The effect of estrone-progesterone treatment on cell proliferation kinetics of hormone-dependent GR mouse mammary tumors.
Hormone-dependent mammary tumors were induced in virgin GR mice by treatment with estrone and progesterone. Discontinuation of hormonal treatment was followed by regression of the tumor. This response to hormone treatment was also observed in the first transplant generation in inbred syngeneic hosts, but after several transplantations the tumor growth became hormone independent. The hormone dependence of the primary tumors and tumors after a single transplantation was demonstrated by growth curves. Furthermore, the cell proliferation kinetics has been investigated in a growing as well as in a regressing hormone-dependent tumor after a single transplantation from the same primary tumor. The experimental data consist of growth curves, percentage-labeled mitoses curves, and labeling indices. Since these data do not contain information concerning the localization of the cell loss in the cell cycle, they were analyzed by a computer method based on three mathematical models differing in respect to the mode of cell loss. All three models gave approximately the same estimates of the cell kinetic parameters in the growing as well as the regressing tumor. The results for the growing, hormone-dependent tumor showed a growth fraction of 62%, a cell production rate of 3.4%/hr, and a cell loss rate of 2.3%/hr. Regression of the tumor after hormonal deprivation was accompanied by a decrease in growth fraction to 18% and a decrease in the cell production rate to 0.9%/hr, while the cell loss rate was unchanged at 2.8%/hr. Furthermore, the discontinuation of hormonal treatment introduced an increase in the mean transit time of the cell cycle, particularly in the mean transit time of the G1 phase. The results might indicate that estrone and progesterone treatment stimulated growth of hormone-dependent GR mouse mammary tumors mainly by an increase of growth fraction and cell production rate.


Pulmonary hypertension surveillance: United States, 2001 to 2010.
Pulmonary hypertension (PH) is an uncommon but progressive condition, and much of what we know about it comes from specialized disease registries. With expanding research into the diagnosis and treatment of PH, it is important to provide updated surveillance on the impact of this disease on hospitalizations and mortality. This study, which builds on previous PH surveillance of mortality and hospitalization, analyzed mortality data from the National Vital Statistics System and data from the National Hospital Discharge Survey between 2001 and 2010. PH deaths were identified using International Classification of Diseases, Tenth Revision codes I27.0, I27.2, I27.8, or I27.9 as any contributing cause of death on the death certificate. Hospital discharges associated with PH were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes 416.0, 416.8, or 416.9 as one of up to seven listed medical diagnoses. The decline in death rates associated with PH among men from 1980 to 2005 has reversed and now shows a significant increasing trend. Similarly, the death rates for women with PH have continued to increase significantly during the past decade. PH-associated mortality rates for those aged 85 years and older have accelerated compared with rates for younger age groups. There have been significant declines in PH-associated mortality rates for those with pulmonary embolism and emphysema. Rates of hospitalization for PH have increased significantly for both men and women during the past decade; for those aged 85 years and older, hospitalization rates have nearly doubled. Continued surveillance helps us understand and address the evolving trends in hospitalization and mortality associated with PH and PH-associated conditions, especially regarding sex, age, and race/ethnicity disparities.


Acoustic Analysis of Voice in Singers: A Systematic Review.
Singers are vocal athletes having specific demands from their voice and require special consideration during voice evaluation. Presently, there is a lack of standards for acoustic evaluation in them. The aim of the present study was to systematically review the available literature on the acoustic analysis of voice in singers. A systematic review of studies on acoustic analysis of voice in singers (PubMed/MEDLINE, CINAHL, Scopus, ProQuest, Cochrane, Ovid, Science Direct, and Shodhganga) was carried out. Key words based on PIO (population-investigation-outcome) were used to develop search strings. Titles and abstracts were screened independently, and appropriate studies were read in full for data extraction. Of the 895 studies, 26 studies met the inclusion criteria. Great variability was noted in the instruments and task used. Different acoustic measures were employed, such as fundamental frequency, perturbation, cepstral, spectral, dysphonia severity index, singing power ratio, and so forth. Overall, a great heterogeneity was noted regarding population, tasks, instruments, and parameters. There is a lack of standardized criteria for the evaluation of singing voice. In order to implement acoustic analysis as a part of comprehensive voice evaluation exclusively for singers, there is a certain need for methodical sound studies.


Efficacy of customised foot orthoses in the treatment of Achilles tendinopathy: study protocol for a randomised trial.
Achilles tendinopathy is a common condition that can cause marked pain and disability. Numerous non-surgical treatments have been proposed for the treatment of this condition, but many of these treatments have a poor or non-existent evidence base. The exception to this is eccentric calf muscle exercises, which have become a standard non-surgical intervention for Achilles tendinopathy. Foot orthoses have also been advocated as a treatment for Achilles tendinopathy, but the long-term efficacy of foot orthoses for this condition is unknown. This manuscript describes the design of a randomised trial to evaluate the efficacy of customised foot orthoses to reduce pain and improve function in people with Achilles tendinopathy. One hundred and forty community-dwelling men and women aged 18 to 55 years with Achilles tendinopathy (who satisfy inclusion and exclusion criteria) will be recruited. Participants will be randomised, using a computer-generated random number sequence, to either a control group (sham foot orthoses made from compressible ethylene vinyl acetate foam) or an experimental group (customised foot orthoses made from semi-rigid polypropylene). Both groups will be prescribed a calf muscle eccentric exercise program, however, the primary difference between the groups will be that the experimental group receive customised foot orthoses, while the control group receive sham foot orthoses. The participants will be instructed to perform eccentric exercises 2 times per day, 7 days per week, for 12 weeks. The primary outcome measure will be the total score of the Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaire. The secondary outcome measures will be participant perception of treatment effect, comfort of the foot orthoses, use of co-interventions, frequency and severity of adverse events, level of physical activity and health-related quality of life (assessed using the Short-Form-36 questionnaire - Version two). Data will be collected at baseline, then at 1, 3, 6 and 12 months. Data will be analysed using the intention to treat principle. This study is the first randomised trial to evaluate the long-term efficacy of customised foot orthoses for the treatment of Achilles tendinopathy. The study has been pragmatically designed to ensure that the study findings are generalisable to clinical practice. Australian New Zealand Clinical Trials Registry Number: ACTRN12609000829213.


Primary paraganglioma of the parathyroid: a case report and clinicopathologic review.
Paragangliomas are relatively uncommon neoplasms that arise in adrenal and extra-adrenal paraganglia of the autonomic nervous system. Parasympathetic paraganglioma develop predominantly in the head and neck. It is exceedingly uncommon to develop a primary intraparathyroid paraganglioma. There is only a single case report in the English literature. The information from the single previous case report (Medline 1960-2009) was combined with this case report. Our patient was a 69 year old woman who presented with a thyroid gland mass, with extension into the substernal space. The patient had a history of renal cell carcinoma removed 18 months before. At surgery, a thyroid lobectomy and a parathyroidectomy were performed. The parathyroid tissue showed a very well defined zellballen arrangement of paraganglion cells within the parenchyma of the parathyroid gland. The cells had ample basophilic, granular cytoplasm. The nuclei were generally round to oval with 'salt-and-pepper' nuclear chromatin distribution. There was a richly vascularized stroma. Mitotic figures, necrosis, invasive growth, and profound nuclear pleomorphism were absent. The neoplastic cells were strongly and diffusely immunoreactive with chromogranin, synaptophysin, CD56, and focally with cyclin-D1. The paraganglioma showed a delicate S-100 protein positive supporting sustentacular framework. Keratin, CD10, PTH, calcitonin and RCC markers were negative. The patient showed no stigmata of Multiple Endocrine Neoplasia (MEN) and has no paraganglioma in any other anatomic site. She is alive without any additional findings 12 months after surgery. Isolated paraganglioma within the parathyroid is rare, and should be separated from parathyroid adenoma, hyperplasia or metastatic disease to assure appropriate management.


Resting-state functional reorganization in Parkinson's disease: An activation likelihood estimation meta-analysis.
Parkinson's disease (PD) is a common progressive neurodegenerative disorder. Studies using resting-state functional magnetic resonance imaging (fMRI) to investigate underlying pathophysiology of motor and non-motor symptoms in PD yielded largely inconsistent results. This quantitative neuroimaging meta-analysis aims to identify consistent abnormal intrinsic functional patterns in PD across studies. We used PubMed to retrieve suitable resting-state studies and stereotactic data were extracted from 28 individual between-group comparisons. Convergence across their findings was tested using the activation likelihood estimation (ALE) approach. We found convergent evidence for intrinsic functional disturbances in bilateral inferior parietal lobule (IPL) and the supramarginal gyrus in PD patients compared to healthy subjects. In follow-up task-based and task-independent functional connectivity (FC) analyses using two independent healthy subject data sets, we found that the regions showing convergent aberrations in PD formed an interconnected network mainly with the default mode network (DMN). Behavioral characterization of these regions using the BrainMap database suggested associated dysfunction of perception and executive processes. Taken together, our findings highlight the role of parietal cortex in the pathophysiology of PD.


Investigation of a transgenic mouse model of familial dilated cardiomyopathy.
We have investigated a transgenic mouse model of inherited dilated cardiomyopathy that stably expresses the ACTC E361G mutation at around 50% of total actin in the heart. F-actin isolated from ACTC E361G mouse hearts was incorporated into thin filaments with native human tropomyosin and troponin and compared with NTG mouse actin by in vitro motility assay. There was no significant difference in sliding speed, fraction of filaments motile or Ca(2+)-sensitivity (ratio EC(50) E361G/NTG=0.95+/-0.08). The Ca(2+)-sensitivity of force in skinned trabeculae from ACTC E361G mice was slightly higher than NTG (EC(50) E361G/NTG=0.78+/-0.04). The molecular phenotype was revealed when troponin was dephosphorylated; Ca(2+)-sensitivity of E361G-containing thin filaments was now lower than NTG (EC(50) E361G(dPTn)/NTG(dPTn)=2.15+/-0.09). We demonstrated that this was due to uncoupling of Ca(2+)-sensitivity from troponin I phosphorylation by comparing Ca(2+)-sensitivity of phosphorylated and dephosphorylated thin filaments. For NTG actin-containing thin filaments EC(50) native/dPTn=3.0+/-0.3 but for E361G-containing thin filaments EC(50) native/dPTn=1.04+/-0.07.We studied contractility in isolated myocytes and found no significant differences under basal conditions. We measured cardiac performance by cine-MRI, echocardiography and with a conductance catheter over a period of 4 to 18 months and found minimal systematic differences between NTG and ACTC E361G mice under basal conditions. However, the increase in septal thickening, ejection fraction, heart rate and cardiac output following dobutamine treatment was significantly less in ACTC E361G mice compared with NTG. We propose that the ACTC E361G mutation uncouples myofilament Ca(2+)-sensitivity from Troponin I phosphorylation and blunts the response to adrenergic stimulation, leading to a reduced cardiac reserve with consequent contractile dysfunction under stress, leading to dilated cardiomyopathy.


A selective emissive chromogenic and fluorogenic seleno-coumarin probe for Cu2+ detection in aprotic media.
A new selenium containing coumarin (compound 7) was designed and synthesized from the amide linkage between coumarin-519 (6) and 2-(butylselanyl)ethanamine (5). The molecular structure of 7 was accurately characterized, and its photophysical properties in acetonitrile, ethanol and chloroform solutions were studied by absorption, stationary and time-resolved fluorescence spectroscopies. Changes in the solvent polarity affected the Stokes shift, quantum yields and lifetime of the excited states. The spectroscopic behavior of compound 7 was evaluated in the presence of different monovalent, divalent and trivalent metallic cations (Na+, K+, Ca2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Pb2+, Hg2+, Hg+, Ag+, Al3+, Fe3+, Ga3+ and Cr3+) in acetonitrile solution. Among the tested cations, 7 exhibited high selective interaction with Cu2+, which was evidenced by the not expected absorption hypsocromic shift (usually coumarin-519 gives red-shifted complexes) and intense chelation-enhanced fluorescence quenching (CHEQ). We performed spectrophotometric and spectrofluorimetric titrations of 7 upon addition of Cu2+. From these data, the minimal detectable and quantifiable amounts were calculated and found to be 0.2 and 0.4 μmol L-1 by absorption and 0.6 and 1.0 μmol L-1 by emission, respectively. The 7-Cu2+ compound presented the 1 : 1 stoichiometry and the stability constant values of absorption and emission were found to be log β = 5.78 and log β = 6.32 respectively. Taking into account the high selectivity of the 7-Cu2+ compound in organic solvent systems, and considering the role of copper in organic transformations, it can be regarded as a promising fluorescent sensor for studies concerning the determination of oxidation-dependent transient entities in organic reactions like those involving cuprates. Additionally, it can be used for the detection and quantification of this metal cation in vitro in aprotic biological systems.


Ascent exhalations of Antarctic fur seals: a behavioural adaptation for breath-hold diving?
Novel observations collected from video, acoustic and conductivity sensors showed that Antarctic fur seals consistently exhale during the last 50-85% of ascent from all dives (10-160 m, n > 8000 dives from 50 seals). The depth of initial bubble emission was best predicted by maximum dive depth, suggesting an underlying physical mechanism. Bubble sound intensity recorded from one seal followed predictions of a simple model based on venting expanding lung air with decreasing pressure. Comparison of air release between dives, together with lack of variation in intensity of thrusting movement during initial descent regardless of ultimate dive depth, suggested that inhaled diving lung volume was constant for all dives. The thrusting intensity in the final phase of ascent was greater for dives in which ascent exhalation began at a greater depth, suggesting an energetic cost to this behaviour, probably as a result of loss of buoyancy from reduced lung volume. These results suggest that fur seals descend with full lung air stores, and thus face the physiological consequences of pressure at depth. We suggest that these regular and predictable ascent exhalations could function to reduce the potential for a precipitous drop in blood oxygen that would result in shallow-water blackout.


Gamma-ray emission concurrent with the nova in the symbiotic binary V407 Cygni.
Novae are thermonuclear explosions on a white dwarf surface fueled by mass accreted from a companion star. Current physical models posit that shocked expanding gas from the nova shell can produce x-ray emission, but emission at higher energies has not been widely expected. Here, we report the Fermi Large Area Telescope detection of variable gamma-ray emission (0.1 to 10 billion electron volts) from the recently detected optical nova of the symbiotic star V407 Cygni. We propose that the material of the nova shell interacts with the dense ambient medium of the red giant primary and that particles can be accelerated effectively to produce pi(0) decay gamma-rays from proton-proton interactions. Emission involving inverse Compton scattering of the red giant radiation is also considered and is not ruled out.


Comparison and Clinical Evaluation of Two Pit and Fissure Sealants on Permanent Mandibular First Molars: An In Vivo Study.
The aim of the study was to compare and evaluate the clinical efficacy of a microfilled pit and fissure sealant and a nanofilled pit and fissure sealant at 3, 6, and 12 months of interval. Samples consisting of 55 healthy 8- to 12-year-old children with deep pits and fissures in mandibular first permanent molars were selected for the study. It was a split mouth design and randomized clinical trial. A total of 110 mandibular first molars were divided into two groups of 55 each: group I Fissurit FX sealant and group II Grandioseal nanofilled fissure sealant. The sealed teeth were clinically evaluated at 3, 6, and 12 months of interval to assess marginal adaptation, sealant retention, fissure caries development, roughness of sealant surface, and change of color around the sealant. The results showed that both Fissurit FX and Grandioseal pit and fissure sealants were effective in preventing dental caries. Marginal adaptation was significantly better with Fissurit FX when compared to Grandioseal pit and fissure sealant. There was no difference in sealant retention between the two groups. The surface roughness of Fissurit FX was high when compared to that of Grandioseal. Statistical analysis was done using the Chi-squared test for intra-group comparison and Fisher's exact test for inter-group comparison. Results were considered statistically significant if p ≤ 0.05. Fissurit FX and Grandioseal pit and fissure sealants provided similar caries preventive effects and there was no difference in retention of sealants over a period of 1 year. However, surface roughness was better with Grandioseal fissure sealants. This study is significant because there is limited evidence about the efficacy of nanofilled pit and fissure sealants in vivo. It will also provide dental practitioners an insight into the clinical efficacy of nanofilled pits and fissure sealant when compared to micro-filled sealant enabling them to make the right choice for the betterment of their dental practice. How to cite this article: Smitha M, Paul ST, Nagaraj T, et al. Comparison and Clinical Evaluation of Two Pit and Fissure Sealants on Permanent Mandibular First Molars: An In Vivo Study. J Contemp Dent Pract 2019;20(10):1151-1158.


Engineering the electronic bandgaps and band edge positions in carbon-substituted 2D boron nitride: a first-principles investigation.
Modification of graphene to open a robust gap in its electronic spectrum is essential for its use in field effect transistors and photochemistry applications. Inspired by recent experimental success in the preparation of homogeneous alloys of graphene and boron nitride (BN), we consider here engineering the electronic structure and bandgap of C2xB1-xN1-x alloys via both compositional and configurational modification. We start from the BN end-member, which already has a large bandgap, and then show that (a) the bandgap can in principle be reduced to about 2 eV with moderate substitution of C (x < 0.25); and (b) the electronic structure of C2xB1-xN1-x can be further tuned not only with composition x, but also with the configuration adopted by C substituents in the BN matrix. Our analysis, based on accurate screened hybrid functional calculations, provides a clear understanding of the correlation found between the bandgap and the level of aggregation of C atoms: the bandgap decreases most when the C atoms are maximally isolated, and increases with aggregation of C atoms due to the formation of bonding and anti-bonding bands associated with hybridization of occupied and empty defect states. We determine the location of valence and conduction band edges relative to vacuum and discuss the implications on the potential use of 2D C2xB1-xN1-x alloys in photocatalytic applications. Finally, we assess the thermodynamic limitations on the formation of these alloys using a cluster expansion model derived from first-principles.


Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans.
Reviews on the safety of glyphosate and Roundup herbicide that have been conducted by several regulatory agencies and scientific institutions worldwide have concluded that there is no indication of any human health concern. Nevertheless, questions regarding their safety are periodically raised. This review was undertaken to produce a current and comprehensive safety evaluation and risk assessment for humans. It includes assessments of glyphosate, its major breakdown product [aminomethylphosphonic acid (AMPA)], its Roundup formulations, and the predominant surfactant [polyethoxylated tallow amine (POEA)] used in Roundup formulations worldwide. The studies evaluated in this review included those performed for regulatory purposes as well as published research reports. The oral absorption of glyphosate and AMPA is low, and both materials are eliminated essentially unmetabolized. Dermal penetration studies with Roundup showed very low absorption. Experimental evidence has shown that neither glyphosate nor AMPA bioaccumulates in any animal tissue. No significant toxicity occurred in acute, subchronic, and chronic studies. Direct ocular exposure to the concentrated Roundup formulation can result in transient irritation, while normal spray dilutions cause, at most, only minimal effects. The genotoxicity data for glyphosate and Roundup were assessed using a weight-of-evidence approach and standard evaluation criteria. There was no convincing evidence for direct DNA damage in vitro or in vivo, and it was concluded that Roundup and its components do not pose a risk for the production of heritable/somatic mutations in humans. Multiple lifetime feeding studies have failed to demonstrate any tumorigenic potential for glyphosate. Accordingly, it was concluded that glyphosate is noncarcinogenic. Glyphosate, AMPA, and POEA were not teratogenic or developmentally toxic. There were no effects on fertility or reproductive parameters in two multigeneration reproduction studies with glyphosate. Likewise there were no adverse effects in reproductive tissues from animals treated with glyphosate, AMPA, or POEA in chronic and/or subchronic studies. Results from standard studies with these materials also failed to show any effects indicative of endocrine modulation. Therefore, it is concluded that the use of Roundup herbicide does not result in adverse effects on development, reproduction, or endocrine systems in humans and other mammals. For purposes of risk assessment, no-observed-adverse-effect levels (NOAELs) were identified for all subchronic, chronic, developmental, and reproduction studies with glyphosate, AMPA, and POEA. Margins-of-exposure for chronic risk were calculated for each compound by dividing the lowest applicable NOAEL by worst-case estimates of chronic exposure. Acute risks were assessed by comparison of oral LD50 values to estimated maximum acute human exposure. It was concluded that, under present and expected conditions of use, Roundup herbicide does not pose a health risk to humans.


Global prevalence and trends of overweight and obesity among preschool children.
Childhood obesity is associated with serious health problems and the risk of premature illness and death later in life. Monitoring related trends is important. The objective was to quantify the worldwide prevalence and trends of overweight and obesity among preschool children on the basis of the new World Health Organization standards. A total of 450 nationally representative cross-sectional surveys from 144 countries were analyzed. Overweight and obesity were defined as the proportion of preschool children with values >2 SDs and >3 SDs, respectively, from the World Health Organization growth standard median. Being "at risk of overweight" was defined as the proportion with values >1 SD and ≤2 SDs, respectively. Linear mixed-effects modeling was used to estimate the rates and numbers of affected children. In 2010, 43 million children (35 million in developing countries) were estimated to be overweight and obese; 92 million were at risk of overweight. The worldwide prevalence of childhood overweight and obesity increased from 4.2% (95% CI: 3.2%, 5.2%) in 1990 to 6.7% (95% CI: 5.6%, 7.7%) in 2010. This trend is expected to reach 9.1% (95% CI: 7.3%, 10.9%), or ≈60 million, in 2020. The estimated prevalence of childhood overweight and obesity in Africa in 2010 was 8.5% (95% CI: 7.4%, 9.5%) and is expected to reach 12.7% (95% CI: 10.6%, 14.8%) in 2020. The prevalence is lower in Asia than in Africa (4.9% in 2010), but the number of affected children (18 million) is higher in Asia. Childhood overweight and obesity have increased dramatically since 1990. These findings confirm the need for effective interventions starting as early as infancy to reverse anticipated trends.


Sex-Dependent Aggregation of Tinnitus in Swedish Families.
Twin and adoption studies point towards a genetic contribution to tinnitus; however, how the genetic risk applies to different forms of tinnitus is poorly understood. Here, we perform a familial aggregation study and determine the relative recurrence risk for tinnitus in siblings (λs). Four different Swedish studies (N = 186,598) were used to estimate the prevalence of self-reported bilateral, unilateral, constant, and severe tinnitus in the general population and we defined whether these 4 different forms of tinnitus segregate in families from the Swedish Tinnitus Outreach Project (STOP, N = 2305). We implemented a percentile bootstrap approach to provide accurate estimates and confidence intervals for λs. We reveal a significant λs for all types of tinnitus, the highest found being 7.27 (95% CI (5.56-9.07)) for severe tinnitus, with a higher susceptibility in women (10.25; 95% CI (7.14-13.61)) than in men (5.03; 95% CI (3.22-7.01)), suggesting that severity may be the most genetically influenced trait in tinnitus in a sex-dependent manner. Our findings strongly support the notion that genetic factors impact on the development of tinnitus, more so for severe tinnitus. These findings highlight the importance of considering tinnitus severity and sex in the design of large genetic studies to optimize diagnostic approaches and ultimately improve therapeutic interventions.


What you count is what you target: the implications of maternal death classification for tracking progress towards reducing maternal mortality in developing countries.
The first target of the fifth United Nations Millennium Development Goal is to reduce maternal mortality by 75% between 1990 and 2015. This target is critically off track. Despite difficulties inherent in measuring maternal mortality, interventions aimed at reducing it must be monitored and evaluated to determine the most effective strategies in different contexts. In some contexts, the direct causes of maternal death, such as haemorrhage and sepsis, predominate and can be tackled effectively through providing access to skilled birth attendance and emergency obstetric care. In others, indirect causes of maternal death, such as HIV/AIDS and malaria, make a significant contribution and require alternative interventions. Methods of planning and evaluating maternal health interventions that do not differentiate between direct and indirect maternal deaths may lead to unrealistic expectations of effectiveness or mask progress in tackling specific causes. Furthermore, the need for additional or alternative interventions to tackle the causes of indirect maternal death may not be recognized if all-cause maternal death is used as the sole outcome indicator. This article illustrates the importance of differentiating between direct and indirect maternal deaths by analysing historical data from England and Wales and contemporary data from Ghana, Rwanda and South Africa. The principal aim of the paper is to highlight the need to differentiate deaths in this way when evaluating maternal mortality, particularly when judging progress towards the fifth Millennium Development Goal. It is recommended that the potential effect of maternity services failing to take indirect maternal deaths into account should be modelled.


Transmembrane S1 mutations in CNGA3 from achromatopsia 2 patients cause loss of function and impaired cellular trafficking of the cone CNG channel.
Achromatopsia 2, an inherited retinal disorder resulting in attenuation or loss of cone function, is caused by mutations in the alpha subunit of the cone cyclic nucleotide-gated (CNG) channel gene CNGA3. Examination of mutations that cluster in the first transmembrane segment of the protein may provide insight into its role in CNG channel structure, function, biogenesis, and pathophysiology. The human CNGA3 gene was tagged at the C terminus with green fluorescent protein. Four mutations, Y181C, N182Y, L186F, and C191Y, were expressed in human embryonic kidney cells. Protein expression was evaluated with immunoblot analysis and cellular localization was determined by immunocytochemistry. Channel function was evaluated by patch-clamp electrophysiology. All the mutations result in loss of channel function, as determined by the failure of cGMP to activate wild-type currents in excised patches. Full-length mutant proteins were synthesized but retained in the endoplasmic reticulum. Glycerol treatment did not rescue channel function nor did coexpression with CNGB3, a subunit of native hetero-tetrameric cone channels. A control mutant, C191S, exhibited cGMP current activation with significantly reduced cooperativity, suggesting that mutations in the first transmembrane domain alter in inter- or intrasubunit communication. The results implicate the first transmembrane segment in both maturation and function of CNG channels. The defects are not reversed with glycerol, a chemical chaperone that rescues channel function in some channelopathies. Molecular analysis of achromatopsia 2 mutations may be useful in evaluating potential therapeutic approaches for treatment of this channelopathy.


European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy.
Spinal muscular atrophy (SMA) used to be one of the most common genetic causes of infant mortality. New disease modifying treatments have changed the disease trajectories and most impressive results are seen if treatment is initiated in the presymptomatic phase of the disease. Very recently, the European Medicine Agency approved Onasemnogene abeparvovec (Zolgensma®) for the treatment of patients with SMA with up to three copies of the SMN2 gene or the clinical presentation of SMA type 1. While this broad indication provides new opportunities, it also triggers discussions on the appropriate selection of patients in the context of limited available evidence. To aid the rational use of Onasemnogene abeparvovec for the treatment of SMA, a group of European neuromuscular experts presents in this paper eleven consensus statements covering qualification, patient selection, safety considerations and long-term monitoring.


Unsettling experiences: A qualitative inquiry into young peoples' narratives of diagnosis for common skin conditions in the United Kingdom.
Skin conditions such as eczema and psoriasis are relatively prevalent health concerns in children, adolescents and young adults. Experiences of these dermatology diagnoses in adolescence have hitherto not been the focus of research, perhaps owing to assumptions that these diagnoses are not particularly impactful or intricate processes, events or labels. We draw on a thematic secondary analysis of in-depth interviews with 42 adolescents and young people living in the United Kingdom and, influenced by the sociologies of diagnosis and time, highlight the psychological, emotional, social and temporal complexities involved in their diagnosis experiences. Firstly, we describe how participants remembered, re- and co-constructed their diagnosis experiences during the interview. Secondly, we explore the pace and rhythm of diagnosis, including mis-diagnoses, highlighting the jarring potential for adolescents on being diagnosed, even for conditions typically deemed minor. Thirdly, we consider the ways in which these diagnoses have the capacity to reformulate notions of past, present and future, including projecting into imagined futures and reinterpreting past bodily sensations. Finally, we examine how memories about and the meaning of diagnosis are revisited, revised and potentially replaced as a child or adolescent grows older, and increases their management of their condition and encounters with healthcare professionals. In unsettling an assumption that diagnosis experiences for adolescents of common skin conditions is unproblematic or straightforward, our qualitative analysis critically engages with and contribute to tenets of health research that are of interest to quantitative and qualitative researchers, clinicians and patients.


Dual function of a bee (Apis cerana) inhibitor cysteine knot peptide that acts as an antifungal peptide and insecticidal venom toxin.
Inhibitor cysteine knot (ICK) peptides exhibit ion channel blocking, insecticidal, and antimicrobial activities, but currently, no functional roles for bee-derived ICK peptides have been identified. In this study, a bee (Apis cerana) ICK peptide (AcICK) that acts as an antifungal peptide and as an insecticidal venom toxin was identified. AcICK contains an ICK fold that is expressed in the epidermis, fat body, or venom gland and is present as a 6.6-kDa peptide in bee venom. Recombinant AcICK peptide (expressed in baculovirus-infected insect cells) bound directly to Beauveria bassiana and Fusarium graminearum, but not to Escherichia coli or Bacillus thuringiensis. Consistent with these findings, AcICK showed antifungal activity, indicating that AcICK acts as an antifungal peptide. Furthermore, AcICK expression is induced in the fat body and epidermis after injection with B. bassiana. These results provide insight into the role of AcICK during the innate immune response following fungal infection. Additionally, we show that AcICK has insecticidal activity. Our results demonstrate a functional role for AcICK in bees: AcICK acts as an antifungal peptide in innate immune reactions in the body and as an insecticidal toxin in venom. The finding that the AcICK peptide functions with different mechanisms of action in the body and in venom highlights the two-pronged strategy that is possible with the bee ICK peptide.


Breast-feeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies.
To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders. Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies. Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little. The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.


Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish.
NDRG4 is a novel member of the NDRG family (N-myc downstream-regulated gene). The roles of NDRG4 in development have not previously been evaluated. We show that, during zebrafish embryonic development, ndrg4 is expressed exclusively in the embryonic heart, the central nervous system (CNS) and the sensory system. Ndrg4 knockdown in zebrafish embryos causes a marked reduction in proliferative myocytes and results in hypoplastic hearts. This growth defect is associated with cardiac phenotypes in morphogenesis and function, including abnormal heart looping, inefficient circulation and weak contractility. We reveal that ndrg4 is required for restricting the expression of versican and bmp4 to the developing atrioventricular canal. This constellation of ndrg4 cardiac defects phenocopies those seen in mutant hearts of heartstrings (hst), the tbx5 loss-of-function mutants in zebrafish. We further show that ndrg4 expression is significantly decreased in hearts with reduced tbx5 activities. Conversely, increased expression of tbx5 that is due to tbx20 knockdown leads to an increase in ndrg4 expression. Together, our studies reveal an essential role of ndrg4 in regulating proliferation and growth of cardiomyocytes, suggesting that ndrg4 may function downstream of tbx5 during heart development and growth.


The Impact of Everyday Discrimination and Racial Identity Centrality on African American Medical Student Well-Being: a Report from the Medical Student CHANGE Study.
Positive psychological well-being is an important predictor of and contributor to medical student success. Previous work showed that first-year African American medical students whose self-concept was highly linked to their race (high racial identity centrality) were at greater risk for poor well-being. The current study extends this work by examining (a) whether the psychological impact of racial discrimination on well-being depends on African American medical students' racial identity centrality and (b) whether this process is explained by how accepted students feel in medical school. This study used baseline data from the Medical Student Cognitive Habits and Growth Evaluation (CHANGE) Study, a large national longitudinal cohort study of 4732 medical students at 49 medical schools in the USA (n = 243). Regression analyses were conducted to test whether medical student acceptance mediated an interactive effect of discrimination and racial identity centrality on self-esteem and well-being. Both racial identity centrality and everyday discrimination were associated with negative outcomes for first-year African American medical students. Among participants who experienced higher, but not lower, levels of everyday discrimination, racial identity centrality was associated with negative outcomes. When everyday discrimination was high, but not low, racial identity was negatively related to perceived acceptance in medical school, and this in turn was related to increased negative outcomes. Our results suggest that discrimination may be particularly harmful for African American students who perceive their race to be central to their personal identity. Additionally, our findings speak to the need for institutional change that includes commitment and action towards inclusivity and the elimination of structural racism.


Modulation of the rectoanal inhibitory reflex (RAIR): qualitative and quantitative evaluation in multiple sclerosis.
Rectoanal inhibitory reflex (RAIR) is a physiological modulated reflex involved in anorectal continence and defined by a relaxation of internal anal sphincter following rectal distension. Its existence depends on intramural autonomic ganglions and its modulation on the integrity of the autonomic nervous system (ANS). The aim of this study was to analyse RAIR modulation in terms of amplitude and duration in multiple sclerosis (MS) patients. Twenty-one patients with MS and 40 control patients had anorectal manometry. Qualitative assessment (presence or absence) of RAIR was evaluated together with its modulation in amplitude and in duration. All patients had present RAIR for each volume of rectal distension (10-50 ml). Seven patients (33.3%) in the MS group had abnormal RAIR modulation in amplitude (odds ratio (OR) = 2.78, compared to control group, p = 0.11). Nine patients (42.9%) in the MS group had abnormal RAIR modulation in duration (p = 0.14, OR = 2.54, compared to control group). Alteration of RAIR modulation was not correlated with Expanded Disability Status Scale, faecal incontinence and constipation (p > 0.05). Course of MS (relapsing-remitting MS or secondary progressive form) seems to be correlated to alteration of modulation in amplitude and in duration (OR = 1.31 and 1.07). Even if our results do not have the required statistical significance (p > 0.05), they are interesting. If RAIR is always present in MS, its modulation seems to be altered. A hypothesis for this lack of RAIR modulation could be the alteration of ANS, often involved in MS besides somatic nervous system lesions.


Assessment of skeletal age in multiple epiphyseal dysplasia.
Determining the skeletal age in patients with multiple epiphyseal dysplasia (MED) is essential for predicting the adult height and guiding the timing of limb lengthening, epiphysiodesis, and other surgical procedures. In the present study, we examined the patterns of skeletal age delay using 3 different methods, the Greulich-Pyle (GP) atlas method, the Tanner-Whitehouse 3 (TW3) method using radius-ulna-short bones (RUS) scoring system, and the TW3 method using the carpal bone maturity scoring system. Left hand radiographs from 23 patients (age range, 3 to 14 y) with MED were examined to determine the skeletal age. We examined the reliability of the 3 different methods and evaluated the difference between the chronological age and the skeletal age. The interobserver and intraobserver reliabilities were higher with the GP atlas method and the TW3 RUS method compared with the TW3 carpal bone maturity scoring system. There was significant skeletal age delay irrespective of the method used (P<0.01). When we used the TW3 carpal method, the pattern of skeletal age delay was significantly distinct from the other 2 methods. According to the measurement method, there was no statistically significant difference in the developmental skeletal age pattern among the COMP gene group, the MATN3 gene group, and other gene groups. Our findings indicate that there is a distinct skeletal maturation pattern in patients with MED. The skeletal age is relatively delayed compared with the chronological age irrespective of the measuring method utilized. However, use of either the GP atlas or the TW3 RUS method provided more accurate information on the skeletal development in the patients with MED than that provided by the TW3 carpal bone maturity scoring system. Level I. Diagnostic study.


Dissemination of multidrug resistant Acinetobacter baumannii in various hospitals of Antananarivo Madagascar.
This study reports the dissemination of multidrug-resistant (MDR) OXA-23-producing Acinetobacter baumannii clones in hospitals in Antananarivo, Madagascar. A total of 53 carbapenem-resistant A. baumannii isolates were obtained from September 2006 to March 2009 in five hospitals. These resistant strains represent 44% of all A. baumannii isolates. The double disk synergy test was performed to screen for production of metallo-beta-lactamases. Polymerase chain reaction (PCR) and DNA sequencing were performed for the detection of bla(AmpC), bla(OXA-51),bla(OXA-23), bla(OXA-24), bla(IMP), bla(VIM). The presence of the insertion sequence ISAba1 relative to blaOXA-23 and blaOXA-51 was assessed by PCR. Isolates were typed by Rep-PCR. All the isolates were MDR and produced the OXA-23 carbapenemase, which was confirmed by sequencing. PCR analysis for AmpC and OXA-51 gave positive results for all strains studied. No isolates produced metallo-beta-lactamases. In all isolates ISAba1 laid upstream of blaOXA-23. The A. baumannii isolates were separated into two genotypes; genotype A had a higher prevalence (41 strains) than genotype B (12 strains). Genotype A was present in four hospitals, whilst genotype B had spread in two hospitals. The high frequency of MDR OXA-23-producing A. baumannii in various hospitals in Antananarivo is curious since carbapenems are not available in Madagascar, but it emphasises the need for infection control procedures and strict adherence to them to prevent the spread of these resistant organisms in Antananarivo and also the need to control the use of carbapenems in the future.


64Cu-Labeled Phosphonate Cross-Bridged Chelator Conjugates of c(RGDyK) for PET/CT Imaging of Osteolytic Bone Metastases.
The goal of this research was to evaluate c(RGDyK) conjugated to phosphonate-based cross-bridged chelators using Cu-free click chemistry in the 4T1 mouse mammary tumor bone metastasis model in comparison with 64Cu-CB-TE2A-c(RGDyK), which previously showed selective binding to integrin αvβ3 on osteoclasts. Two phosphonate-based cross-bridged chelators (CB-TE1A1P and CB-TE1K1P) were conjugated to c(RGDyK) through bio-orthogonal strain-promoted alkyne-azide cycloaddition. In vitro and in vivo evaluation of the 64Cu-labeled TE1A1P-DBCO-c(RGDyK) (AP-c(RGDyK)), TE1K1P-PEG4-DBCO-c(RGDyK) (KP-c(RGDyK)), and CB-TE2A-c(RGDyK) were compared in the 4T1 mouse model of bone metastasis. The affinities of the unconjugated and chelator-c(RGDyK) analogs for αvβ3 integrin were determined using a competitive-binding assay. For in vivo evaluation, BALB/c mice were injected with 1 × 105 4T1/Luc cells in the left ventricle. Formation of metastases was monitored by bioluminescence imaging (BLI) followed by small-animal PET/CT 2 h postinjection of radiotracers. The chelator-peptide conjugates showed similar affinity to integrin αvβ3, in the low nM range. PET imaging demonstrated a higher uptake in bones having metastases for all 64Cu-labeled c(RGDyK) analogs compared with bones in nontumor-bearing mice. The correlation between uptake of 64Cu-AP-c(RGDyK) and 64Cu-KP-c(RGDyK) in bones with metastases based on PET/CT imaging, and osteoclast number based on histomorphometry, was improved over the previously investigated 64Cu-CB-TE2A-c(RGDyK). These data suggest that the phosphonate chelator conjugates of c(RDGyK) peptides are promising PET tracers suitable for imaging tumor-associated osteoclasts in bone metastases.


Percutaneous Tendon Needling without Ultrasonography for Lateral Epicondylitis.
Percutaneous ultrasonic tendon needling has been used to treat persistent lateral epicondylitis, and its efficacy has been demonstrated. However, whether ultrasonography is necessary remains unclear. The purpose of this retrospective study was to evaluate the efficacy of percutaneous tendon needling without ultrasonography for lateral epicondylitis. A total of 36 patients who underwent tendon needling without ultrasonography for lateral epicondylitis were retrospectively included in the study. The tendinotic lesion was needled by fenestration approximately 20-30 times without sonographic assistance. The Visual Analogue Scale (VAS) pain score, the grip strength, and success rates were assessed at baseline and at 1, 3, 6, and 12 months after treatment. The Nirschl tennis elbow score was evaluated at baseline and at 6 and 12 months after the needling procedure. The mean VAS pain score and grip strength at 3, 6, and 12 months significantly improved compared to the baseline values. At 6 and 12 months, the success rates had significantly increased compared to the rates at 1 month. The mean Nirschl scores at 6 and 12 months were significantly better than the baseline value. No severe complications were observed during the study period. Percutaneous tendon needling without ultrasonography is a simple and safe technique. The procedure is effective for lateral epicondylitis that is unresponsive to conventional conservative treatments.


Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study.
This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer's disease (AD). In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife.


From housing to homes: a review of the literature on housing approaches for psychiatric consumer/survivors.
In this paper, we review the literature on housing for psychiatric consumer/survivors since the publication of the Nelson and Smith Fowler (1987) review more than a decade ago. First, we review research and propose a definition to contrast key features of three approaches to housing: (a) custodial, (b) supportive, and (c) supported. Second, we examine studies of the relationships between the characteristics of housing and adaptational outcomes for residents (e.g., personal empowerment). Third, we review studies which have examined out-comes for residents for these three different housing approaches. We conclude by critically reflecting on the values and research of the different approaches to housing, to make recommendations for future policy and planning, practice, and research.


Nondispersive infrared spectrometry for 13CO2/12CO2-measurements: a clinically feasible analyzer for stable isotope breath tests in gastroenterology.
13C-urea breath tests have become clinical routine for the diagnosis of Helicobacter pylori infection and other isotope breath tests have been invented e.g. for gastric emptying or quantitative liver function testing. Recently, isotope-selective nondispersive infrared spectrometers (NDIRS) have been developed for the analysis of the 13CO2/12CO2-enrichment in breath. In this study, we prospectively tested the validity of a newly developed NDIRS in comparison to isotope ratio mass spectrometry (IRMS). 142 patients with dyspeptic symptoms were tested for Helicobacter pylori infection using the 13C-urea breath test. The isotope ratio analysis of the breath samples was performed in duplicate both using IRMS and NDIRS. The results of the baseline-corrected 13CO2-exhalation values between IRMS and NDIRS were in excellent agreement. The mean difference between both methods was 0.28 +/- 1.93 delta/1000. Evaluating the qualitative urea breath test results in reference to IRMS as the reference the NDIRS had a sensitivity of 97.8% and a specificity of 98.9%. The isotope-selective nondispersive infrared spectroscopy is going to become a reliable, but low-cost and easy-to-operate alternative to expensive isotope ratio mass spectrometry in the analysis of 13C-breath tests.


Comparison of media literacy and usual education to prevent tobacco use: a cluster-randomized trial.
Media literacy programs have shown potential for reduction of adolescent tobacco use. We aimed to determine if an anti-smoking media literacy curriculum improves students' media literacy and affects factors related to adolescent smoking. We recruited 1170 9th-grade students from 64 classrooms in 3 public urban high schools. Students were randomized by classroom to a media literacy curriculum versus a standard educational program. In an intent-to-treat analysis, we used multilevel modeling to determine if changes in study outcomes were associated with the curricular intervention, controlling for baseline student covariates and the clustering of students within classrooms. Among participants, mean age was 14.5 years and 51% were male, with no significant differences in baseline characteristics between groups. Smoking media literacy changed more among intervention participants compared with control participants (0.24 vs. 0.08, p < .001). Compared with controls, intervention students exhibited a greater reduction in the perceived prevalence of smoking (-14.0% vs. -4.6%, p < .001). Among those initially susceptible to smoking, intervention participants more commonly reverted to being nonsusceptible post-intervention (24% vs. 16%, p = .08). A school-based media literacy curriculum is more effective than a standard educational program in teaching media literacy and improving perceptions of the true prevalence of smoking among adolescents.


Misregulation of polo-like protein kinase 1, P53 and P21WAF1 in epithelial ovarian cancer suggests poor prognosis.
Polo-like protein kinase 1 (PLK1), P53 and P21WAF1 are relevant to cell cycle checkpoints and cancer biology. Misregulation of PLK1, P53 and P21WAF1 has been detected in several types of malignant tumors. The present study aimed to clarify the role of PLK1, P53 and P21WAF1 in the prognosis of ovarian cancer. PLK1 and P53 shRNA lentiviral plasmids were transfected into SK-OV-3 cells, respectively. Cell proliferation, apoptosis and invasion were examined by MTT assay, flow cytometry and Matrigel assay, respectively. Survival time of the animals was observed in a xenograft model. Expression levels of PLK1, P53 and P21WAF1 were detected in different ovarian tissues by immunohistochemistry and western blot analysis. Their correlations to the clinicopathologic characteristics of the epithelial ovarian cancer (EOC) cases and their interrelationships were analyzed. Risk factors of prognosis for EOC were determined by logistic regression analysis. The survival time of EOC patients was measured by Kaplan-Meier analysis. After PLK1 or P53 knockdown, proliferation of the SK-OV-3 cells was inhibited, the apoptosis rate was increased, and cell invasion was suppressed in vitro, and the survival time was prolonged in the animals. Expression levels of P53, p-P53 (Ser15), P21WAF1, growth arrest and DNA damage‑inducible gene 45 (GADD45) and 14-3-3σ were upregulated in the SK-OV-3 cells after PLK1 knockdown, but downregulated after P53 knockdown. Higher expression levels of PLK1 and P53 were observed in patients with a higher FIGO stage and worse histological differentiation, but lower P21WAF1 was noted at a higher FIGO stage. Negative correlations were observed between expression of PLK1 and P53 and P53 and P21WAF1 in the EOC cases. PLK1, P53 and P21WAF1 could be used to assess the prognosis of EOC, respectively, but only PLK1 was found to be an independent prognostic factor. The overall survival time of subjects exhibiting PLK1-positive/P53-positive expression and PLK1-positive/P21WAF1-negative expression was obviously shorter than the other patient groups at the end of the follow-up. These results indicate that PLK1 is implicated in ovarian carcinogenesis and may owe its ability to inhibition of the activity of P53. In addition, misregulation of PLK1 coincident with P53 and P21WAF1 in EOC suggests poor prognosis.


Modifiable cardiovascular disease risk factors among adults in southern Ethiopia: a community-based cross-sectional study.
To assess the prevalence, magnitude and factors associated with the number of major modifiable cardiovascular disease (CVD) risk factors. Community-based cross-sectional study. General population in urban and rural Wolaita, southern Ethiopia. A total of 2483 adults aged 25-64 years were selected using the three-stage random sampling. Prevalence of major modifiable CVD risk factors, co-occurrences and the number of modifiable CVD risk factors. The major modifiable CVD risk factors documented in the Wolaita area were smoking with a weighted prevalence of 0.8%, hypercholesterolaemia 5.0%, hypertriglyceridaemia 15.5%, low high-density lipoprotein cholesterol (HDL-C) 31.3%, high systolic blood pressure 22.2%, high diastolic blood pressure 22.4%, physical inactivity 44.1%, obesity 2.8% and hyperglycaemia 3.7%. The numbers of participants having ≥1, ≥2 and ≥3 major modifiable CVD risk factors in the study area were 2013, 1201 and 576 with a weighted prevalence of 75.8%, 42.3% and 19.4%, respectively. In general, there were 28 different combinations of major modifiable CVD risk factor co-occurrences. The combination of physical inactivity with low HDL-C was found in 19.7% of the study participants, followed by physical inactivity with hypertension of 17.8%. Urban residence, male gender, sugar-sweetened food consumption and older age had a positive association with the number of major modifiable CVD risk factors, while being a farmer had a negative association. The prevalence and magnitude of major modifiable CVD risk factors in the study area were high. The components of the most prevalent combinations of major modifiable CVD risk factors should be targeted. Therefore, public health measures against major modifiable CVD risk factors such as promotion of physical exercise and reduction of sugar-sweetened food consumption have to be taken, targeting the vulnerable groups such as urban residents and older age.


An Out-of-Core GPU based dimensionality reduction algorithm for Big Mass Spectrometry Data and its application in bottom-up Proteomics.
Modern high resolution Mass Spectrometry instruments can generate millions of spectra in a single systems biology experiment. Each spectrum consists of thousands of peaks but only a small number of peaks actively contribute to deduction of peptides. Therefore, pre-processing of MS data to detect noisy and non-useful peaks are an active area of research. Most of the sequential noise reducing algorithms are impractical to use as a pre-processing step due to high time-complexity. In this paper, we present a GPU based dimensionality-reduction algorithm, called G-MSR, for MS2 spectra. Our proposed algorithm uses novel data structures which optimize the memory and computational operations inside GPU. These novel data structures include Binary Spectra and Quantized Indexed Spectra (QIS). The former helps in communicating essential information between CPU and GPU using minimum amount of data while latter enables us to store and process complex 3-D data structure into a 1-D array structure while maintaining the integrity of MS data. Our proposed algorithm also takes into account the limited memory of GPUs and switches between in-core and out-of-core modes based upon the size of input data. G-MSR achieves a peak speed-up of 386x over its sequential counterpart and is shown to process over a million spectra in just 32 seconds. The code for this algorithm is available as a GPL open-source at GitHub at the following link: https://github.com/pcdslab/G-MSR.


Puteibacter caeruleilacunae gen. nov., sp. nov., a facultatively anaerobic bacterium isolated from Yongle Blue Hole in the South China Sea.
Blue holes are unique geomorphological units characterized by steep redox and biogeochemical gradients. Yongle Blue Hole is located on the largest atoll (Yongle Atoll) of the western Xisha Islands in the South China Sea. A Gram-stain-negative, facultatively anaerobic, non-motile, non-flagellated marine bacterium with creamy white colonies, designated JC036T, was isolated from Yongle Blue Hole. Cells were short-rod-shaped and catalase-negative. 16S rRNA gene sequence analysis showed that sequence similarities were lower than 91.6 % against all validly named species in the family Prolixibacteraceae; a reconstructed phylogenetic tree indicated that strain JC036T formed a lineage with strains in the family Prolixibacteraceae. Growth occurred at 4-37 °C (optimum, 28 °C), at pH 5.0-9.0 (optimum, 7.0) and in the presence of 2-6 % (w/v) NaCl (optimum, 3 %). The prevalent isoprenoid quinone of strain JC036T was menaquinone-7 (MK-7). Iso-C15 : 0 and iso-C17 : 0 3-OH were the predominant fatty acids. The major polar lipids included a phospholipid, phosphatidylethanolamine, an aminophospholipid and four unidentified lipids. The genomic DNA G+C content of strain JC036T was 37.8 mol%. Based on physiological and biochemical characteristics and whole genome comparisons, we propose a new genus and species, Puteibacter caeruleilacunae gen. nov., sp. nov., within the family Prolixibacteraceae. The type strain of Puteibacter caeruleilacunae is JC036T (=JCM 33128T=MCCC 1K03579T). From this study, a deeper understanding of the community of the microorganism and their roles in biogeochemical cycles, especially anaerobic bacteria, is provided.


Propagation through heterogeneous substrates in simple excitable media models.
The interaction of waves and obstacles is simulated by adding heterogeneities to a FitzHugh-Nagumo model and a cellular automata model. The cellular automata model is formulated to account for heterogeneities by modelling the interaction between current sources and current sinks. In both models, wave fronts propagate if the size of the heterogeneities is small, and block if the size of the heterogeneities is large. For intermediate values, wave fronts break up into numerous spiral waves. The theoretical models give insights concerning spiral wave formation in heterogeneous excitable media. (c) 2002 American Institute of Physics.


Cell-to-cell communication--periodontal regeneration.
Although regenerative treatment options are available, periodontal regeneration is still regarded as insufficient and unpredictable. This review article provides scientific background information on the animated 3D film Cell-to-Cell Communication - Periodontal Regeneration. Periodontal regeneration is understood as a recapitulation of embryonic mechanisms. Therefore, a thorough understanding of cellular and molecular mechanisms regulating normal tooth root development is imperative to improve existing and develop new periodontal regenerative therapies. However, compared to tooth crown and earlier stages of tooth development, much less is known about the development of the tooth root. The formation of root cementum is considered the critical element in periodontal regeneration. Therefore, much research in recent years has focused on the origin and differentiation of cementoblasts. Evidence is accumulating that the Hertwig's epithelial root sheath (HERS) has a pivotal role in root formation and cementogenesis. Traditionally, ectomesenchymal cells in the dental follicle were thought to differentiate into cementoblasts. According to an alternative theory, however, cementoblasts originate from the HERS. What happens when the periodontal attachment system is traumatically compromised? Minor mechanical insults to the periodontium may spontaneously heal, and the tissues can structurally and functionally be restored. But what happens to the periodontium in case of periodontitis, an infectious disease, after periodontal treatment? A non-regenerative treatment of periodontitis normally results in periodontal repair (i.e., the formation of a long junctional epithelium) rather than regeneration. Thus, a regenerative treatment is indicated to restore the original architecture and function of the periodontium. Guided tissue regeneration or enamel matrix proteins are such regenerative therapies, but further improvement is required. As remnants of HERS persist as epithelial cell rests of Malassez in the periodontal ligament, these epithelial cells are regarded as a stem cell niche that can give rise to new cementoblasts. Enamel matrix proteins and members of the transforming growth factor beta (TGF-ß) superfamily have been implicated in cementoblast differentiation. A better knowledge of cell-to-cell communication leading to cementoblast differentiation may be used to develop improved regenerative therapies to reconstitute periodontal tissues that were lost due to periodontitis.


Secondary electrospray ionization ion mobility spectrometry/mass spectrometry of illicit drugs.
A secondary electrospray ionization (SESI) method was developed as a nonradioactive ionization source for ion mobility spectrometry (IMS). This SESI method relied on the gas-phase interaction between charged particles created by electrospray ionization (ESI) and neutral gaseous sample molecules. Mass spectrometry (MS) was used as the detection method after ion mobility separation for ion identification. Preliminary investigations focussed on understanding the ionization process of SESI. The performance of ESI-IMS and SESI-IMS for illicit drug detection was evaluated by determining the analytical figures of merit. In general, SESI had a higher ionization efficiency for small volatile molecules compared with the electrospray method. The potential of developing a universal interface for both GC- and LC-MS with an addition stage of mobility separation was demonstrated.


Effects of a finite outer scale on the measurement of atmospheric-turbulence statistics with a Hartmann wave-front sensor.
Phase-structure and aperture-averaged slope-correlated functions with a finite outer scale are derived based on the Taylor hypothesis and a generalized spectrum, such as the von Kármán modal. The effects of the finite outer scale on measuring and determining the character of atmospheric-turbulence statistics are shown especially for an approximately 4-m class telescope and subaperture. The phase structure function and atmospheric coherent length based on the Kolmogorov model are approximations of the formalism we have derived. The analysis shows that it cannot be determined whether the deviation from the power-law parameter of Kolmogorov turbulence is caused by real variations of the spectrum or by the effect of the finite outer scale.


Prediction of lymph node metastases in vulvar cancer: a review.
The aim of this study was to review the literature on currently available non- and minimally-invasive diagnostic methods and analysis of primary tumor characteristics for prediction of inguinofemoral lymph node metastases in patients with primary squamous cell carcinoma of the vulva. We used the English language literature in PubMed and reference lists from selected articles. Search terms included vulvar carcinoma, prognosis, lymph node metastases, ultrasound, computer tomography, magnetic resonance imaging, positron emission tomography, and sentinel lymph node. No study type restrictions were imposed. Currently no noninvasive imaging techniques exist that are able to predict lymph node metastases with a high enough negative predictive value. A depth of invasion < or =1 mm is the only histopathologic parameter that can exclude patients for complete inguinofemoral lymphadenectomy. No other clinicopathologic parameter allows exclusion of lymph node metastases with a high enough negative predictive value. The minimally invasive sentinel node procedure is a promising technique for selecting patients for complete lymphadenectomy, but its safety has not been proven yet.


Production of antimicrobial defensin in Nicotiana benthamiana with a potato virus X vector.
A recombinant plasmid, pTXS.TH, was constructed to express the gene-encoding wasabi (Wasabia japonica) defensin with the potato virus X (PVX) vector. pTXS.TH allows the expression of defensin in the host Nicotiana benthamiana, and the defensin protein WT1 can be purified from virus-infected leaves by heat treatment and affinity chromatography. WT1 exhibits strong antifungal activity toward the phytopathogenic fungi Magnaporthe grisea (50% inhibitory concentration [IC50] = 5 microg/ml) and Botrytis cinerea (IC50 = 20 microg/ml) but is weakly active against the phytopathogenic bacterium Pseudomonas cichorii. This virus-mediated expression system is a rapid and efficient method to produce and characterize antimicrobial proteins in plants. It is particularly useful for the study of proteins that are difficult to produce with other expression systems.


An economical and environmentally friendly oxidative biaryl coupling promoted by activated MnO2.
An activated manganese dioxide (MnO2)-BF3·OEt2 oxidation system was developed to efficiently mediate the intramolecular as well as intermolecular biaryl coupling. The oxidative coupling proceeds smoothly at ambient temperature to deliver the corresponding five- to eight-membered tricyclic products in good to excellent yields. The employment of the combination of MnO2 and BF3·OEt2 is attractive on the basis of economical and environmental issues.


Conformational Switch Regulates the DNA Cytosine Deaminase Activity of Human APOBEC3B.
The APOBEC3B (A3B) single-stranded DNA (ssDNA) cytosine deaminase has important roles in innate immunity but is also a major endogenous source of mutations in cancer. Previous structural studies showed that the C-terminal catalytic domain of human A3B has a tightly closed active site, and rearrangement of the surrounding loops is required for binding to substrate ssDNA. Here we report structures of the A3B catalytic domain in a new crystal form that show alternative, yet still closed, conformations of active site loops. All-atom molecular dynamics simulations support the dynamic behavior of active site loops and recapitulate the distinct modes of interactions that maintain a closed active site. Replacing segments of A3B loop 1 to mimic the more potent cytoplasmic deaminase APOBEC3A leads to elevated ssDNA deaminase activity, likely by facilitating opening of the active site. These data collectively suggest that conformational equilibrium of the A3B active site loops, skewed toward being closed, controls enzymatic activity by regulating binding to ssDNA substrates.


Working Hours Flexibility and Timing of Retirement: Findings from Europe.
This study investigates how flexibility in working hours affects retirement timing. It tests the assumption that decreasing weekly working hours delays retirement and extends working life. Using data from four waves of the Survey of Health, Ageing and Retirement in Europe (SHARE) and of the English Longitudinal Study of Ageing (ELSA), we analyze whether a shift from full-time to part-time work delays retirement. Results show that older workers who reduce their working hours retire earlier than those who stay in full-time employment. The effect is stronger in Central and Eastern Europe than in Scandinavian countries. No interaction effects for gender and work strain are found. We conclude that part-time work at the end of the career, as a means to extend working life, should be reevaluated.


Tactile orientation perception: an ideal observer analysis of human psychophysical performance in relation to macaque area 3b receptive fields.
The ability to resolve the orientation of edges is crucial to daily tactile and sensorimotor function, yet the means by which edge perception occurs is not well understood. Primate cortical area 3b neurons have diverse receptive field (RF) spatial structures that may participate in edge orientation perception. We evaluated five candidate RF models for macaque area 3b neurons, previously recorded while an oriented bar contacted the monkey's fingertip. We used a Bayesian classifier to assign each neuron a best-fit RF structure. We generated predictions for human performance by implementing an ideal observer that optimally decoded stimulus-evoked spike counts in the model neurons. The ideal observer predicted a saturating reduction in bar orientation discrimination threshold with increasing bar length. We tested 24 humans on an automated, precision-controlled bar orientation discrimination task and observed performance consistent with that predicted. We next queried the ideal observer to discover the RF structure and number of cortical neurons that best matched each participant's performance. Human perception was matched with a median of 24 model neurons firing throughout a 1-s period. The 10 lowest-performing participants were fit with RFs lacking inhibitory sidebands, whereas 12 of the 14 higher-performing participants were fit with RFs containing inhibitory sidebands. Participants whose discrimination improved as bar length increased to 10 mm were fit with longer RFs; those who performed well on the 2-mm bar, with narrower RFs. These results suggest plausible RF features and computational strategies underlying tactile spatial perception and may have implications for perceptual learning.


Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM.
To correlate muscle biopsy findings with prebiopsy and postbiopsy clinical course and response to therapy in polymyositis (PM) and sporadic inclusion body myositis (IBM). Existence of pure PM has recently been questioned; subsequently, the definition and criteria for diagnosing PM were debated. Patient records, follow-up information, and muscle biopsies were analyzed in 107 patients whose biopsies were initially read as PM and IBM. The patients fell into three groups by combined biopsy and clinical criteria: PM, 27 patients; IBM, 64 patients; PM/IBM, 16 patients with biopsy diagnosis of PM but clinical features of IBM. For the three groups, the respective mean periods from disease onset to end of follow-up were 5.9, 8.5, and 9.6 years. Another autoimmune disease was present in 4 of 27 PM, 8 of 64 IBM, and 1 of 16 PM/IBM cases. An autoimmune serologic marker occurred in one-third of each group. Nineteen PM patients had no associated autoimmune disease or marker. Nonnecrotic fiber invasion by mononuclear cells appeared in all IBM, 17 of 27 PM, and 13 of 16 PM/IBM patients. The density of both invaded fibers and cytochrome-c oxidase-negative fibers was higher in IBM and PM/IBM than in PM. Immunotherapy improved 22 of 27 PM patients but had only transient beneficial effects in 2 of 32 IBM and 1 of 14 PM/IBM patients. 1) Sixteen of 43 patients (37%) with biopsy features of polymyositis (PM) had clinical features of inclusion body myositis (IBM). 2) Absence of canonical biopsy features of IBM from clinically affected muscles of IBM patients challenges biopsy criteria for IBM, or the IBM markers appear late in some patients, or their distribution in muscle is patchy and restricted compared with that of the inflammatory exudate. 3) The muscle biopsy is a reliable instrument in the diagnosis of PM and IBM in close to 85% of the patients. Errors of diagnosis in the remaining 15% can be avoided or reduced by combined evaluation of the clinical and pathologic findings.


A three-dimensional approach to mitotic chromosome structure: evidence for a complex hierarchical organization.
We describe findings on the architecture of Drosophila melanogaster mitotic chromosomes, made using a three-dimensional-oriented structural approach. Using high-voltage and conventional transmission electron microscopy combined with axial tomography and digital contrast-enhancement techniques, we have for the first time visualized significant structural detail within minimally perturbed mitotic chromosomes. Chromosomes prepared by several different preparative procedures showed a consistent size hierarchy of discrete chromatin structural domains with cross-sectional diameters of 120, 240, 400-500, and 800-1,000 A. In fully condensed, metaphase-arrested chromosomes, there is evidence for even larger-scale structural organization in the range of 1,300-3,000-A size. The observed intrachromosomal arrangements of these higher-order structural domains show that both the radial loop and sequential helical coiling models of chromosome structure are over-simplifications of the true situation. Finally, our results suggest that the pathway of chromatin condensation through mitosis consists of concurrent changes occurring at several levels of chromatin organization, rather than a strictly sequential folding process.


A comparative study of Ligophorus uruguayense and L. saladensis (Monogenea: Ancyrocephalidae) from Mugil liza (Teleostei: Mugilidae) in southern Brazil.
Representatives of Ligophorus Euzet et Suriano, 1977 were found on the gills of Mugil liza Valenciennes caught in southern Brazil. They were identified as Ligophorus uruguayense Failla Siquier et Ostrowski de Núñez, 2009 and Ligophorus saladensis Marcotegui et Martorelli, 2009, even though specific identification proved to be difficult due to inconsistencies in some diagnostic features reported for these two species. Therefore, a combined morphological and molecular approach was used to critically review the validity of these species, by means of phase contrast and confocal fluorescence microscopical examination of sclerotised hard parts, and assessing the genetic divergence between L. saladensis, L. uruguayense and their congeners using rDNA sequences. The main morphological differences between the two species relate to the shape of the accessory piece of the penis and the median process of the ventral bar. The accessory piece in L. uruguayense is shorter than in L. saladensis, has a cylindrical, convex upper lobe and straight lower lobe (vs with the distal tip of the lower lobe turning away from the upper lobe in the latter species). The ventral bar has a V-shaped anterior median part in L. uruguayense (vs U-shaped in L. saladensis). The two species are suggested to be part of a species complex together with L. mediterraneus Sarabeev, Balbuena et Euzet, 2005. We recommend to generalise such comparative assessment of species of Ligophorus for a reliable picture of the diversity and diversification mechanisms within the genus, and to make full use of its potential as an additional marker for mullet taxonomy and systematics.


State responses to the malpractice insurance "crisis" of the 1970s: an empirical assessment.
Almost all states enacted legislation in response to the rapid rise in malpractice insurance premiums which occurred during the mid-1970s. After describing the types of statutory changes enacted, this study evaluates the influence of these changes on levels and growth of premiums paid by general practitioners, ophthalmologists, and orthopedic surgeons during 1974-78. The empirical results of the study presented here give no indication that individual state legislative actions, or actions taken collectively, had their intended effects on premiums. Several explanations for this result are explored.


Selection of RNAs that bind to duplex DNA at neutral pH.
RNA that are capable of binding duplex DNA in a site-specific manner have potential applications in gene therapy strategies. Such RNAs might be targeted to DNA sequences in a gene promoter and prevent initiation of transcription by occluding transcription factors and/or RNA polymerases. RNA oligonucleotides that bind homopurine/homopyrimidine DNA sequences by forming triple-helical complexes involving T.A.T and C+.G.C base-triplets can be rationally designed. However, the formation of such pyrimidine motif triple helices typically requires mildly acidic conditions. In addition, the proper oligonucleotide sequence must be optimally presented within a longer RNA transcript if it is to be synthesized in vivo. To address these issues, RNAs were selected from pools of random sequences for binding to a homopurine/homopyrimidine DNA sequence. RNAs selected for binding the duplex DNA target between pH 6.5 and pH 7.4 were characterized by sequence analysis and binding studies. All RNAs isolated by selection and amplification were found to contain a pyrimidine recognition sequence for binding the duplex DNA target via conventional triple helix formation. The selected approximately 85 nt RNAs have dissociation constants that approach, but do not surpass, the binding affinity of a 21 nt RNA oligonucleotide that binds the DNA target sequence by forming a canonical triple helix. The presence of a pyrimidine recognition sequence within a longer RNA transcript is not sufficient for high affinity. Experimental data and secondary structure predictions suggest that the context of the pyrimidine recognition sequence within selected RNAs is a very important determinant of DNA binding affinity. These studies provide insight into the development of RNA transcripts that may function as gene-specific repressors by forming triple helices with DNA in vivo.


Prevalence of major depression, simple phobia, and other psychiatric disorders in patients with long-standing type I diabetes mellitus.
To examine the prevalence of psychiatric disorders in patients with long-standing type I diabetes mellitus, we assessed a series of candidates for pancreas transplantation. Using the Diagnostic Interview Schedule, six-month and lifetime prevalences of psychiatric disorders were established for the candidates and their potential donors (first-degree relatives). Excluding tobacco use disorder and psychosexual dysfunction, 38 diabetic subjects (51%) received one or more psychiatric diagnoses. The lifetime prevalence of major depression was comparable for female (11 of 48 [22.9%]) and male (seven of 27 [25.9%]) diabetics; both rates were significantly higher than rates in first-degree relatives and the general population. Among female diabetics, the six-month and lifetime prevalences of simple phobia were increased vs donors and the general population; among male diabetics, the lifetime prevalence of antisocial personality disorder was greater than that in the general population. None of these disorders was found to be related to the duration of diabetes or the presence of various complications. The data suggest that increased rates of psychiatric disorder in type I diabetics have both gender-independent and gender-related components.


Increased alpha-subunit response coexist with increased TSH response to TRH test in healthy individuals.
The alpha-subunit (Alpha-SU) response to TRH was studied to examine the response of alpha-SU under TRH stimulation in normal situation. Thirty seven healthy individuals were included in the study. They were divided into two groups according to the data taken: A with TSH equal or more than seven fold the basal values (0: 3.14+/-1.2 microU/ml., 30 after TRH: 20.22+/-4.6 microU/ml) and B with TSH 2 to 6 fold the basal values (0: 0.5+/-0.1 microU/ml., 30 after TRH: 2.9+/-0.5 microU/ml). Both groups exhibited similar FT3 and FT4 levels. In group A, prolactin displayed a 3 fold increase from the basal values, whereas alpha-SU increased 4 fold with a difference being statistically significant (p<0.001). In contrast, in group B individuals neither prolactin nor alpha-SU exhibited any significant difference from the basal values. The expression of alpha-SU upon TRH stimulation is dependent on the TSH basal values.


Inflammatory alterations in mesenteric adipose tissue in Crohn's disease.
Abnormalities of fat in the mesentery including adipose tissue hypertrophy and fat wrapping have been long recognized on surgical specimens as characteristic features of Crohn's disease. However, the importance, origin, and significance of the mesenteric fat hypertrophy in this chronic inflammatory disease are unknown. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a crucial factor involved in the homeostasis of adipose tissue, a major source of biologically active mediators. Intra-abdominal fat accumulation was quantified using a magnetic resonance imaging method in patients with Crohn's disease and controls. PPARgamma and inflammatory cytokines synthesized by mesenteric adipose tissues were assessed by quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. In vivo, patients with Crohn's disease have an important accumulation of intra-abdominal fat. This mesenteric obesity, present from the onset of the disease, is associated with overexpression of PPARgamma and tumor necrosis factor (TNF)-alpha, synthesized, at least in part, by adipocytes. These results suggest that confined increased PPARgamma mesenteric concentrations could lead to the mesenteric fat hypertrophy, which could actively participate through the synthesis of TNF-alpha in the inflammatory response.


Molecular dissection of telomeric repeat-containing RNA biogenesis unveils the presence of distinct and multiple regulatory pathways.
Telomeres are transcribed into telomeric repeat-containing RNA (TERRA), large, heterogeneous, noncoding transcripts which form part of the telomeric heterochromatin. Despite a large number of functions that have been ascribed to TERRA, little is known about its biogenesis. Here, we present the first comprehensive analysis of the molecular structure of TERRA. We identify biochemically distinct TERRA complexes, and we describe TERRA regulation during the cell cycle. Moreover, we demonstrate that TERRA 5' ends contain 7-methylguanosine cap structures and that the poly(A) tail, present on a fraction of TERRA transcripts, contributes to their stability. Poly(A)(-) TERRA, but not poly(A)(+) TERRA, is associated with chromatin, possibly reflecting distinct biological roles of TERRA ribonucleoprotein complexes. In support of this idea, poly(A)(-) and poly(A)(+) TERRA molecules end with distinct sequence registers. We also determine that the bulk of 3'-terminal UUAGGG repeats have an average length of 200 bases, indicating that the length heterogeneity of TERRA likely stems from its subtelomeric regions. Finally, we find that TERRA is regulated during the cell cycle, being lowest in late S phase and peaking in early G(1). Our analyses offer the basis for investigating multiple regulatory pathways that affect TERRA synthesis, processing, turnover, and function.


Multiple organ failure syndrome.
Although many new areas of research are directed at the regulatory aspects of the metabolic response, the prognosis of MOF remains poor. Critical care nurses, challenged to provide a supportive environment during this life-threatening syndrome, must understand its onset, clinical patterns, and prolonged support required by patients. Such knowledge will enable critical care nurses to detect subtle changes while monitoring clinical status, and facilitate timely interventions in order to decrease the morbidity and mortality associated with MOF.


Can segmental mobility be increased by cervical arthroplasty?
OBJECTIVE Many reports have successfully demonstrated that cervical disc arthroplasty (CDA) can preserve range of motion after 1- or 2-level discectomy. However, few studies have addressed the extent of changes in segmental mobility after CDA or their clinical correlations. METHODS Data from consecutive patients who underwent 1-level CDA were retrospectively reviewed. Indications for surgery were medically intractable degenerative disc disease and spondylosis. Clinical outcomes, including visual analog scale (VAS)-measured neck and arm pain, Neck Disability Index (NDI), and Japanese Orthopaedic Association (JOA) scores, were analyzed. Radiographic outcomes, including C2-7 Cobb angle, the difference between pre- and postoperative C2-7 Cobb angle (ΔC2-7 Cobb angle), sagittal vertical axis (SVA), the difference between pre- and postoperative SVA (ΔSVA), segmental range of motion (ROM), and the difference between pre- and postoperative ROM (ΔROM), were assessed for their association with clinical outcomes. All patients underwent CT scanning, by which the presence and severity of heterotopic ossification (HO) were determined during the follow-up. RESULTS A total of 50 patients (mean age 45.6 ± 9.33 years) underwent a 1-level CDA (Prestige LP disc) and were followed up for a mean duration of 27.7 ± 8.76 months. All clinical outcomes, including VAS, NDI, and JOA scores, improved significantly after surgery. Preoperative and postoperative ROM values were similar (mean 9.5° vs 9.0°, p > 0.05) at each indexed level. The mean changes in segmental mobility (ΔROM) were -0.5° ± 6.13°. Patients with increased segmental mobility after surgery (ΔROM > 0°) had a lower incidence of HO and HO that was less severe (p = 0.048) than those whose ΔROM was < 0°. Segmental mobility (ROM) was significantly lower in patients with higher HO grade (p = 0.012), but it did not affect the clinical outcomes. The preoperative and postoperative C2-7 Cobb angles and SVA remained similar. The postoperative C2-7 Cobb angles, SVA, ΔC2-7 Cobb angles, and ΔSVA were not correlated to clinical outcomes after CDA. CONCLUSIONS Segmental mobility (as reflected by the mean ROM) and overall cervical alignment (i.e., mean SVA and C2-7 Cobb angle) had no significant impact on clinical outcomes after 1-level CDA. Patients with increased segmental mobility (ΔROM > 0°) had significantly less HO and similarly improved clinical outcomes than those with decreased segmental mobility (ΔROM < 0°).


Discovery of electric devil's staircase in perovskite antiferroelectric.
The devil's staircase, describing step-like function for two competing frequencies, is well known over a wide range of dynamic systems including Huyghens' clocks, Josephson junction, and chemical reaction. In condensed matter physics, the devil's staircase has been observed in spatially modulated structures, such as magnetic ordering. It draws widespread attentions because it plays a crucial role in the fascinating phenomena including phase-locking behaviors, commensurate-incommensurate phase transition, and spin-valve effect. Here, we report the observation of polymorphic phase transitions consisting of several steps in PbZrO3-based system-namely, electric devil's staircase-originated from competing ferroelectric and antiferroelectric interactions. We fully characterize a specific electric dipole configuration by decomposing this competitive interaction in terms of basic structure and modulation function. Of particular interest is that the occurrence of many degenerate electric dipole configurations in devil's staircase enables superior energy storage performance. These observations are of great significance for exploring more substantive magnetic-electric correspondence and engineering practical high-power antiferroelectric capacitors.


Mechanical metamaterials with negative compressibility transitions.
When tensioned, ordinary materials expand along the direction of the applied force. Here, we explore network concepts to design metamaterials exhibiting negative compressibility transitions, during which a material undergoes contraction when tensioned (or expansion when pressured). Continuous contraction of a material in the same direction of an applied tension, and in response to this tension, is inherently unstable. The conceptually similar effect we demonstrate can be achieved, however, through destabilizations of (meta)stable equilibria of the constituents. These destabilizations give rise to a stress-induced solid-solid phase transition associated with a twisted hysteresis curve for the stress-strain relationship. The strain-driven counterpart of negative compressibility transitions is a force amplification phenomenon, where an increase in deformation induces a discontinuous increase in response force. We suggest that the proposed materials could be useful for the design of actuators, force amplifiers, micromechanical controls, and protective devices.


Chemotaxis of the marine bacterium Vibrio furnissii to sugars. A potential mechanism for initiating the chitin catabolic cascade.
Immense quantities of chitin are catabolized by marine bacteria, and this process involves at least three signal transduction systems in Vibrio furnissii. One system, chemotaxis to chitin oligosaccharides, is probably used to colonize chitin particles. But how do the first few cells find this highly insoluble polysaccharide? The following hypothesis is proposed to answer this question: the bacteria respond to soluble chemo-attractants in exudates from injured organisms. Virtually all chitin-producing organisms also contain glucose and/or trehalose, often at high concentrations such as trehalose in insect hemolymph. Chemotaxis of V. furnissii was therefore studied with a variety of sugars. Fructose, ribose, and glycerol are catabolites but not attractants. The cells exhibit weak constitutive taxis to Glc and GlcNAc. After induction, they show a weak response to galactose but are strongly attracted to the following substrates of the phosphoenolpyruvate:glycose phosphotransferase system (PTS): GlcNAc, trehalose, glucose, sucrose, mannose, and mannitol. There is a rough qualitative but no quantitative correlation between the rate of phosphorylation and the chemotactic response to PTS sugars. Trehalose is especially noteworthy because it is phosphorylated at a very rapid rate by uninduced cells but is not an attractant until the cells are induced. We suggest that unidentified inducible factors link the PTS to chemotaxis.


Diagnosis and treatment of biliary tract complications after orthotopic liver transplantation.
Biliary tract complications are a continuing source of morbidity after liver transplantation. In a 3.5-year period we performed 264 liver transplants in 226 patients (132 adults, 94 children). Biliary tract reconstruction was via Roux limb choledochojejunostomy (n = 144) or choledochocholedochostomy (n = 118). Fifty (19.1%) biliary complications occurred, and 35 (13.4%) necessitated operative repair. The incidence was similar in adults and children and after each method of reconstruction. Risk factors were vascular thrombosis and reduced-sized transplants. Diagnosis was based on the algorithmic use of multiple modalities with early biliary visualization. Roux limb complications usually occurred in the first month after transplant and necessitated operative intervention, whereas duct-to-duct problems appeared later and were more accessible to percutaneous or endoscopic manipulations. Eight (6.8%) patients required conversion to a Roux limb, whereas 8/15 (53.3%) cases of biliary stricture were successfully managed nonoperatively. Three (1.3%) patients and four (1.5%) grafts were lost as a result of biliary complications. One-year actuarial patient survival is 76.4% with a mean follow-up of 13.2 months. Early recognition of biliary complications and prompt interventional therapy can effectively prevent long-term sequelae. Although choledochocholedochostomy is more physiologic and expeditious, Roux-en-Y choledochojejunostomy remains a safe and versatile alternative and is the preferred method of reconstruction in select cases.