Nanoinjection system for precise direct delivery of biomolecules into single cells.
Intracellular delivery of functional molecules such as proteins, transcription factors and DNA is effective and promising in cell biology. However, existing transfection methods are often unsuitable to deliver big molecules into cells or require carriers such as viruses and peptides specific to the target molecules. In addition, the nature of bulk processing does not generally provide accurate dose control of individual cells. The concept of single-cell-based material injection based on electrokinetic pumping through nanocapillaries could overcome these problems, yet the fabrication and operation of nanoscale 3-dimensional structures have remained unsolved. In this research, a hybrid (PDMS/glass) microfluidic chip with a true 3-dimensional nanoinjection structure (called "nanoinjection system") is presented. The nanoinjection structure was fabricated by femtosecond-laser (fs-laser) ablation in a single solid glass, which showed very successful delivery of red fluorescent protein (RFP) and expression of plasmid DNA in several different types of cells. This system is promising in that the amount of molecules to be delivered is controllable and the processed cells are systematically separated into a harvesting chamber, which can radically improve the purity of the processed cells. In addition, it was confirmed that the cells were healthy even after the molecule injection for a few seconds, indicating that the injection time can be significantly elongated, further improving the delivery efficiency of biomolecules without affecting the cell viability. We envision that the nanoinjection system having the major features of being carrier-free and dose-controllable, having an unlimited injection period, and ease of harvesting will greatly contribute to the next-generation research studies in the fields of cell biology and cell therapeutics.


Coffee. Facts and controversies.
In this article, we review current literature on coffee, both regular and decaffeinated, and its potential effects in humans. Moderate coffee consumption is believed to have no persistent effect on blood pressure. Large intake of coffee may increase total cholesterol levels; boiled coffee increases cholesterol levels more than filtered coffee. Consuming more than four cups per day may be associated with increased risk of acute myocardial infarction. There appears to be an association between urinary bladder cancer and coffee consumption. No association was found between ingestion of coffee and incidence of duodenal ulcer and ulcerative colitis. Increased coffee consumption by pregnant women appears to decrease fetal birth weight. Fetal heart rate, respiration, and both maternal and fetal anemia are increased with coffee consumption but coffee has not been shown to be teratogenic. Coffee consumption appears to pose no particular threat in most people if consumed in moderation. Naturally decaffeinated, filter-brewed coffee further diminishes its potential harmful effects.


Effect of luteinizing hormone-releasing hormone analogs on the rat ovarian follicle development.
Our objective was to study the direct action of luteinizing hormone-releasing hormone (LHRH) agonist buserelin and LHRH antagonist Cetrorelix (SB-75) on cell proliferation and differentiation in the rat ovarian follicle. Preovulatory follicles were isolated from PMSG-primed immature rats and incubated in the presence or absence of hCG (10 IU/ml), buserelin (10(-9)-10(-6) M) or Cetrorelix (10(-9)-10(-6) M) for 12 h in vitro. Buserelin induced meiotic maturation of the follicle-enclosed oocytes dose-dependently. The percentage of oocytes with germinal vesicle breakdown at 10(-6) M buserelin (73.3%) did not differ from that of hCG-treated control (73.3%). Buserelin also significantly stimulated prostaglandin E2 and progesterone production by follicles, but not estradiol production. Granulosa cells were obtained from the preovulatory follicles and cultured for 5 days. Epidermal growth factor (EGF) stimulated granulosa cell growth at concentrations of 1, 10 and 100 ng/ml. In contrast, both buserelin and Cetrorelix inhibited granulosa cell growth dose-dependently in the range of 10(-10)-10(-5) M, with Cetrorelix inducing a greater growth inhibition than buserelin. Electrophoretic analysis of genomic DNA extracted from granulosa cells treated with 10(-6) M concentration of either LHRH analog revealed a definitive ladder pattern of oligonucleosomal length DNA fragments characteristic of apoptosis. Western blotting detected that EGF-induced tyrosine phosphorylation was not affected by either analog. These results demonstrate that LHRH agonist and antagonist inhibit directly proliferation of granulosa cells through apoptosis, without interference with EGF receptor phosphorylation, whereas LHRH agonist stimulates cell differentiation in the preovulatory follicle.


A comparative evaluation of three high efficiency disposable dialyzers.
Until recently all disposable dialyzers have had a poorer overall performance than the best non-disposable dialyzer, the Meltec multipoint. The three disposables considered here (Gambro Lundia Nova, Cordis HFAK 4 and Rhone Poulenc RP 5) all have clearance of small molecules close to or, for the HFAK 4, just above that of the multipoint though their middle molecular clearance is not quite as good as the multipoint. The HFAK 4 has a better basal ultranfiltration rate but a poorer maximum ultrafiltration capacity. The RP 5 has a higher residual blood volume than the multipoint. In other respects the dialyzers are almost interchangeable and are reasonable alternatives to the multipoint in those centers which can afford single use disposable dialyzers.


The OsNLP3/4-OsRFL module regulates nitrogen-promoted panicle architecture in rice.
Rice panicles, a major component of yield, are regulated by phytohormones and nutrients. How mineral nutrients promote panicle architecture remains largely unknown. Here, we report that NIN-LIKE PROTEIN3 and 4 (OsNLP3/4) are crucial positive regulators of rice panicle architecture in response to nitrogen (N). Loss-of-function mutants of either OsNLP3 or OsNLP4 produced smaller panicles with reduced primary and secondary branches and fewer grains than wild-type, whereas their overexpression plants showed the opposite phenotypes. The OsNLP3/4-regulated panicle architecture was positively correlated with N availability. OsNLP3/4 directly bind to the promoter of OsRFL and activate its expression to promote inflorescence meristem development. Furthermore, OsRFL activates OsMOC1 expression by binding to its promoter. Our findings reveal the novel N-responsive OsNLP3/4-OsRFL-OsMOC1 module that integrates N availability to regulate panicle architecture, shedding light on how N nutrient signals regulate panicle architecture and providing candidate targets for the improvement of crop yield.


Patient Safety Incidents and Nursing Workload.
to identify the relationship between the workload of the nursing team and the occurrence of patient safety incidents linked to nursing care in a public hospital in Chile. quantitative, analytical, cross-sectional research through review of medical records. The estimation of workload in Intensive Care Units (ICUs) was performed using the Therapeutic Interventions Scoring System (TISS-28) and for the other services, we used the nurse/patient and nursing assistant/patient ratios. Descriptive univariate and multivariate analysis were performed. For the multivariate analysis we used principal component analysis and Pearson correlation. 879 post-discharge clinical records and the workload of 85 nurses and 157 nursing assistants were analyzed. The overall incident rate was 71.1%. It was found a high positive correlation between variables workload (r = 0.9611 to r = 0.9919) and rate of falls (r = 0.8770). The medication error rates, mechanical containment incidents and self-removal of invasive devices were not correlated with the workload. the workload was high in all units except the intermediate care unit. Only the rate of falls was associated with the workload.


Analyzing patterns-of-treatment data to provide feedback to physicians.
Physicians' practice patterns can be influenced through feedback programs. The purpose of this article is to define a methodology that provides the feedback information necessary to affect physicians' practice patterns, using data collected by a large multispecialty physician group and individualized feedback plans for primary care physicians.


Cardiopulmonary effects of desflurane in ponies, after induction of anaesthesia with xylazine and ketamine.
Cardiopulmonary parameters were measured in 12 ponies (small horses) before anaesthesia and, following induction with xylazine and ketamine, during maintenance of anaesthesia with desflurane. In six of the ponies (group A) anaesthesia was maintained for three hours with desflurane at an end-tidal concentration of 7.4 per cent. In the other six ponies (group B), anaesthesia was maintained in the same way for one hour and then the effects of end-tidal desflurane concentrations of 7.4 per cent and 9.6 per cent with and without artificial ventilation were investigated. In group A ponies the arterial blood pressure and the systemic vascular resistance index (SVRI) decreased significantly during the first 45 minutes of anaesthesia but recovered with time. The cardiac index and heart rates were unchanged throughout the measurement period but arterial carbon dioxide tensions increased significantly. In group B ponies, with either mode of ventilation, increasing desflurane concentration resulted in decreases in arterial blood pressure, cardiac index and mixed venous oxygen tension, although the changes were not always statistically significant. There were marked individual differences in the cardiovascular responses to the high desflurane concentrations, the minimum mean arterial blood pressure ranging from 35 to 62 mm Hg, and the cardiac index from 23 to 50 ml/kg/min. The study concludes that during maintenance of anaesthesia with end tidal concentrations of desflurane of 7.4 per cent, cardiac index is well maintained and the initial fall in arterial blood pressures results from a fall in SVRI. However, increasing the concentration of desflurane causes a fall in blood pressure due to cardiac depression.


Change of the guard in obstetrics and gynaecology: projected retirement to 2025.
The purpose of the paper is to forecast retirement of the specialist obstetricians and gynaecologists in Australia to 2025. The gender and hours of work of younger and older cohorts were compared to determine the likely impacts of the transition from older to younger cohorts. The paper used the Australian Institute of Health and Welfare's annual Medical Labour Force Surveys to examine trends in attrition of obstetricians and gynaecologists over the age of 45 years from the workforce and to predict their rate of retirement to 2025. The projection results show that between the years 2000 and 2025, 59% of the obstetricians and gynaecologists would retire. The rising proportion of women in obstetrics and gynaecology and shorter working hours of both men and women will have a compounding effect on physician retirement. The paper concludes that the changes in practice, increasing feminisation and retirement from the workforce coupled with higher female population growth in the childbearing years and slightly higher fertility mean that ensuring an adequate obstetricians and gynaecologists in Australia will be a significant challenge over the next 20 years. There is the potential for shortages in obstetric care with particular risks for rural areas.


Detection of hypoxia-evoked ATP release from chemoreceptor cells of the rat carotid body.
The carotid body (CB) is a chemosensory organ that detects changes in chemical composition of arterial blood and maintains homeostasis via reflex control of ventilation. Thus, in response to a fall in arterial PO(2) (hypoxia), CB chemoreceptors (type I cells) depolarize, and release neurotransmitters onto afferent sensory nerve endings. Recent studies implicate ATP as a key excitatory neurotransmitter released during CB chemoexcitation, but direct evidence is lacking. Here we use the luciferin-luciferase bioluminescence assay to detect ATP, released from rat chemoreceptors in CB cultures, fresh tissue slices, and whole CB. Hypoxia evoked an increase in extracellular ATP, that was inhibited by L-type Ca(2+)channel blockers and reduced by the nucleoside hydrolase, apyrase. Additionally, iberiotoxin (IbTX; 100 nM), a blocker of O(2)-sensitive Ca(2+)-dependent K(+) (BK) channels, stimulated ATP release and largely occluded the effect of hypoxia. These data strongly support a neurotransmitter role for ATP in carotid body function.


Intranuclear Actin Structure Modulates Mesenchymal Stem Cell Differentiation.
Actin structure contributes to physiologic events within the nucleus to control mesenchymal stromal cell (MSC) differentiation. Continuous cytochalasin D (Cyto D) disruption of the MSC actin cytoskeleton leads to osteogenic or adipogenic differentiation, both requiring mass transfer of actin into the nucleus. Cyto D remains extranuclear, thus intranuclear actin polymerization is potentiated by actin transfer: we asked whether actin structure affects differentiation. We show that secondary actin filament branching via the Arp2/3 complex is required for osteogenesis and that preventing actin branching stimulates adipogenesis, as shown by expression profiling of osteogenic and adipogenic biomarkers and unbiased RNA-seq analysis. Mechanistically, Cyto D activates osteoblast master regulators (e.g., Runx2, Sp7, Dlx5) and novel coregulated genes (e.g., Atoh8, Nr4a3, Slfn5). Formin-induced primary actin filament formation is critical for Arp2/3 complex recruitment: osteogenesis is prevented by silencing of the formin mDia1, but not its paralog mDia2. Furthermore, while inhibition of actin, branching is a potent adipogenic stimulus, silencing of either mDia1 or mDia2 blocks adipogenic gene expression. We propose that mDia1, which localizes in the cytoplasm of multipotential MSCs and traffics into the nucleus after cytoskeletal disruption, joins intranuclear mDia2 to facilitate primary filament formation before mediating subsequent branching via Arp2/3 complex recruitment. The resulting intranuclear branched actin network specifies osteogenic differentiation, while actin polymerization in the absence of Arp2/3 complex-mediated secondary branching causes adipogenic differentiation. Stem Cells 2017;35:1624-1635.


Escherichia coli endonuclease III is not an endonuclease but a beta-elimination catalyst.
The oligonucleotide [5'-32P]pdT8d(-)dTn, containing an apurinic/apyrimidinic (AP) site [d(-)], yields three radioactive products when incubated at alkaline pH: two of them, forming a doublet approximately at the level of pdT8dA when analysed by polyacrylamide-gel electrophoresis, are the result of the beta-elimination reaction, whereas the third is pdT8p resulting from beta delta-elimination. The incubation of [5'-32P]pdT8d(-)dTn, hybridized with poly(dA), with E. coli endonuclease III yields two radioactive products which have the same electrophoretic behaviour as the doublet obtained by alkaline beta-elimination. The oligonucleotide pdT8d(-) is degraded by the 3'-5' exonuclease activity of T4 DNA polymerase as well as pdT8dA, showing that a base-free deoxyribose at the 3' end is not an obstacle for this activity. The radioactive products from [5'-32P]pdT8d(-)dTn cleaved by alkaline beta-elimination or by E. coli endonuclease III are not degraded by the 3'-5' exonuclease activity of T4 DNA polymerase. When DNA containing AP sites labelled with 32P 5' to the base-free deoxyribose labelled with 3H in the 1' and 2' positions is degraded by E. coli endonuclease VI (exonuclease III) and snake venom phosphodiesterase, the two radionuclides are found exclusively in deoxyribose 5-phosphate and the 3H/32P ratio in this sugar phosphate is the same as in the substrate DNA. When DNA containing these doubly-labelled AP sites is degraded by alkaline treatment or with Lys-Trp-Lys, followed by E. coli endonuclease VI (exonuclease III), some 3H is found in a volatile compound (probably 3H2O) whereas the 3H/32P ratio is decreased in the resulting sugar phosphate which has a chromatographic behaviour different from that of deoxyribose 5-phosphate. Treatment of the DNA containing doubly-labelled AP sites with E. coli endonuclease III, then with E. coli endonuclease VI (exonuclease III), also results in the loss of 3H and the formation of a sugar phosphate with a lower 3H/32P ratio that behaves chromatographically as the beta-elimination product digested with E. coli endonuclease VI (exonuclease III). From these data, we conclude that E. coli endonuclease III cleaves the phosphodiester bond 3' to the AP site, but that the cleavage is not a hydrolysis leaving a base-free deoxyribose at the 3' end as it has been so far assumed. The cleavage might be the result of a beta-elimination analogous to the one produced by an alkaline pH or Lys-Trp-Lys. Thus it would seem that E. coli 'endonuclease III' is, after all, not an endonuclease.


A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration.
Mutations in the CLN2 gene, which encodes a lysosomal serine protease, tripeptidyl-peptidase I (TPP I), result in an autosomal recessive neurodegenerative disease of children, classical late-infantile neuronal ceroid lipofuscinosis (cLINCL). cLINCL is inevitably fatal, and there currently exists no cure or effective treatment. In this report, we provide the characterization of the first CLN2-targeted mouse model for cLINCL. CLN2-targeted mice were fertile and apparently healthy at birth despite an absence of detectable TPP I activity. At approximately 7 weeks of age, neurological deficiencies became evident with the onset of a tremor that became progressively more severe and was eventually accompanied by ataxia. Lifespan of the affected mice was greatly reduced (median survival, 138 d), and extensive neuronal pathology was observed including a prominent accumulation of cytoplasmic storage material within the lysosomal-endosomal compartment, a loss of cerebellar Purkinje cells, and widespread axonal degeneration. The CLN2-targeted mouse therefore recapitulates much of the pathology and clinical features of cLINCL and represents an animal model that should provide clues to the normal cellular function of TPP I and the pathogenic processes that underlie neuronal death in its absence. In addition, the CLN2-targeted mouse also represents a valuable model for the evaluation of different therapeutic strategies.


Structural elements of the Streptomyces oriC region and their interactions with the DnaA protein.
Streptomycetes differ from other prokaryotic organisms in their mycelial life cycle and in possessing a large, linear, GC-rich chromosome. To deduce structural features of the Streptomyces origin of chromosomal replication, the oriC sequences of three Streptomyces species (S. antibioticus, S. chrysomallus and S. lividans) were compared. In Streptomyces, the oriC region contains 19 DnaA boxes whose location, orientation and spacing are conserved. The consensus sequence of the DnaA box identified within Streptomyces oriC is (T/C)(T/C)(G/A/C)TCCACA (preferred bases underlined). The interactions of DnaA with DNA fragments containing single, two or three DnaA boxes were studied using surface plasmon resonance. The dissociation constant (KD) for specific binding of individual DnaA boxes varied between 12 and 78 nM. Streptomyces oriC does not contain the three AT-rich 13-mer direct repeats present in the 5' part of the Escherichia coli oriC region. However, short AT-rich sequences are distributed among the DnaA boxes of Streptomyces oriC. Repeated attempts to unwind Streptomyces oriC have been unsuccessful. It remains to be elucidated whether DnaA interacts with putative accessory proteins which help in unwinding Streptomyces oriC.


[The determination of DNA adducts in liver and lung of mice exposed to dimethylnitrosamine].
The purpose of this study was to assess the role of dimethylnitrosamine (DMN) in DNA lesions and to determine the levels of O6-methyl-guanine (O6-mGua) and N-7-methyl-guanine (m7-Gua). Mice were treated with 10 ppm DMN in drinking water for 1, 2, 4, 8, 16 and 32 days. The average dosage of DMN was 2 mg/kg/day, DNA was isolated from liver and lung specimens, and its purine bases separated by high-performance liquid chromatography with fluorescence detection. The results showed the presence of O6-mGua and m7-Gua in the DNA following administration of DMN. The m7-Gua was found to be unsteady. O6-mGua decreased rapidly after 1 and 2 days treatment with DMN, but was raised after 32 days with continuous exposure. These findings suggest that damaged DNA would be repaired in vivo, but with continuous exposure to DMN, O6-mGua would accumulate in the DNA and this might be the cause of tumor induction.


Influence of Hyaluronic Acid Transitions in Tumor Microenvironment on Glioblastoma Malignancy and Invasive Behavior.
The extracellular matrix (ECM) is critical in tumor growth and invasive potential of cancer cells. In glioblastoma tumors, some components of the native brain ECM such as hyaluronic acid (HA) have been suggested as key regulators of processes associated with poor patient outlook such as invasion and therapeutic resistance. Given the importance of cell-mediated remodeling during invasion, it is likely that the molecular weight of available HA polymer may strongly influence GBM progression. Biomaterial platforms therefore provide a unique opportunity to systematically examine the influence of the molecular weight distribution of HA on GBM cell activity. Here we report the relationship between the molecular weight of matrix-bound HA within a methacrylamidefunctionalized gelatin (GelMA) hydrogel, the invasive phenotype of a patient-derived xenograft GBM population that exhibits significant in vivo invasivity, and the local production of soluble HA during GBM cell invasion. Hyaluronic acid of different molecular weights spanning a range associated with cell-mediated remodeling (10, 60, and 500 kDa) was photopolymerized into GelMA hydrogels, with cell activity compared to GelMA only conditions (-HA). Polymerization conditions were tuned to create a homologous series of GelMA hydrogels with conserved poroelastic properties (i.e., shear modulus, Poisson's ratio, and diffusivity). GBM migration was strongly influenced by HA molecular weight; while markers associated with active remodeling of HA (hyaluronan synthase and hyaluronidase) were found to be uninfluenced. These results provide new information regarding the importance of local hyaluronic acid content on the invasive phenotype of GBM.


Predicting institutional long-term care admission in dementia: a mixed-methods study of informal caregivers' reports.
To investigate agreement between: (1) expected reasons and actual reasons for admission of people with dementia according to informal caregivers; (2) scores on measurement instruments prior to admission and the actual reasons for admission according to informal caregivers. Timely admission of people with dementia is a crucial issue. Information is highly warranted on whether informal caregivers are capable of prior identification of causes of admission and, can thus be considered a reliable prospective source on causes of admission. A cohort study among informal caregivers of people with dementia who made a transition to institutional long-term care. Qualitative data on the expected and actual reasons for admission were collected via open-ended questions at baseline and follow-up. Furthermore, at baseline, data were collected using measurement instruments to measure pre-admission characteristics. Interviews took place between November 2010-April 2012. After categorizing the answers, the agreement between the expected and actual reasons was calculated. Furthermore, bivariate associations were calculated between the actual reasons for admission and scores on corresponding measurement instruments. For most informal caregivers, there was agreement between their statements on the expected reason and the actual reason for admission. A third of the caregivers showed no conformity. Bivariate associations showed that there is also agreement between the actual reasons for admission and scores on corresponding measurement instruments. Informal caregivers can be considered reliable sources of information regarding what causes the admission of a person with dementia. Professional care should anticipate informal caregivers' statements and collaborate with them to strive for timely and appropriate admission.


Farnesol-induced growth inhibition in Saccharomyces cerevisiae by a cell cycle mechanism.
The growth of budding yeast, Saccharomyces cerevisiae, was inhibited in medium containing 25 microM farnesol (FOH). The FOH-treated cells were still viable, and were characterized by a transition from budded to unbudded phase as well as a significant loss of intracellular diacylglycerol (DAG). FOH-induced growth inhibition could be effectively prevented by the coaddition of a membrane-permeable DAG analogue which can activate yeast protein kinase C (PKC). However, yeast cell growth was not initiated upon addition of the PKC activator when the cells had been pretreated with FOH for 20 min. The failure in cell growth recovery was believed to be due to a signalling-mediated cell cycle arrest in FOH-pretreated cells. Differential display analysis demonstrated that the expression of cell cycle genes encoding DNA ligase (CDC9) and histone acetyltransferase (HAT2) was strongly repressed in FOH-treated cells. Repression of the expression of these genes was effectively cancelled when cells were grown in medium supplemented with DAG. The authors propose an interference with a phosphatidylinositol-type signalling which is involved in cell cycle progression as a cause of FOH-induced growth inhibition in yeast cells.


RANKL cytokine: from pioneer of the osteoimmunology era to cure for a rare disease.
Since its identification, the RANKL cytokine has been demonstrated to play a crucial role in bone homeostasis and lymphoid tissue organization. Genetic defects impairing its function lead to a peculiar form of autosomal recessive osteopetrosis (ARO), a rare genetic bone disease presenting early in life and characterized by increased bone density due to failure in bone resorption by the osteoclasts. Hematopoietic stem cell transplantation (HSCT) is the only option for the majority of patients affected by this life-threatening disease. However, the RANKL-dependent ARO does not gain any benefit from this approach, because the genetic defect is not intrinsic to the hematopoietic osteoclast lineage but rather to the mesenchymal one. Of note, we recently provided proof of concept of the efficacy of a pharmacological RANKL-based therapy to cure this form of the disease. Here we provide an overview of the diverse roles of RANKL in the bone and immune systems and review the clinical features of RANKL-deficient ARO patients and the results of our preclinical studies. We emphasize that these patients present a continuous worsening of the disease in the absence of a cure and strongly wish that the therapy we propose will be further developed.


Dynamic surface deformation of silicone elastomers for management of marine biofouling: laboratory and field studies using pneumatic actuation.
Many strategies have been developed to improve the fouling release (FR) performance of silicone coatings. However, biofilms inevitably build on these surfaces over time. Previous studies have shown that intentional deformation of silicone elastomers can be employed to detach biofouling species. In this study, inspired by the methods used in soft-robotic systems, controlled deformation of silicone elastomers via pneumatic actuation was employed to detach adherent biofilms. Using programmed surface deformation, it was possible to release > 90% of biofilm from surfaces in both laboratory and field environments. A higher substratum strain was required to remove biofilms accumulated in the field environment as compared with laboratory-grown biofilms. Further, the study indicated that substratum modulus influences the strain needed to de-bond biofilms. Surface deformation-based approaches have potential for use in the management of biofouling in a number of technological areas, including in niche applications where pneumatic actuation of surface deformation is feasible.


Community composition of invasive, outbreak, and non-pest snail species along a source spring-to-fishpond gradient in a spatially structured aquacultural region.
Agricultural lands are integrated into and interact with natural areas. Such is the case of Emek HaMa'ayanot, northern Israel, comprising a springs-rich area characterized by multiple land-uses, including spring-water-based aquaculture, recreational springs, and nature reserves. Aquacultural farms suffer from pest snails that carry fish disease; in the study region, these species are invasive (Thiara scabra, Tarebia granifera, Pseudosuccinea columella) and outbreak endemic (Melanoides tuberculata). Previous snail control efforts have focused on individual fishponds without considering management on larger environmental scales in the waterways from the source springs to the fish farms. To broaden our understanding of the status of the pest snail problem in the study area prior to suggesting environmental managerial solutions, we quantified changes in the community composition of snail species along the springs-to-fishponds gradients in a spatially explicit system. We found a remarkable increase in pest snail abundances along these gradients, indicating that pest snails might be invading upstream towards the springs. There were always nearly 100% pest snails in the endpoint sites for water tracks that ended in fishponds. Moreover, pest snails dominated the site when it was used as a fishpond, even though the site was also a spring. In contrast, in a water track that does not end in a fish farm, the relative abundances of non-pest snail species was similar between the source spring and the downstream endpoint, in spite of an increase in pest snail abundance at a midpoint site. These results suggest that invasive pest snails are actively moving upstream and that the fishponds have a marked upstream effect on the ability of non-pest snails to resist pest species invasions. We suggest further investigation of possible strategies for biocontrol of the observed invasion of the snails into natural areas as a basis for environmental management efforts. Finally, the observations made during this study could have practical global implications for snail management in aquaculture and agriculture, and for the control of snails and snail vectors implicated in animal and human diseases.


Primary sclerosing cholangitis.
Primary sclerosing cholangitis is the classic hepatobiliary manifestation of inflammatory bowel disease and is generally chronic and progressive. Patients frequently present with asymptomatic, anicteric cholestasis, but many develop progressive biliary strictures with time, leading to recurrent cholangitis, biliary cirrhosis, and end-stage liver disease. Medical treatment does not slow the progression of disease, and many patients need liver transplantation, after which recurrent disease is a risk. The increased incidence of hepatobiliary cancer, which is not related to the underlying severity of biliary fibrosis, is of particular concern. Risk of colorectal cancer is also increased in patients with coexistent inflammatory bowel disease. Mechanistic insights have arisen from studies of secondary sclerosing cholangitis, in which a similar clinical profile is associated with a specific cause, and genomic studies have elucidated potential disease-initiating pathways in the primary form. The close association between inflammatory bowel disease and primary sclerosing cholangitis underscores the need to further understand the role of environmental factors in generation of lymphocytes that are postulated to be retargeted, deleteriously, to the biliary tree. Treatment of primary sclerosing cholangitis is confined to supportive measures, but advances in pathobiology suggest that new stratified approaches will soon be available.


Clinicopathologic features and prognostic analysis of MSI-high colon cancer.
The objectives of the study were to estimate the incidence and clarify the clinicopathologic feature of sporadic microsatellite instability (MSI)-high (MSI-H) colon cancer. Furthermore, the role of MSI in colon cancer prognosis was also investigated. Microsatellite status was identified by genotyping. The clinicopathologic differences between two groups (MSI-H vs. MSI-L/S) and the prognostic value of MSI were analyzed. From 1993 to 2006, 709 sporadic colon cancer patients were enrolled. MSI-H colon cancers showed significant association with poorly differentiated (28.3% vs. 7.2%, p = 0.001), proximally located (76.7% vs. 34.5%, p = 0.001), more high mucin-containing tumor (10.0% vs. 5.1%, p = 0.001) and female predominance (56.7% vs. 30.2%, p = 0.001). In multivariate analysis, MSI-H is an independent factor for better overall survival (HR, 0.459; 95% CI, 0.241-0.872, p = 0.017). Based on the hospital-based study, MSI-H colon cancers demonstrated distinguished clinicopathologic features from MSI-L/S colon cancers. MSI-H is an independent favorable prognostic factor for overall survival in colon cancer.


Alterations in lipoprotein composition in peritoneal dialysis patients.
Dyslipidemia is common among patients with end-stage renal disease, whether treated by hemodialysis (HD) or peritoneal dialysis (PD). To better understand the specific lipoprotein abnormalities in PD patients, we measured the lipid and apolipoprotein (Apo) composition of the four major classes of plasma lipoproteins in PD patients, HD patients, and healthy control subjects: very low density (VLDL), intermediate density (IDL), low density (LDL), and high density lipoproteins (HDL). Fasting plasma samples were obtained from 15 nondiabetic PD patients, 15 nondiabetic HD patients, and 16 healthy control subjects, all from a cross section of patients and subjects in the region of Göteborg, Sweden. Lipoproteins were isolated by preparative ultracentrifugation, and lipid and apolipoprotein concentrations were measured by gas chromatography and electroimmunoassay, respectively. Alterations in lipoprotein composition were apparent in all four lipoprotein density classes from PD and HD patients. VLDL contained a significantly higher concentration of ApoCIII in both HD and PD patients, and an elevation of free cholesterol, triglyceride, ApoB, ApoCII, and ApoE in PD patients. IDL from both PD and HD patients contained an excess of free and esterified cholesterol and triglyceride and significantly elevated levels of ApoB, ApoCII, ApoCIII, and ApoE. LDL had a higher concentration of ApoB in PD patients and elevated triglyceride and ApoCIII in both PD and HD patients. HDL isolated from PD patients had lower free cholesterol and ApoAI levels compared to control subjects, but these were not significantly different from HD patients. An increase in lipid and apolipoprotein mass in IDL, and an enrichment of ApoCIII in VLDL, IDL, and LDL were observed in both HD and PD patients. The predominant alteration in lipoprotein composition distinguishing PD patients from HD patients was an elevation of ApoB in LDL. Further study of these alterations in lipoprotein composition in PD patients will be helpful in understanding the underlying causes of dyslipidemia and, ultimately, to the selection of hypolipidemic drugs or other treatments to reduce the cardiovascular risks associated with dyslipidemia in these patients.


Axonal transport of cytoskeletal proteins in oculomotor axons and their residence times in the axon terminals.
Cytoskeletal protein transport and metabolism are studied in the somatic motor and parasympathetic axons of the chicken oculomotor system. Kinetic analyses of pulse-labeled proteins indicate that the neurofilaments are transported 2-3 times more rapidly in the somatic motor axons than in the parasympathetic axons. By contrast, the transport rates of the slow component b (SCb) proteins are very similar in these axons. The parasympathetic axons terminate in the ciliary ganglion, and radiolabeling curves from the ciliary ganglion can be used to study the kinetics of cytoskeletal protein removal from the terminals. The rate of removal directly determines the residence time of the cytoskeletal proteins in the ciliary ganglion, and the residence time directly affects the shape and amplitude of the transport curves of the ganglion. A computer model was used to analyze these transport curves and to determine the half-residence time of the cytoskeletal proteins in the terminal regions. From the computer experiments, we estimate that the half-residence times of the neurofilament proteins actin and tubulin are 2, 3.5, and 7 d, respectively. The differences between the half-residence times of the cytoskeletal proteins indicate that the rate of protein removal from the terminals differs for these proteins. On the basis of these results, we propose that the removal mechanisms critically control the composition of the cytoskeleton in the terminal regions. Through their effects on its composition, the removal mechanisms have a crucial role in converting the cytoskeleton of the axon proper into the specialized cytoskeleton of the axon terminal.


The burden of cholera in the slums of Kolkata, India: data from a prospective, community based study.
To conduct a prospective, community based study in an impoverished urban site in Kolkata (formerly Calcutta) in order to measure the burden of cholera, describe its epidemiology, and search for potential risk factors that could be addressed by public health strategies. The study population was enumerated at the beginning and end of the study period. Surveillance through five field outposts and two referral hospitals for acute, watery, non-bloody diarrhoea was conducted from 1 May 2003 to 30 April 2004. Data and a stool sample for culture of Vibrio cholerae were collected from each patient. Treatment was provided in accordance with national guidelines. From 62 329 individuals under surveillance, 3284 diarrhoea episodes were detected, of which 3276 (99%) had a stool sample collected and 126 (4%) were culture confirmed cholera. Nineteen (15%) were children less than 2 years of age, 29 (23%) had severe dehydration, and 48 (38%) were hospitalised. Risk factors for cholera included a household member with cholera during the period of surveillance, young age, and lower educational level. There was a substantial burden of cholera in Kolkata with risk factors not easily amenable to intervention. Young children bear the brunt not only of diarrhoeal diseases in general, but of cholera as well. Mass vaccination could be a potentially useful tool to prevent and control seasonal cholera in this community.


Sialocintigraphy versus ultrasonography of the salivary glands in patients first diagnosed with Sjögren's syndrome.
Sjögren's syndrome (SjS) is an autoimmune disease characterized by distraction of particularly salivary and lacrimal glands. The aim of the present study was to compare salivary gland scintigraphy (SGS) and salivary gland ultrasonography (SUS) in identifying salivary gland function in patients first diagnosed with SjS. We recruited 20 such patients with SjS (5 male, 15 female, aged from 35 to 65 y, mean age 52, standard deviation: +/-5 y. All patients were submitted to SUS and SGS longitudinal and transverse images. Before the scintiscan, patients fasted for 6 h. Technetium-99m pertechnetate ((99m)Tc-PT) 110 MBq was injected intravenously (i.v.) and simultaneous multi-frames dynamic acquisition was performed for 30 min. In two patients who had discordant results between SUS and US, labial biopsy was performed. Dynamic acquisition curves for 30 sec for the parotid and the submandibular glands were generated. For each gland we have calculated: (a) the maximum uptake (MU): the ratio between the mean counts in the gland at 20 min and the background activity and (b) the outflow efficiency (OE): the ratio between the minimum counts after lemon juice stimulation at 30 min and the counts at 20 min. The results showed abnormal scintiscans with low MU and high OE in one or more of the glands, in 17/20 patients. These results were confirmed by SUS in 15 cases and in two cases labial biopsy confirmed the diagnosis made by SGS while SUS was negative. In the remaining 3/20 cases of SjS both tests, SUS and SGS, showed normal results. Discrepancies between SGS findings and labial biopsy as found in two of our cases have been reported by others and may be due among other causes to early lymphocytic infiltration in SjS. Normal findings of SGS have also been reported. In conclusion, in cases first diagnosed with SjS, the function of the parotid and the submandibular glands was better identified by the SGS as compared to SUS. Although SGS is a more complex and expensive examination, it should be preferred to SUS as more sensitive and indicating the stage of SjS.


Management of corticosteroid-dependent eosinophilic interstitial nephritis: A case report.
Drug-induced acute interstitial nephritis (DI-AIN) is an important cause of acute kidney injury. In renal biopsy specimens, tubulitis with eosinophilic infiltration is suggestive of DI-AIN. Although corticosteroid therapy and discontinuation of the offending drug can improve renal dysfunction in most cases of DI-AIN, some patients experience AIN recurrence, leading to corticosteroid dependency. Corticosteroid-dependent eosinophilic interstitial nephritis presents a difficult dilemma in diagnosis and information regarding optimum management is limited. A 25-year-old man, who received treatment with carbamazepine, zonisamide, valproate, and lacosamide for temporal lobe epilepsy, showed an increase in serum creatinine level from 0.98 to 1.29 mg/dL over a period of 6 months. Although he exhibited no symptoms, his serum creatinine level continued to increase to 1.74 mg/dL. Renal biopsy revealed tubulitis and interstitial inflammatory infiltrates with eosinophils. Immunological and ophthalmological examinations showed no abnormal findings, and thus, his renal dysfunction was presumed to be caused by DI-AIN. Although oral prednisolone (PSL) administration (40 mg/d) and discontinuation of zonisamide immediately improved his renal function, AIN recurred 10 months later. The increase in PSL dose along with discontinuation of valproate and lacosamide improved renal function. However, 10 months later, recurrent AIN with eosinophilic infiltration was confirmed by further biopsy. The patient was therefore diagnosed with corticosteroid-dependent eosinophilic interstitial nephritis. To prevent life-threatening epilepsy, carbamazepine could not be discontinued; hence, he was treated with an increased dose of PSL (60 mg/d) and 1500 mg/d of mycophenolate mofetil (MMF). MMF was well tolerated and PSL was successfully tapered to 5 mg/d; renal function stabilized over a 20-month period. The presence of underdetermined autoimmune processes and difficulties in discontinuing the putative offending drug discontinuation are contributing factors to corticosteroid dependency in patients with eosinophilic interstitial nephritis. MMF may be beneficial in the management of corticosteroid-dependent eosinophilic interstitial nephritis by reducing the adverse effects related to high-dose and long-term corticosteroid use.


Quantifying Physical Thrombus Characteristics on Cardiovascular Biomaterials Using MicroCT.
Hemocompatibility is a critical consideration when designing cardiovascular devices. Methods of assessing hemocompatibility range from in vitro protein adsorption and static platelet attachment to in vivo implantation. A standard preclinical assessment of biomaterial hemocompatibility is ex vivo quantification of thrombosis in a chronic arteriovenous shunt. This technique utilizes flowing blood and quantifies platelet accumulation and fibrin deposition. However, the physical parameters of the thrombus have remained unknown. This study presents the development of a novel method to quantify the 3D physical properties of the thrombus on different biomaterials: expanded polytetrafluoroethylene and a preclinical hydrogel, poly(vinyl alcohol). Tubes of 4-5 mm inner diameter were exposed to non-anticoagulated blood flow for 1 hour and fixed. Due to differences in biomaterial water absorption properties, unique methods, requiring either the thrombus or the lumen to be radiopaque, were developed to quantify average thrombus volume within a graft. The samples were imaged using X-ray microcomputed tomography (microCT). The methodologies were strongly and significantly correlated to caliper-measured graft dimensions (R2 = 0.994, p < 0.0001). The physical characteristics of the thrombi were well correlated to platelet and fibrin deposition. MicroCT scanning and advanced image analyses were successfully applied to quantitatively measure 3D physical parameters of thrombi on cardiovascular biomaterials under flow.


Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms.
Severe vitamin B(12) deficiency produces a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regression, which respond remarkably rapidly to supplementation. The underlying mechanisms may involve delayed myelination or demyelination of nerves; alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio; imbalance of neurotrophic and neurotoxic cytokines; and/or accumulation of lactate in brain cells. This review summarizes the current knowledge concerning infantile vitamin B(12) deficiency, including a pooled analysis of case studies of infants born to mothers with untreated pernicious anemia or a strict vegetarian lifestyle and a discussion of the mechanisms that may underlie the manifestations of deficiency.


Direct and indirect resistance of sugarcane to Diatraea saccharalis induced by jasmonic acid.
Treating plants with synthetic jasmonic acid (JA) induces a defensive response similar to herbivore attack, and is a potential strategy for integrated pest management. Despite the importance of sugarcane, its JA-induced defences have not yet been studied. We investigated the effects of JA treatment on the direct and indirect resistance of sugarcane to the key-pest and specialist herbivore Diatraea saccharalis and the generalist Spodoptera frugiperda. Indirect defences were examined by testing the attraction of Cotesia flavipes, a sugarcane-borer parasitoid, to JA-induced volatile. The results showed that JA-treated sugarcane did not affect the weight gain of the two larvae. However, in dual-choice assays, both species preferred to feed on mock rather than JA-treated plants. Leaf colorimetric analyses showed that visual cues are unlikely to be involved in larval preference, whereas results from olfactometric assays revealed that D. saccharalis preferred JA-induced over mock plant volatiles. After 48 h of treatment, JA-treated plants emitted a volatile blend attractive to C. flavipes, comprised mainly of sesquiterpenes. However, the parasitoid did not discriminate JA-treated from host-damaged plant volatiles. When the wasps were given a choice between JA-treated and JA-treated + host-damaged plants, they preferred the latter, which emitted a more complex blend, suggesting that JA treatment likely does not hamper host-finding. We concluded that JA induces the emission of volatiles that are attractive to the sugarcane borer parasitoid, as well as an antixenosis type of resistance in sugarcane against the two pests, although neither volatiles nor visual cues alone are involved in the underlying mechanism.


Rational Design of SARS-CoV-2 Spike Glycoproteins To Increase Immunogenicity By T Cell Epitope Engineering.
The current COVID-19 pandemic caused by SARS-CoV-2 has resulted in millions of confirmed cases and thousands of deaths globally. Extensive efforts and progress have been made to develop effective and safe vaccines against COVID-19. A primary target of these vaccines is the SARS-CoV-2 spike (S) protein, and many studies utilized structural vaccinology techniques to either stabilize the protein or fix the receptor-binding domain at certain states. In this study, we extended an evolutionary protein design algorithm, EvoDesign, to create thousands of stable S protein variants without perturbing the surface conformation and B cell epitopes of the S protein. We then evaluated the mutated S protein candidates based on predicted MHC-II T cell promiscuous epitopes as well as the epitopes' similarity to human peptides. The presented strategy aims to improve the S protein's immunogenicity and antigenicity by inducing stronger CD4 T cell response while maintaining the protein's native structure and function. The top EvoDesign S protein candidate (Design-10705) recovered 31 out of 32 MHC-II T cell promiscuous epitopes in the native S protein, in which two epitopes were present in all seven human coronaviruses. This newly designed S protein also introduced nine new MHC-II T cell promiscuous epitopes and showed high structural similarity to its native conformation. The proposed structural vaccinology method provides an avenue to rationally design the antigen's structure with increased immunogenicity, which could be applied to the rational design of new COVID-19 vaccine candidates.


Prenatal development of retinogeniculate axons in the macaque monkey during segregation of binocular inputs.
In the fetal monkey the projections from the two eyes are initially completely intermingled within the dorsal lateral geniculate nucleus (DLGN) before separating into eye-specific layers (). To assess the cellular basis of this developmental process, we examined the morphological properties of individual retinogeniculate axons in prenatal monkeys of known gestational ages. The period studied spanned the time from when binocular overlap has been reported to be maximum, circa embryonic (E) day 77 through E112, when the segregation process is already largely completed in the caudal portion of the nucleus. Retinogeniculate fibers were labeled by making small deposits of DiI crystals into the fixed optic tract. After adequate time was allowed for diffusion of the tracer, fibers were visualized by confocal microscopy, and morphometric measures were made from photomontages. This revealed that retinogeniculate fibers in the embryonic monkey undergo continuous growth and elaboration during binocular overlap and subsequent segregation. Importantly, very few side-branches were found along the preterminal axon throughout the developmental period studied. Thus, restructuring of retinogeniculate fibers does not underlie the formation of eye-restricted projections in the primate. Rather, the results support the hypothesis that binocular segregation in the embryonic monkey is caused by the loss of retinal fibers that initially innervate inappropriate territories ().


A home-based exercise intervention for caregivers of persons with dementia: study protocol for a randomised controlled trial.
Family members, who provide the majority of care for persons with dementia, are especially vulnerable to developing depression. Interventions targeting their depressive symptoms have been proposed but their efficacies vary considerably. It has been suggested that interventions carried out in the home setting and involving both caregivers and care recipients are more efficacious. This study aims to compare the efficacy of a home-based structured exercise programme involving both persons with dementia and their caregivers with nonexercise social contact control in treating depression among caregivers. This is a parallel-group, assessor-blind, randomised controlled trial. A total of 136 caregiver-care-recipient dyads (i.e. 272 participants in total) will be recruited and randomly allocated to either a home-based structured exercise (sitting Tai Chi) group or a social contact control group. The trial comprises a 3-month intervention phase followed by an extended observation phase of another 3 months. All participants will be assessed at baseline, 6th week, 12th week and 24th week. The primary outcome will be the reduction in depression among caregivers as measured by the Hamilton Rating Scale for Depression. The secondary outcomes will be burden, quality of life, cognitive performance and balance ability of the caregivers, as well as the neuropsychiatric symptoms, cognitive function, balance and functional abilities of the persons with dementia. We will also examine whether the brain-derived neurotrophic factor gene modulates mood changes in response to exercise. The findings offer a potential avenue of intervention by providing a low-cost, safe and effective treatment for depression among dementia caregivers, which may in turn also benefit the care recipients. ClinicalTrials.gov Identifier: NCT02132039 , registered on 28 April 2014.


Pannexin 1 channels in skeletal muscles.
Normal myotubes and adult innervated skeletal myofibers express the glycoprotein pannexin1 (Panx1). Six of them form a "gap junction hemichannel-like" structure that connects the cytoplasm with the extracellular space; here they will be called Panx1 channels. These are poorly selective channels permeable to ions, small metabolic substrate, and signaling molecules. So far little is known about the role of Panx1 channels in muscles but skeletal muscles of Panx1(-/-) mice do not show an evident phenotype. Innervated adult fast and slow skeletal myofibers show Panx1 reactivity in close proximity to dihydropyridine receptors in the sarcolemma of T-tubules. These Panx1 channels are activated by electrical stimulation and extracellular ATP. Panx1 channels play a relevant role in potentiation of muscle contraction because they allow release of ATP and uptake of glucose, two molecules required for this response. In support of this notion, the absence of Panx1 abrogates the potentiation of muscle contraction elicited by repetitive electrical stimulation, which is reversed by exogenously applied ATP. Phosphorylation of Panx1 Thr and Ser residues might be involved in Panx1 channel activation since it is enhanced during potentiation of muscle contraction. Under denervation, Panx1 levels are upregulated and this partially explains the reduction in electrochemical gradient, however its absence does not prevent denervation-induced atrophy but prevents the higher oxidative state. Panx1 also forms functional channels at the cell surface of myotubes and their functional state has been associated with intracellular Ca(2+) signals and regulation of myotube plasticity evoked by electrical stimulation. We proposed that Panx1 channels participate as ATP channels and help to keep a normal oxidative state in skeletal muscles.


The role of endogenous opioid peptides in physiological and pharmacological reward responses--a survey of present-day knowledge.
Endogenous opioid peptides (EOP) participate in a variety of physiological and pharmacological responses that can be recognized by: increased concentrations of EOP in the cerebrospinal fluid; a combination of euphoria and analgesia; and suppression of the responses by specific opiate antagonists. Application of these responses is exemplified in acupuncture, in self-stimulation via hypothalamic electrodes, and in food and fluid consumption. For example, intake of sweet solutions exerts a biphasic effect: in the beginning pain threshold is elevated, but later on tolerance to morphine-induced analgesia develops. A supply of 2% NaCl also stimulates fluid intake as well as raising the pain threshold. Stress-induced analgesia is due to coupled release of ACTH and beta-endorphin from the pituitary. In man, large variations in pain sensitivity may be related to the level of intrinsic EOP.


Identification of members of the family Enterobacteriaceae by the R-B system.
The R-B system was evaluated in parallel with conventional bacteriological procedures for the identification of members of the family Enterobacteriaceae by using bacterial strains from a variety of clinical specimens and from stock cultures. The R-B tests found to be reliable were, in decreasing order, the reactions for phenylalanine deaminase, hydrogen sulfide, and indole, the production of gas from glucose, and the decarboxylation of ornithine. The reactions in the R-B system found to be unreliable were motility, the decarboxylation of lysine, and the fermentation of both glucose and lactose. In addition, the reactions of the R-B system were more difficult to read and interpret than those of the conventional system. On the basis of this evaluation, it was concluded that the R-B system is not an acceptable alternative to the conventional methods in the identification of the Enterobacteriaceae.


AFLP markers in a molecular linkage map of maize: codominant scoring and linkage group ditsribution.
We exploited the AFLP technique to saturate a RFLP linkage map derived from a maize mapping population. By using two restriction enzyme, EcoRI and PstI, differing in methylation sensitivity, both in combination with MseI, we detected 1568 bands of which 340 where polymorphic. These were added to the exitsing RFLP marker data to study the effects of incorporation of AFLPs produced by different restriction-enzyme combinations upon genetic maps. Addition of the AFLP data resulted in greater genome coverage, both through linking previously separate groups and the extension of other groups. The increase of the total map length was mainly caused by the addition of markers to telomeric regions, where RFLP markers were poorly represented. The percentage of informative loci was significantly different between the EcoRI and PstI assays. There was also evidence that PstI AFLP markers were more randomly distributed across chromosomes and chromosome regions, while EcoRI AFLP markers clustered mainly at centomeric regions. The more-random ditsribution of PstI AFLP markers on the genetic map reported here may reflect a preferential localisation of the markers in the hypomethylated telomeric regions of the chromosomes.


Evaluation of the Universal Prevention Program Klasse2000 in Fourth Grade Primary School Children: Protocol for a Propensity Score-Matching Approach.
Klasse2000 is the most widely adopted school-based prevention program in Germany. It addresses health promotion, addiction, and violence prevention in primary schools. As a universal prevention program, it has reached more than 1.4 million German children in the past 25 years. The effectiveness of Klasse2000 will be evaluated with a large representative survey among students. Students who have participated in the prevention program (intervention group) will be compared with students who did not participate (control group). The comparison will cover the following outcome domains: well-being, self-esteem, emotion regulation, food habits, behavioral problems, and school and classroom atmosphere. Furthermore, victimization and perpetration regarding bullying, alcohol consumption, smoking, and media consumption are assessed. To control for potential group differences, treatment effects will be estimated using propensity score-matching, which matches students from the intervention and control groups based on an identical propensity score or a propensity score that does not differ by more than a previously defined distance. The treatment effect will then be estimated in the matched sample taking the matching process into account. Enrollment of schools began in March 2017. A total of 6376 students participated in the survey (n=4005 in control group; n=2371 in Klasse2000). The parent survey was returned by 52.13% (3324/6376) of parents. Results are expected in mid-2020. The results on the effectiveness of the Klasse2000 prevention program will form an empirical basis for legitimizing universal prevention programs and for planning future prevention approaches. German Clinical Trials Register DRKS00014332; https://tinyurl.com/y2trvq4p. DERR1-10.2196/14371.


Chaperone use by residents during pelvic, breast, testicular, and rectal exams.
We designed a questionnaire survey to study internal medicine residents' plans to use a chaperone during the pelvic, breast, rectal, and testicular examinations. We found chaperone use by male and female residents differed markedly, and neither group planned to use chaperones universally. When examining female patients, male residents overall were very likely to use a chaperone during a pelvic exam, but less likely for the breast exam and rectal exam. For the female resident, there was a significantly lower likelihood of using chaperones during the pelvic, breast, or rectal exams. There was a much lower rate of chaperone use during the sensitive portions of the male physical examination compared with the female examination, with somewhat higher use by female residents. We concluded that male and female residents differ significantly in their patterns of chaperone use. It would be valuable to develop guidelines for chaperone use to help residents understand the issues involved in the choices, and to protect the residents from the possible medico-legal consequences of forgoing chaperones.


Long-term clinical outcomes of submacular blood removal with isolated autologous retinal pigment epithelium-choroid patch graft transplantation in long-standing large-sized submacular hematomas: An Indian experience.
To study the outcomes of submacular blood removal with isolated autologous full-thickness retinal pigment epithelial (RPE)-choroid patch graft transplantation in long-standing large-sized submacular hematomas in Indian population. A retrospective study was done on eight consecutive patients of long-standing large-sized submacular hematoma from east India. In all cases, 23G vitrectomy was performed with the induction of retinal detachment (performed with or without 38G or 41G subretinal cannula) and a temporal 180° retinectomy was done. Submacular blood along with choroidal neovascular tissue was removed. A full-thickness RPE-choroid autologous patch graft was taken from a relatively healthy quadrant at the mid periphery and then the graft transferred under perfluorocarbon liquid (PFCL) to place it in the subfoveal area. Then, retina was re-attached using PFCL and laser completed. Silicone oil (5000 cst) was used as a tamponade. Post-operatively, wide-field fundus photographs (Optos), serial optical coherence tomography (OCT), indocyanine green angiography (ICGA), and multifocal electroretinography (ERG) were done. The mean age of the patients at presentation was 67.88 ± 10.03 years. Mean pre-operative best corrected visual acquity (BCVA) was 2.64 ± 0.3 log MAR and mean postoperative BCVA was 1.095 ± 0.27 log MAR (P < 0.05). The mean follow-up was 20 ± 16.57 months. ICG showed re-vascularization of translocated graft in all at 2 months. Multifocal ERG (after 6 months) showed some waveform in all. None of the cases developed re-bleed. Removal of submacular blood and neovascular membrane with autologous RPE-choroid graft is a viable option in cases with long-standing large submacular hematomas.


Social Media Use and Youth Mental Health: Intervention-Focused Future Directions.
The purpose of this review is to highlight the challenges related to the study of the relationship between social media use and youth mental health and propose a path forward in intervention-focused research. Recent findings relay the need to conceptualize the effects of social media use on youth mental health in a nuanced way. Unique, discrete social media experiences may either contribute to an individual's well-being, ill-being, or both. Social media use may contribute to well-being for one person, but ill-being for another. Similarly, social media use may contribute to well-being for one person at one point in their life but then contribute to ill-being at a different point in their life. As such, it is difficult to make broad overarching conclusions about this incredibly nuanced relationship. Intervention-focused research include authors' plans to create a social media single session intervention (SSI) designed to promote insight about social media's effects on well- or ill-being, as well as self-efficacy and knowledge to make changes to social media use.


Effect of multiple micronutrient versus iron-folate supplementation during pregnancy on intrauterine growth.
This review examines the effects of prenatal multiple micronutrient (MM) supplementation (≥5 micronutrients) on intrauterine growth. We identified publications from 16 randomized controlled trials through PubMed and EMBASE database searches. Meta-analyses were performed by pooling results, and sub-analyses by timing of intervention and amount of iron were also done. The primary outcome measures were birthweight, low birthweight (LBW; <2,500 g) and small for gestational age (SGA). Prenatal MM supplementation significantly reduced the incidence of LBW (risk ratio, RR: 0.86; 95% CI: 0.81-0.92) and SGA (RR: 0.83; 95% CI: 0.73-0.95) compared to iron-folate supplementation; mean birthweight was significantly higher by 55 g for MM with borderline increases in gestational age. MM supplementation was associated with larger decreases in the risk of LBW and SGA in the subgroup of trials that used supplements containing 60 mg of iron, but were not statistically significantly different from those for trials that used 30 mg iron. Prenatal MM supplementation improved intrauterine growth and can be recommended instead of prenatal IFA supplements in settings where micronutrient deficiencies are common.


Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency.
Patients with adrenal insufficiency (AI) have impaired health-related quality of life (HRQoL), which is thought to be in part due to unphysiological glucocorticoid replacement therapy. The aim was to compare once-daily hydrocortisone (HC) dual-release tablet (modified-release) with conventional HC therapy regarding clinical data and HRQoL. We conducted an open, prospective trial at one endocrine center. There were 15 of 26 patients with primary AI, nine of 18 patients with secondary AI, and six congenital adrenal hyperplasia patients switched to modified-release HC therapy by their own decision. We evaluated clinical outcome and disease-specific HRQoL by using AddiQoL questionnaire at baseline and at follow-up (median 202 days (85-498)). Patients on modified-release HC (n=30) showed significant decreases in BMI (26.0±0.75-25.6±0.71, P for change=0.006) and HbA1c (6.04±0.29-5.86±0.28, P for change=0.005), whereas patients remaining on conventional HC (n=20) showed no change in these parameters (P for interaction=0.029 and 0.017 respectively). No significant change in AddiQoL score were found in the modified-release HC group (83.8 baseline and 84.9 at follow-up; P for change=0.629). In the conventional HC group, there was a significant decrease in scores (84.0 baseline and 80.9 at follow-up; P for change=0.016), with a between-treatment P for interaction of 0.066. The fatigue subscore of AddiQoL showed the same pattern with a significant decrease (P for change=0.024) in patients on conventional HC therapy (P for interaction=0.116). Modified-release HC decreases BMI and HbA1c compared with conventional HC treatment. In addition, it seems to stabilize HRQoL over time.


Supination External Rotational Ankle Fracture Injury Pattern Correlation With Regional Bone Density.
Rotational ankle fractures can present with an array of possible osseous and ligamentous injury combinations in reliable anatomic locations. What accounts for these different injury patterns and whether specific patient and injury factors underlie the different injury patterns is unclear. The purpose of this study was to determine whether causative factors exist that could account for the various injury patterns seen with rotational ankle fractures. A registry of operatively treated supination external rotation stage IV (SER IV) ankle fractures was used to identify patients. Computed tomography imaging was used to calculate regional bone density by using average Hounsfield unit measurements on axial images from the distal tibia and fibula. Patients were grouped into those with no posterior or medial malleolar fracture (equivalent group), those with either a posterior or medial malleolus fracture (bimalleolar group), and those with both posterior and medial malleolar fractures (trimalleolar group). Sixty-seven patients met inclusion criteria. Regional bone density at the ankle, as measured with Hounsfield units, was significantly higher in the equivalent group (371) than in the bimalleolar group (271, P < .0001) and trimalleolar group (228, P < .0001). Logistic regression analyses identified regional bone density as a significant predictor of a medial malleolus fracture ( P = .002) and of a posterior malleolus fracture ( P = .005). In our cohort of SER IV ankle fractures, regional bone density at the ankle significantly correlated with the presence and number of malleolar fractures compared with ligamentous ruptures. Treating surgeons can use this information to anticipate bone quality during operative fixation based on ankle fracture injury pattern. In addition, the presence of a trimalleolar ankle fracture was a significant indicator of poor bone quality and may represent the first clinical sign of abnormal bone metabolism in many patients. Level III, prognostic retrospective cohort study.


Effects of Ginger Intake on Chemotherapy-Induced Nausea and Vomiting: A Systematic Review of Randomized Clinical Trials.
Nausea and vomiting are the most common side effects of chemotherapy. They must be managed because they can increase the risk of malnutrition in patients, which can adversely affect treatment. The objective of this study was to evaluate the effect of ginger supplementation as an adjuvant treatment for alleviating chemo We checked. therapy-induced nausea and vomiting (CINV). This study searched for randomized controlled trials (RCTs) related to ginger supplement intake for CINV in three electronic databases (i.e., Medline (PubMed), Embase, and Web of Science). The search period ranged from each database's first date of service to 5 November 2021. Two investigators independently performed abstract screenings, full-text screenings, data extraction, and risk of bias analyses (ROB). The Cochrane ROB tool was used for the assessment of ROB. This study systematically reviewed 23 RCTs. The effects of ginger supplementation were compared to those of placebo or antiemetic agents. This study conducted a meta-analysis after classifying the effects of ginger supplementation on acute and delayed CINV into subgroups due to the clinical heterogeneity between these RCTs. The results showed that the incidence of acute nausea (p = 0.53), the incidence of delayed nausea (p = 0.31), the incidence of acute vomiting (p = 0.09), and the incidence of delayed vomiting (p = 0.89) were not significantly different between the ginger supplement intake group and the control group. However, it was found that the ginger supplement intake group, which took not more than 1 g of ginger supplementation per day for above four days, had significantly less acute vomiting than the control group (OR 0.30; 95% CI 0.12 to 0.79; p = 0.02; I2 = 36%). Ginger supplementation may reduce the incidence of acute chemotherapy-induced vomiting. However, this study could not confirm the effects of ginger supplementation on the incidence of chemotherapy-induced nausea and delayed vomiting. Therefore, it will be necessary to conduct additional studies with sufficient sample sizes using high-quality RCTs to evaluate the effects of ginger supplementations based on the results of this study.


Laparoscopic resection of colonic lipomas: When and why?
Male, >60 FINAL DIAGNOSIS: Colonic lipoma Symptoms: Rectal bleeding • abdominal pain • fatique • abdominal distention - Clinical Procedure: Laparoscopic resection Specialty: General surgery. We aimed to review and discuss the clinical picture and management of 4 patients who underwent laparoscopic colonic resection with a definitive pathology of colonic lipoma. Colonic lipomas are rare benign nonepithelial tumors of the colon. They begin to be symptomatic when they reach a certain size, although the presentation can vary. Different endoscopic and surgical treatment strategies have been reported in the literature. Four male patients who underwent laparoscopic colonic resection and had definitive diagnosis of colonic lipoma were included in this report. All patients were over 60 years old. The first case presented with massive rectal bleeding. Obstructive symptoms and intermittent bleeding were prominent in the second and third cases. Abdominal pain and discomfort was present in the forth case. In the first 2 cases, abdominal CTs were suggestive of colonic lipoma and laparoscopic ileocecal resection was performed. However, malignancy could not be ruled out in the other 2 cases due to large size and heterogeneous appearance of the lesions and inconclusive endoscopic biopsies consisted of ulcer with exudate and inflammatory cells. Laparoscopic left and right hemicolectomy was performed in the third and forth cases, respectively. There were no complications in any patients. Laparoscopic resection can be the first choice in treatment of colonic lipomas with various presentations. Wider resections should be considered in cases with uncertain diagnosis.


Molecular complementarity II: energetic and vectorial basis of biological homeostasis and its implications for death.
The energetic basis of molecular complementarity is presented. In biological systems requiring both homeostasis and non-equilibrium state maintenance, molecular complementarity provides a framework for the co-existence of these states within an organism. Smoothly changing homeostatic and thermodynamic systems, such as regulation of pH or an ensemble of asynchronous muscle crossbridges, are modeled using Liapunov functions. When biological systems undergo discontinuous state changes, such as the initiation of the heartbeat, life/death transition or the detachment of molecules, alternative analytical systems such as catastrophe theory provide information that continuous analytical methods cannot. Catastrophe theory produces a model of biology in which death can occur by two distinct mechanisms: loss of homeostatic control or loss of sufficient free energy. Molecular complementarity buffers molecules from temporal and physical changes. The usefulness of molecular complementarity is limited to association energies near the ambient energy, kT. Within this range, complementarity will alter molecular functions and will convert scalar biochemical reactions into vectorial physiological processes. Both thermodynamic and catastrophic models can be used to link energetic and homeostatic processes: the former providing quantitative information from continuous systems; the latter providing qualitative information from discontinuous systems involving state changes.


Evaluation of Topical Mitomycin-C Eye Drops After Reconstructive Surgery for Anophthalmic Contracted Socket.
To report the outcomes of using topical mitomycin-C (MMC) after reconstructive surgery for contracted socket and to compare the results with those of the conventional postoperative treatment. The medical records of patients who underwent reconstructive surgery for contracted anophthalmic socket were retrospectively reviewed. Based on the postoperative treatment protocol, two groups of patients were identified; group I (15 patients) who received topical MMC drops (0.02%) 4 times daily for 6 weeks and group II (15 patients) who received the conventional treatment (topical antibiotic-steroid combination). Preoperative data were extracted for age, gender, cause and timing of anophthalmia, history of previous surgeries, preoperative forniceal depth and socket volume (SV). The main postoperative outcome measures were superior fornix depth (SFD), inferior fornix depth (IFD) and SV at the end of 6th postoperative month. Prosthesis fitting and complications were also considered for analysis. The mean preoperative IFD was 1.67±0.04 mm in group I and 1.58±0.37 mm in group II, by the end of the 6th postoperative month it increased to 6.1 ±0.27 mm and 5.12 ±0.25mm, respectively. The mean preoperative SFD in group I was 8.3±0.9 mm and 8.9±1.1 mm in group II, by the end of the 6th postoperative month SFD became 13.4±1.2 mm and 10.2±1.4 mm in groups I and II, respectively. The mean SV measured six months postoperatively was 1.9±0.2 mL and 1.3±0.09 mL in groups I and II, respectively. These differences in the postoperative SFD, IFD and SV between both groups were statistically significant. More cases reported successful fitting in group I than in group II but this difference was not statistically significant. Postoperative use of topical MMC is associated with higher forniceal depth and greater SV when compared to the conventional treatment in socket reconstructive surgeries with amniotic membrane graft (AMG).


Separating contributions of hearing, lexical knowledge, and speech production to speech-perception scores in children with hearing impairments.
Open-set word and sentence speech-perception test scores are commonly used as a measure of hearing abilities in children and adults using cochlear implants and/or hearing aids. These tests are usually presented auditorily with a verbal response. In the case of children, scores are typically lower and more variable than for adults with hearing impairments using similar devices. It is difficult to interpret children's speech-perception scores without considering the effects of lexical knowledge and speech-production abilities on their responses. This study postulated a simple mathematical model to describe the effects of hearing, lexical knowledge, and speech production on the perception test scores for monosyllabic words by children with impaired hearing. Thirty-three primary-school children with impaired hearing, fitted with hearing aids and/or cochlear implants, were evaluated using speech-perception, reading-aloud, speech-production, and language measures. These various measures were incorporated in the mathematical model, which revealed that performance in an open-set word-perception test in the auditory-alone mode is strongly dependent on residual hearing levels, lexical knowledge, and speech-production abilities. Further applications of the model provided an estimate of the effect of each component on the overall speech-perception score for each child.


High intraoperative inspiratory oxygen fraction and risk of major respiratory complications.
High inspiratory oxygen fraction ( FIO2 ) may improve tissue oxygenation but also impair pulmonary function. We aimed to assess whether the use of high intraoperative FIO2 increases the risk of major respiratory complications. We studied patients undergoing non-cardiothoracic surgery involving mechanical ventilation in this hospital-based registry study. The cases were divided into five groups based on the median FIO2 between intubation and extubation. The primary outcome was a composite of major respiratory complications (re-intubation, respiratory failure, pulmonary oedema, and pneumonia) developed within 7 days after surgery. Secondary outcomes included 30-day mortality. Several predefined covariates were included in a multivariate logistic regression model. The primary analysis included 73 922 cases, of whom 3035 (4.1%) developed a major respiratory complication within 7 days of surgery. For patients in the high- and low-oxygen groups, the median FIO2 was 0.79 [range 0.64-1.00] and 0.31 [0.16-0.34], respectively. Multivariate logistic regression analysis revealed that the median FIO2 was associated in a dose-dependent manner with increased risk of respiratory complications (adjusted odds ratio for high vs low FIO2 1.99, 95% confidence interval [1.72-2.31], P -value for trend <0.001). This finding was robust in a series of sensitivity analyses including adjustment for intraoperative oxygenation. High median FIO2 was also associated with 30-day mortality (odds ratio for high vs low FIO2 1.97, 95% confidence interval [1.30-2.99], P -value for trend <0.001). In this analysis of administrative data on file, high intraoperative FIO2 was associated in a dose-dependent manner with major respiratory complications and with 30-day mortality. The effect remained stable in a sensitivity analysis controlled for oxygenation. NCT02399878.


Discrepancies between proxy estimates and patient reported, health related, quality of life: minding the gap between patient and clinician perceptions in heart failure.
Health related quality of life (HRQoL) is rarely routinely measured in the clinical setting. In the absence of patient reported data, clinicians rely on proxy and informal estimates to support clinical decisions. This study compares clinician estimates (proxy) with patient reported HRQoL in patients with advanced heart failure and examines factors influencing discrepancies. Seventy-five patients with heart failure, (22 females, 53 males) completed the EQ-5D-5L questionnaire. Thirty-nine clinicians (11 medical, 23 nursing, 5 allied health) completed the proxy version (V1) producing 194 dyads. Correlation was assessed using Spearman's rank tests, systematic bias was examined with Bland-Altman analyses. Inter-rater agreement at the domain level, was investigated using linear weighted Kappa statistics while factors influencing the IRG were explored using independent student t-tests, analysis of variance and regression. There was a moderate positive correlation between clinician HRQoL estimates and patient reported utility (r = 0.38; p < .0005). Mean clinician estimates were higher than patient reported utility (0.60 vs 0.54; p = 0.008), with significant underestimation of reported problems apparent in three of the five EQ-5D-5L domains. Patient sex (female), depressed mood and frailty were all associated with an increased inter-rater gap. Clinicians in this sample overestimated HRQoL. Factors affecting the inter-rater gap, including sex and depression, support formal HRQoL screening to enhance clinical conversations and decision making. The discrepancy also supports regulatory restriction on the use of expert opinion in the development of QALYs in health economic analysis.


Quantification of physiological kinetic tremor and its correlation with aging.
Tremor is the most common movement disorder characterized by repetitive and stereotyped movements. The analysis of hand-drawing movements is commonly used in the evaluation of patients with tremor. The data collection conducted under kinetic conditions and while performing a voluntary movement highlights the kinetic tremor. Most investigations on tremor attempt to understand its relation to neuromuscular dysfunctions. Therefore, there is a lack of studies that aim to investigate the complex relation between the physiological tremor and aging, especially in kinetic conditions. In this context, the main motivation of this research was to generalize the results obtained in Almeida et al., a study that quantified age-related changes in the kinetic tremor of clinically healthy individuals. For this, a number of features extracted from tremor activity, obtained from digitized drawings of Archimedes' spirals, were analyzed. The analyses followed the sequence: Linearization of the Archimedes' spiral; Estimate of tremor activity; Data pre-processing; Feature extraction from the tremor activity; and Application of Linear Discriminant Analysis (LDA) technique as described in Almeida et al.. The generalization of the obtained results showed that the method based on LDA allows for a linear correlation between physiological kinetic tremor and aging.


Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia.
The aim was to assess relative contributions of gastric volumes (GV) and gastric emptying (GE) to meal size and postprandial symptoms in patients with functional dyspepsia. Patients with chronic upper gastrointestinal symptoms were prospectively evaluated. GV during fasting and after 300 mL Ensure was measured with 99m Tc-single-photon emission computed tomography imaging and solid GE (99m Tc-egg) by scintigraphy. Maximum tolerated volume (MTV) and symptoms were measured after Ensure challenge. Of 57 adult patients evaluated, 39 (23 women, 16 men) met Rome II criteria for functional dyspepsia and had no other diagnosis to account for dyspepsia. The most frequent symptoms were abdominal pain (90%), pain predominantly after meals (76%), nausea (85%), and early fullness after meals (79%). Relative to established laboratory normal values, MTV was abnormal in 82%, aggregate symptom score >209 in 72%, GE (at 1 hour) accelerated in 41%, GE (at 4 hours) delayed in 41%, and postmeal GV reduced in 52%. Lower body mass was associated with lower MTV and higher postchallenge symptoms. Lower fasting (not postprandial) GV and faster GE were independent predictors of lower MTV, explaining 18% of the variance after adjusting for body weight (32% of variance). GE was an independent predictor of postchallenge symptoms (10% of variance) after adjusting for volume ingested (10%), age (20%), and weight (10%). In adults with functional dyspepsia seen in a tertiary referral practice, decreased meal size and postmeal symptoms are associated with low fasting GV and faster GE. These data provide physiologic targets for ameliorating symptoms of functional dyspepsia.


Peripheral nerve protein expression and carbonyl content in N,N-diethlydithiocarbamate myelinopathy.
Human exposure to dithiocarbamates results from their uses as pesticides, in manufacturing, and as pharmaceutical agents. Neurotoxicity is an established hazard of dithiocarbamate exposure and has been observed in both humans and experimental animals. Previous studies have shown that the neurotoxicity of certain dithiocarbamates, including N,N-diethyldithiocarbamate (DEDC), disulfiram, and pyrrolidine dithiocarbamate, can manifest as a primary myelinopathy of peripheral nerves. Because increased levels of copper in peripheral nerves and elevated levels of lipid peroxidation products accompany DEDC-induced lesions, it has been suggested that the disruption of copper homeostasis and increased oxidative stress may contribute to myelin injury. To further assess the biological impact of DEDC-mediated lipid peroxidation in nerves, the changes in protein expression levels resulting from DEDC exposure were determined. In addition, protein carbonyl content in peripheral nerves was also determined as an initial assessment of protein oxidative damage in DEDC neuropathy. Rats were exposed to DEDC by intra-abdominal osmotic pumps for eight weeks and proteins extracted from the sciatic nerves of DEDC-exposed animals and from non-exposed controls. The comparison of protein expression levels using two-dimensional difference gel electrophoresis demonstrated significant changes in 56 spots of which 46 were identified by MALDI-TOF/MS. Among the proteins showing increased expression were three isoforms of glutathione transferase, important for the detoxification of reactive alpha,beta-unsaturated aldehydes generated from lipid peroxidation. The increased expression of one isoform, glutathione transferase pi, was localized to the cytoplasm of Schwann cells using immunohistochemistry. An immunoassay for nerve protein carbonyls demonstrated a significant increase of approximately 2-fold for the proteins isolated from DEDC-exposed rats. These data support the ability of DEDC to promote protein oxidative damage in peripheral nerves and to produce sufficient lipid peroxidation in either myelin or another component of the Schwann cell to elicit a protective cellular response to oxidative stress.


Identification of the pore-forming region of the outer chloroplast envelope protein OEP16.
The chloroplast outer envelope protein OEP16 forms a cation-selective high conductance channel with permeability to amines and amino acids. The region of OEP16 directly involved in channel formation has been identified by electrophysiological analysis of a selection of reconstituted OEP16 mutants. Because analysis of these mutants depended on the use of recombinant protein, we evaluated the electrophysiological properties of OEP16 isolated directly from pea chloroplasts and of the recombinant protein produced in Escherichia coli. The results show that the basic properties like conductance, selectivity, and open probability of the channel formed by native pea OEP16 are comparable with the channel activity formed by the recombinant source of the protein. Following electrophysiological analysis of OEP16 mutants we found that point mutations and insertion of additional amino acid residues in the region of the putative helix 1 (Glu(73) to Val(91)) did not change the properties of the OEP16 channel. The only exception was a Cys(71)-->Ser mutation, which led to a loss of the CuCl(2) sensitivity of the channel. Analysis of N- and C-terminal deletion mutants of OEP16 and mutants containing defined shuffled domains indicated that the minimal continuous region of OEP16, which is able to form a channel in liposomes, lies in the first half of the protein between amino acid residues 21 and 93.


The effect of pregnancy on footprint parameters. A prospective investigation.
Pregnancy produces significant alterations in the posture of the pregnant woman; however, gait changes that occur during pregnancy have not been adequately evaluated in the literature. This prospective investigation of the footprints of 25 pregnant women from early pregnancy to just prior to parturition revealed a significant increase in the base of gait during walking. This change in gait function may be a compensatory mechanism to improve locomotor stability, and may have important implications for foot function and development of lower-extremity pathology in pregnant women.


Nutrient and hormonal regulation of the threshold of glucose-stimulated insulin secretion in isolated rat pancreases.
This study demonstrates that the threshold of glucose-stimulated insulin secretion can be regulated in vivo by long term hormonal and nutrient modifications. The sensitivity of the pancreatic B-cell to glucose stimulation was determined by examining the pattern of insulin release from pancreases perfused with linear glucose gradients. Male rats infused with ovine PRL for 4 days and rats receiving five hourly injections of glucose had a lower threshold and enhanced rates of insulin release at all stimulatory glucose concentrations. Infusion of bGH for 4 days was without effect on glucose gradient-stimulated insulin release. Fasting the rats for 48 h resulted in an elevation of the threshold and a substantial reduction in the extent of insulin release. To determine possible processes involved in these long term modifications of the threshold of glucose-stimulated insulin secretion, the in vitro effect of potentiators of insulin release was examined. Forskolin, glucagon, cholecystokinin, and carbamylcholine were able to lower the threshold and increase the extent of insulin release. This suggests that the long term regulation of insulin secretion may modulate processes controlling cAMP concentrations and the hydrolysis of phosphoinositides in pancreatic B-cells. Also, the proposed incretin gastric inhibitory polypeptide was capable of lowering the threshold and increasing insulin secretion at stimulatory glucose concentrations. The consequences of a decreased threshold is a markedly enhanced insulin secretion at normal serum glucose concentrations.


Chemosensory loss: functional consequences of the world trade center disaster.
Individuals involved in rescue, recovery, demolition, and cleanup at the World Trade Center (WTC) site were exposed to a complex mixture of airborne smoke, dust, combustion gases, acid mists, and metal fumes. Such exposures have the potential to impair nasal chemosensory (olfactory and trigeminal) function. The goal of this study was to evaluate the prevalence of chemosensory dysfunction and nasal inflammation among these individuals. We studied 102 individuals who worked or volunteered at the WTC site in the days and weeks during and after 11 September 2001 (9/11) and a comparison group with no WTC exposure matched to each participant on age, sex, and job title. Participants were comprehensively evaluated for chemosensory function and nasal inflammation in a single session. Individual exposure history was obtained from self-reported questionnaires. The prevalence of olfactory and trigeminal nerve sensitivity loss was significantly greater in the WTC-exposed group relative to the comparison group [prevalence ratios (95% confidence intervals) = 1.96 (1.2-3.3) and 3.28 (2.7-3.9) for odor and irritation thresholds, respectively]. Among the WTC responders, however, individuals caught in the dust cloud from the collapse on 9/11 exhibited the most profound trigeminal loss. Analysis of the nasal lavage samples supported the clinical findings of chronic nasal inflammation among the WTC-exposed cohort. The prevalence of significant chemosensory impairment in the WTC-exposed group more than 2 years after their exposure raises concerns for these individuals when the ability to detect airborne odors or irritants is a critical safety factor. This outcome highlights the need for chemosensory evaluations among individuals with exposure to acute high or chronic levels of airborne pollutants.


High spatial resolution distributed fiber strain sensor based on phase-OFDR.
A novel method to realize high spatial resolution distributed strain measurement is proposed based on phase demodulation scheme of optical frequency domain reflectometry (OFDR). Strain information can be demodulated directly by analyzing the phase change of Rayleigh backscattered light. Strain location can be obtained with high spatial resolution by cross-correlation method using a wide scanning range of tunable laser source. Based on the above scheme, breakpoint detection with 0.1 mm spatial resolution has been demonstrated, static and dynamic strain up to 100 Hz could be distributedly measured with 10 cm spatial resolution over 200 m sensing fiber, and the minimum measurable strain is about 1 με.


Hemorrhagic cystitis after allogeneic hematopoietic cell transplantation: risk factors, graft source and survival.
Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well known. We evaluated HC in a large cohort (n=1321, 2003-2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute GVHD, fever, severe thrombocytopenia and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III-IV) was associated with increased treatment-related mortality but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis, and early interventions to limit its severity are still needed.


Pediatric Cytochrome P450 Activity Alterations in Nonalcoholic Steatohepatitis.
Variable drug responses depend on individual variation in the activity of drug-metabolizing enzymes, including cytochrome P450 enzymes (CYP). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in hepatic drug metabolism. Compared with adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYP enzymes in children and adolescents. Healthy and nonalcoholic fatty liver disease pediatric subjects aged 12-21 years inclusive received an oral cocktail of four probe drugs: caffeine (CYP1A2, 100 mg), omeprazole (CYP2C19, 20 mg), losartan (CYP2C9, 25 mg), and midazolam (CYP3A4, 2 mg). Venous blood and urine were collected before administration and 1, 2, 4, and 6 hours after administration. Concentrations of the parent drugs and CYP-specific metabolites were quantified in plasma and urine using liquid chromatography with tandem mass spectrometry. In plasma, the decreased metabolic area under the curve (AUC) ratio, defined as the metabolite AUC to parent AUC, of omeprazole indicated significant decreases of CYP2C19 (P = 0.002) enzymatic activities in NASH adolescents, while the urine analyses did not show significant differences and were highly variable. A comparison between the present in vivo pediatric studies and a previous ex vivo study in adults indicates distinct differences in the activities of CYP1A2 and CYP2C9. These data demonstrate that pediatric NASH presents an altered pattern of CYP activity and NASH should be considered as a confounder of drug metabolism for certain CYP enzymes. These differences could lead to future investigations that may reveal unexpected variable drug responses that should be considered in pediatric dosage recommendations.