling of the laser to computer controlled programs to reshape the cornea. The use of synthetic material inlays and intrastromal corneal ring implants are also being developed to modify the refractive status of the cornea.


A Sensitivity Analysis of fMRI Balloon Model.
Functional magnetic resonance imaging (fMRI) allows the mapping of the brain activation through measurements of the Blood Oxygenation Level Dependent (BOLD) contrast. The characterization of the pathway from the input stimulus to the output BOLD signal requires the selection of an adequate hemodynamic model and the satisfaction of some specific conditions while conducting the experiment and calibrating the model. This paper, focuses on the identifiability of the Balloon hemodynamic model. By identifiability, we mean the ability to estimate accurately the model parameters given the input and the output measurement. Previous studies of the Balloon model have somehow added knowledge either by choosing prior distributions for the parameters, freezing some of them, or looking for the solution as a projection on a natural basis of some vector space. In these studies, the identification was generally assessed using event-related paradigms. This paper justifies the reasons behind the need of adding knowledge, choosing certain paradigms, and completing the few existing identifiability studies through a global sensitivity analysis of the Balloon model in the case of blocked design experiment.


Learning Expressionlets via Universal Manifold Model for Dynamic Facial Expression Recognition.
Facial expression is a temporally dynamic event which can be decomposed into a set of muscle motions occurring in different facial regions over various time intervals. For dynamic expression recognition, two key issues, temporal alignment and semantics-aware dynamic representation, must be taken into account. In this paper, we attempt to solve both problems via manifold modeling of videos based on a novel mid-level representation, i.e., expressionlet. Specifically, our method contains three key stages: 1) each expression video clip is characterized as a spatial-temporal manifold (STM) formed by dense low-level features; 2) a universal manifold model (UMM) is learned over all low-level features and represented as a set of local modes to statistically unify all the STMs; and 3) the local modes on each STM can be instantiated by fitting to the UMM, and the corresponding expressionlet is constructed by modeling the variations in each local mode. With the above strategy, expression videos are naturally aligned both spatially and temporally. To enhance the discriminative power, the expressionlet-based STM representation is further processed with discriminant embedding. Our method is evaluated on four public expression databases, CK+, MMI, Oulu-CASIA, and FERA. In all cases, our method outperforms the known state of the art by a large margin.


Characterization of mutationally altered dihydropteroate synthase and its ability to form a sulfonamide-containing dihydrofolate analog.
Among spontaneous mutants of Escherichia coli selected for resistance against sulfonamides, thermosensitive strains were found. These were shown to possess a changed dihydropteroate synthase (EC 22.214.171.124), which had a substantially higher Km value for its normal substrate, p-aminobenzoic acid, and an about 150-fold higher Km for sulfonamides. The mutationally changed dihydropteroate synthase was found to be thermosensitive by in vitro assays. The thermosensitivity was used as an enzyme marker to demonstrate the complex formation between 2-amino-4-hydroxy-6-pyrophosphorylmethyl pteridine and sulfonamides by partially purified dihydropteroate synthase. The formation of folate from 2-amino-4-hydroxy-6-pyrophosphorylmethyl pteridine and p-aminobenzoylglutamic acid by dihydropteroate synthase was found to be very sensitive to inhibition by sulfonamides and very inefficient with the mutationally changed enzyme.


Size fractions of dust and amount of associated metals on leaf surface and inner wax of 15 plant species at Beijing roadside.
To provide more insight into the removal ability of urban air dust and associated metals by plant leaves, and thus guide urban green planning to improve air quality, 15 plant species leaves collected from Beijing roadside were analyzed for size fractions of leaf surface dust (SD) and inner wax dust (WD). Seven associated metals Cd, Cr, Cu, Fe, Mn, Pb and Zn were also measured. Metal Accumulation Index (MAI) was calculated for different species leaves at various dust sizes and soluble forms, respectively. Cluster analysis was used for the plant species and correlations between dust and metal concentrations and for inter-metal concentrations were calculated for both surface and inner wax dust. Mean leaf total dust TD (SD + WD), SD and WD were measured as 1159, 817 and 342 mg m-2, respectively, with the highest values observed all in Euonymus japonicus. Most species leaves collected larger ratios of SD than WD except Salix babylonica and Robinia pseudoacacia. While SD was presented at all particle size fractions for all plants, nearly all species leaves collected higher proportions of WD >10 µm. Mean metal levels of leaf TD of all species ranged from high to low as Fe > Cr > Zn > Pb > Cu > Mn > Cd, but with different orders for individual species. Metals were observed in all sizes of SD/WD, although the size distributions were various for certain metals. Intercorrelations of metal concentrations in leaf SD/WD were positively significant except Pb, which may have different emission sources. Species Prunus cerasifera f. atropurpurea, Syringa oblata, Malus micromalu, Koelreuteria paniculata and Robinia pseudoacacia may possess better overall metal collection ability due to their relatively higher MAI values, but species Euonymus japonicus, Malus micromalu, Ligustrum x vicaryi and Koelreuteria paniculata were identified as the best choices in removing air dust based on cluster analysis and suggested to be planted at heavy trafficked road site for air quality improvement.


A single liquid-chromatographic procedure for therapeutic monitoring of theophylline, acetaminophen, or ethosuximide.
Simultaneous and semi-automated determinations of theophylline, acetaminophen, and ethosuximide from human serum are possible through use of a programmable autoinjector, an isocratic mobile phase, and reversed-phase "high-performance" liquid chromatography on a muBondapak C18 column. To avoid salt damage to the valves and the fittings of the autoinjector and solvent pump, we used only volatile, ion-pairing buffers such as triethylamine/acetic acid or N-ethylmorpholine/acetic acid at apparent pH 4.8 in acetonitrile/water (1/11 by vol). With this method we can separate theophylline, acetaminophen, and ethosuximide from 26 other drugs, metabolites, and related substances. Results by this procedure and the EMIT procedure for theophylline and ethosuximide in patient and control sera correlated well (r = 0.944 and 0.968, respectively). We conclude that this single chromatographic system reliably and economically yields analysis of three widely used therapeutic drugs on a routine or emergency basis.


Assessment and personalised advice for fatigue in systemic lupus erythematosus using an innovative digital tool: the Lupus Expert system for the Assessment of Fatigue (LEAF) study.
Fatigue is reported as the most prevalent symptom by patients with systemic lupus erythematosus (SLE). Fatigue management is complex due to its multifactorial nature. The aim of the study was to assess the usefulness of an innovative digital tool to manage fatigue in SLE, in a completely automated manner. The «Lupus Expert System for Assessment of Fatigue» (LEAF) is free digital tool which measures the intensity and characteristics of fatigue and assesses disease activity, pain, insomnia, anxiety, depression, stress, fibromyalgia and physical activity using validated patient-reported instruments. Then, LEAF automatically provides personalised feedback and recommendations to cope with fatigue. Between May and November 2022, 1250 participants with SLE were included (95.2% women, median age 43yo (IQR: 34-51)). Significant fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue <34) was reported by 78.9% of patients. In univariate analysis, SLE participants with fatigue were more likely to be women (p=0.01), perceived their disease as more active (p<0.0001), had higher levels of pain (p<0.0001), anxiety (p<0.0001), depression (p<0.0001), insomnia (p<0.0001), stress (p<0.0001) and were more likely to screen for fibromyalgia (p<0.0001), compared with patients without significant fatigue. In multivariable analysis, parameters independently associated with fatigue were insomnia (p=0.0003), pain (p=0.002), fibromyalgia (p=0.008), self-reported active SLE (p=0.02) and stress (p=0.045). 93.2% of the participants found LEAF helpful and 92.3% would recommend it to another patient with SLE. Fatigue is commonly severe in SLE, and associated with insomnia, pain, fibromyalgia and active disease according to patients' perspective. Our study shows the usefulness of an automated digital tool to manage fatigue in SLE.


The gist of Anne Treisman's revolution.
Anne Treisman investigated many aspects of perception, and in particular the roles of different forms of attention. Four aspects of her work are reviewed here, including visual search, set mean perception, perception in special populations, and binocular rivalry. The importance of the breakthrough in each case is demonstrated. Search is easy or slow depending on whether it depends on the application of global or focused attention. Mean perception depends on global attention and affords simultaneous representation of the means of at least two sets of elements, and then of comparing them. Deficits exhibited in Balint's or unilateral neglect patients identify basic sensory system mechanisms. And, the ability to integrate binocular information for stereopsis despite simultaneous binocular rivalry for color, demonstrates the division of labor underlying visual system computations. All these studies are related to an appreciation of the difference between perceiving the gist of a scene, its elements or objects, versus perceiving the details of the scene and its components. This relationship between Anne Treisman's revolutionary discoveries and the concept of gist perception is the core of the current review.


Ketamine inhibits lipopolysaccharide-induced astrocytes activation by suppressing TLR4/NF-ĸB pathway.
Ketamine has been reported to exert anti-inflammatory effects on astrocytes stimulated by lipopolysaccharide (LPS) in vitro and in vivo. However, the mechanism has not been elicited clearly. The aim of this study was to investigate the effects of ketamine on TLR4 expression and NF-ĸB-p65 phosphorylation, as well as the production of proinflammatory cytokines in LPS challenged astrocytes. Astrocytes were stimulated with LPS (1µg/ ml) in the absence and presence of various concentrations of ketamine (10, 100, 1000µM). The concentrations of IL-1β, IL-6 and TNF-α were measured by ELISA, the expression of glial fibrillary acidic protein (GFAP) in astrocytes was detected by immunofluorescence staining, the level of phosphorylated NF-ĸB p65 and the expression of TLR4 were detected by western blotting. LPS increased TLR4 expression and the phosphorylation of NF-ĸB p65 subunit as well as GFAP expression and the production of IL-1β, IL-6 and TNF-α in cultured astrocytes. Ketamine (100 and 1000 µM) reduced the expression of GFAP and the production of these proinflammatory cytokines, inhibited the expression of TLR4 and attenuated the phosphorylation of NF-ĸB p65 in astrocytes challenged by LPS. The inhibitory effects of ketamine on LPS-induced astrocytes activation and inflammation response may be mediated by suppressing NF-ĸB activation through reducing the expression of TLR4.


Nasolabial Ulcerated Placard Revealing a Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma.
Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is a rare entity representing less than 1% of cutaneous lymphomas. It has an aggressive clinical manifestation with a poor prognosis. It is characterized by cytotoxic and epidermotropic CD8+ proliferation. It also expresses the TIA-1 marker. We report a new case for its display and aggressive character, diagnostic difficulty, and good therapeutic response to chemotherapy. This is a 62-year-old female patient admitted to the hospital for a nasolabial ulcerated placard evolving for two years. Clinical examination revealed submandibular lymph nodes. The specimen analysis associated with anatomoclinical manifestation was concluded for a primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. Tumor extent assessment did not show any secondary localization. The blood tests and serology were unremarkable. The patient had benefited from a CHOEP-type multidrug therapy protocol with complete healing of the lesion after three courses of chemotherapy.


Effects of alternative methyl group acceptors on the growth energetics of the O-demethylating anaerobe Holophaga foetida.
The anaerobic bacterium Holophaga foetida can metabolize the methyl groups of methoxylated aromatic compounds either to acetate or to dimethyl sulphide. The effects of this metabolic flexibility were investigated under conditions of excess; substrate (batch culture) and substrate limitation (chemostat culture). Growth yield data suggest that transfer of the methyl groups to sulphide, in contrast to the homoacetogenic transfer to CO2, was not coupled to energy conservation. Under conditions of excess substrate, methyl groups were quantitatively transferred to sulphide. Growth yields decreased but growth rates increased upon the addition of sulphide during exponential growth in pH- and sulphide-regulated batch cultures. From the measured growth yields, the Gibbs free energy dissipation of catabolism plus anabolism ( ) was calculated using stoichiometric equations incorporating biomass formation (macrochemical equations). The observed increase in growth rate correlated well with an increase in , suggesting a relationship between growth kinetics and growth energetics. During steady-state growth in pH- and sulphide-regulated chemostat culture, a considerable fraction of the methyl groups was converted to acetate, despite the presence of sulphide. This resulted in similar growth yields and correspondingly similar values in the presence and absence of sulphide. Apparently, H. foetida uncouples catabolism and anabolism in batch culture under conditions of excess substrate to a greater extent than in the chemostat under substrate limitation, by transferring the methyl groups quantitatively to sulphide and thereby dissipating the Gibbs free energy change of the methyl transfer. The physiological significance of these findings could be that H. foetida adjusts the energetics of its metabolism to the growth conditions (i) to maximize the growth rate if substrate is available in excess or, (ii) to maximize the growth yield if substrate is limiting.


The expressed protein in glyphosate-tolerant soybean, 5-enolpyruvylshikimate-3-phosphate synthase from Agrobacterium sp. strain CP4, is rapidly digested in vitro and is not toxic to acutely gavaged mice.
The safety of 5-enolpyruvylshikimate-3-phosphate synthase enzyme derived from Agrobacterium sp. strain CP4 (CP4 EPSPS) was assessed. CP4 EPSPS is the only protein introduced by genetic manipulation that is expressed in glyphosate-tolerant soybeans, which are being developed to provide new weed-control options for farmers. Expression of this protein in plants imparts high levels of glyphosate tolerance. The safety of CP4 EPSPS was ascertained by evaluating both physical and functional characteristics. CP4 EPSPS degrades readily in simulated gastric and intestinal fluids, suggesting that this protein will be degraded in the mammalian digestive tract upon ingestion as a component of food or feed, There were no deleterious effects due to the acute administration of CP4 EPSPS to mice by gavage at a high dosage of 572 mg/kg body wt, which exceeds 1000-fold tha anticipated consumption level of food products potentially containing CP4 EPSPS protein. CP4 EPSPS does not pose any important allergen concerns because this protein does not possess characteristics typical of allergenic proteins. These data, in combination with seed compositional analysis and animal feeding studies, support the conclusion that glyphosate-tolerant soybean are as safe and nutritious as traditional soybeans currently being marketed.


Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: A systematic review and meta-analysis.
Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease of multiple joints that puts the patient at high risk for developing cardiovascular diseases (CVDs). The aim of the present study was to conduct an up-to-date systematic review and meta-analysis of published randomized controlled trials (RCTs) to assess potential changes in RA disease activity, inflammation, and CVD risk after oral intake of ω-3 polyunsaturated fatty acids. Publications up to July 31, 2016 were examined using the PubMed, SCOPUS, and EMBASE databases. English language; human subjects; both sexes; RCTs; oral intake of ω-3 fatty acids; minimum duration of 3 mo; and no medication change throughout intervention. The Cochrane Risk of Bias tool was used to assess quality of trials. We included 20 RCTs, involving 717 patients with RA in the intervention group and 535 RA patients in the control group. Despite the evidence of overall low quality of trials, consumption of ω-3 fatty acids was found to significantly improve eight disease-activity-related markers. Regarding inflammation, only leukotriene B4 was reduced (five trials, standardized mean difference [SMD], -0.440; 95% confidence interval [CI], -0.676 to -0.205; I2 = 46.5%; P < 0.001). A significant amelioration was found for blood triacylglycerol levels (three trials, SMD, -0.316; 95% CI, -0.561 to -0.070; I2 = 0.0%; P = 0.012). The beneficial properties of ω-3 polyunsaturated fatty acids on RA disease activity confirm the results of previous meta-analyses. Among five proinflammatory markers evaluated, only leukotriene B4 was found to be reduced. However, a positive effect on blood lipid profile of patients with RA was evident, perhaps for the first time.


Centrosomal Nlp is an oncogenic protein that is gene-amplified in human tumors and causes spontaneous tumorigenesis in transgenic mice.
Disruption of mitotic events contributes greatly to genomic instability and results in mutator phenotypes. Indeed, abnormalities of mitotic components are closely associated with malignant transformation and tumorigenesis. Here we show that ninein-like protein (Nlp), a recently identified BRCA1-associated centrosomal protein involved in microtubule nucleation and spindle formation, is an oncogenic protein. Nlp was found to be overexpressed in approximately 80% of human breast and lung carcinomas analyzed. In human lung cancers, this deregulated expression was associated with NLP gene amplification. Further analysis revealed that Nlp exhibited strong oncogenic properties; for example, it conferred to NIH3T3 rodent fibroblasts the capacity for anchorage-independent growth in vitro and tumor formation in nude mice. Consistent with these data, transgenic mice overexpressing Nlp displayed spontaneous tumorigenesis in the breast, ovary, and testicle within 60 weeks. In addition, Nlp overexpression induced more rapid onset of radiation-induced lymphoma. Furthermore, mouse embryonic fibroblasts (MEFs) derived from Nlp transgenic mice showed centrosome amplification, suggesting that Nlp overexpression mimics BRCA1 loss. These findings demonstrate that Nlp abnormalities may contribute to genomic instability and tumorigenesis and suggest that Nlp might serve as a potential biomarker for clinical diagnosis and therapeutic target.


Quality assurance in ambulatory care.
Many of the methods for evaluating the quality of ambulatory care are costly, cumbersome, and possibly counterproductive. Major developments in evaluating the quality of the doctor-patient relationship are needed before a general assessment of the quality of ambulatory care is possible. Nonetheless, limited reviews based on insurance claims data can efficiently improve certain aspects of ambulatory care.


Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study.
Background: The benefits of the use of folic acid supplements (FASs) during the periconception period to prevent neural tube defects and to ensure normal brain development in offspring are well known. There is concern, however, about the long-term effects of the maternal use of high dosages of FASs that exceed the Tolerable Upper Intake Level (UL) (≥1000 μg/d) on child neurocognitive outcomes.Objective: The objective of the study was to examine the association between the use of high dosages of FASs during pregnancy and child neuropsychological development at ages 4-5 y.Design: The multicenter prospective mother-child cohort study, the Infancia y Medio Ambiente (INMA) Project, was conducted in 4 regions of Spain: Asturias, Sabadell, Gipuzkoa, and Valencia. Pregnant women were recruited between 2003 and 2008. Data on 1682 mother-child pairs were included in the final analyses. The pregnant women completed an interviewer-administered questionnaire that was validated to estimate typical dietary folate intake and the use of FASs at 10-13 and 28-32 wk of gestation. Neuropsychological development scores at 4-5 y of age were estimated with the use of the McCarthy Scales of Children's Abilities. Multiple linear regression and meta-analysis were used to obtain combined-effect estimates.Results: During the periconception period, one-third of the women (n = 502) took FAS dosages ≥1000 μg/d. The use of FAS dosages ≥1000 μg/d in this period was negatively associated with several neuropsychological outcomes scores in children: global verbal (β = -2.49; 95% CI: -4.71, -0.27), verbal memory (β = -3.59; 95% CI: -6.95, -0.23), cognitive function of posterior cortex (β = -2.31; 95% CI: -4.45, -0.18), and cognitive function of left posterior cortex (β = -3.26; 95% CI: -5.51, -1.01).Conclusions: The use of FAS dosages exceeding the UL (≥1000 μg/d) during the periconception period was associated with lower levels of cognitive development in children aged 4-5 y. The use of FAS dosages ≥1000 μg/d during pregnancy should be monitored and prevented as much as possible, unless medically prescribed.


Chlorothalonil exposure and cancer incidence among pesticide applicator participants in the agricultural health study.
Chlorothalonil is a broad spectrum, non-systemic fungicide widely used to control diseases affecting over 50 fruit, vegetable, and agricultural crops. Despite its extensive use for over 30 years, little is known about the potential human carcinogenicity associated with the routine application of chlorothalonil. Rodent studies have shown evidence of renal tubular carcinomas and adenomas. We explored cancer incidence with chlorothalonil exposure using data from the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. Licensed private and commercial pesticide applicators were recruited into this study from 1993 to 1997. Detailed information regarding pesticide use was obtained via self-administered questionnaires. Cancer incidence was followed through December 31, 2004. Chlorothalonil exposure was classified by lifetime exposure days and intensity-weighted lifetime exposure days, and then categorized into tertiles. The intensity-weighted lifetime exposure days metric was calculated based on a complex algorithm which includes pesticide application methods among other factors. This may increase or decrease exposure. Of the 47,625 pesticide applicators included in this analysis, 3657 applicators reported using chlorothalonil with a median of 3.5 application days per year. Chlorothalonil was not associated with overall cancer incidence, nor did we find any association with colon, lung, and prostate cancers--the only cancers for which we had sufficient numbers to explore associations. We did not find any strong evidence for an association between chlorothalonil and the cancers investigated. Although animal studies have suggested renal cancer may be associated with chlorothalonil, we had insufficient data to evaluate this cancer.


Difficulties in the Management of Placenta Accreta Spectrum in Hospitals with Limited Resources.
Placenta accreta spectrum (PAS) is a serious diseases, and the recommendation is that the treatment is conducted in centers of excellence. Such hospitals are not easy to find in low- and middle-income countries. We seek to describe the process of prenatal diagnosis, surgical management, and postnatal histological analysis in a low-income country referral hospital with limited resources. A descriptive, retrospective study was carried out including patients with a pre- or intraoperative diagnosis of PAS. The clinical results of the patients were studied as well as the results of the prenatal ultrasound and the correlation with the postnatal pathological diagnosis. In total, 129 patients were included. Forty-eight of them had a prenatal PAS ultrasound diagnosis (37.2%). In the remaining 81 (62.8%), the diagnosis was intraoperative.Although hysterectomy was performed in all cases, one-third of the patients (31%) did not have a histological study of the uterus. In 40% of the patients who had a histological study, PAS was not reported by the pathologist. The frequency of prenatal diagnosis and the availability of postnatal histological studies were very low in the studied population. Surgical skill, favored by a high flow of patients, is an important factor to avoid complications in settings with limited resources.


Exploring protein myristoylation in Toxoplasma gondii.
Toxoplasma gondii is an important human and veterinary pathogen and the causative agent of toxoplasmosis, a potentially severe disease especially in immunocompromised or congenitally infected humans. Current therapeutic compounds are not well-tolerated, present increasing resistance, limited efficacy and require long periods of treatment. On this context, searching for new therapeutic targets is crucial to drug discovery. In this sense, recent works suggest that N-myristoyltransferase (NMT), the enzyme responsible for protein myristoylation that is essential in some parasites, could be the target of new anti-parasitic compounds. However, up to date there is no information on NMT and the extent of this modification in T. gondii. In this work, we decided to explore T. gondii genome in search of elements related with the N-myristoylation process. By a bioinformatics approach it was possible to identify a putative T. gondii NMT (TgNMT). This enzyme that is homologous to other parasitic NMTs, presents activity in vitro, is expressed in both intra- and extracellular parasites and interacts with predicted TgNMT substrates. Additionally, NMT activity seems to be important for the lytic cycle of Toxoplasma gondii. In parallel, an in silico myristoylome predicts 157 proteins to be affected by this modification. Myristoylated proteins would be affecting several metabolic functions with some of them being critical for the life cycle of this parasite. Together, these data indicate that TgNMT could be an interesting target of intervention for the treatment of toxoplasmosis.


βPS-Integrin acts downstream of Innexin 2 in modulating stretched cell morphogenesis in the Drosophila ovary.
During oogenesis, a group of specialized follicle cells, known as stretched cells (StCs), flatten drastically from cuboidal to squamous shape. While morphogenesis of epithelia is critical for organogenesis, genes and signaling pathways involved in this process remain to be revealed. In addition to formation of gap junctions for intercellular exchange of small molecules, gap junction proteins form channels or act as adaptor proteins to regulate various cellular behaviors. In invertebrates, gap junction proteins are Innexins. Knockdown of Innexin 2 but not other Innexins expressed in follicle cells attenuates StC morphogenesis. Interestingly, blocking of gap junctions with an inhibitor carbenoxolone does not affect StC morphogenesis, suggesting that Innexin 2 might control StCs flattening in a gap-junction-independent manner. An excessive level of βPS-Integrin encoded by myospheroid is detected in Innexin 2 mutant cells specifically during StC morphogenesis. Simultaneous knockdown of Innexin 2 and myospheroid partially rescues the morphogenetic defect resulted from Innexin 2 knockdown. Furthermore, reduction of βPS-Integrin is sufficient to induce early StCs flattening. Taken together, our data suggest that βPS-Integrin acts downstream of Innexin 2 in modulating StCs morphogenesis.


Impact of a healthy nails program on nail-biting in Turkish schoolchildren: a controlled pretest-posttest study.
This study was conducted to examine the effect of a healthy nails program on nail-biting in Turkish schoolchildren. This quasi-experimental study was of pretest-posttest control group design. A total of 50 students of a primary school formed the intervention group, while 53 students from the same school formed the control group. Data were collected with a demographic form, a nail-biting follow-up form, and photographs of the fingernails. It was found that 68.9% of students were biting seven or more of their nails; 46.6% had damaged nail beds. In the intervention group, the rate of the children who were not biting their nails (baseline = 0%, 4th week = 56.0%, 8th week = 64.0%) increased significantly compared to the control group (baseline = 0%, 4th week = 15.1%, 8th week = 18.9%). Outcomes indicate the efficacy of the healthy nails program in reducing the nail-biting problem in schoolchildren.


Biomarkers for predicting clinical response to immunosuppressive therapy in aplastic anemia.
The decision to select hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) as initial therapy in acquired aplastic anemia (AA) is currently based on patient age and the availability of a human leukocyte antigen (HLA)-matched donor. Although IST is a promising treatment option, the ability to predict its long-term outcomes remains poor due to refractoriness, relapses, and the risk of clonal evolution. Several predictive biomarkers for response to IST have been posited, including age, gender, pre-treatment blood cell counts, cytokines, gene mutations, paroxysmal nocturnal hemoglobinuria (PNH), and telomere length (TL). While previous studies have provided substantial biological insights into the utility of IST, the prognostic power of the reported biomarkers is currently insufficient to contribute to clinical decision making. Recently, a large retrospective analysis proposed the combination of minor PNH clones and TL as an efficient predictor of IST response. Identification of a reliable predictor would provide a useful tool for determining the most appropriate treatment choice for AA patients, including up-front HSCT from HLA-matched unrelated donor. The present review summarizes studies evaluating the utility of biomarkers in predicting the clinical response to IST of patients with AA, and provides a baseline for prospective studies aimed at validating previously reported biomarkers.


Long-term Clinical Outcomes After Bilateral Implantation of Two Trifocal Diffractive IOLs.
To show clinical outcomes after bilateral implantation of either a hydrophobic FineVision POD F GF or a hydro-philic FineVision POD F intraocular lens (IOL) (Beaver-Visitec International, Inc). A total of 110 patients with cataract were randomized to receive either POD F GF or POD F IOLs and followed up for 2 years. The measurements included refraction, monocular and binocular uncorrected and corrected distance (UDVA and CDVA), intermediate (UIVA and DCIVA), and near (UNVA and DCNVA) visual acuities, defocus curve, photopic and mesopic contrast sensitivity, photic phenomena, and patient-reported outcomes. The mean spherical equivalent was similar in both groups and stable across visits (< 0.25 diopters [D]). At 2 years, 81.8% and 90.5% of eyes were within ±0.50 D in the POD F GF and POD F IOL groups, respectively (100% for ±1.00 D in both groups). At 2 years, 100% and 90.5% of the patients presented a binocular CDVA of 20/25 or better; 93.9% and 85.7% of patients a DCIVA of 20/25 or better and 87.5% and 70% of patients a DCNVA of 20/25 or better, for the POD F GF and POD F IOL groups, respectively. The defocus curve showed continuous visual acuity, being 20/32 or better in both groups over a 4.50 D range. Both groups presented good contrast sensitivity for photopic and mesopic conditions, and the size and intensity of halo and glare phenomena were similar between the two. Both groups also included a high percentage of patients who reported that they had stopped wearing glasses and greater than 80% satisfaction and recommendation levels. This study showed comparable long-term visual and refractive outcomes of both IOL models after cataract surgery. [J Refract Surg. 2023;39(12):798-807.].


High tidal volume ventilation does not exacerbate acid-induced lung injury in infant rats.
The impact of mechanical ventilation with high V(T)-low PEEP in infant rats with preinjured lungs is unknown. After tracheal instillation of saline or acid, two week old rats were ventilated with V(T) 7 mL/kg and PEEP 5 cm H₂O or V(T) 21 mL/kg and PEEP 1cm H₂O for 4 h. Airway resistance and the coefficient of tissue elastance, measured via low-frequency forced-oscillation technique, and quasi-static pressure-volume curves deteriorated less with high V(T)-low PEEP when compared with low V(T)-high PEEP. IL-6 concentration in bronchoalveolar lavage fluid (BALF) did not differ between all ventilated groups. Moreover, differences in BALF protein concentration and histological lung injury scores were independent of applied ventilation strategies. In contrast to experimental studies with adult rats, short-term mechanical ventilation with high V(T)-low PEEP is not deleterious when compared to low V(T)-high PEEP in both healthy and pre-injured infant rat lungs. Our results call for caution when extrapolating data from adult studies and highlight the need for age-specific animal models.


Coupled photonic crystal heterostructure nanocavities.
We show the first experimental demonstration of multiple heterostructure photonic crystal cavities being coupled together to form a chain of coupled resonators with up to ten cavities. This system allows us to engineer the group velocity of light over a wide range. Devices were fabricated using 193 nm deep UV lithography and standard silicon processing technology. Structures were analysed using both coupled resonator and photonic bandstructure theory, and we highlight the discrepancies arising from subtle imperfections of the fabricated structure.


[Ventral intercorporeal traction spondylodesis of the lumbar spine].
At 35.7% the average rate of pseudarthrosis following ventral spondylodesis of a segment of the lumbar spine is very high. The inadequate degree of primary stability in the segment to be ankylosed is seen as the fundamental reason for this. In the present paper an implant made of a nickel-titanium alloy ("Memory Alloy") is described, which is inserted intercorporeally and immobilizes the moving segment by traction. Experiments in sheep have confirmed that the anchorages of the implant are stable; it was also established that bony fusion occurred both around the implant as well as through it. Observations thus far in 10 patients treated by this method have shown that the implant remains stably anchored, and in some cases clear signs of bone bridge formation were demonstrable on radiographs after only a short time. If the primary stability provided by the Memory implant continues to be thus confirmed, postoperative hospitalization will in future be limited to a few days.


Do people with disabilities experience disparities in cancer care? A systematic review.
Over 1.3 billion people, or 16% of the world's population, live with some form of disability. Recent studies have reported that people with disabilities (PwD) might not be receiving state-of-the-art treatment for cancer as their non-disabled peers; our objective was to systematically review this topic. A systematic review was undertaken to compare cancer outcomes and quality of cancer care between adults with and without disabilities (NIHR Prospero register ID number: CRD42022281506). A search of the literature was performed in July 2022 across five databases: EMBASE, Medline, Cochrane Library, Web of Science and CINAHL databases. Peer-reviewed quantitative research articles, published in English from 2000 to 2022, with interventional or observational study designs, comparing cancer outcomes between a sample of adult patients with disabilities and a sample without disabilities were included. Studies focused on cancer screening and not treatment were excluded, as well as editorials, commentaries, opinion papers, reviews, case reports, case series under 10 patients and conference abstracts. Studies were evaluated by one reviewer for risk of bias based on a set of criteria according to the SIGN 50 guidelines. A narrative synthesis was conducted according to the Cochrane SWiM guidelines, with tables summarizing study characteristics and outcomes. This research received no external funding. Thirty-one studies were included in the systematic review. Compared to people without disabilities, PwD had worse cancer outcomes, in terms of poorer survival and higher overall and cancer-specific mortality. There was also evidence that PwD received poorer quality cancer care, including lower access to state-of-the-art care or curative-intent therapies, treatment delays, undertreatment or excessively invasive treatment, worse access to in-hospital services, less specialist healthcare utilization, less access to pain medications and inadequate end-of-life quality of care. Limitations of this work include the exclusion of qualitative research, no assessment of publication bias, selection performed by only one reviewer, results from high-income countries only, no meta-analysis and a high risk of bias in 15% of included studies. In spite of these limitations, our results show that PwD often experience severe disparities in cancer care with less guideline-consistent care and higher mortality than people without disabilities. These findings raise urgent questions about how to ensure equitable care for PwD; in order to prevent avoidable morbidity and mortality, cancer care programs need to be evaluated and urgently improved, with specific training of clinical staff, more disability inclusive research, better communication and shared decision-making with patients and elimination of physical, social and cultural barriers.


Temporal trends in retinal detachment incidence in Scotland between 1987 and 2006.
Rhegmatogenous retinal detachment (RRD) is a common and sight-threatening condition. The reported incidence of RRD has varied considerably in published literature and few studies have examined the temporal trends in incidence rate over a long time period. Our aim is to examine the time trends of primary RRD in Scotland. We obtained linked hospital episode statistics data for all patients admitted with a primary diagnostic code of RRD in Scotland between 1987 and 2006. Using this database as an estimate of RRD incidence, we calculated the annual age- and sex-specific incidence rates of RRD in Scotland. Log-linear Poisson regression analysis was used to explore age, period and cohort trends. The overall age-standardised incidence of RRD in Scotland has steadily increased from 9.36 per 100 000 (95% CI 8.19 to 10.53) in 1987 to 13.61 per 100 000 (95% CI 12.25 to 14.97) in 2006 with an average annual increase of 1.9% (p<0.001) during the 20-year period. Men have been affected more frequently than women in all age groups with a significant temporal trend towards earlier age of onset. The peak incidence of RRD in men and women is in the sixth decade of life. No significant period or recent birth cohort trend effects were found. The estimated incidence of RRD is within the range reported from previous population-based studies worldwide. The rise in RRD incidence between 1987 and 2006 is attributed in part to the changing demographic in Scotland. There is an increasing sex imbalance in incidence, with men being affected more frequently and at a younger age.


Regional abundances of binder of sperm (BSP) proteins are negatively associated with the quality of frozen-thawed bovine spermatozoa.
The localization and abundance of the sperm BSP proteins correlate with in vitro fertility in domestic bulls used in artificial insemination service. Binder of sperm (BSP) proteins, secreted mainly by the accessory sex glands, are the major protein family present in bovine seminal plasma and on the sperm surface after ejaculation. In vivo, BSP proteins facilitate sperm capacitation and sperm reservoir formation; however, their impact on sperm function within the in vitro systems is less clear. Therefore, this biomarker-based study aimed to characterize the localization and abundance of BSP proteins from in vitro processed frozen-thawed bovine spermatozoa. Using image-based flow cytometry and Western blotting, BSP protein localization, abundance, membrane and acrosomal integrity were investigated in the supernatant (nonmotile) and pellet (motile) fractions of gradient-separated bull spermatozoa. Spermatozoa from the supernatant fraction had high enrichment of all BSP proteins investigated (BSP1, BSP3, BSP5; P < 0.05) when compared to the pellet fraction. In the pellet fraction, BSP1 and BSP3 bound predominately to the acrosomal region, whereas BSP5 had a high affinity for the midpiece. However, in the supernatant fraction, BSP proteins predominately coated the entire sperm surface resulting in the loss of regional specificity. High BSP protein abundance in the spermatozoa also correlated with acrosome and membrane damage. Whereas a high abundance of BSP5 correlated with low embryo cleavage rates, high abundance of BSP1 on the sperm head coincided with a high blastocyst rate. Therefore, changes in the quantity and localization of specific BSP proteins could act as potential biomarkers of sperm quality and fertility.


Stern layer formation induced by hydrophobic interactions: a molecular level study.
The molecular ionic surface structure and charge of the electric double layer around a nanodroplet and its structural change induced by hydrophobic effects are measured using vibrational coherent surface scattering spectroscopy, second harmonic scattering, and electrokinetic mobility measurements. Tetraalkylammonium chloride salts were added to negatively charged nanoscopic oil droplets in water. When we vary the alkyl chain length of the cation from CH3 to C4H10, both the size of the cation and its hydrophobic interaction are increased. We find that tetramethylammonium ions change the electrokinetic potential and the water structure but do not detectably adsorb to the interface. Tetrapropylammonium and tetrabutylammonium ions clearly adsorb to the interface. The corresponding (Stern) layer appears to be a mixed monolayer of anions and cations. An estimate of the amount of cations in the Stern layer is also made.


Physician Assistant Education Association: Past, Present, and Future.
The Physician Assistant Education Association (PAEA), known as the Association of Physician Assistant Programs (APAP) until 2006, is the professional organization that represents physician assistant (PA) programs in the United States. Its mission is to "pursue excellence, foster faculty development, advance the body of knowledge that defines quality education and patient-centered care, and promote diversity in all aspects of PA education." PAEA has played an important role in promoting and shaping the educational mission of the PA profession. PAEA experienced a modest beginning, but it has evolved quickly as it increased its governance structure, staff, budget, and member services to support a rapidly growing profession over the last couple of decades. PAEA's current progress has positioned the profession well to increase our national visibility and our ability to affect the future of health care delivery. The future of PA education and PAEA will certainly be impacted by our continuing ability to adapt to change and to be visionary in our approach to the significant challenges we will face. Collectively, the Association staff, volunteers, and members will strive to fulfill its mission.


Impact of oral potentially malignant disorders on quality of life.
Oral potentially malignant disorders (OPMDs) could have a significant psychological impact on patients, principally because of the unknown risk of malignant transformation, while the physical and functional impairments could differ. This study aimed to assess the impact of three different OPMDs and their disease stages on the quality of life (QoL) of affected patients. Oral leukoplakia (OL), oral lichen planus (OLP) and oral submucous fibrosis (OSF) patients who were undergoing treatment at an oral medicine clinic of a dental teaching hospital in India were the study population. All subjects completed the recently developed OPMDQoL questionnaire and a short form 12 item (version 2) health survey questionnaire (SF-12v2). OPMDQoL questionnaire consists of 20 items over four dimensions. A higher score denotes poor OHRQoL. SF-12v2 has two components, a Physical Component Summary (PCS) and Mental Component Summary (MCS). A total of 150 subjects (50 each of OL, OLP and OSF) participated. OL patients (37.7 ± 7.9) reported significantly better OPMDQoL scores than OLP (47.3 ± 5.8) and OSF (45.4 ± 9.2) patients. OLP patients reported significant problems in obtaining a clear diagnosis for their condition, more so than the other OPMDs. OL patients reported fewer problems for the dimension, "physical impairment and functional limitations" than the OLP and OSF patients. A significant trend was observed with the overall OPMDQoL and MCS, deteriorating as the disease stage increased. OLP and OSF have a significant impact on the QoL of affected individuals: OL less so. Increasing stage of the disease is associated with worsening QoL.


CD1a and MHC class I follow a similar endocytic recycling pathway.
CD1 proteins are a family of major histocompatibility complex (MHC) class I-like antigen-presenting molecules that present lipids to T cells. The cytoplasmic tails (CTs) of all human CD1 isoforms, with the exception of CD1a, contain tyrosine-based sorting motifs, responsible for the internalization of proteins by the clathrin-mediated pathway. The role of the CD1a CT, which does not possess any sorting motifs, as well as its mode of internalization are not known. We investigated the internalization and recycling pathways followed by CD1a and the role of its CT. We found that CD1a can be internalized by a clathrin- and dynamin-independent pathway and that it follows a Rab22a- and ADP ribosylation factor (ARF)6-dependent recycling pathway, similar to other cargo internalized independent of clathrin. We also found that the CD1a CT is S-acylated. However, this posttranslational modification does not determine the rate of internalization or recycling of the protein or its localization to detergent-resistant membrane microdomains (DRMs) where we found CD1a to be enriched. We also show that plasma membrane DRMs are essential for efficient CD1a-mediated antigen presentation. These findings place CD1a closer to MHC class I in its trafficking and potential antigen-loading compartments among CD1 isoforms. Furthermore, we identify CD1a as a new marker for the clathrin- and dynamin-independent and DRM-dependent pathway of internalization as well as the Rab22a- and ARF6-dependent recycling pathway.


Genetic and environmental factors affecting the suitability of dogs as Guide Dogs for the Blind.
Many dogs are found to be unsuitable for training as guide dogs for the blind. Consequently the Royal Guide Dogs for the Blind Association of Australia has embarked on a breeding program to produce a strain of labrador dogs which is suitable for guide dog training.The most common reasons for rejecting dogs are fearfulness, dog distraction, excitability, health and physical reasons and hip dysplasia. The selection program seems to have been successful in improving the success rate mainly by lowering fearfulness, but there has not been a continuing improvement. This is probably due to continual introduction of dogs from other populations into the breeding program.Males suffer from a higher rejection rate due to dog distraction and a lower rejection rate due to fearfulness and excitability than females, so that there is little sex difference in overall success rate.The heritability of success (0.44) is high enough to predict further progress from selection, again mainly against fearfulness.Variation in environment prior to 6 weeks of age, in age when dogs were placed into a private home and in age when males were castrated, had little effect on the success rate.


Past Experiences of Getting Bullied and Assaulted and Posttraumatic Stress Disorder (PTSD) After a Severe Traumatic Event in Adulthood: A Study of World Trade Center (WTC) Responders.
Although experiencing bullying and other forms of assault is associated with adverse physical, emotional, and psychological consequences, the long-term consequences, especially in the aftermath of a severe trauma in adulthood, is not known. This study examined the relationship between history of being bullied and/or assaulted and posttraumatic stress disorder (PTSD) symptoms among responders to the World Trade Center (WTC) disaster. During 2015-16, a modified life events checklist was administered to responders at Stony Brook WTC Health Program. WTC-related PTSD symptoms were assessed by PTSD checklist (PCL). Longitudinal mixed models examined associations between bullying, other forms of assault, and severity and chronicity of PTSD symptoms. Approximately 13% of 920 responders had probable WTC-PTSD (PCL≥44). Being bullied in childhood was associated with increased odds of WTC-PTSD (adjusted odds ratio [aOR] =7.34; 95% confidence interval [CI] = 2.12-25.34), adjusted for demographics, other stressors, and WTC exposures. PTSD odds decreased over time among those not bullied (aOR 0.82; 95% CI: 0.73-0.92), but not among victims. Experiencing physical, sexual, or verbal assaults during adulthood, also had a significant association with WTC-PTSD (aOR 4.64; 95% CI: 1.98-10.92). Findings suggest being bullied in childhood and/or assaulted in adulthood can increase PTSD risk and progression after mass trauma.


The effect of monensin on chitin synthesis in Candida albicans blastospores.
Monensin, a monovalent cation ionophore, was used to investigate some steps of the wall synthesis and morphogenesis in Candida albicans blastospores. In the presence of the drug, the pathogenic yeast developed enormous wall and septum thickenings that reacted intensely and specifically with wheat germ agglutinin and chitinase coupled to colloidal gold and fluorescein isothiocyanate. Therefore, the aberrant zones are interpreted as sites of chitin accumulation. The increased production of this homopolymer, also demonstrated by the chemical analysis of cell wall preparations, implies that monensin interferes in some way with the regulatory factors that normally control, in space and time, chitin synthetase activity.


[Number of positive central cervical lymph nodes for predicting lateral cervical lymph node metastasis in patients with papillary thyroid carcinoma].
The aim of this study was to evaluate the number of central cervical lymph node metastasis (CCLNM) in predicting lateral cervical lymph node metastasis (LCLNM) in patients with papillary thyroid carcinoma (PTC). From January 2005 to October 2010, a total of 133 patients diagnosed as PTC underwent central and lateral cervical lymph node dissection were enrolled in this study. Quantitative analysis was performed to explore the correlation between the number of CCLNM and LCLNM. The sensitivity of central cervical node metastasis to predict lateral cervical node metastasis was 84.7%(61/72), and the positive predictive value (PPV) was 66.3% (61/92). The incidence of lateral cervical LNM was correlated with the number of CCLNM (r=0.911, P=0.004). The LCLNM rates in patients with number of CCLNM <2 and ≥ 2 were 54.5% (12/22) and 70.0% (49/70), respectively, with a non-significant difference (P=0.181). The LCLNM rates in patients with number of CCLNM < 3 and ≥ 3 were 50.0% (19/38) and 77.8% (42/54), showing a significant difference (P=0.006). The LCLNM rates in patients with number of CCLNM <4 and ≥ 4 were 55.1% (27/49) and 79.1% (34/43), with a significant difference (P=0.015). The LCLNM rates in patients with number of CCLNM <5 and ≥ 5 with the LLNM rate were 57.6% (34/59) and 81.8% (27/33), showing a significant difference (P=0.019). The LCLNM rates in patients with number of CCLNM <6 and ≥ 6 were 60.0% (39/65) and 81.5% (22/27), showing a significant difference (P=0.047). CCLNM has a significant association with LCLNM in patients with papillary thyroid carcinoma. LCLNM is mainly observed in patients with ≥ 3 CCLNM. Therefore, the number of CLNM ≥ 3 may be a valuable predictor of lateral cervical lymph node metastasis, and lateral cervical lymph node dissection should be considered.


Triglyceride lowering by omega-3 fatty acids: a mechanism mediated by N-acyl taurines.
Interest in omega-3 fatty acids (colloquially known as fish oils) to lower residual cardiovascular risk in statin-treated patients has increased markedly in the wake of recent cardiovascular outcome trials. The triglyceride-lowering effects of omega-3 fatty acids are generally thought to occur by reduced hepatic VLDL production. In this issue of the JCI, Grevengoed et al. used mouse models and human plasma samples to reveal an additional mechanism whereby these polyunsaturated fatty acids can lower plasma triglycerides. Their findings indicate that omega-3 fatty acid-derived N-acyl taurines (NATs) greatly accumulate in bile and also in plasma following omega-3 supplementation. The authors further show that one of these NATs (C22:6 NAT) inhibited intestinal triglyceride hydrolysis and lipid absorption, which resulted in lower plasma triglycerides and protection against hepatic triacylglycerol accumulation in mice fed a high-fat diet. The findings open a potential avenue for triglyceride lowering by omega-3 fatty acids conjugated to taurine.


Heart rate reactivity and current post-traumatic stress disorder when data are missing.
This study demonstrates that auxiliary and exclusion criteria variables increase the effectiveness of missing imputation in correcting underestimation of physiologic reactivity in relation to post-traumatic stress disorder (PTSD) caused by deleting cases with missing physiologic data. This study used data from survivors of the 1995 Oklahoma City bombing and imputed missing heart rate data using auxiliary and exclusion criteria variables. Logistic regression was used to examine heart rate reactivity in relation to current PTSD. Of 113 survivors who participated in the bombing study's 7-year follow-up interview, 42 (37%) had missing data on heart rate reactivity due to exclusion criteria (medical illness or use of cardiovascular or psychotropic medications) or non-participation. Logistic regression results based on imputed heart rate data using exclusion criteria and auxiliary (the presence of any current PTSD arousal symptoms) variables showed that survivors with current bombing-related PTSD had significantly higher heart rates at baseline and recovered more slowly back to baseline heart rate during resting periods than survivors without current PTSD, while results based on complete cases failed to show significant correlations between current PTSD and heart rates at any assessment points. Suggested methods yielded an otherwise undetectable link between physiology and current PTSD.


Numerical models of sunspot formation and fine structure.
Sunspots are central to our understanding of solar (and stellar) magnetism in many respects. On the large scale, they link the magnetic field observable in the photosphere to the dynamo processes operating in the solar interior. Properly interpreting the constraints that sunspots impose on the dynamo process requires a detailed understanding of the processes involved in their formation, dynamical evolution and decay. On the small scale, they give an insight into how convective energy transport interacts with the magnetic field over a wide range of field strengths and inclination angles, leading to sunspot fine structure observed in the form of umbral dots and penumbral filaments. Over the past decade, substantial progress has been made on both observational and theoretical sides. Advanced ground- and space-based observations have resolved, for the first time, the details of umbral dots and penumbral filaments and discovered similarities in their substructures. Numerical models have advanced to the degree that simulations of entire sunspots with sufficient resolution to resolve sunspot fine structure are feasible. A combination of improved helioseismic inversion techniques with seismic forward modelling provides new views on the subsurface structure of sunspots. In this review, we summarize recent progress, with particular focus on numerical modelling.


Time to onset of neuropathic pain reduction: A retrospective analysis of data from nine controlled trials of pregabalin for painful diabetic peripheral neuropathy and postherpetic neuralgia.
These retrospective analyses of daily mean pain scores from nine placebo-controlled trials of pregabalin at 150, 300, or 600 mg/day (pregabalin, n = 1205; placebo, n = 772) examined time to significant reduction of pain during the first 2 weeks of treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. Time to onset of reduction in pain-defined as the first day for which patients treated with pregabalin had significant reductions (P < 0.05) in mean pain score compared with the placebo group for that day and the subsequent day-was calculated for all treatment groups demonstrating statistically significant reduction in pain at trial end point. The time to a 1-point or greater improvement in mean pain score was measured for each patient who was a responder at end point (30% or greater improvement in mean pain score). In seven of the nine trials (representing 11 of 14 pregabalin arms), significant reduction in pain was achieved at end point. The time to onset for reduction in pain was treatment Day 1 or 2 in nine of these successful treatment arms. Individual responder analysis confirmed that responders in the pregabalin groups reported a 1-point or greater pain reduction earlier than responders in placebo groups (P < 0.0001). However, this analysis is not a direct estimate of the likelihood that an individual patient would experience noticeable pain relief by the end of the second day. Overall, for patients who will respond to pregabalin, statistically significant and sustained reduction of pain associated with diabetic peripheral neuropathy and posttherapeutic neuralgia occurs early, usually by the end of 2 days of pregabalin treatment.


Benign symptomatic hyperandrogenism in a postmenopausal woman.
Hyperandrogenemia in postmenopausal women requires an evaluation to exclude pathologic ovarian or adrenal causes. Our patient exhibited no signs of hypercortisolism, congenital adrenal hyperplasia, or adrenal or ovarian neoplasia based on biochemical testing and pelvic sonography. We hypothesized that unexplained androgen excess in our patient was due to the development of gonadotropin-dependent excess ovarian stromal androgen production. This syndrome may be comparable to gestational hyperreactio luteinalis where elevated gonadotropins stimulate ovarian stromal androgen production. If tumor can confidently be excluded, such women may benefit from gonadotropin suppression with long-acting GnRH-a.


[Kinetics of cellular elements in the neointima of synthetic prostheses implanted into the rabbit aorta during development of experimental atherosclerosis].
Experimental atherosclerosis in 30 rabbits was combined with the implantation into the abdominal aorta of the synthetic prosthesis MPL-79. Formation of neointima and transformation of mesenchymal cells into the endothelial ones are studied using scanning and translucent electron microscopy and autoradiography. Neointimal hyperplasia is shown to result in significant narrowing of the prosthesis lumen up to its complete occlusion. It is important that neointima fibroplasia is particularly intense against the background of progressing atherosclerosis.


[Treatment of premenstrual syndrome with Chinese medicine formula, baixiangdan capsule: implications for neuron viability and GABA(A) receptor modulation in rat cortex].
To explore the effects of Baixiangdan capsule (BXD), a Chinese medicinal formula, on the premenstrual syndrome (PMS) rats with Liver-qi invasion and the possible underlying micro-mechanisms. Wistar rats were randomly assigned to two groups, nomal group and BXD group After evaluated by macro-behavior observation and open-field test, MTT assay and the whole-cell patch clamp recording were performed respectively to evaluate the effects of serum from BXD capsule-treated rats on the viability and GABA(A) R-induced currents of cortical neurons in vitro. In the open-field test, the crossing score, rearing score and total score of BXD rats decreased significantly (P < 0.05), compared by the normal rats. Compared with cells exposed to serum of normal rats, the viability values of those incubated with serum of BXD group for 24 h and 48 h significantly increased (P < 0.05), measured by MTT assay. The results of whole-cell patch clamp recording showed that concentration-response relationship curves revealed an EC50 value of (29.0 +/- 4.4) micromol x L(-1) and a Hill coefficient of 1.07 for normal-exposed cultures, (63.5 +/- 8.2) micromol x L(-1), 1.04 for BXD-exposed cultures after incubation for 24 h. Furthermore, the difference in EC50 values was statistically significant (P < 0.01), that in the Hill coefficient was not obvious. BXD capsule could significantly decrease crossing score and total score of open-field test and effectively enhance the neuron viability and GABA(A) receptor activity in rat cortex. Paeonimetabolins I and paeonol may play a significant role in treating PMS model rats with Liver-qi invasion by BXD capsule, and paeonol may target at GABA(A) receptor, especially.


It is rocket science - why dietary nitrate is hard to 'beet'! Part I: twists and turns in the realization of the nitrate-nitrite-NO pathway.
Dietary nitrate (found in green leafy vegetables, such as rocket, and in beetroot) is now recognized to be an important source of nitric oxide (NO), via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. While this pathway may now seem obvious, its realization followed a rather tortuous course over two decades. Early steps included the discovery that nitrite was a source of NO in the ischaemic heart but this appeared to have deleterious effects. In addition, nitrate-derived nitrite provided a gastric source of NO. However, residual nitrite was not thought to be absorbed systemically. Nitrite was also considered to be physiologically inert but potentially carcinogenic, through N-nitrosamine formation. In Part 1 of a two-part Review on the nitrate-nitrite-NO pathway we describe key twists and turns in the elucidation of the pathway and the underlying mechanisms. This provides the critical foundation for the more recent developments in the nitrate-nitrite-NO pathway which are covered in Part 2.


DNA from mollusc shell: a valuable and underutilised substrate for genetic analyses.
Mollusc shells are an abundant resource that have been long used to predict the structures of ancient ecological communities, examine evolutionary processes, reconstruct paleoenvironmental conditions, track and predict responses to climatic change, and explore the movement of hominids across the globe. Despite the ubiquity of mollusc shell in many environments, it remains relatively unexplored as a substrate for molecular genetic analysis. Here we undertook a series of experiments using the New Zealand endemic greenshell mussel, Perna canaliculus, to explore the utility of fresh, aged, beach-cast and cooked mollusc shell for molecular genetic analyses. We find that reasonable quantities of DNA (0.002-21.48 ng/mg shell) can be derived from aged, beach-cast and cooked mussel shell and that this can routinely provide enough material to undertake PCR analyses of mitochondrial and nuclear gene fragments. Mitochondrial PCR amplification had an average success rate of 96.5% from shell tissue extracted thirteen months after the animal's death. A success rate of 93.75% was obtained for cooked shells. Amplification of nuclear DNA (chitin synthase gene) was less successful (80% success from fresh shells, decreasing to 10% with time, and 75% from cooked shells). Our results demonstrate the promise of mollusc shell as a substrate for genetic analyses targeting both mitochondrial and nuclear genes.


Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer.
Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Detection of ctDNA and recurrence-free interval (RFI). After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.


Mandatory contrast-enhanced venography to detect deep-vein thrombosis (DVT) in studies of DVT prophylaxis: upsides and downsides.
The introduction of venography into patient care was a major advance because it was the first accurate method for the diagnosis of DVT. Compression ultrasound has since become the preferred test for patients with suspected DVT because, unlike venography, it is simple, non-invasive and widely available. Venography has facilitated the development and approval of new anticoagulants and remains widely used as an efficacy outcome in trials of venous thromboembolism prevention. Most thrombi detected by screening venography are, however, small and unimportant for patients. In order to calculate the trade-off between an asymptomatic thrombus and a bleed we require an estimate of the number of asymptomatic thrombi that must be prevented to avoid a patient-important thrombus. A credible estimate of this ratio is not available. Therefore when used as a measure of efficacy in trials of thromboprophylaxis, venography has limitations for comparing the relative effects of alternative antithrombotic agents on outcomes important to patients.


The effect of trimethoprim on macromolecular synthesis in Escherichia coli.
In trimethoprim-inhibited RC(str) strains of Escherichia coli, the expression of the RC control of stable RNA synthesis arose primarily from a decrease in the intracellular concentrations of glycine and methionine, and not from inhibition of the initiation of new protein chains. In non-supplemented cultures, experiments with rifampicin showed that the immediate response to the addition of trimethoprim was a rapid decrease in the rate of initiation of RNA chains. This was followed after a few minutes by a sufficiently large fall in the rate of endogenous synthesis of nucleotide bases to cause a decrease in the rate of RNA chain polymerization. Inhibition of RNA chain initiation was thus overridden by an accumulation of DNA-dependent RNA polymerases upon the cistrons. RC(rel) strains also accumulated polymerases upon the DNA in similar circumstances, but did not suffer the initial effects on chain initiation. If purines were supplied before adding trimethoprim, RC(str) strains polymerized RNA chains at normal rates, but initiation rates were permanently decreased. In either situation, an increased% of the RNA formed was mRNA. However, in RC(rel) strains supplemented with bases, trimethoprim did not affect either the rate of initiation of new chains or their rates of polymerization or the relative rates of synthesis of stable RNA and mRNA. Protein synthesis was also severely inhibited by trimethoprim. Though the addition of glycine and methionine to base-supplemented, trimethoprim-inhibited RC(str) strains did not apparently affect the decreased rate of protein synthesis, RNA accumulation resumed at its normal rate. Thus, the inhibition of protein chain initiation had no effect on the rate of RNA accumulation in either RC(str) or RC(rel) bacteria. The RC control does not express itself through inhibitions of protein synthesis at this level.


Audience as analyst: Dennis Potter's The Singing Detective.
Author Dennis Potter has written an exceptional psychoanalytically informed television series in The Singing Detective. Potter succeeds by echewing the usual portrayal of psychoanalysis in cinema and television as a therapy which the viewer observes but instead creates, by means of the content and structure of the series, a production that forces the audience into a role of analyst. The story of the current life and the childhood of the protagonist, Philip Marlow, has depth and context which allows the audience to examine the personality of Marlow, including character pathology and traits, sexuality, fantasy, dreams, and delusions from several metapsychological viewpoints. Potter allows the audience to use the dynamic, genetic, topographic, and, most unusual in drama, structural viewpoints. The audience can experience aspects of an analyst's experience, including the process of formulating and evaluating over time analytic hypotheses and coping with emotional reactions to the material which at times has transferencelike qualities.


The Transmission Dynamics of a Compartmental Epidemic Model for COVID-19 with the Asymptomatic Population via Closed-Form Solutions.
Unlike previous viral diseases, COVID-19 has an "asymptomatic" group that has no symptoms but can still spread the disease to others at the same rate as symptomatic patients who are infected. In the literature, the mass action or standard incidence rates are considered for compartmental models with asymptomatic compartment for studying the transmission dynamics of COVID-19, but the quarantined adjusted incidence rate is not. To bridge this gap, we developed a Susceptible Asymptomatic Infectious Quarantined (SAIQ) model with a Quarantine-Adjusted (QA) incidence to investigate the emergence and containment of COVID-19. COVID-19 models are investigated using various methods, but only a few studies take into account closed-form solutions. The knowledge of closed-form solutions simplifies the construction of the various epidemic indicators that describe the epidemic phenomenon and makes the sensitivity analysis to variations in the data under consideration possible. The closed-form solutions of the systems of four nonlinear first-order ordinary differential equations (ODEs) are established. The Epidemic Peak (EP), Force of Infection (FOI) and Rate of Infection (ROI) are the important indicators for the control and prevention of disease. We examined these indicators using closed-form solutions and particular parameter values. Different disease control scenarios are thoroughly examined. The four scenarios to analyze COVID-19 propagation and containment are (i) lockdown, (ii) quarantine and other preventative measures, (iii) stabilizing the basic reproduction rate to a level where the pandemic can be contained and (iv) containing the epidemic through an appropriate combination of lockdown, quarantine and other preventative measures.


A combined irradiance-transmittance solar spectrum and its application to photovoltaic efficiency calculations.
SOLTRAN is a flexible computer model for the direct solar beam intensity spectrum at the earth's surface. It has been derived by combining the extra-terrestrial solar spectrum with the atmospheric transmittance spectrum. Application of SOLTRAN to the calculation of the potential efficiency of photovoltaic cells demonstrates the effect of atmospheric absorption bands. These bands prevent unequivocal assignment of optimum energy gap values.


The psychosocial treatments interview for anxiety disorders. A method for assessing psychotherapeutic procedures in anxiety disorders.
The authors report on development, reliability, and findings of the Psychosocial Treatments Interview (PTI) to assess treatments reported by patients in a naturalistic study of the longitudinal course of anxiety disorders. The PTI ascertains frequency of different types of psychosocial treatments, based on patients' reports. The PTI showed good internal consistency and very good interrater reliability. At first 6-month follow-up, the most common modalities were supportive, medication discussion, and dynamic intervention. Combinations were common. Delivery of treatments differed by site. Overall, the PTI fills a methodological need for the assessment of the treatments reported by patients in naturalistic follow-up studies.


Coulomb interactions in charged fluids.
The use of Ewald summation schemes for calculating long-range Coulomb interactions, originally applied to ionic crystalline solids, is a very common practice in molecular simulations of charged fluids at present. Such a choice imposes an artificial periodicity which is generally absent in the liquid state. In this paper we propose a simple analytical O(N(2)) method which is based on Gauss's law for computing exactly the Coulomb interaction between charged particles in a simulation box, when it is averaged over all possible orientations of a surrounding infinite lattice. This method mitigates the periodicity typical of crystalline systems and it is suitable for numerical studies of ionic liquids, charged molecular fluids, and colloidal systems with Monte Carlo and molecular dynamics simulations.


Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.
Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.


[Various aspects of the effect of nutritional factors on the metabolism and biological action of aflatoxin B1 in the rat liver].
Interrelationships between the quality of nutrition, oxidative hydroxylation of aflatoxin B1 and lipid peroxidation were studied in biomembranes of hepatocyte endoplasmic reticulum of growing male rats of the WAG strain. Activity of the liver microsomal monooxygenase, lipid peroxidation as well as metabolism of aflatoxin B1 were shown to depend on presence of three essential amino acids (lysine, methionine and threonine) and vitamins A, E and C. Deficiency of these compounds altered the aflatoxin metabolism causing formation of highly reactive metabolites, which might accelerate the carcinogenic effect of the xenobiotic. However, formation of free toxic metabolites of aflatoxin was stimulated under conditions of balanced nutrition as a result of which its toxic effect might be increased.


Role of parthenolide in paclitaxel-induced oxidative stress injury and impaired reproductive function in rat testicular tissue.
The chemotherapeutic agent paclitaxel (PTX) causes testicular toxicity due to oxidative stress. Parthenolide (PTL), the active ingredient of the Tanacetum parthenium plant, is used to treat inflammation, dizziness, and spasms. In the present study, we evaluated the therapeutic effect of PTL on PTX-induced testicular toxicity in rats and its role in reproductive function. To this end, 6 groups were formed: control, PTX, sham, T1, T2, and T3. After testicular toxicity was induced in rats with 8 mg/kg PTX, the rats were treated with 1 mg/kg, 2 mg/kg, and 4 mg/kg PTL for 14 days. GSH and MDA levels were measured in rat testicular tissue after the last dose of PTL was administered. To determine the damage caused by PTX to testicular tissue by detecting 8-OHdG and iNOS, sections were prepared and examined histopathologically and immunohistochemically. Furthermore, the gene expressions and enzymatic activities of SOD, CAT, GPx, GST, and GR were investigated in all groups. After PTL treatment, MDA, 8-OHdG, and iNOS levels decreased while GSH levels increased in testicular tissue. Increased levels of antioxidant genes and enzymes also reduced oxidative stress. Additionally, the expression levels of the Dazl, Ddx4, and Amh genes, which are involved in gametogenesis and sperm production, decreased in case of toxicity and increased with PTL treatment. The data from this study show that PTL may have a therapeutic effect in the treatment of testicular damage by eliminating the oxidative stress-induced damage caused by PTX in testicular tissue, providing an effective approach to alleviating testicular toxicity, and playing an important role in reproduction/sperm production, especially at a dose of 4 mg/kg.


The N400 component in parents of children with specific language impairment.
Children with specific language impairment (SLI) often have a family history of language disorder. In this study, ERPs in response to a visual semantic priming task were recorded in parents of children with SLI. Despite equal performance, the ERPs displayed differences in language processing: larger N400 amplitudes indicated that the parents, especially the fathers, were less primed by the preceding context. Difference waveforms showed that the fathers of SLI children, contrary to controls, had less differentiated responses to congruent versus incongruent sentences. We propose that the N400 observations may be residual markers of past language deficiencies in the fathers. No differences in the N400 effect were found in the mothers of SLI children.


Time course and distribution of tungsten-laden macrophages in the hilar lymph nodes of the dog lung after experimental instillation of calcium tungstate into the left apical bronchus.
We sprayed a tungsten powder (CaWO4) into the airway of a single lobe (left apical) of the dog lung in order to study: (a) the kinetics of particle translocation from the bronchoalveolar lining to hilar lymph nodes, and (b) the sorting in lung lymph nodes of inhaled microcrystals. We found that the transport of the tungsten particles to the regional lymph node takes at least 24 hours and reaches its peak at day 7. In situ detection of tungsten by elemental particle analysis of lymph node sections by scanning electron microscopy allowed precise mapping of the marker in the node; the method was complemented by light microscopy and thin-section electron microscopy of the same nodes. Virtually all of the lymph node tungsten was located inside macrophages. The first tungsten-positive macrophages seen in the regional lymph nodes (day 1 to day 3) were restricted to the subcapsular space. This was followed by massive filling of the same sinus and of the narrow interfollicular areas by the particle-laden macrophages (day 3 to day 7). The even distribution of the tungsten-bearing phagocytes found in these anatomical regions of the node indicated that the subcapsular area in the dog was a continuous domain rather than the segmented region observed in nodes of common laboratory animals such as the rat. By day 7 after tungsten instillation, a moderate number of tungsten-positive macrophages was also detected in the paracortical region of the node. Finally, the presence of tungsten-bearing macrophages was extended to the outer lymph node medulla (day 7 to day 14); here, the macrophages were located in association with cords of plasmacytes and showed interdigitations with these lymphocytes. Only minimal amounts of tungsten were detected inside lymphoid follicles in association with dendritic cells. Some of the tungsten initially deposited in the airway of the apical left lung lobe was detected in contralateral hilar lymph nodes. We conclude that: (i) particle translocation from the alveolus to regional lymph nodes is a slow process that is mediated by pulmonary macrophages, in agreement with the findings of Harmsen et al Science 230:1277, 1985); (ii) in the lymph node, particle-bearing macrophages are sorted through narrow interfollicular sinuses into the outer medulla where they interact extensively with plasma cells; (iii) the migrating macrophages cannot penetrate the follicular domains of the node; minute quantities of exogenous particles may, nevertheless, be transferred from macrophages to follicular dendritic cells; and (iv) contralateral drainage may be a feature of the lymphatic system in the lung.


Molecular dynamics simulations of alkaline earth metal ions binding to DNA reveal ion size and hydration effects.
The identity of metal ions surrounding DNA is key to its biological function and materials applications. In this work, we compare atomistic molecular dynamics simulations of double strand DNA (dsDNA) with four alkaline earth metal ions (Mg2+, Ca2+, Sr2+, and Ba2+) to elucidate the physical interactions that govern DNA-ion binding. Simulations accurately model the ion-phosphate distance of Mg2+ and reproduce ion counting experiments for Ca2+, Sr2+, and Ba2+. Our analysis shows that alkaline earth metal ions prefer to bind at the phosphate backbone compared to the major groove and negligible binding occurs in the minor groove. Larger alkaline earth metal ions with variable first solvation shells (Ca2+, Sr2+, and Ba2+) show both direct and indirect binding, where indirect binding increases with ion size. Mg2+ does not fit this trend because the strength of its first solvation shell predicts indirect binding only. Ions bound to the phosphate backbone form fewer contacts per ion compared to the major groove. Within the major groove, metal ions preferentially bind to guanine-cystosine base pairs and form simultaneous contacts with the N7 and O6 atoms of guanine. Overall, we find that the interplay among ion size, DNA-ion interaction, and the size and flexibility of the first solvation shell are key to predicting how alkaline earth metal ions interact with DNA.


Well-timed, brief inhibition can promote spiking: postinhibitory facilitation.
Brief synaptic inhibition can overwhelm a nearly coincident suprathreshold excitatory input to preclude spike generation. Surprisingly, a brief inhibitory event that occurs in a favorable time window preceding an otherwise subthreshold excitation can facilitate spiking. Such postinhibitory facilitation (PIF) requires that the inhibition has a short (decay) time constant tauinh. The timescale ranges of tauinh and of the window (width and timing) for PIF depend on the rates of neuronal subthreshold dynamics. The mechanism for PIF is general, involving reduction by hyperpolarization of some excitability-suppressing factor that is partially recruited at rest. Here we illustrate and analyze PIF, experimentally and theoretically, using brain stem auditory neurons and a conductance-based five-variable model. In this auditory case, PIF timescales are in the sub- to few millisecond range and the primary mechanistic factor is a low-threshold potassium conductance gKLT. Competing dynamic influences create the favorable time window: hyperpolarization that moves V away from threshold and hyperexcitability resulting from reduced gKLT. A two-variable reduced model that retains the dynamics only of V and gKLT displays a similar time window. We analyze this model in the phase plane; its geometry has generic features. Further generalizing, we show that PIF behavior may occur even in a very reduced model with linear subthreshold dynamics, by using an integrate-and-fire model with an accommodating voltage-dependent threshold. Our analyses of PIF provide insights for fast inhibition's facilitatory effects in longer trains. Periodic subthreshold excitatory inputs can lead to firing, even one for one, if brief inhibitory inputs are interleaved within a range of favorable phase lags. The temporal specificity of inhibition's facilitating effect could play a role in temporal processing, in sensitivity to inhibitory and excitatory temporal patterning, in the auditory and other neural systems.


Vector control of snail-mediated human trematode infections.
Inspite of the recent general acceptance of the use of safe and effective chemotherapeutic drugs in the treatment of major human trematode infections, vector control e.g. control of the snail intermediate host will continue to play an important role in programmes for controlling schistosomiasis, clonorchiasis, opisthorchiasis and paragonimiasis. The main vector control measures are: a) use of chemical pesticides or molluscicides and plants showing molluscicidal properties; b) biological control through introduction of competitor species or natural enemies of snails; c) alteration of the environment either by application of one or a combination of the following; drainage, filling, ponding, clearing of vegetation and regulation of use of water for agricultural purposes.


[Evaluation of health risks of residents of Novokuibyshevsk].
The globally accepted procedure for assessing the human health and the special software "MedEcoRISK" programme (Saint Petersburg) were used in Novokuibyshevsk (Samara Region), the center of petroleum-refining and petrochemical industry. The surveys did not yield contradictory results and they were complementary in providing evidence for that the population's health status has become much worse due to high ambient air pollution. The findings were used for basic information in the system of measures to reduce health risks.


Effects of Microbes from Coal-Related Commercial Humic Substances on Hydroponic Crop Cultivation: A Microbiological View for Agronomical Use of Humic Substances.
Here, coal-related humic substances (HSs) were examined to confirm whether sterilization treatments induce their inferior ability to stimulate lettuce in hydroponic cultivations. Interestingly, a drastic reduction in both lettuce biomass and microbial colony-forming units of the crop culture solutions was observed when the autoclaved HSs were treated. Some microbial genera (i.e., Bacillus and Aspergillus) identifiable in the bare HS-treated hydroponic systems were able to be isolated by direct inoculation of bare HS powders on conventional microbial nutrients, supporting that flourishing microbes in the hydroponic cultivations derive from bare HSs-treated. Moreover, coincubation of some isolated bacterial and fungal strains (i.e., Bacillus and Aspergillus genera) from HSs with lettuce resulted in a significant increase in plant biomass and enhanced resistance to NaCl-related abiotic stresses. Microbial volatile organic compounds renowned for plant stimulation were detected by using solid-phase microextraction coupled with gas chromatography-mass spectrometry. It was finally confirmed that the isolates are capable of utilizing carbon substrates such as pectin and tween 20 or 40, which are relevant to those of microbes isolated from peat and leonardite (i.e., HS extraction sources). Overall, our results suggest that microbiological factors could be considered when commercial coal-related HSs are applied in hydroponic crop cultivations.


Mega2: validated data-reformatting for linkage and association analyses.
In a typical study of the genetics of a complex human disease, many different analysis programs are used, to test for linkage and association. This requires extensive and careful data reformatting, as many of these analysis programs use differing input formats. Writing scripts to facilitate this can be tedious, time-consuming, and error-prone. To address these issues, the open source Mega2 data reformatting program provides validated and tested data conversions from several commonly-used input formats to many output formats. Mega2, the Manipulation Environment for Genetic Analysis, facilitates the creation of analysis-ready datasets from data gathered as part of a genetic study. It transparently allows users to process genetic data for family-based or case/control studies accurately and efficiently. In addition to data validation checks, Mega2 provides analysis setup capabilities for a broad choice of commonly-used genetic analysis programs. First released in 2000, Mega2 has recently been significantly improved in a number of ways. We have rewritten it in C++ and have reduced its memory requirements. Mega2 now can read input files in LINKAGE, PLINK, and VCF/BCF formats, as well as its own specialized annotated format. It supports conversion to many commonly-used formats including SOLAR, PLINK, Merlin, Mendel, SimWalk2, Cranefoot, IQLS, FBAT, MORGAN, BEAGLE, Eigenstrat, Structure, and PLINK/SEQ. When controlled by a batch file, Mega2 can be used non-interactively in data reformatting pipelines. Support for genetic data from several other species besides humans has been added. By providing tested and validated data reformatting, Mega2 facilitates more accurate and extensive analyses of genetic data, avoiding the need to write, debug, and maintain one's own custom data reformatting scripts. Mega2 is freely available at https://watson.hgen.pitt.edu/register/.


FLT3-internal tandem duplication in a pediatric patient with t(8;21) acute myeloid leukemia.
Patients diagnosed with t(8;21)-acute myeloid leukemia (AML) are currently considered to have good prognoses, but about half of these patients relapse. FLT3-internal tandem duplication (ITD) is generally thought to be strongly associated with poor prognosis in AML, but is rarely reported in patients with t(8;21)-AML. Expression of the neural cell-adhesion molecule (CD56) is also associated with a significantly shorter complete remission duration and survival in patients with t(8;21)-AML. Patients with t(8;21)-AML expressing CD56 have been reported to exhibit a higher incidence of granulocytic sarcoma (GS), and t(8;21)-AML with GS results in a less favorable prognosis than AML with this translocation alone. Here, we report on a 15-year-old girl with t(8;21)-AML having both CD56 expression and FLT3-ITD. This patient underwent unrelated donor bone marrow transplantation and achieved complete remission, but thereafter presented with obstructive jaundice caused by GS compression of the common bile duct without bone marrow invasion at relapse. Autopsy revealed multiple nodules of the stomach membrane and invasion into the head of the pancreas. For earlier detection of relapse, we suggest that it would be useful to examine existence of GS in CD56-positive t(8;21)-AML patients at diagnosis and hematologic remission. Even though t(8;21)-AML is less likely to co-occur with FLT3-ITD in pediatric patients, this report suggests that prognostic factors, including FLT3 and KIT genes and the surface marker CD56, should be analyzed in these patients.


Renewal-process approximation of a stochastic threshold model for electrical neural stimulation.
In a recent set of modeling studies we have developed a stochastic threshold model of auditory nerve response to single biphasic electrical pulses (Bruce et al., 1999c) and moderate rate (less than 800 pulses per second) pulse trains (Bruce et al., 1999a). In this article we derive an analytical approximation for the single-pulse model, which is then extended to describe the pulse-train model in the case of evenly timed, uniform pulses. This renewal-process description provides an accurate and computationally efficient model of electrical stimulation of single auditory nerve fibers by a cochlear implant that may be extended to other forms of electrical neural stimulation.


Frequency of musculoskeletal injuries and risk factors associated with injuries incurred in Quarter Horses during races.
To determine the frequency and anatomic location of musculoskeletal injuries incurred by Quarter Horses during races and to compare data from injured horses and matched control horses. Matched case-control study. 97 Quarter Horses that sustained a musculoskeletal injury during races and 291 horses from the same races that were not injured. Data examined included racing history, race-entrant characteristics, racing events determined by analysis of videotapes of races, and, when performed, results of prerace physical inspections. Data for injured horses were compared with data for control horses, using conditional logistic regression. Incidence of a catastrophic injury among Quarter Horses during races was approximately 0.8/1,000 race starts, whereas incidence of musculoskeletal injury during racing was approximately 2.2/1,000 race starts. Odds of musculoskeletal injury were approximately 8 times greater among horses assessed to be at increased risk of injury on the basis of results of prerace physical inspection than for horses not considered to be at increased risk of injury. Evidence was lacking that 2-year-old horses were at increased risk of injury or that sex influenced the risk of injury among Quarter Horses during races. Incidence of racing injury among Quarter Horses appears to be lower than that observed among Thoroughbreds. Regulatory veterinarians can identify horses at increased risk of injury on the basis of prerace physical inspection, indicating that these inspections could be used to reduce the risk of injury during races.