Multiple Independent Gene Disorders Causing Bardet-Biedl Syndrome, Congenital Hypothyroidism, and Hearing Loss in a Single Indian Patient.
We report a 20-year-old, female, adopted Indian patient with over 662 Mb regions of homozy-gosity who presented with intellectual disability, ataxia, schizophrenia, retinal dystrophy, moder-ate-to-severe progressive sensorineural hearing loss (SNHL), congenital hypothyroidism, cleft mi-tral valve with mild mitral valve regurgitation, and dysmorphic features. Exome analysis first on a clinical basis and subsequently on research reanalysis uncovered pathogenic variants in three nu-clear genes following two modes of inheritance that were causal to her complex phenotype. These included (1) compound heterozygous variants in BBS6 potentially causative for Bardet-Biedl syn-drome 6; (2) a homozygous, known pathogenic variant in the stereocilin (STRC) gene associated with nonsyndromic deafness; and (3) a homozygous variant in dual oxidase 2 (DUOX2) gene asso-ciated with congenital hypothyroidism. A variant of uncertain significance was identified in a fourth gene, troponin T2 (TNNT2), associated with cardiomyopathy but not the cleft mitral valve, with mild mitral regurgitation seen in this case. This patient was the product of an apparent first-degree relationship, explaining the multiple independent inherited findings. This case high-lights the need to carefully evaluate multiple independent genetic etiologies for complex pheno-types, particularly in the case of consanguinity, rather than presuming unexplained features are expansions of known gene disorders.


Electrochemical treatment of pharmaceutical wastewater by combining anodic oxidation with ozonation.
Wastewater effluents from sewage treatment plants (STP) are important point sources for residues of pharmaceuticals and complexing agents in the aquatic environment. For this reason a research project, which started in December 2006, was established to eliminate pharmaceutical substances and complexing agents found in wastewater as micropollutants. For the treatment process a combination of anodic oxidation by boron-doped diamond (BDD) electrodes and ozonation is examined and presented. For the ozone production a non-conventional, separate reactor was used, in which ozone was generated by electrolysis with diamond electrodes For the determination of the achievable remediation rates four complexing agents (e.g., EDTA, NTA) and eight pharmaceutical substances (e.g., diazepam, carbamazepin) were analyzed in several test runs under different conditions (varied flux, varied current density for the diamond electrode and the ozone producing electrode of the ozone generator, different packing materials for the column in the ozone injection system). The flowrates of the treated water samples were varied from 3 L/h up to 26 L/h. For the anodic oxidation the influence of the current density was examined in the range between 22.7 and 45.5 mA/cm(2), for the ozone producing reactor two densities (1.8 a/cm(2) and 2.0 A/cm(2)) were tested. Matrix effects were investigated by test runs with samples from the effluent of an STP and synthetic waste water. Therefore the impact of the organic material in the samples could be determined by the comparison of the redox potential and the achievable elimination rates of the investigated substances. Comparing both technologies anodic oxidation seems to be superior to ozonation in each investigated area. With the used technology of anodic oxidation elimination rates up to 99% were reached for the investigated pharmaceutical substances at a current density of 45.5 mA/cm(2) and a maximum sample flux of 26 L/h.


An exploration of ex-boarding school adults' attachment styles and substance use behaviours.
Our study examines the relationship between boarding school attendance, adult attachment styles, parental bonding, and substance use, aiming was to quantitatively investigate if caregiver deprivation caused by boarding contributes to enduring outcomes in adults. In a sample of 149 adults, measures included AUDIT and DUDIT (substance use), Parental Bonding Instrument (parental care), and Experiences in Close Relationships (adult attachment). Pearson's correlation revealed a significant negative association between age at first boarding and anxiety, avoidant attachment styles, and poorer parental care, whilst a significant positive relationship was identified between age at first boarding and perceived parental care. This was supported by a hierarchical regression which demonstrated that the model predicted 29% of the variance in age at first boarding. These results contribute towards the formulation and treatment of ex-boarders and to research considering the effects of boarding school experiences on difficulties in adult life.


Modulation of pore sizes of titanium dioxide photocatalysts by a facile template free hydrothermal synthesis method: implications for photocatalytic degradation of rhodamine B.
Mesoporous TiO2 photocatalysts were prepared in ethanol media by using relatively green, template free sol-gel technique. A mild hydrothermal treatment procedure was employed to tune the pore sizes of the materials. Comprehensive techniques that include powder X-ray diffraction, diffuse reflectance spectroscopy, specific surface area analysis, electron microscopy, FT-IR, TGA, and ζ-potential measurements were used to characterize the titania materials. Porosity (pore size and pore volume) of the materials were found to be key factors for the variation in the rate of photocatalytic degradation of rhodamine B; in addition to specific surface area, and surface hydroxyl groups. An increase in porosity permits effective transport of the dye molecules resulting in an increase in the rate of the degradation in materials having larger pores. A detailed electrospray ionization-mass spectrometric (ESI-MS) study was carried out for selected materials to identify photodegraded intermediates and products formed during the degradation of rhodamine B. In addition, experiments were also carried out to understand the role of reactive oxygen species (ROS). In summary, this work provides a simple way to tune pore sizes without the use of any template and an insight into the influence of pore size for the photocatalytic degradation of rhodamine B.


Ratings of Hand Activity and Force Levels among Women and Men Who Perform Identical Hand-Intensive Work Tasks.
We compared hand activity and force ratings in women and men doing identical hand-intensive work tasks. Musculoskeletal disorders are more common in women and hand-intensive work leads to an increased risk of these disorders. Knowledge of the gender influence in the rating of work exposure is lacking. The aim of this study was to investigate whether women and men performing identical hand-intensive work tasks were equally rated using hand activity and normalized peak force levels with the Hand Activity Threshold Limit Value®. Fifty-six workers participated, comprising 28 women-men pairs. Four observers-two woman-man pairs-were also involved. Self-ratings and observers' ratings of hand activity and force level were collected. The results of these ratings showed no significant gender differences in self-rated hand activity and force, as well as observer-rated hand activity. However, there was a significant gender difference in the observer-rated force, where the women were rated higher (mean (SD): women 3.9 (2.7), men 3.1 (1.8) (p = 0.01)). This difference remained significant in the adjusted model (p = 0.04) with grip strength and forearm-finger anthropometrics. The results provide new insights that observers' estimates of force can be higher in women compared with men in the same work tasks. Force should be further investigated and preferably compared to objective measurements.


Iroki: automatic customization and visualization of phylogenetic trees.
Phylogenetic trees are an important analytical tool for evaluating community diversity and evolutionary history. In the case of microorganisms, the decreasing cost of sequencing has enabled researchers to generate ever-larger sequence datasets, which in turn have begun to fill gaps in the evolutionary history of microbial groups. However, phylogenetic analyses of these types of datasets create complex trees that can be challenging to interpret. Scientific inferences made by visual inspection of phylogenetic trees can be simplified and enhanced by customizing various parts of the tree. Yet, manual customization is time-consuming and error prone, and programs designed to assist in batch tree customization often require programming experience or complicated file formats for annotation. Iroki, a user-friendly web interface for tree visualization, addresses these issues by providing automatic customization of large trees based on metadata contained in tab-separated text files. Iroki's utility for exploring biological and ecological trends in sequencing data was demonstrated through a variety of microbial ecology applications in which trees with hundreds to thousands of leaf nodes were customized according to extensive collections of metadata. The Iroki web application and documentation are available at https://www.iroki.net or through the VIROME portal http://virome.dbi.udel.edu. Iroki's source code is released under the MIT license and is available at https://github.com/mooreryan/iroki.


Hooked on a feeling: Repetitive cognition and internalizing symptomatology in relation to autism spectrum symptomatology.
Repetitive cognition, including rumination such as that seen in depression, has been shown to correlate with depression symptoms in both typically developing individuals and individuals with autism spectrum disorder. Repetitive cognition is more common in autism spectrum disorder than in typically developing peers, as is depression; thus, this study evaluated the role of repetitive cognition in relation between autism spectrum symptomatology and depressive symptomatology. In all, 200 typically developing adults completed self-report questionnaires measuring autism spectrum symptomatology, different forms of repetitive cognition (general perseveration and depressive rumination), depression, and rejection sensitivity. Perseveration was found to mediate the relation between autism spectrum symptoms and depression, and to partially mediate the relation between autism spectrum symptoms and rejection sensitivity. We conclude that it is of vital importance to consider cognition when considering depression in autism spectrum disorder.


Pancreatic adenocarcinoma: the different CT criteria for peripancreatic major arterial and venous invasion.
To establish preliminarily the different diagnostic criteria for peripancreatic arterial and venous invasion in pancreatic carcinoma by comparing their multidetector-row computed tomography (MDCT) appearances with surgical exploration. Among 101 patients with pancreatic carcinoma examined by MDCT, 54 candidates accepting surgery were preoperatively evaluated for vascular invasion based on CT signs (A-E): arterial embedment in tumor or venous obliteration; tumor involvement exceeding one-half of the circumference of the vessel; vessel wall irregularity; vessel caliber stenosis; teardrop superior mesenteric vein (SMV). The peripancreatic major vessels (n = 224) were examined carefully by surgeons during the operation. During surgical exploration, 78 vessels were found to be invaded. With sign A (B, C, or D) as the CT criterion for peripancreatic vascular invasion, the sensitivity of arterial and venous invasion was 66% (97%, 45%, or 41%) and 14% (49%, 63%, or 55%), respectively; the specificity of absence of arterial and venous invasion was 100% (91%, 99%, or 100%) and 100% (all 100%). In this study, there were 3 SMVs appearing teardrop (sign E), which were all confirmed to be invaded. It is recommended that the CT diagnostic criteria for arterial and venous invasion should be dealt with differently. The criteria of arterial invasion are the presence of sign A or the combination of sign B with one of signs C and D. The criteria of venous invasion are the presence of one of the following signs: sign A, sign B, sign C, sign D, and sign E.


In vivo modeling of myosin binding protein C familial hypertrophic cardiomyopathy.
Myosin binding protein C (MyBP-C) is an integral part of the striated muscle sarcomere. As is the case for other sarcomeric genes in human populations, multiple mutations within the gene have been linked to familial hypertrophic cardiomyopathy. Although some MyBP-C lesions are the result of missense mutations, most show truncated polypeptides lacking either the myosin or myosin and titin binding sites. Previously, we generated transgenic (TG) mice with cardiac-specific expression of a MyBP-C mutant lacking the myosin and titin binding domains. Surprisingly, the mutant protein was stable and made up a majority of the MyBP-C species, with concomitant reductions in endogenous MyBP-C such that overall MyBP-C stoichiometry was conserved. In the present study, we created a second series of TG mice that express, in the heart, a mutant MyBP-C lacking only the myosin binding site. In contrast to the previous data for the MyBP-C lacking both titin and myosin binding sites, only very modest levels of protein were found, consistent with data obtained from human biopsies in which mutated MyBP-C could not be detected. Despite normal levels of wild-type MyBP-C, there were significant changes in the structure and ultrastructure of the heart. Fiber mechanics showed decreased unloading shortening velocity, maximum shortening velocity, and relative maximal power output.


New femoral designs: do they influence stress shielding?
Virtually all contemporary cementless femoral hip stems are designed with the goals of achieving immediate and long-term stability, restoring hip mechanics, and minimizing thigh pain. However, the incorporation of features specifically intended to minimize stress-mediated bone resorption (stress shielding) has been variable. Attempts to reduce bone loss through stem design have yielded inconsistent results and, in certain instances, early and catastrophic failure. Prior beliefs regarding the determinants of stress shielding were based upon the qualitative assessment of bone loss using plain radiographs. These are being challenged, particularly with regard to the role of porous coating level. This is in large part due to the refinement and widespread availability of dual-energy xray absorptiometry (DEXA), which allows quantitative assessment of bone mineral density both pre- and postoperatively. The available evidence indicates stem stiffness plays a dominant role. Progressive bone loss through stress shielding has potentially dire consequences. While such problems have not manifested as severe or widespread clinical issues, the preservation of femoral bone stock is an important and desirable goal.


Hypereosinophilia and recurrent angioneurotic edema in a 2 1/2-year-old girl.
A 2 1/2-year-old girl presented with monthly episodes of angioneurotic edema, eruption of pruritic papules, and fever. During acute episodes, white blood cell counts rose as high as 52,100/cu mm with 62% eosinophils, and body weights increased up to 20% of remission weight. Short courses of prednisone acetate caused rapid defervescence, resolution of angioneurotic edema, and lowering of eosinophil counts. In a one-year follow-up no evidence was found for cardiac or other visceral organ involvement. Findings of extensive diagnostic evaluations revealed no evidence for atopy, neoplasm, collagen-vascular disease, or parasitic infestation. Results of immunologic studies were essentially normal with the exception that this patient had a high level of circulating activated helper T cells. Biopsy specimens of the skin lesions revealed dermal infiltration of lymphocytes and eosinophils with deposition of eosinophil major basic protein in the extracellular matrix. Awareness of this clinical entity and its distinction from the hypereosinophilic syndrome is important because of its favorable prognosis and rapid response to corticosteroid therapy.


Laboratory and on-road evaluations of cabin air filters using number and surface area concentration monitors.
An automotive cabin air filter's effectiveness for removing airborne particles was determined both in a laboratory wind tunnel and in vehicle on-road tests. The most penetrating particle size for the test filter was approximately 350 nm, where the filtration efficiency was 22.9 and 17.4% at medium and high fan speeds, respectively. The filtration efficiency increased for smaller particles and was 43.9% for 100 nm and 72.0% for 20 nm particles at a medium fan speed. We determined the reduction in passenger exposure to particles while driving in freeway traffic caused by a vehicle ventilation system with a cabin air filter installed. Both particle number and surface area concentration measurements were made inside the cabin and in the surrounding air. At medium fan speed, the number and surface area concentration-based exposure reductions were 65.6 +/- 6.0% and 60.6 +/- 9.4%, respectively. To distinguish the exposure reduction contribution from the filter alone and the remainder of the ventilation system, we also performed tests with and without the filter in place using the surface area monitors. The ventilation system operating in the recirculation mode with the cabin air filter installed provided the maximum protection, reducing the cabin particle concentration exponentially over time and usually taking only 3 min to reach 10 microm2/cm3 (a typical office air condition) under medium fan speed.


A combined experimental-computational investigation of carbon dioxide capture in a series of isoreticular zeolitic imidazolate frameworks.
A series of five zeolitic imidazolate frameworks (ZIFs) have been synthesized using zinc(II) acetate and five different 4,5-functionalized imidazole units, namely ZIF-25, -71, -93, -96, and -97. These 3-D porous frameworks have the same underlying topology (RHO) with Brunauer-Emmet-Teller surface areas ranging from 564 to 1110 m(2)/g. The only variation in structure arises from the functional groups that are directed into the pores of these materials, which include -CH(3), -OH, -Cl, -CN, -CHO, and -NH(2); therefore these 3-D frameworks are ideal for the study of the effect of functionality on CO(2) uptake. Experimental results show CO(2) uptake at approximately 800 Torr and 298 K ranging from 0.65 mmol g(-1) in ZIF-71 to 2.18 mmol g(-1) in ZIF-96. Molecular modeling calculations reproduce the pronounced dependence of the equilibrium adsorption on functionalization and suggest that polarizability and symmetry of the functionalization on the imidazolate are key factors leading to high CO(2) uptake.


Oncostatin M protects rod and cone photoreceptors and promotes regeneration of cone outer segment in a rat model of retinal degeneration.
Retinitis pigmentosa (RP) is a group of photoreceptor degenerative disorders that lead to loss of vision. Typically, rod photoreceptors degenerate first, resulting in loss of night and peripheral vision. Secondary cone degeneration eventually affects central vision, leading to total blindness. Previous studies have shown that photoreceptors could be protected from degeneration by exogenous neurotrophic factors, including ciliary neurotrophic factor (CNTF), a member of the IL-6 family of cytokines. Using a transgenic rat model of retinal degeneration (the S334-ter rat), we investigated the effects of Oncostatin M (OSM), another member of the IL-6 family of cytokines, on photoreceptor protection. We found that exogenous OSM protects both rod and cone photoreceptors. In addition, OSM promotes regeneration of cone outer segments in early stages of cone degeneration. Further investigation showed that OSM treatment induces STAT3 phosphorylation in Müller cells but not in photoreceptors, suggesting that OSM not directly acts on photoreceptors and that the protective effects of OSM on photoreceptors are mediated by Müller cells. These findings support the therapeutic strategy using members of IL-6 family of cytokines for retinal degenerative disorders. They also provide evidence that activation of the STAT3 pathway in Müller cells promotes photoreceptor survival. Our work highlights the importance of Müller cell-photoreceptor interaction in the retina, which may serve as a model of glia-neuron interaction in general.


Exploring HIV risk perception and behaviour in the context of antiretroviral treatment: results from a township household survey.
The objective of this cross-sectional household survey was to assess factors influencing HIV risk perception, behaviour and intervention uptake in a community characterised by high HIV prevalence and availability of antiretroviral therapy (ART). The survey was conducted in Khayelitsha, South Africa and involved two-stage sampling with self-weighting clusters and random selection of households within clusters. One man and woman between 14 and 49 years old was interviewed in each household; 696 men and 879 women were interviewed for a response rate of 84% and 92% respectively. Ninety-three percent and 94% were sexually active with median age of sexual debut 15.3 and 16.5 years. Eighty-three percent and 82% reported a partner at the time of interview and 29% and 8% had additional partner(s). Forty-one percent and 33% reported condom use during the last sexual encounter. Thirty-seven percent of men not using condoms did not as they believed their partner to be faithful, whilst 27% of women did not as their partner refused. Twenty-eight percent and 53% had been tested for HIV. Having undergone HIV testing was not associated with condom usage, whilst current relationship status was the strongest association with condom usage for both men and women. In spite of a relatively high uptake of condoms and testing as well as ART availability, the HIV epidemic has continued unabated in Khayelitsha. Even greater coverage of preventive interventions is required, together with a national social and political environment that builds on the availability of both preventive and treatment services.


Initial characterization of the complement activating compounds in extracts of smokeless tobacco.
Aqueous extracts of smokeless tobacco (ST) have been shown to be potent activators of complement. However, the mechanisms by which smokeless tobacco activates complement are not well understood. This study was undertaken to identify the complement activating compounds in ST extracts. The approximate molecular size of the activating agent(s) in smokeless tobacco was determined by dialyzing aqueous extracts of loose leaf chewing tobacco (1S1), dry snuff (1S2), and moist snuff (1S3). Following dialysis (total dilution effect of 1:10(9)), using a membrane with a molecular weight retention limit of 12-14 kDa, all extracts retained full capacity to activate serum complement as determined by a hemolytic assay. Fractionation of the extracts by gel filtration chromatography revealed that the complement activating agents in ST were high molecular weight compounds that eluted between 400 kDa and the void volume (1500 kDa) of a Sephacryl S300 column. The high molecular weight complement-activating peak was isolated and found to be a more potent complement activator than the unfractionated extract. The chemical nature of the complement activating compounds was determined by subjecting the extracts to boiling for 30 min, an organic extraction with chloroform/methanol 2:1, or treatment with a DNAse/RNAse enzyme cocktail. None of these treatments destroyed the capacity of ST extracts to activate complement, suggesting that the activating agents may be carbohydrate-like. Finally, an extraction protocol designed to remove polyphenols significantly diminished the complement activating capacity of the ST extracts. These results clearly demonstrate that the complement activating substances in smokeless tobacco extracts may be large (>400 kDa) polyphenol-containing compounds (i.e. tannins). Identification of this agent(s) will be important for distinguishing the mechanism of smokeless tobacco-induced complement activation.


Turkish nurses' experiences of verbal abuse at work.
In the health sector anywhere in the world, nurses make up one of the groups that are most exposed to violence such as sexual harassment, verbal abuse, and physical abuse. This descriptive study investigated the experience of verbal abuse among 339 hospital nurses in Turkey. Findings indicate that the most frequent and most severe forms of verbal abuse reported were judging and criticizing, accusing and blaming, and abusive anger; the most common emotional reactions were anger, followed by shame, humiliation, and frustration; and most nurses used engaging in negative activities to cope with verbal abuse. The results of the study suggest that hospitals must adopt zero-tolerance policies for professional verbal abuse.


Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.


[Changes in lectin-induced agglutination of human tumor cells during the process of their reversion].
The concanavalin A-induced agglutination of cultivated cells of human osteosarcoma Sa-4 was studied in the process of their reversion caused by high polar compounds, dimethylsulphoxide (DMSO) and dimethylformamide (DMFA). Primarily lectin induced an expressed ability to agglutination in Sa-4 cells. In the process of tumour cell reversion under the effect of chemical inducers their agglutination decreases. After the DMSO and DMFA removal the osteosarcoma cells return to their initial state showing a high agglutination. Other high-polar compounds (N-methylformamide and dimethylacetamide) induced no reversion of Sa-4 cells and no agglutination of them as well.


The impact of implicit and explicit bias about disabilities on parent experiences and information provided during prenatal screening and testing.
Prenatal screening technology has consistently raised concerns regarding the conversations and information provided about disabilities, particularly given that research shows trauma related to negative prenatal screening and diagnosis experiences among parents of children with Down syndrome.1 OBJECTIVE: To determine what information obstetric medical providers (OB/MFMs) are most and least likely to provide when delivering prenatal screening/testing results about Down syndrome (DS), the subsequent impact of bias on prenatal screening experiences, and how these issues can be addressed through training, resources, and professional guidelines. Online surveys were distributed to parents of children with DS born between 2016 and 2021 via local DS organizations and the national DS Diagnosis Network (April 2020-December 2021). Of the 242 parents who completed the survey, a majority indicated that OB/MFMs were most likely to discuss medical issues and reproductive options while less than 40% reported that OB/MFMs discussed psychosocial outcomes, supports, and services. Respondents reported that the 61.3% of OB/MFMs who delivered the diagnosis as bad news or said "I'm sorry" were significantly less likely than their counterparts to provide information about life outcomes, supports and services, condition-specific resources, or more comprehensive prenatal care. Qualitative responses about screening/diagnosis experiences provided further context about the impact of implicit and explicit bias on the provision of accurate, up-to-date information. To meet information needs during prenatal screening, OB/MFMs need access to accurate, balanced, and up-to-date information about disabilities and more training on disability cultural competency and how to deliver prenatal screening/testing results without implicit or explicit bias.


The dynamics of infant visual foraging.
Human infants actively forage for visual information from the moment of birth onward. Although we know a great deal about how stimulus characteristics influence looking behavior in the first few postnatal weeks, we know much less about the intrinsic dynamics of the behavior. Here we show that a simple stochastic dynamical system acts quantitatively like 4-week-old infants on a range of measures if there is hysteresis in the transitions between looking and looking away in the model system. The success of this simple three-parameter model suggests that visual foraging in the first few weeks after birth may be influenced more by noise and hysteresis in underlying neural mechanisms than by how infants process visual information after a look begins.


Comparison of the pathogenicity of Nipah virus isolates from Bangladesh and Malaysia in the Syrian hamster.
Nipah virus is a zoonotic pathogen that causes severe disease in humans. The mechanisms of pathogenesis are not well described. The first Nipah virus outbreak occurred in Malaysia, where human disease had a strong neurological component. Subsequent outbreaks have occurred in Bangladesh and India and transmission and disease processes in these outbreaks appear to be different from those of the Malaysian outbreak. Until this point, virtually all Nipah virus studies in vitro and in vivo, including vaccine and pathogenesis studies, have utilized a virus isolate from the original Malaysian outbreak (NiV-M). To investigate potential differences between NiV-M and a Nipah virus isolate from Bangladesh (NiV-B), we compared NiV-M and NiV-B infection in vitro and in vivo. In hamster kidney cells, NiV-M-infection resulted in extensive syncytia formation and cytopathic effects, whereas NiV-B-infection resulted in little to no morphological changes. In vivo, NiV-M-infected Syrian hamsters had accelerated virus replication, pathology and death when compared to NiV-B-infected animals. NiV-M infection also resulted in the activation of host immune response genes at an earlier time point. Pathogenicity was not only a result of direct effects of virus replication, but likely also had an immunopathogenic component. The differences observed between NiV-M and NiV-B pathogeneis in hamsters may relate to differences observed in human cases. Characterization of the hamster model for NiV-B infection allows for further research of the strain of Nipah virus responsible for the more recent outbreaks in humans. This model can be used to study NiV-B pathogenesis, transmission, and countermeasures that could be used to control outbreaks.


Influence of respiratory distress syndrome on body composition after preterm birth.
To observe changes in body composition during the first week after birth, in preterm neonates with and without respiratory distress syndrome (RDS), so as to be able to provide optimal fluid and energy intake. Twenty four babies with RDS and 19 healthy preterm babies, with gestational ages ranging from 26-36 weeks, were studied daily for the first week after birth. Total body water (TBW) was measured using bioelectrical impedance analysis. The babies were weighed daily and a record made of fluid and energy intake. Body solids were calculated as the difference between body weight and TBW. There was a highly significant reduction in body weight by the end of the week, with the RDS babies losing more than the healthy babies (RDS 7.6%; non-RDS 3.7%). There was no significant difference in the amount of TBW at birth in the babies with and without RDS (RDS 85.1%; non-RDS 85.5%) and both groups lost the same amount of body water (RDS 10.9%; non-RDS 9.9%) by the end of the first week. The amount of total body water lost was unrelated to the volume of fluid administered. There was a loss of body solids during the first day in the RDS group, but, overall, there was a highly significant increase in both groups between birth and day 7, which was greater in the healthy babies (RDS 13.0%; non-RDS 42.7%). Loss of body water after birth occurs to the same extent in healthy preterm neonates and in babies with RDS and is unrelated to the volume of fluid administered. Given adequate nutritional support, an increase in body solids can accompany early postnatal weight loss and begins almost immediately after birth, in both healthy preterm babies and babies with RDS.


[Treatment with low-dose acetylsalicylic acid can reduce risk of pre-eclampsia in high-risk pregnant women].
Pre-eclampsia is a major contributor to perinatal morbidity and mortality. Large studies of high-risk pregnant women have shown reduced risk of developing pre-eclampsia when they are treated with low-dose acetylsalicylic acid in early pregnancy. Treatment is also effective in preventing intrauterine growth restriction, preterm birth and perinatal death. No major side effects, including risk of malformations or miscarriage, are reported. It is important that general practitioners are aware of women who have an increased risk of developing pre-eclampsia, so that treatment with 100 mg of acetylsalicylic acid can be started early in pregnancy.


Review of sorption and diffusion of lipophilic molecules in cuticular waxes and the effects of accelerators on solute mobilities.
Many agrochemicals are applied to the leaf surfaces of crop plants. Systemic chemicals have to penetrate through the cuticle, which forms an effective transport barrier. The barrier properties of cuticles are mainly due to the cuticular waxes deposited as partially crystalline aggregates on the outer surfaces of leaves. Substances increasing the mobilities of agrochemicals in cuticular waxes are called accelerators and it is shown that they act as plasticizers when absorbed by cuticular waxes. They decrease the barrier properties of the waxes and thus increase the mobilities of the agrochemicals through them. In order to analyse the efficiency of different accelerators, the sorption and mobility of both agrochemicals and accelerators within cuticular waxes was measured. Such information was used to establish correlations between the internal concentrations of accelerators and their mobility-enhancing effects on agrochemicals in the cuticle. This, in turn, allowed the determination and comparison of the intrinsic effects of different accelerators and to rationalize the effect of accelerators on the cuticular permeability of agrochemicals. Results describing the sorption (partition coefficients) and mobility (diffusion coefficients) of lipophilic organic molecules in reconstituted cuticular waxes from different plant species, and the effect of two different classes of accelerators (alcohol ethoxylates and n-alkyl esters), on the mobility of organic molecules are presented and discussed.


Variable response of three Trifolium repens ecotypes to soil flooding by seawater.
Despite concerns about the impact of rising sea levels and storm surge events on coastal ecosystems, there is remarkably little information on the response of terrestrial coastal plant species to seawater inundation. The aim of this study was to elucidate responses of a glycophyte (white clover, Trifolium repens) to short-duration soil flooding by seawater and recovery following leaching of salts. Using plants cultivated from parent ecotypes collected from a natural soil salinity gradient, the impact of short-duration seawater soil flooding (8 or 24 h) on short-term changes in leaf salt ion and organic solute concentrations was examined, together with longer term impacts on plant growth (stolon elongation) and flowering. There was substantial Cl(-) and Na(+) accumulation in leaves, especially for plants subjected to 24 h soil flooding with seawater, but no consistent variation linked to parent plant provenance. Proline and sucrose concentrations also increased in plants following seawater flooding of the soil. Plant growth and flowering were reduced by longer soil immersion times (seawater flooding followed by drainage and freshwater inputs), but plants originating from more saline soil responded less negatively than those from lower salinity soil. The accumulation of proline and sucrose indicates a potential for solute accumulation as a response to the osmotic imbalance caused by salt ions, while variation in growth and flowering responses between ecotypes points to a natural adaptive capacity for tolerance of short-duration seawater soil flooding in T. repens. Consequently, it is suggested that selection for tolerant ecotypes is possible should the predicted increase in frequency of storm surge flooding events occur.


Torsion of wandering spleen.
Wandering spleen is characterized by ectopic localization of spleen owing to the lack or weakening of the major splenic ligaments. In present study, two cases with torsion of wandering spleen were reported. The first case was a 30-year-old female who was admitted to emergency department with acute abdominal pain and vomiting. Abdominal Ultrasonography and computed tomography showed a round solid hypodense mass that was located in the left hypochondriac region of abdomen. At laparotomy, the patient was found to have torsion of a wandering spleen with complete infarction and pancreatic tail infarction. Splenectomy and distal pancreatectomy were performed. The second patient was a 19-year-old female. She was admitted to emergency department with abdominal pain. Axial computed tomography (CT) showed pelvic mass that indicated a possibility of a wandering spleen. The wandering spleen was removed with its long pedicle because of infarction. Torsion of wandering spleen must be considered in differential diagnosis of acute abdomen when a palpable painful abdominal mass is present on physical examination, and the spleen is absent in its normal anatomical location on radiological examination (Fig. 4, Ref. 8). Full Text (Free, PDF) www.bmj.sk.


Quantitative proteomic analysis of Giardia duodenalis assemblage A: A baseline for host, assemblage, and isolate variation.
Giardia duodenalis is a gastrointestinal protozoan parasite of vertebrates and is a species complex comprised of eight assemblages, with the zoonotic assemblage A one of two subtypes infective for humans. With increasing genomic and transcriptomic data publicly available through the centralized giardiaDB.org, we have quantitatively analyzed the proteomes of eight G. duodenalis assemblage A strains (seven A1 and one A2) to provide a proteomic baseline to complement the available data. A nonredundant total of 1197 subassemblage A1 proteins and 719 subassemblage A2 proteins were identified with an average of 770 proteins in each strain. The eight strains were also searched against both assemblage A genome sequences (subassemblage A1 and A2 genomes) and demonstrated subassemblage specific differences in protein identifications, especially for variable gene families. Substantial differences were observed in the numbers and abundance in the variable surface protein family, and two different variable surface protein expression profiles that were independent of host origin, subassemblage, or geographic origin. We hypothesize that this variation in surface antigen switching events may be related to karotype and chromosomal variation, which would indicate an assemblage-independent mechanism of diversity generation in G. duodenalis. All MS data have been deposited in the ProteomeXchange with identifier PXD001272 (http://proteomecentral.proteomexchange.org/dataset/PXD001272).


Modified FGF Hydrogel for Effective Axon Formation by Enhanced Regeneration of Myelin Sheath of Schwann Cells Using Rat Model.
An acute spinal cord injury (SCI) is a debilitating event for which there is no targeted or effective treatment. Previous studies have shown that fibroblast growth factor (bFGF) and Schwann cells (SC) exert a protective effect on the injured tissues. Because of their easy injectability and strength, hydrogels are considered to be ideal candidates for creating loadable tissues. However, the application and mechanism of bFGF-hydrogels have not been explored. We synthesized a new class of bFGF-hydrosol and evaluated its safety and biocompatibility in vitro and in vivo. Next, an SCI rat model was established to evaluate the effect of the hydrosol on an SCI by detecting various pro-inflammatory markers and evaluating the injury. The ability of hydrosol to promote axon formation was evaluated by detecting corresponding indexes, and its ability to promote remyelination was evaluated by detecting the corresponding indexes in Schwann cells. A novel in situ injectable hydrogel containing bFGF (HA-bFGF) was synthesized and found to have better biocompatibility than other gels. HA-bFGF helped to repair tissue damage after an SCI in vivo. Our mechanistic investigation also showed that HA-bFGF improved axon formation after an SCI by facilitating the regeneration of myelin sheath of Schwann cells. In this study, we found that HA-bFGF could promote neural restoration and tissue recovery after an SCI. Our results indicate that hydrogels loaded with bFGF can alleviate a spinal cord injury by promoting the remyelination of Schwann cells, reducing inflammation at the injured site, and ultimately promoting axon generation.


Evaluation of a risk assessment questionnaire used to target tuberculin skin testing in children.
Universal tuberculin skin testing of children has been shown to be costly and inefficient. In response, several authorities have recommended targeted screening based on epidemiological risk. In 1996, the New York City Department of Health (NYCDOH) developed questions to identify children who require a tuberculin skin test. To determine the sensitivity, specificity, and predictive validity of the NYCDOH tuberculosis risk assessment questionnaire. Prospective criterion standard study in which tuberculin skin tests and the NYCDOH questionnaire were administered simultaneously between August 1996 and January 1998. Specific questions asked about contact with a tuberculosis case, birth in or travel to endemic areas, regular contact with high-risk adults, and human immunodeficiency virus infection in the child. Ambulatory clinic in South Bronx, New York, NY. Consecutive sample of 2920 children aged 1 to 18 years. Sensitivity, specificity, positive and negative predictive values of the questionnaire, and odds ratio (OR) of reactive skin test results. The NYCDOH questionnaire identified 413 children (14%) as having at least 1 risk factor. Of these, 23 (5.6%) had a positive skin test result; 4 (0.16%) of the 2507 without risk factors had a positive result. Results for the full NYCDOH questionnaire were sensitivity, 85.2%; specificity, 86.0%; negative predictive value, 99.8%; positive predictive value, 5.4%; and OR, 35.2 (95% confidence interval, 12.1-102.4). The NYCDOH questionnaire is a valid instrument for identifying children for tuberculin skin testing.


Partial protection by lipoic acid against carboplantin-induced ototoxicity in rats.
To investigate the alterations in auditory brainstem evoked responses (ABRs) and the changes of carboplatin-induced ototoxicity in the cochlear oxidant/antioxidant systems and otoprotection by an antioxidant lipoate. Male wistar rats were divided into four groups and treated as follows: 1) vehicle (saline) control, 2) carboplatin (256 mg/kg, i.p.), 3) lipoate (100 mg/kg, i.p.), 4) lipoate + carboplatin. Post-treatment ABRs were performed after four days and rats were sacrificed with their cochleae harvested and analyzed. Carboplatin significantly elevated ABR threshold above the pretreatment thresholds. Lipoate+carboplatin treated rats showed decreased elevation of hearing threshold. Carboplatin significantly depleted cochlear reduced to oxizized glutathione (GSH/GSSG) ratio, whereas lipoate+carboplatin treatment increased GSH/GSSG ratio. Carboplatin significantly decreased cochlear copper zinc-superoxide dismutase (CuZn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and glutathione-S-transferase (GST) activities and enzyme protein expressions and a significant increase in Mn-SOD activity, protein expression and malondialdehyde (MDA) level. Cochlear antioxidant enzyme activities, enzyme protein expressions and MDA level were partially restored in lipoate+carboplatin treated rats, compared to carboplatin alone. Carboplatin-induced ototoxicity is related to impairment of cochlear antioxidant system and otoprotection conferred by lipoate is associated with partial sparing of the cochlear antioxidant defense system.


Peripheral vascular effects of nitroglycerin in a conscious rat model of heart failure.
The effects of intravenous nitroglycerin (NG; 2, 8, 32 micrograms/kg) on cardiocirculatory dynamics were evaluated in control normal (C) and chronically volume-overloaded [high-output heart failure (aortocaval fistula), HCO] conscious rats. Pressures were recorded in the left ventricle, the caudal artery, and the right atrium. Regional blood flows were determined by radioactive microsphere injection into the left ventricle with reference sampling from the caudal artery. Cardiac output (CO) was 289 ml . min-1 . kg in C and did not change with NG; however, in HCO systemic CO was decreased 31, 23, and 23% by NG from 350 ml . min-1 . kg. In both groups left ventricular end-diastolic pressure was reduced (C, 8.4-5.0; HCO, 19.8-12.7 mmHg); however, central venous pressure was reduced only in C (1.2-0.3 mmHg). During NG primarily at 2 and 8 micrograms/kg, arterial blood flow was lower and vascular resistance was higher in HCO compared with C in the following regions: kidney, ileum, jejunum, skin, heart, spleen, stomach, and testes, whereas no major differences were noted in the cerebellum, cerebrum, liver, or skeletal muscle. Thus acute NG infusion is a more potent regional vasodilator in C than in HCO. It is suggested that this difference is related to a more powerful NG-induced sympathetic reflex activation in the HCO group, which strongly attenuates the direct vasodilator effect of NG that was apparent in C.


Dietary patterns: biomarkers and chronic disease risk.
With increasing appreciation of the complexity of diets consumed by free-living individuals, there is interest in the assessment of the overall diet or dietary patterns in which multiple related dietary characteristics are considered as a single exposure. The 2 most frequently used methods to derive dietary patterns use (i) scores or indexes based on prevailing hypotheses about the role of dietary factors in disease prevention; and (ii) factors and clusters from exploration of available dietary data. A third method, a hybrid of the hypothesis-driven and data-driven methods, attempts to predict food combinations related to nutrients or biomarkers with hypothesized associations with particular health outcomes. Dietary patterns derived from the first 2 approaches have been examined in relation to nutritional and disease biomarkers and various health outcomes, and generally show the desirable dietary pattern to be consistent with prevalent beliefs about what constitutes a healthful diet. Results from observational studies suggest that the healthful dietary patterns were associated with significant but modest risk reduction (15%-30%) for all-cause mortality and coronary heart disease. Findings for various cancers have been inconsistent. The available randomized controlled intervention trials with a long-term follow-up to examine dietary patterns in relation to health outcome have generally produced null findings. Novel findings with the potential to change existing beliefs about diet and health relationships are yet to emerge from the dietary patterns research. The field requires innovation in methods to derive dietary patterns, validation of prevalent methods, and assessment of the effect of dietary measurement error on dietary patterns.


Psychopathology in paraneoplastic encephalopathy: an electroclinical observation.
The psychopathologic, electroclinical, and pathologic signs in a patient suffering from paraneoplastic encephalomyelopathy are discussed. The occurrence of the syndrome is stressed since this topic is scarcely mentioned in the psychiatric literature. If mental disturbances are particularly prominent, as is often the case in limbic involvement, they may lead to referral to a psychiatric ward and even diagnostic error.


Binding of FITC-labelled lectins to the gastrointestinal epithelium of the rat.
Biotechnology uses lectin genes to transfect into crop plants for protection against insects and nematodes. On the other hand, the information is limited on lectin-binding properties of cells in the gastrointestinal tract. Therefore, binding of a panel of FITC-labelled plant lectins to gastrointestinal cells of the rat was studied. In the stomach, cytoplasmic staining of parietal cells by PHA appeared to be due to glycoproteins attached to the tubulovesicles. PNA also stained the parietal cells, but only in the isthmus and neck regions, reacting with desialylated glycoproteins. WGA bound to the mucous neck cells with higher affinity than to the surface and foveolar mucous cells. The mucous cells were also stained by SNA-I, UEA-I and, less intensively, by LCA. Chief cells did not show detectable reaction with any of the applied lectins. Binding of PHA to gastric cells showed differences when compared with the results of in vivostudies. Small intestinal brush border was stained with UEA-I and SNA-I, the latter lectin also strongly stained the surface of small intestinal crypts. Both lectins reacted with the mucus of goblet cells. In the large intestine UEA-I and SNA-I stained the goblet cells at the base and upper part of the crypts, respectively. Accordingly, we provided evidences for the unique lectin-binding phenotype of the various segments of the gastrointestinal tract.


Geometrically invariant watermarking using feature points.
This paper presents a new approach for watermarking of digital images providing robustness to geometrical distortions. The weaknesses of classical watermarking methods to geometrical distortions are outlined first. Geometrical distortions can be decomposed into two classes: global transformations such as rotations and translations and local transformations such as the StirMark attack. An overview of existing self-synchronizing schemes is then presented. Theses schemes can use periodical properties of the mark, invariant properties of transforms, template insertion, or information provided by the original image to counter geometrical distortions. Thereafter, a new class of watermarking schemes using the image content is presented. We propose an embedding and detection scheme where the mark is bound with a content descriptor defined by salient points. Three different types of feature points are studied and their robustness to geometrical transformations is evaluated to develop an enhanced detector. The embedding of the signature is done by extracting feature points of the image and performing a Delaunay tessellation on the set of points. The mark is embedded using a classical additive scheme inside each triangle of the tessellation. The detection is done using correlation properties on the different triangles. The performance of the presented scheme is evaluated after JPEG compression, geometrical attack and transformations. Results show that the fact that the scheme is robust to these different manipulations. Finally, in our concluding remarks, we analyze the different perspectives of such content-based watermarking scheme.


Childhood trauma and insulin resistance in patients suffering from depressive disorders.
Insulin resistance (IR) is a metabolic dysfunction often co-morbid with major depressive disorder (MDD). The paths to development of MDD remain largely unspecified, highlighting a need for identification of risk factors. Here, we tested whether specific subscales of childhood trauma as well as family history of type-2 diabetes (Fam-Hx-Dm2) are risk factors for development of metabolic dysfunction and severity of depressive symptoms. We used a sample of 45 adults suffering from MDD that was well-characterized for insulin resistance and sensitivity as assessed by measures of fasting plasma glucose (FPG) plasma insulin (FPI) levels, body mass index (BMI), weight, homeostasis model assessment of insulin sensitivity (HOMA), Matsuda index as well as both glucose and insulin responses to oral glucose challenges. Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS-21). Physical, sexual and emotional abuse as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. First- or second-degree relatives with type-2 diabetes defined fam-Hx-DM2. Individuals reporting higher rates of emotional abuse were more likely to have greater IR as showed by elevated FPI levels and HOMA. No association was found with any of the other subscales of childhood trauma (e.g., physical abuse). Similarly, Fam-Hx-DM2 was associated with greater degree of IR as shown by elevated FPI, HOMA, but also FPG, weight and BMI. Moreover, we report a relationship and interaction between Fam-Hx-DM2 and emotional abuse on severity of depressive symptoms. Specifically, emotional abuse and Fam-HX-DM2 predicted severity of depressive symptoms at HDRS-21. Also, severity of depressive symptoms was greater with higher reported rates of emotional abuse but only in patients with negative Fam-Hx-Dm2. Individuals reporting higher emotional abuse and negative Fam-Hx-Dm2 also showed higher FPG levels. Conversely, individuals reporting higher emotional abuse and positive Fam-Hx-Dm2 showed higher FPI levels. This data suggest that Fam-Hx-Dm2 may define two different metabolic endophenotypes. Our findings suggest that Fam-HX-DM2 and emotional abuse represent separate risk factors for developing metabolic dysfunction (i.e.: IR) in patients suffering from MDD, and that the effects of emotional abuse on psychiatric illness may depend upon the personal characteristics, including Fam-Hx-DM2.


Continuous detection of extracellular ATP on living cells by using atomic force microscopy.
Atomic force microscopy is a powerful technique used to investigate the surface of living cells under physiological conditions. The resolution of the instrument is mainly limited by the softness of living cells and the interactions with the scanning tip (cantilever). Atomic force microscopy, in combination with myosin-functionalized cantilevers, was used in the detection of ATP concentrations in solution and on living cells. Functionally active tips were used to scan the surface of cells in culture and to show that the CFTR+ cell line (S9) had a basal surface ATP concentration that could be detected with atomic force microscopy (n = 10). ATP-dependent signals were not detectable in cells scanned with noncoated or heat-inactivated enzyme-coated tips (n = 9). Enzymatically active tips may serve as a model for future development of atomic force microscopy biosensors that can simultaneously detect topographical and biologically important compounds at the surface microenvironment of living cells.


Using PCs for effective case-mix based budgeting.
Precise statistical budgeting remains an underused cost-control technique in healthcare organizations, despite the increasing need for such techniques resulting from national movement toward prospective pricing and managed care. As revenues are capped, the use of precise case-mix based statistical budgeting to reduce unit costs has become one of the few strategies available to financial managers to assure profitability. The use of personal computers with database and spreadsheet software can facilitate effective case-mix based budgeting.


P50 variations in Behcet`s patients without neurologic findings.
In the present study, subclinical lesion involvement was investigated using the P50 component in Behcet`s patients without neurological manifestation. We performed this clinical research in Erciyes University, Faculty of Medicine between December 2000 and November 2001. The studies were carried out on 18 Behcet`s patients without neurologic findings and 18 volunteers for control. Standard Ag/AgCl electrodes in plastic cups were used for monopolar EEG derivations. They were attached with electrode paste and tape at the Cz (vertex) according to the 10-20 system. The auditory stimuli were delivered in pairs. The P50 waves, which may be taken from approximately 50 msec from the stimuli, were collected by computer system. Amplitudes and latencies of the P50 components were measured in the same system. This study showed that the suppression of P50 responses performed by the test stimuli, was significantly more decreased in Behcet`s patients than the control subjects. The decrease of the suppression of the auditory P50 response to repeated stimuli reflects a deficit in the central nervous system`s ability, such as attention, cognition, and sensory input in Behcet`s patients and can be used as a neurophysiological marker in subclinical lesions in these patients.


Isocaloric intake of a high-fat diet modifies adiposity and lipid handling in a sex dependent manner in rats.
High-fat (HF) diet feeding usually leads to hyperphagia and body weight gain, but macronutrient proportions in the diet can modulate energy intake and fat deposition. The mechanisms of fat accumulation and mobilization may differ significantly between depots, and gender can also influence these differences. To investigate, in rats of both sexes, the effect of an isocaloric intake of a diet with an unbalanced proportion of macronutrients on fatty acid composition of visceral and subcutaneous adipose tissues and how this is influenced by both dietary fatty acids and levels of proteins involved in tissue lipid handling. Eight-week-old Wistar rats of both sexes were fed a control diet (3% w/w fat) or high-fat diet (30% w/w fat) for 14 weeks. Fatty acid composition was analyzed by gas-chromatography and levels of LPL, HSL, α2-AR, β3-AR, PKA and CPT1 were determined by Western blot. The HF diet did not induce hyperphagia or body weight gain, but promoted an increase of adiposity index only in male rats. HF diet produced an increase of the proportion of MUFA and a decrease in that of PUFA in both adipose depots and in both sexes. The levels of proteins involved in the adrenergic control of the lipolytic pathway increased in the gonadal fat of HF females, whereas LPL levels increased in the inguinal fat of HF males and decreased in that of females. Sexual dimorphism in adiposity index reflects a differential sex response to dietary fatty acid content and could be related to the levels of the proteins involved in tissue lipid management.


Detection and clinical significance of CEACAM5 methylation in colorectal cancer patients.
Colorectal cancer (CRC) is a globally common cancer, and the serum carcinoembryonic antigen (sCEA) is widely applied as a diagnostic and prognostic tumor marker in CRC. This study aimed to elucidate the mechanism of CEA expression and corresponding clinical features to improve prognostic assessments. In CRC cells, hypomethylation of the CEACAM5 promoter enhanced CEA expression in HCT116 and HT29 cells with 5-aza-2'-deoxycytidine (5-Aza-dC) treatment. Our clinical data indicated that 64.7% (101/156) of CRC patients had an sCEA level above the normal range, and 76.2% (77/101) of those patients showed a lower average CpG methylation level of the CEACAM5 promoter. The methylation analysis showed that both CRC cell lines and patient samples shared the same critical methylation CpG regions at -200 to -500 and -1000 to -1400 bp of the CEACAM5 promoter. Patients with hypermethylation of the CEACAM5 promoter showed features of a BRAF mutation, TGFB2 mutation, microsatellite instability-high, and preference for right-sided colorectal cancer and peritoneal seeding presentation that had a similar clinical character to the consensus molecular subtype 1 (CMS1) of colorectal cancer. Additionally, hypermethylation of the CEACAM5 promoter combined with evaluated sCEA demonstrated the worst survival among the patients. Therefore, the methylation status of the CEACAM5 promoter also served as an effective biomarker for assessing disease prognosis. Results indicated that DNA methylation is a major regulatory mechanism for CEA expression in colorectal cancer. Moreover, our data also highlighted that patients in a subgroup who escaped from inactivation by DNA methylation had distinct clinical and pathological features and the worst survival.


Age-related differences in working memory and force control under dual-task conditions.
The aim of this study was to investigate the relationship between force control and cognitive performance under dual-task conditions in younger (18-22 years) and older adults (65-77 years). Cognitive (n-back test) and motor performance (force-tracking) was measured independently and simultaneously. Results indicated overall age-related differences for the n-back and the force-tracking task. Age-related differences increased during dual-task conditions. While younger adults exhibited no decrease in cognitive or motor performance during dual-task conditions, older adults showed a decrease in motor and cognitive performance. Additionally, when older adults made an error in the cognitive task they tended to show greater variability in the force-tracking task. These results suggest that cognitive motor deficits are responsible for older adults' performance decrements under dual-task conditions.


On-pump and off-pump coronary artery bypass grafting in the elderly: predictors of adverse outcome.
To establish the role that coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) may have in improving perioperative outcomes of patients 70 years of age and older. Coronary revascularization in elderly patients is associated with morbidity and mortality rates higher than those observed in younger patients. The impact of CABG without CPB on perioperative outcomes has not been clearly established. This retrospective, nonrandomized study consisted of 1,872 CABG patients. Of these, 1389 underwent CABG with CPB (CPB group) and 483 patients underwent CABG without CPB (off-pump group). Preoperative variables and outcomes were compared between the two groups. Multivariate logistic regression analysis was used to identify independent predictors of mortality, stroke, and adverse outcome. Demographics, Canadian Cardiovascular Society staging, operative priority, and other preoperative variables were comparable between the two groups. The prevalence of previous myocardial infarction was higher in the CPB group (62.6% vs 56.7%; p < 0.005), whereas the prevalence of calcified aorta and preoperative renal failure were higher in the off-pump group (5.4% vs 9.5%; p = 0.04 and 1.7% vs 3.3%; p = 0.04, respectively). Although the graft/patient ratio was higher in the CPB group (3.4 vs 1.9), these patients displayed more extensive coronary artery involvement. At univariate analysis, patients in the off-pump group had a higher rate of freedom from complications (88.2% vs 81.3%; p < 0.005) and a lower incidence of stroke (2.1% vs 4.2%; p = 0.034) than patients in the CPB group. Although there was a trend for a higher actual mortality in the off-pump group (4.8% vs 3.7%; p = ns), the risk adjusted mortality in this group was lower (1.9% vs 2.1%). Multivariate analysis showed that while the use of CPB correlated independently with an increased risk of overall complications, it was not associated with a higher probability of death or stroke. This investigation suggests that elderly patients undergoing CABG may benefit from off-pump revascularization, as the use of CPB correlated independently with an increased risk of overall complications. However, CPB did not emerge as an independent predictor of death or stroke at multivariate analysis.


Development and Validation of a Prognostic Nomogram to Guide Decision-Making for High-Grade Digestive Neuroendocrine Neoplasms.
The objective of this study was to develop and validate a nomogram to predict 1-year overall survival (OS) and 2-year OS in patients with high-grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy. We performed a retrospective analysis of 223 patients with NENs of the gut and hepato-biliary-pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one. The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C-index was 0.761 for OS, and the bias-corrected C-index was 0.744. Predictions correlated well with observed 1-year and 2-year outcomes (judged by eye). The area under the time-dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log-rank p < .001). The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials. The high-grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum-based chemotherapy may not bring clinical benefit for the low-risk patients.


Using High Content Imaging to Quantify Target Engagement in Adherent Cells.
Quantitating the interaction of small molecules with their intended protein target is critical for drug development, target validation and chemical probe validation. Methods that measure this phenomenon without modification of the protein target or small molecule are particularly valuable though technically challenging. The cellular thermal shift assay (CETSA) is one technique to monitor target engagement in living cells. Here, we describe an adaptation of the original CETSA protocol, which allows for high throughput measurements while retaining subcellular localization at the single cell level. We believe this protocol offers important advances to the application of CETSA for in-depth characterization of compound-target interaction, especially in heterogeneous populations of cells.


Determinants of financial performance of home-visit nursing agencies in Japan.
Japan has the highest aging population in the world and promotion of home health services is an urgent policy issue. As home-visit nursing plays a major role in home health services, the Japanese government began promotion of this activity in 1994. However, the scale of home-visit nursing agencies has remained small (the average numbers of nursing staff and other staff were 4.2 and 1.7, respectively, in 2011) and financial performance (profitability) is a concern in such small agencies. Additionally, the factors related to profitability in home-visit nursing agencies in Japan have not been examined multilaterally and in detail. Therefore, the purpose of the study was to examine the determinants of financial performance of home-visit nursing agencies. We performed a nationwide survey of 2,912 randomly selected home-visit nursing agencies in Japan. Multinomial logistic regression was used to clarify the determinants of profitability of the agency (profitable, stable or unprofitable) based on variables related to management of the agency (operating structure, management by a nurse manager, employment, patient utilization, quality control, regional cooperation, and financial condition). Among the selected home-visit nursing agencies, responses suitable for analysis were obtained from 1,340 (effective response rate, 46.0%). Multinomial logistic regression analysis showed that both profitability and unprofitability were related to multiple variables in management of the agency when compared to agencies with stable financial performance. These variables included the number of nursing staff/rehabilitation staff/patients, being owned by a hospital, the number of cooperative hospitals, home-death rate among terminal patients, controlling staff objectives by nurse managers, and income going to compensation. The results suggest that many variables in management of a home-visit nursing agency, including the operating structure of the agency, regional cooperation, staff employment, patient utilization, and quality control of care, have an influence in both profitable and unprofitable agencies. These findings indicate the importance of consideration of management issues in achieving stable financial performance in home-visit nursing agencies in Japan. The findings may also be useful in other countries with growing aging populations.


Vax2 regulates retinoic acid distribution and cone opsin expression in the vertebrate eye.
Vax2 is an eye-specific homeobox gene, the inactivation of which in mouse leads to alterations in the establishment of a proper dorsoventral eye axis during embryonic development. To dissect the molecular pathways in which Vax2 is involved, we performed a transcriptome analysis of Vax2(-/-) mice throughout the main stages of eye development. We found that some of the enzymes involved in retinoic acid (RA) metabolism in the eye show significant variations of their expression levels in mutant mice. In particular, we detected an expansion of the expression domains of the RA-catabolizing enzymes Cyp26a1 and Cyp26c1, and a downregulation of the RA-synthesizing enzyme Raldh3. These changes determine a significant expansion of the RA-free zone towards the ventral part of the eye. At postnatal stages of eye development, Vax2 inactivation led to alterations of the regional expression of the cone photoreceptor genes Opn1sw (S-Opsin) and Opn1mw (M-Opsin), which were significantly rescued after RA administration. We confirmed the above described alterations of gene expression in the Oryzias latipes (medaka fish) model system using both Vax2 gain- and loss-of-function assays. Finally, a detailed morphological and functional analysis of the adult retina in mutant mice revealed that Vax2 is necessary for intraretinal pathfinding of retinal ganglion cells in mammals. These data demonstrate for the first time that Vax2 is both necessary and sufficient for the control of intraretinal RA metabolism, which in turn contributes to the appropriate expression of cone opsins in the vertebrate eye.


The National Asthma Campaign Manchester Asthma and Allergy Study.
The NACManchester Asthma and Allergy Study is a prospective study of the development of asthma and allergies in childhood. The subjects (995 children at age 3 years) were recruited in utero by screening parents in the antenatal clinic using skin prick testing and a questionnaire regarding allergic diseases. Children were assigned to risk groups according to parental atopic status (high risk, both parents atopic; medium risk, one parent atopic; low risk, neither parent atopic). A subgroup of those at high risk (with no pets in the home) was randomized to stringent environmental control (allergen impermeable covers for the parental and infant bed, hot washing of bedding weekly, HEPA vacuum cleaner, hard floor for the nursery), and the remainder followed a normal regime. The children have been followed prospectively. The environmental influences are very clearly defined. Measurements of environmental exposures include levels of house dust mite; cat and dog allergens during pregnancy and early life; pet ownership and exposure; childcare arrangements; number of siblings; vaccination uptake; thorough dietary questionnaire; and endotoxin exposure. Further unique objective outcome in the cohort is the assessment of lung function in preschool children using specific airways resistance, which at age 3 years clearly reflects both genetic and environmental influences.


Nitrite and nitrate pharmacokinetics in the dog, sheep, and pony.
Elimination kinetics of nitrite and nitrate in the dog, sheep, and pony were determined. The elimination half-lives of nitrite were 0.499, 0.475, and 0.566 hours in the dog, sheep, and pony, respectively; those of nitrate were 44.681, 4.233, and 4.821 hours. Apparent specific volumes of distribution (V'd) of nitrite were variable among the 3 species--1,623.7 ml/kg in the dog, 278.0 ml/kg in the sheep, and 191.6 ml/kg in the pony. The V'd of nitrate were less varied--dog, 238.5 ml/kg; sheep, 291.1 ml/kg; and pony, 209.3 ml/kg. In the in vitro studies on protein binding in canine plasma, the extent of nitrite-protein binding varied directly with concentrations of 5 to 25 mug of NO2 minus/ml (4.5 to 13.6% bound), but inversely with concentrations of 50 to 100 mug of NO2 minus/ml (9.8 to 8.8% bound). Less than 1% of nitrate was bound to canine plasma at equimolar concentrations (5 to 100 mug of NO3 minus/ml).


Serotonin uptake by bovine pulmonary artery endothelial cells in culture. I. Characterization.
Serotonin (5-HT) uptake by bovine pulmonary artery endothelial cells in culture was measured at 5-HT concentrations of 1.5 X 10(-8) to 10(-3) M. The uptake increased linearly at concentrations of 10(-5) to 10(-3) M 5-HT, and the slope for uptake was 1.276 X 10(6) pmol 5-HT X 10(6) cells-1 X 30 min-1 X M concentration-1. The slope for uptake at 5-HT concentrations less than 10(-7) M was 7.10 X 10(6) pmol X 10(6) cells-1 X 30 min-1 X M concentration-1. With subtraction of the slope for linear uptake obtained at high concentrations of 5-HT from total uptake of 5-HT, a curve showing saturable uptake at concentrations greater than 10(-6) to 10(-5) M was obtained. Lineweaver-Burk analysis of the data yielded a saturated value of high-affinity transport of 6.25 pmol X 10(6) cells-1 X 30 min-1 and a Km of 10(-6) M. At 5-HT concentrations of 1.5 X 10(-8) to 5 X 10(-7) M, uptake was inhibited 75-80% by exposure to 4 degrees C or by absence of sodium in the medium; absence of sodium did not affect uptake at 5-HT concentrations greater than 10(-5) M, and 4 degrees C was less effective in inhibiting uptake at high 5-HT concentrations. Imipramine markedly inhibited uptake at low, but not at high, 5-HT concentrations. Ouabain only partially inhibited 5-HT uptake, but inhibition was more pronounced at low 5-HT concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)


Investigation of ( S)-(-)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase.
The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of ( S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (minimum inhibitory concentrations (MICs) = 0.096-6.2 μM) but is inactive against nontuberculosis mycobacteria and Gram-positive and Gram-negative pathogens (MICs > 1000 μM). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a Ki of approximately 1 μM through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosyl-l-methionine (SAM) to generate the toxic metabolite 5'-deoxyadenosine. Cell studies demonstrate acidomycin selectively accumulates in M. tuberculosis providing a mechanistic basis for the observed antibacterial activity. The development of spontaneous resistance by M. tuberculosis to acidomycin was difficult, and only low-level resistance to acidomycin was observed by overexpression of BioB. Collectively, the results provide a foundation to advance acidomycin and highlight BioB as a promising target.


Effect of commercial marinades on the mutagenic activity, sensory quality and amount of heterocyclic amines in chicken grilled under different conditions.
The effect of processing conditions on the mutagenic activity and sensory quality of everyday food was studied by investigating grilled chicken samples seasoned with four different marinades and grilled at temperatures of about 110, 170 and 220 degrees C. The amounts of the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5,-b]pyridine were determined only in samples grilled at 220 degrees C, using a gas chromatography-mass spectrometry technique with negative-ion chemical ionization. Sensory quality was determined using the extended ranking test method and the mutagenic activity using the Ames Salmonella assay. At 220 degrees C one of the marinades decreased the mutagenic activity in the chicken samples compared with the unseasoned control or samples treated with the other marinades. Great variations, without any clear correlation with mutagenicity, were observed in the amounts of heterocyclic amines between chicken samples treated with the same or different marinades. At the grilling temperatures of 170 degrees C and 110 degrees C the mutagenic activities of the chicken samples were lower or they were non-mutagenic. There was no correlation between mutagenic activity and sensory quality of the products. The samples with high mutagenic activity were ranked to be as good as the samples with lower or no mutagenicity. The results show that it is possible to prepare grilled products with reduced mutagenicity without compromising their sensory quality. It was also evident that marinades can have a reducing effect on the mutagenicity of grilled chicken. Variation observed in the amounts of heterocyclic amines between equivalent products makes it difficult to estimate their concentration in everyday foods.


The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations.
The aim of this retrospective study was to determine the prevalence of lysosomal storage disorders (LSDs) in the Czech Republic. The data on cases diagnosed between 1975 and 2008 were collected and analyzed. The overall prevalence of LSDs in the Czech population (12.25 per 100,000) is comparable to that reported for the countries with well-established and advanced diagnostics of LSDs such as the Netherlands (14 per 100,000), Australia (12.9 per 100,000) and Italy (12.1 per 100,000). Relatively higher prevalence of LSDs was reported in the north of Portugal (25 per 100,000). Thirty-four different LSDs were diagnosed in a total of 478 individuals. Gaucher disease was the most frequent LSD with a birth prevalence of 1.13 per 100,000 births. The most frequent LSD groups were lipidoses, mucopolysaccharidoses, and neuronal ceroid lipofuscinoses, with combined prevalences of 5.0, 3.72, and 2.29 per 100,000 live births, respectively. Glycoproteinoses (0.57 per 100,000 live births), glycogenosis type II (0.37), and mucolipidoses (0.31) rarely occur in the Czech population, and a range of other LSDs have not been detected at all over the past three decades. Knowledge of the birth prevalence and carrier frequency of particular disorders is important in genetic counselling for calculation of the risk for the disorder in the other members of affected families. Earlier diagnosis of these disorders will permit timely intervention and may also result in lowering of the number of newborns with LSDs.


Risk of secondary osteoporosis due to lobular cholestasis in non-cirrhotic primary biliary cholangitis.
It remains unclear whether primary biliary cholangitis (PBC) represents a risk factor for secondary osteoporosis. A case-control study was conducted to examine bone mineral density and bone turnover markers in middle-aged postmenopausal PBC patients without liver cirrhosis. We compared the incidence of low bone mineral density between propensity-score matched subgroups of PBC patients and healthy controls and investigated the mechanisms underlying unbalanced bone turnover in terms of the associations between bone turnover markers and PBC-specific histological findings. Our analysis included 128 consecutive PBC patients, all postmenopausal women aged in their 50s or 60s, without liver cirrhosis or fragility fracture at the time of PBC diagnosis. The prevalence of osteoporosis was significantly higher in the PBC group than in the control group (26% vs 10%, P = 0.015, the Fisher exact probability test). In most PBC patients (95%), the level of bone-specific alkaline phosphatase was above the normal range, indicating increased bone formation. On the other hand, the urine type I collagen-cross-linked N-telopeptide showed variable levels among our PBC patients, indicating unbalanced bone resorption. Advanced fibrosis was associated with low bone turnover. Lobular cholestasis, evaluated as aberrant keratin 7 expression in hepatocytes, showed significant negative correlations with bone formation and resorption, indicating low bone turnover. Our results show that, compared with healthy controls, even non-cirrhotic PBC patients have significantly higher risk of osteoporosis. Moreover, lobular cholestasis was associated with low bone turnover, suggesting this feature of PBC may itself cause secondary osteoporosis in PBC patients.


The effects of education on anxiety levels in patients receiving chemotherapy for the first time: an integrative review.
Anxiety is one of the most common symptoms experienced by patients receiving their first chemotherapy treatment. Improper prevention and management of anxiety can lead to poor psychosocial outcomes, dissatisfaction with care, and decreased adherence to treatment. A review of the literature was conducted to analyze the effectiveness of patient education at decreasing anxiety. Consistencies were found throughout the literature regarding patient education for this population. Information regarding side effects of treatment, side-effect management strategies, and orientation to the infusion center are the most important topics of education that reduce anxiety. In addition, education performed by nurses before the first chemotherapy infusion in a quiet environment is most effective. Integration of effective patient education programs improves holistic care by increasing emphasis on psychosocial aspects of oncology.


Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation.
To compare the incidence and severity of postoperative complications after oesophagectomy for carcinoma of the oesophagus and gastro-oesophageal junction (GOJ) after randomized accrual to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT). Neoadjuvant therapy improves long-term survival after oesophagectomy. To date, evidence is insufficient to determine whether combined nCT, or nCRT alone, is the most beneficial. Patients with carcinoma of the oesophagus or GOJ, resectable with a curative intention, were enrolled in this multicenter trial conducted at seven centres in Sweden and Norway. Study participants were randomized to nCT or nCRT followed by surgery with two-field lymphadenectomy. Three cycles of cisplatin/5-fluorouracil was administered in all patients, while 40 Gy of concomitant radiotherapy was administered in the nCRT group. Of the randomized 181 patients, 91 were assigned to nCT and 90 to nCRT. One-hundred-and-fifty-five patients, 78 nCT and 77 nCRT, underwent resection. There was no statistically significant difference between the groups in the incidence of surgical or nonsurgical complications (P-value = 0.69 and 0.13, respectively). There was no 30-day mortality, while the 90-day mortality was 3% (2/78) in the nCT group and 6% (5/77) in the nCRT group (P = 0.24). The median Clavien-Dindo complication severity grade was significantly higher in the nCRT group (P = 0.001). There was no significant difference in the incidence of complications between patients randomized to nCT and nCRT. However, complications were significantly more severe after nCRT. The trial was registered in the Clinical Trials Database (registration number NCT01362127).


Eyeblink Conditioning in Schizophrenia: A Critical Review.
There is accruing evidence of cerebellar abnormalities in schizophrenia. The theory of cognitive dysmetria considers cerebellar dysfunction a key component of schizophrenia. Delay eyeblink conditioning (EBC), a cerebellar-dependent translational probe, is a behavioral index of cerebellar integrity. The circuitry underlying EBC has been well characterized by non-human animal research, revealing the cerebellum as the essential circuitry for the associative learning instantiated by this task. However, there have been persistent inconsistencies in EBC findings in schizophrenia. This article thoroughly reviews published studies investigating EBC in schizophrenia, with an emphasis on possible effects of antipsychotic medication and stimulus and analysis parameters on reports of EBC performance in schizophrenia. Results indicate a consistent finding of impaired EBC performance in schizophrenia, as measured by decreased rates of conditioning, and that medication or study design confounds do not account for this impairment. Results are discussed within the context of theoretical and neurochemical models of schizophrenia.


Coupling DNA barcodes and exon-capture to resolve the phylogeny of Turridae (Gastropoda, Conoidea).
Taxon sampling in most phylogenomic studies is often based on known taxa and/or morphospecies, thus ignoring undescribed diversity and/or cryptic lineages. The family Turridae is a group of venomous snails within the hyperdiverse superfamily Conoidea that includes many undescribed and cryptic species. Therefore 'traditional' taxon sampling could constitute a strong risk of undersampling or oversampling Turridae lineages. To minimize potential biases, we establish a robust sampling strategy, from species delimitation to phylogenomics. More than 3,000 cox-1 "barcode" sequences were used to propose 201 primary species hypotheses, nearly half of them corresponding to species potentially new to science, including several cryptic species. A 110-taxa exon-capture tree, including species representatives of the diversity uncovered with the cox-1 dataset, was build using up to 4,178 loci. Our results show the polyphyly of the genus Gemmula, that is split into up to 10 separate lineages, of which half would not have been detected if the sampling strategy was based only on described species. Our results strongly suggest that the use of blind, exploratory and intensive barcode sampling is necessary to avoid sampling biases in phylogenomic studies.


The psychosocial impact of Klinefelter syndrome and factors influencing quality of life.
There is considerable information regarding the medical and cognitive aspects of Klinefelter syndrome yet little research regarding its psychosocial impact. This study investigates the personal impact of Klinefelter syndrome and the influence of age at diagnosis, clinical, social, and demographic factors on adult quality of life outcomes. Men from across Australia, diagnosed with KS at different ages, were recruited through multiple sources. Participants completed a questionnaire assessing subjective well-being, body image, self-esteem, mental health, social support, and general health. Eighty-seven individuals self-completed the questionnaire. All outcomes were much poorer for the study population than for the general male population. Individuals diagnosed later in life reported many of the same symptoms as those diagnosed at younger ages. Employment status, social support, and phenotypic features were the strongest predictors of psychosocial outcomes. Age at diagnosis was not as influential because it did not correlate with phenotypic severity score. This is the first quantitative study to show Klinefelter syndrome has a significant personal impact. Men diagnosed with Klinefelter syndrome later in life reported similar difficulties as those at younger ages, suggesting that they would benefit from early detection and intervention. Understanding factors influencing this can assist in providing adequate services to individuals with Klinefelter syndrome, their partners, families, and the health professionals caring for them.


Biodiversity improves water quality through niche partitioning.
Excessive nutrient loading of water bodies is a leading cause of water pollution worldwide, and controlling nutrient levels in watersheds is a primary objective of most environmental policy. Over the past two decades, much research has shown that ecosystems with more species are more efficient at removing nutrients from soil and water than are ecosystems with fewer species. This has led some to suggest that conservation of biodiversity might be a useful tool for managing nutrient uptake and storage, but this suggestion has been controversial, in part because the specific biological mechanisms by which species diversity influences nutrient uptake have not been identified. Here I use a model system of stream biofilms to show that niche partitioning among species of algae can increase the uptake and storage of nitrate, a nutrient pollutant of global concern. I manipulated the number of species of algae growing in the biofilms of 150 stream mesocosms that had been set up to mimic the variety of flow habitats and disturbance regimes that are typical of natural streams. Nitrogen uptake rates, as measured by using (15)N-labelled nitrate, increased linearly with species richness and were driven by niche differences among species. As different forms of algae came to dominate each unique habitat in a stream, the more diverse communities achieved a higher biomass and greater (15)N uptake. When these niche opportunities were experimentally removed by making all of the habitats in a stream uniform, diversity did not influence nitrogen uptake, and biofilms collapsed to a single dominant species. These results provide direct evidence that communities with more species take greater advantage of the niche opportunities in an environment, and this allows diverse systems to capture a greater proportion of biologically available resources such as nitrogen. One implication is that biodiversity may help to buffer natural ecosystems against the ecological impacts of nutrient pollution.


[Aphakia and mesopic vision (author's transl)].
The results of investigations on the twilight vision of aphakic eyes are given. In the daylight seeing range all the subjects had satisfactory visual acuity, whereas in the mesopic range, on corresponding tests, definite difficulties were recognisable for a large proportion of the subjects.


Investigating the relationship between grape cell wall polysaccharide composition and the extractability of phenolic compounds into Shiraz wines. Part I: Vintage and ripeness effects.
Phenolic compounds play an important role in colour stability and sensory properties of red wine. This study evaluated berry skin cell wall composition and how this influences grape and wine phenolics at different ripeness levels (21°Brix, 23°Brix, and 25°Brix) over two consecutive vintages. The vintage effect was highly significant, especially in the pectin fraction of the grape cell walls and affected the concentrations of certain phenolics extracted. The climatic variance between the seasons might have influenced the differences observed in the grape cell wall compositions. Firstly, a higher grape and wine phenolic content, especially in polymeric phenols, was found in 2015 wines. Additionally, grape berry cell walls, especially at the earliest stages of ripening, were found to be more intact in 2015 than in 2016. Thus, a possible relationship was found between the degree of berry intactness, especially for pectin-rich components, and the corresponding phenolic extractability during the winemaking.


Positive versus negative modulation of different endogenous chemokines for CC-chemokine receptor 1 by small molecule agonists through allosteric versus orthosteric binding.
7 transmembrane-spanning (7TM) chemokine receptors having multiple endogenous ligands offer special opportunities to understand the molecular basis for allosteric mechanisms. Thus, CC-chemokine receptor 1 (CCR1) binds CC-chemokine 3 and 5 (CCL3 and CCL5) with K(d) values of 7.3 and 0.16 nm, respectively, as determined in homologous competition binding assays. However, CCL5 appears to have a >10,000-fold lower affinity in competition against (125)I-CCL3. Mutational mapping revealed that CCL3 and CCL5 both are strongly affected by systematic truncations of the N-terminal extension, whereas only CCL5 and not CCL3 activation is affected by substitutions in the main ligand binding pocket including the conserved GluVII:06 anchor point. A series of metal ion chelator complexes were found to act as full agonists on CCR1 and to be critically affected by the same substitutions in the main ligand binding pocket as CCL5 but not by mutations in the extracellular domain. In agreement with the overlapping binding sites, the small non-peptide agonists displaced radiolabeled CCL5 with high affinity. Interestingly, the same compounds acted as allosteric enhancers of the binding of CCL3, with which they did not overlap in binding site, leading to an increased B(max) and affinity of this chemokine mainly due to an increased association rate. It is concluded that a small molecule agonist through binding deep in the main ligand binding pocket can act as an allosteric enhancer for one endogenous chemokine and at the same time as a competitive blocker of the binding of another endogenous chemokine.


MicroRNA function and dysregulation in bone tumors: the evidence to date.
Micro ribonucleic acids (miRNAs) are small non-coding RNA segments that have a role in the regulation of normal cellular development and proliferation including normal osteogenesis. They exert their effects through inhibition of specific target genes at the post-transcriptional level. Many miRNAs have altered expression levels in cancer (either increased or decreased depending on the specific miRNA). Altered miRNA expression profiles have been identified in several malignancies including primary bone tumors such as osteosarcoma and Ewing's sarcoma. It is thought that they may function as tumor suppressor genes or oncogenes and hence when dysregulated contribute to the initiation and progression of malignancy. miRNAs are also thought to have a role in the development of bone metastases in other malignancies. In addition, evidence increasingly suggests that miRNAs may play a part in determining the response to chemotherapy in the treatment of osteosarcoma. These molecules are readily detectable in tissues, both fresh and formalin fixed paraffin embedded and, more recently, in blood. Although there are fewer published studies regarding circulating miRNA profiles, they appear to reflect changes in tissue expression. Thus miRNAs may serve as potential indicators of disease presence but more importantly, may have a role in disease characterization or as potential therapeutic targets. This review gives a brief overview of miRNA biochemistry and explores the evidence to date implicating these small molecules in the pathogenesis of bone tumors.


Prospects for the therapeutic use of antigene oligonucleotides.
An outgrowth of classic nucleic acid interaction studies, oligonucleotide-directed triple helix formation is a unique method for creating highly specific chemical ligands that recognize and bind to particular sequences of duplex DNA. Under permissive conditions, these oligonucleotide-based compounds can approach or exceed the binding affinity and sequence specificity of natural DNA-binding proteins. Triple helix recognition has been found to be useful in certain cell-free applications including precise chromosome fragmentation. It has been proposed that such oligonucleotides could also form the basis for gene-targeted (antigene) drugs that might repress transcription from undesired genes in living cells. However, current strategies for oligonucleotide-directed triple helix formation suffer from important constraints involving requirements for stabilizing binding conditions, restrictions on permitted target sequences, and inefficient nuclear delivery of oligonucleotides. Implementation of oligonucleotide-directed triple helix formation as a viable approach to cancer therapy must therefore await clever solutions to a series of fascinating problems.