Access and quality of parks and associations with obesity: A cross-sectional study.
Public health is increasingly engaging with multi-faceted obesity prevention efforts. Although parks represent key community assets for broader public health, they may not be distributed equitably and associations with obesity are equivocal. We investigated park access and quality relative to deprivation and obesity with individual-level data from the Yorkshire Health Study. Compared to the least deprived areas, the moderately and most deprived areas had a greater park access and park quality in terms of features and amenities. However, parks in the moderately and most deprived areas also had the most safety concerns and incivilities. Although deprivation was associated with obesity, contrary to current policy guidance, both park access and quality appear less important for understanding variations in obesity within this study. Although sub-group analyses by deprivation tertile revealed that low quality park amenities in highly and moderately deprived areas may be important for understanding obesity prevalence, all other associations were non-significant.


Flavanone-rich citrus beverages counteract the transient decline in postprandial endothelial function in humans: a randomised, controlled, double-masked, cross-over intervention study.
Specific flavonoid-rich foods/beverages are reported to exert positive effects on vascular function; however, data relating to effects in the postprandial state are limited. The present study investigated the postprandial, time-dependent (0-7 h) impact of citrus flavanone intake on vascular function. An acute, randomised, controlled, double-masked, cross-over intervention study was conducted by including middle-aged healthy men (30-65 years, n 28) to assess the impact of flavanone intake (orange juice: 128·9 mg; flavanone-rich orange juice: 272·1 mg; homogenised whole orange: 452·8 mg; isoenergetic control: 0 mg flavanones) on postprandial (double meal delivering a total of 81 g of fat) endothelial function. Endothelial function was assessed by flow-mediated dilatation (FMD) of the brachial artery at 0, 2, 5 and 7 h. Plasma levels of naringenin/hesperetin metabolites (sulphates and glucuronides) and nitric oxide species were also measured. All flavanone interventions were effective at attenuating transient impairments in FMD induced by the double meal (7 h post intake; P<0·05), but no dose-response effects were observed. The effects on FMD coincided with the peak of naringenin/hesperetin metabolites in circulation (7 h) and sustained levels of plasma nitrite. In summary, citrus flavanones are effective at counteracting the negative impact of a sequential double meal on human vascular function, potentially through the actions of flavanone metabolites on nitric oxide.


Effects of atriopeptin III on isolated rat afferent and efferent arterioles.
The effects of atriopeptin III (AP III) on in vitro prepared afferent (AA) and efferent arterioles (EA) from rat kidneys were tested in a system in which lumen diameter could be measured. AP III (10(-13)-10(-7) M) had no effect on lumen diameter of AA that were not preconstricted. When AA were preconstricted with either angiotensin II (ANG II) or norepinephrine (NE), however, AP III increased lumen diameter in a concentration-dependent manner to the preconstriction baseline value. Maximal vasodilation occurred at 10(-10) M AP III. Unlike AA, EA constricted by 50% to 10(-10) M AP III further constricted EA that were pretreated with ANG II or NE. Dilation in ANG II-preconstricted AA to AP III was not inhibited by indomethacin. Constriction of EA to AP III was not altered by [Sar1-Ala8] ANG II, enalapril, OKY 046, or phentolamine. Results indicate that in isolated renal arterioles AP III dilates preconstricted AA but constricts EA that have either not been pretreated or have been preconstricted with other agonists. The effect of AP III on preconstricted AA does not require vasodilator prostaglandin mediation. The constrictor effect of AP III on EA is not dependent on angiotensin, thromboxane, or alpha-adrenergic mediation.


Oral tolerance to nickel requires CD4+ invariant NKT cells for the infectious spread of tolerance and the induction of specific regulatory T cells.
Previously, oral administration of nickel to C57BL/6 wild-type (WT) mice was shown to render both their splenic T cells and APCs (i.e., T cell-depleted spleen cells) capable of transferring nickel tolerance to naive syngeneic recipients. Moreover, sequential adoptive transfer experiments revealed that on transfer of tolerogenic APCs and immunization, the naive T cells of the recipients differentiated into regulatory T (Treg) cells. Here, we demonstrate that after oral nickel treatment Jalpha18(-/-) mice, which lack invariant NKT (iNKT) cells, were not tolerized and failed to generate Treg cells. However, transfer of APCs from those Jalpha18(-/-) mice did tolerize WT recipients. Hence, during oral nickel administration, tolerogenic APCs are generated that require iNKT cell help for the induction of Treg cells. To obtain this help, the tolerogenic APCs must address the iNKT cells in a CD1-restricted manner. When Jalpha18(-/-) mice were used as recipients of cells from orally tolerized WT donors, the WT Treg cells transferred the tolerance, whereas WT APCs failed to do so, although they proved tolerogenic on transfer to WT recipients. However, Jalpha18(-/-) recipients did become susceptible to the tolerogenicity of transferred WT APCs when they were reconstituted with IL-4- and IL-10-producing CD4(+) iNKT cells. We conclude that CD4(+) iNKT cells are required for the induction of oral nickel tolerance and, in particular, for the infectious spread of tolerance from APCs to T cells. Once induced, these Treg cells, however, can act independently of iNKT cells.


Remobilization does not restore immobilization-induced adhesion of capsule and restricted joint motion in rat knee joints.
Joint immobilization, which is used in orthopaedic treatments and observed in bedridden people, usually causes restricted joint motion. Decreased joint motion diminishes activities of daily living and increases burden of nursing-care. The purpose of this study was to clarify the reversibility of immobilization-induced capsular changes and restricted joint motion in rat knee joints. The unilateral knee joints of adult male rats were immobilized with an internal fixator for 1, 2, 4, 8, and 16 weeks as a model of immobilization after surgery or disuse of the joint. After the fixation devices were removed, the rats were allowed to move freely for 16 weeks. Sham-operated rats were used as controls. Sagittal sections at medial midcondylar regions were made and assessed with histological, histomorphometric, and immunohistochemical methods. Joint motion was measured using a custom-made device under x-ray control after removal of the periarticular muscles. In the 1/16-week and 2/16-week immobilization-remobilization (Im-Rm) groups, cord-like structures connecting the superior and inferior portions of the posterior capsule (partial adhesion) were observed without restricted joint motion. In the 4/16-, 8/16-, and 16/16-week Im-Rm groups, global adhesion of the posterior capsule and restricted joint motion were observed. The restricted joint motion was not completely restored after incision of the posterior capsule. These data indicate that immobilization alone causes irreversible capsular changes and arthrogenic restricted joint motion. Besides the joint capsule, other arthrogenic factors such as ligaments might influence the restricted joint motion. Prolonged immobilization over 4 weeks should be avoided to prevent irreversible joint contracture.


Widespread white matter degeneration preceding the onset of dementia.
Brain atrophy in subjects with mild cognitive impairment (MCI) introduces partial volume effects, limiting the sensitivity of diffusion tensor imaging to white matter microstructural degeneration. Appropriate correction isolates microstructural effects in MCI that might be precursors of Alzheimer's disease (AD). Forty-eight participants (18 MCI, 15 AD, and 15 healthy controls) had magnetic resonance imaging scans and clinical evaluations at baseline and follow-up after 36 months. Ten MCI subjects were diagnosed with AD at follow-up and eight remained MCI. Free-water (FW) corrected measures on the white matter skeleton were compared between groups. FW corrected radial diffusivity, but not uncorrected radial diffusivity, was increased across the brain of the converted group compared with the nonconverted group (P < .05). The extent of increases was similar to that found comparing AD with controls. Partial volume elimination reveals microstructural alterations preceding dementia. These alterations may prove to be an effective and feasible early biomarker of AD.


Dimming the "Halo" Around Monogamy: Re-assessing Stigma Surrounding Consensually Non-monogamous Romantic Relationships as a Function of Personal Relationship Orientation.
Previous research suggests that both monogamous and consensually non-monogamous (CNM) participants rate monogamous targets more positively. However, this pattern of stigma toward CNM relationships and the "halo effect" surrounding monogamy is at odds with the view that people typically favor members from their own groups over members of other groups. In the current research, we sought to re-examine the halo effect, using a more direct measure of stigma (i.e., desired social distance), in a methodological context that differentiates between the three most common types of CNM relationships. A convenience sample (N = 641) of individuals who self-identified as monogamous (n = 447), open (n = 80), polyamorous (n = 62), or swinger (n = 52) provided social distance ratings in response to these same relationship orientations in a counterbalanced order. Congruent with prior findings, CNM participants favored monogamous targets over CNM targets as a broad category (replicating the halo effect). However, results indicated this effect dissipated when participants were asked to differentiate between relationships they identify with, and other CNM relationships. Furthermore, supplementary findings suggest that monogamous targets were perceived to be the least promiscuous and were associated with the lowest perceived sexually transmitted infection (STI) rates, while swinger targets were perceived as the most promiscuous and were associated with the highest perceived STI rates. Consequently, our results imply social distance is partly attributable to the perception of STI risk, but not perceptions of promiscuity.


Variations on a theme: Polycomb group proteins in plants.
Polycomb group (PcG) proteins evolved early in evolution, probably in the common ancestor of animals and plants. In some unicellular organisms, such as Chlamydomonas and Tetrahymena, PcG proteins silence genes in heterochromatin, suggesting an ancestral function in genome defence. In angiosperms, the PcG system controls many developmental transitions. A PcG function in the vernalization response evolved especially in Brassicaceaea. Thus, the role of PcG proteins has changed during evolution to match novel needs. Recent studies identified many proteins associated with plant PcG protein complexes. Possible functions of these interactions are discussed here. We highlight recent findings about recruitment of PcG proteins in plants in comparison with animal system. Through the new data, a picture emerges in which PcG protein complexes do not function in sequential linear pathways but as dynamically interacting networks allowing stabilizing feedback loops. We discuss how the interplay between different PcG protein complexes can enable establishment, maintenance, and epigenetic inheritance of H3K27me3.


Implementing a breast cancer registry and treatment plan/summary program in clinical practice: a pilot program.
There is a need to better measure and improve the quality of oncology care and improve communication with patients and other providers. The American Society of Clinical Oncology Breast Cancer Registry (BCR) pilot evaluated the feasibility and acceptability of prospective data collection for quality assessment in daily clinical practice. Data were used to create and share treatment plans/summaries (TPSs) at the point of care. Using a web-based tool, 20 diverse practices entered clinical data on each new early-stage breast cancer patient into the BCR for 14 months (September 2009 through November 2010). The tool created individual TPSs that were shared with patients. Practices received practice-specific and aggregate BCR quality measures data, participated in a survey, and received a participation stipend. Twenty practices entered 2014 patients into the BCR, collecting demographic, clinical, and treatment information. Fifty-two percent of practice participants replied to an end-of-pilot survey: 73% were satisfied with the BCR and web-based tool, 31% expressed concern regarding time and effort, and 52% reported additional practice costs during the pilot. Among those who created or shared the TPSs, 90% thought the documents improved oncologist-patient communication, and 95% favored using BCR data for practice quality improvement. Prospective data collection for quality assessment is feasible and allows sharing of TPSs with patients at the point of care. Future efforts should focus on decreasing implementation burden to practices, broadening participation, examining costs, and, most importantly, assessing its effects on patient outcomes.


Calcitriol-mediated hypercalcemia secondary to granulomatous disease caused by soft-tissue filler injection: a case report.
Soft-tissue filler (STF) injections have been used worldwide for cosmetic reasons. In most cases, they are not approved by the United States Food and Drug Administration (FDA). Regulatory boards in Latin American countries do not allow the medical use of STF injections; however, these injections are still widely used. A case of calcitriol-mediated hypercalcemia with ectopic calcifications, chronic kidney disease, nephrolithiasis and calcinosis is presented. The reported case highlights the consequences of STF use, including calcitriol-mediated hypercalcemia secondary to granulomatous reactions years after an esthetic procedure.


Caffeic Acid Phenethyl Ester Assisted by Reversible Electroporation-In Vitro Study on Human Melanoma Cells.
Melanoma is one of the most serious skin cancers. The incidence of this malignant skin lesion is continuing to increase worldwide. Melanoma is resistant to chemotherapeutic drugs and highly metastatic. Surgical resection can only be used to treat melanoma in the early stages, while chemotherapy is limited due to melanoma multi-drug resistance. The overexpression of glutathione S-transferase (GST) may have a critical role in this resistance. Caffeic acid phenethyl ester (CAPE) is a natural phenolic compound, which occurs in many plants. Previous studies demonstrated that CAPE suppresses the growth of melanoma cells and induces reactive oxygen species generation. It is also known that bioactivation of CAPE to its corresponding quinone metabolite by tyrosinase would lead to GST inhibition and selective melanoma cell death. We investigated the biochemical toxicity of CAPE in combination with microsecond electropermeabilization in two human melanoma cell lines. Our results indicate that electroporation of melanoma cells in the presence of CAPE induced high oxidative stress, which correlates with high cytotoxicity. Moreover, it can disrupt the metabolism of cancer cells by inducing apoptotic cell death. Electroporation of melanoma cells may be an efficient CAPE delivery system, enabling the application of this compound, while reducing its dose and exposure time.


Systematic review: societal cost of illness of inflammatory bowel disease is increasing due to biologics and varies between continents.
Knowledge of the cost of illness of inflammatory bowel disease (IBD) is essential for health policy makers worldwide. To assess the cost of illness of IBD from the societal perspective taking into account time trends and geographical differences. A systematic review of all population-based studies on cost of illness of IBD published in Embase, Medline, Web of Science and Google Scholar. Methodology of included studies was assessed and costs were adjusted to 2018 US dollars. Study methodologies differed considerably, with large differences in perspective, valuation method and population. For prevalent Crohn's disease (CD) cases in the last ten years annual healthcare costs were in Asia $4417 (range $1230-$31 161); Europe $12 439 ($7694-$15 807) and North America $17 495 ($14 454-$20 535). For ulcerative colitis (UC), these were $1606 ($309-$14 572), $7224 ($3228-$9779) and $13 559 ($13 559-$13 559). The main cost driver was medication, the cost of which increased considerably between 1985 and 2018, while outpatient and inpatient costs remained stable. IBD had a negative impact on work productivity. Annual costs of absenteeism for CD and UC were in Asia (with presenteeism) $5638 ($5638-$5638) and $4828 ($4828-$4828); Europe $2660 ($641-$5277) and $2394 ($651-$5992); North America $752 ($307-$1303) and $1443 ($85-$2350). IBD societal cost of illness is increasing, driven by growing costs of medication, and varies considerably between continents. While biologic therapy was expected to decrease inpatient costs by reducing hospitalisations and surgery, these costs have not declined.


Parent ratings of ability to consent for clinical trials in fragile X syndrome.
Advances in understanding neurobiology and intellectual disabilities have led to clinical trials testing new medications. This study assessed parents' perceptions of the ability of their son or daughter with fragile X syndrome (FXS), an inherited form of intellectual disability, to participate in the consent process for clinical trials. Four hundred twenty-two families participated in a survey that included six items assessing various aspects of the ability to provide consent. A rank ordering of decisional tasks was found. The easiest task was to understand that the medication was different from his or her medical treatment; the most difficult was the ability to understand and weigh the potential benefits and risks of study participation. Factor analysis suggested that despite the range in difficulty, the six items were best summarized by a single decisional ability score. Parents of 29% of males reported that their son was not at all capable of participating, but the remainder exhibited a range of decisional skills. Factors associated with this variability include age and parents' willingness to enroll their child in clinical trials. We conclude that many individuals with FXS appear to be able to participate at some level in the consent or assent process, but will likely need individualized support to maximize effective participation.


Gene expression module-based chemical function similarity search.
Investigation of biological processes using selective chemical interventions is generally applied in biomedical research and drug discovery. Many studies of this kind make use of gene expression experiments to explore cellular responses to chemical interventions. Recently, some research groups constructed libraries of chemical related expression profiles, and introduced similarity comparison into chemical induced transcriptome analysis. Resembling sequence similarity alignment, expression pattern comparison among chemical intervention related expression profiles provides a new way for chemical function prediction and chemical-gene relation investigation. However, existing methods place more emphasis on comparing profile patterns globally, which ignore noises and marginal effects. At the same time, though the whole information of expression profiles has been used, it is difficult to uncover the underlying mechanisms that lead to the functional similarity between two molecules. Here a new approach is presented to perform biological effects similarity comparison within small biologically meaningful gene categories. Regarding gene categories as units, a reduced similarity matrix is generated for measuring the biological distances between query and profiles in library and pointing out in which modules do chemical pairs resemble. Through the modularization of expression patterns, this method reduces experimental noises and marginal effects and directly correlates chemical molecules with gene function modules.


Alpha-theta brainwave neurofeedback training: an effective treatment for male and female alcoholics with depressive symptoms.
This was an experimental study of 14 alcoholic outpatients using the Peniston and Kulkosky (1989, 1991) brainwave treatment protocol for alcohol abuse. After temperature biofeedback pretraining, experimental subjects completed 20 40-minute sessions of alpha-theta brainwave neurofeedback training (BWNT). Experimentally treated alcoholics with depressive syndrome showed sharp reductions in self-assessed depression (Beck's Depression Inventory). On the Millon Clinical Multiaxial Inventory-I, the experimental subjects showed significant decreases on the BR scores: schizoid, avoidant, dependent, histrionic, passive-aggression, schizotypal, borderline, anxiety, somatoform, hypomanic, dysthmic, alcohol abuse, drug abuse, psychotic thinking, and psychotic depression. Twenty-one-month follow-up data indicated sustained prevention of relapse in alcoholics who completed BWNT.


Two versions of perspectives on caring for older patients scale: Translation and psychometric testing among Chinese nursing students.
This study aimed to translate the Perspectives on Caring for Older Patients scale into Chinese, both the full and the shortened versions, and test its psychometric properties among Chinese nursing students. In this methodological research, the scale were translated and administered to 307 nursing students recruited from two universities in mainland China. The psychometric testing mainly included internal consistency reliability using Cronbach's alphas, 2-week test-retest reliability using the intraclass correlation coefficient, convergent validity with Kogan's Attitude toward Older People scale, and factorial validity using exploratory factor analysis. Cronbach's alphas for the full and the shortened version scales were 0.77 and 0.75, respectively. The intraclass correlation coefficient values of both versions exceeded 0.70 and their scores were moderately correlated with the Kogan's Attitude toward Older People scale's scores. While exploratory factor analyses revealed a six-factor structure for the full version with factor loadings of five items below 0.3, the shortened version identified two factors with all factor loadings above 0.3. This study concluded that the psychometric properties of the full version scale were adequate and similar to those of the shortened version except for factorial validity.


Studies of thymic factors. I. Evaluation of the mouse rosette assay for thymic hormone.
The restoration of sensitivity to azathioprine of athymic (nu/nu) mouse splenic rosette-forming cells (RFC) has been used by others to assay thymic hormone. These previous studies have led to the conclusion that a major factor in the development of autoimmunity in New Zealand (NZ) mice and patients with systemic lupus erythematosus (SLE) is the premature loss of thymic hormone. We have studied the mouse rosette assay and find that poly A-Poly U and single stranded DNA, in addition to thymosin, restored azathioprine sensitivity to nu/nu RFC. Thus, other substances may mimic thymic hormone, perhaps via the cyclic AMP system. Furthermore, antibodies to T cells were found to interfere with the assay. Sera from old NZ mice which contain naturally occurring thymocytotoxic antibodies (NTA) failed to restore azathioprine sensitivity. Small quantities of NTA prevented normal sera from functioning in the assay. We conclude that the role of thymic hormone(s) in the development of autoimmunity in NZ mice and patients with SLE must be completely reevaluated.


Genetically transmitted cholinergic hyperresponsiveness predisposes to experimental asthma.
The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.


Encapsulating MnSe Nanoparticles Inside 3D Hierarchical Carbon Frameworks with Lithium Storage Boosted by in Situ Electrochemical Phase Transformation.
Electrode materials that act through the electrochemical conversion mechanism, such as metal selenides, have been considered as promising anode candidates for lithium-ion batteries (LIBs), although their fast capacity attenuation and inadequate electrical conductivity are impeding their practical application. In this work, these issues are addressed through the efficient fabrication of MnSe nanoparticles inside porous carbon hierarchical architectures for evaluation as anode materials for LIBs. Density functional theory simulations indicate that there is a completely irreversible phase transformation during the initial cycle, and the high structural reversibility of β-MnSe provides a low energy barrier for the diffusion of lithium ions. Electron localization function calculations demonstrate that the phase transformation leads to high charge transfer kinetics and a favorable lithium ion diffusion coefficient. Benefitting from the phase transformation and unique structural engineering, the MnSe/C chestnut-like structures with boosted conductivity deliver enhanced lithium storage performance (885 mA h g-1 at a current density of 0.2 A g-1 after 200 cycles), superior cycling stability (a capacity of 880 mA h g-1 at 1 A g-1 after 1000 cycles), and outstanding rate performance (416 mA h g-1 at 2 A g-1).


Influence of calcium-entry blockade on vasoconstrictor responses in feline mesenteric vascular bed.
The subtypes of postjunctional alpha-adrenoceptors activated by neuronally released and exogenous norepinephrine and the source of calcium used for vasoconstrictor responses were investigated in the feline mesenteric vascular bed. Under constant flow conditions, intra-arterial injections of phenylephrine and UK14304, alpha 1- and alpha 2-adrenoceptor agonists, increased mesenteric arterial perfusion pressure in a dose-related manner. Prazosin, an alpha 1-antagonist, reduced vasoconstrictor responses to phenylephrine without altering responses to UK14304. Yohimbine, an alpha 2-antagonist, reduced responses to UK14304 without altering responses to phenylephrine. The same pattern of blockade was observed in animals pretreated with 6-hydroxydopamine to destroy the integrity of adrenergic terminals. Responses to phenylephrine and UK14304 were reduced by nitrendipine, a calcium-entry blocking agent, and this agent decreased vasoconstrictor responses to sympathetic nerve stimulation, tyramine, and norepinephrine. Responses to sympathetic nerve stimulation were selectively blocked by prazosin, but responses to norepinephrine were selectively blocked by yohimbine. Vasoconstrictor responses to tyramine were reduced by both prazosin and yohimbine. Nitrendipine also reduced responses to angiotensin II, U46619, a prostaglandin endoperoxide analogue, Bay K 8644, and potassium chloride. These data suggest the presence of alpha 1- and postjunctional alpha 2-adrenoceptors and support the hypothesis that norepinephrine released by nerve excitation acts mainly on alpha 1-receptors but that exogenous norepinephrine acts primarily on alpha 2-receptors. However, norepinephrine released by tyramine acts on both receptor subtypes. Nitrendipine inhibited responses to the alpha 1- and alpha 2-adrenoceptor agonists as well as those to nerve released and exogenous norepinephrine, the calcium agonist, Bay K 8644, and to other vasoconstrictor agents. These data suggest that in the feline mesenteric vascular bed, an extracellular source of calcium ions is required for vasoconstriction induced by a variety of mechanisms including activation of alpha 1- and postjunctional alpha 2-adrenoceptors.


Posterior corrective surgery with a multilevel transforaminal lumbar interbody fusion and a rod rotation maneuver for patients with degenerative lumbar kyphoscoliosis.
The purpose of this study was to assess the clinical results of posterior corrective surgery using a multilevel transforaminal lumbar interbody fusion (TLIF) with a rod rotation (RR) and to evaluate the segmental corrective effect of a TLIF using CT imaging. The medical records of 15 consecutive patients with degenerative lumbar kyphoscoliosis (DLKS) who had undergone posterior spinal corrective surgery using a multilevel TLIF with an RR technique and who had a minimum follow-up of 2 years were retrospectively reviewed. Radiographic parameters were evaluated using plain radiographs, and segmental correction was evaluated using CT imaging. Clinical outcomes were evaluated with the Scoliosis Research Society Patient Questionnaire-22 (SRS-22) and the SF-36. The mean follow-up period was 46.7 months, and the mean age at the time of surgery was 60.7 years. The mean total SRS-22 score was 2.9 before surgery and significantly improved to 4.0 at the latest follow-up. The physical functioning, role functioning (physical), and social functioning subcategories of the SF-36 were generally improved at the latest follow-up, although the changes in these scores were not statistically significant. The bodily pain, vitality, and mental health subcategories were significantly improved at the latest follow-up (p < 0.05). Three complications occurred in 3 patients (20%). The Cobb angle of the lumbar curve was reduced to 20.3° after surgery. The overall correction rate was 66.4%. The pelvic incidence-lumbar lordosis (preoperative/postoperative = 31.5°/4.3°), pelvic tilt (29.2°/18.9°), and sagittal vertical axis (78.3/27.6 mm) were improved after surgery and remained so throughout the follow-up. Computed tomography image analysis suggested that a 1-level TLIF can result in 10.9° of scoliosis correction and 6.8° of lordosis. Posterior corrective surgery using a multilevel TLIF with an RR on patients with DLKS can provide effective correction in the coronal plane but allows only limited sagittal correction.


Fault detection for planetary gearbox based on an enhanced average filter and modulation signal bispectrum analysis.
Transient impulses are important information for machinery fault diagnosis. However, the transient features contained in the vibration signals generated by planetary gearboxes are usually immersed by a large amount of background noise and harmonic components. Even mathematical morphology (MM) is an excellent anti-noise signal processing method that can directly extract the geometry of impulse features in the time domain, but the four basic operators of MM can only extract one-way impulses while cannot extract the bidirectional impulses effectively at the same time. To accurately extract the impulse feature information, a novel method for fault detection of planetary gearbox based on an enhanced average (EAVG) filter and modulated signal bispectrum (MSB) is proposed. Firstly, the properties of the extracted impulses based on the four basic operators of MM will be divided into two categories of enhanced average operators. The four EAVG filters consist of the average weighted combination of enhanced average operators, and then the best EAVG filter is selected based on correlation coefficient to implement on the original vibration signal. It allows EAVG filter to extract positive and negative impulses of vibration signal, thereby improving the accuracy of planetary gearbox fault detection. Subsequently, the performance of the EAVG filter is influenced by the length of its structural element (SE), which is adaptively determined using an indicator based kurtosis. Then, the EAVG filter selects the optimal SE length to eliminate the interference of background noise and harmonic components to enhance the impulse components of the vibration signal. However, the nonlinear modulation components that are related to the fault types and severities are not extracted exactly and still remained in the filtered signal by EAVG. Finally, the MSB is utilized to the EAVG filtered signal to decompose the modulated components and extract the fault features. The advantages of EAVG over average (AVG) filter are clarified in the simulation study. In addition, the EAVG-MSB is validated by analyzing the vibration signals of planetary gearboxes with sun gear chipped tooth, sun gear misalignment and bearing inner race fault. The results indicate that the EAVG-MSB is effective and accurate in feature extraction compared with the combination morphological filter-hat transform (CMFH) and average combination difference morphological filter (ACDIF), and the feasibility of the EAVG-MSB are proved for planetary gearbox condition monitoring and fault diagnosis.


Effects of inhibition of proteoglycan synthesis on the differentiation of cultured rat Schwann cells.
Schwann cells synthesize two heparan sulfate proteoglycans, one that is a component of the Schwann cell basement membrane and a smaller one that is an integral component of the Schwann cell plasma membrane. To determine the functions of these molecules, Schwann cell-nerve cell cultures were grown in medium containing a specific inhibitor of proteoglycan biosynthesis, 4-methylumbelliferyl-beta-D-xyloside. Treatment with 1 mM beta-D-xyloside caused a 90% reduction in the accumulation of 35SO4-labeled proteoglycans in the cell layer of the cultures. Gel filtration analysis revealed that both the basement membrane and plasma membrane proteoglycans were affected. Inhibition of proteoglycan biosynthesis was accompanied by an inhibition of laminin deposition into extracellular matrix as determined by immunostaining of cultures and by immunoblotting of cell-associated proteins. This occurred even though there was no decrease in the amount of laminin detected in the medium of beta-D-xyloside-treated cultures. Deposition of collagen type IV was similarly affected. In addition, there was no myelin produced in beta-D-xyloside treated cultures. However, when beta-xyloside-treated cultures were supplied with exogenous basement membrane, Schwann cells produced numerous myelin segments. These results indicate that Schwann cell proteoglycans play an essential role in basement membrane assembly, and that the integral plasma membrane proteoglycan is not required for the basement membrane to exert its effects on Schwann cell differentiation.


Middle Ear Osteoma Causing Mixed Hearing Loss: A Case Report.
Osteomas of the middle ear are rare benign tumors. Their consequences and symptoms are due to their specific location, such as the promontory or the epitympanum and their contact with the facial nerve, the semicircular canal, the ossicles, and the oval or round windows. We report a very unusual case of middle ear osteoma (MEO) in a 23-year-old male patient causing a right mixed hearing loss by contacting and overwhelming the incus and stapes. The lesion was also closely attached to the tympanic portion of the fallopian canal. Since the stapes was not clearly visible behind the lesion, careful observation was preferred to surgery owing to the high risk of inner ear damage and facial palsy with removal of the lesion. MEOs are rarely situated at this critical site. Regular clinical and computerized tomography monitoring is warranted to check their growth. This case also supports the etiological theory of chronic middle ear inflammation causing osteomas.


The Association of a Mediterranean-Style Diet Pattern with Polycystic Ovary Syndrome Status in a Community Cohort Study.
Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women. While lifestyle management is first-line treatment in PCOS, the dietary intake of women with PCOS is unclear and there is no research assessing dietary patterns of women with and without PCOS. The aim of this study was to examine dietary patterns in a large cohort of women with and without PCOS. Data were from 7569 participants in the 1973-1978 cohort of the Australian Longitudinal Study on Women's Health population assessed at 2009 (Survey 5) (n = 414 PCOS, n = 7155 non-PCOS). Dietary patterns were evaluated using factor analysis and multiple logistic regressions assessed their associations with PCOS status. Three dietary patterns were identified that explained 27% of the variance in food intake between women with and without PCOS: Non-core foods; Meats and take-away and Mediterranean-style. The Mediterranean-style dietary pattern was independently associated with PCOS status. On adjusted analysis for each 1 SD increase in the Mediterranean-style dietary pattern, there was a 26% greater likelihood that women had PCOS. This may indicate an improvement in the quality of dietary intake following a diagnosis of PCOS. Future research should examine the contribution of dietary patterns to the incidence and severity of PCOS and the potential for modification of dietary patterns in the lifestyle management of PCOS.


Engineering redox cofactor regeneration for improved pentose fermentation in Saccharomyces cerevisiae.
Pentose fermentation to ethanol with recombinant Saccharomyces cerevisiae is slow and has a low yield. A likely reason for this is that the catabolism of the pentoses D-xylose and L-arabinose through the corresponding fungal pathways creates an imbalance of redox cofactors. The process, although redox neutral, requires NADPH and NAD+, which have to be regenerated in separate processes. NADPH is normally generated through the oxidative part of the pentose phosphate pathway by the action of glucose-6-phosphate dehydrogenase (ZWF1). To facilitate NADPH regeneration, we expressed the recently discovered gene GDP1, which codes for a fungal NADP+-dependent D-glyceraldehyde-3-phosphate dehydrogenase (NADP-GAPDH) (EC 18.104.22.168), in an S. cerevisiae strain with the D-xylose pathway. NADPH regeneration through an NADP-GAPDH is not linked to CO2 production. The resulting strain fermented D-xylose to ethanol with a higher rate and yield than the corresponding strain without GDP1; i.e., the levels of the unwanted side products xylitol and CO2 were lowered. The oxidative part of the pentose phosphate pathway is the main natural path for NADPH regeneration. However, use of this pathway causes wasteful CO2 production and creates a redox imbalance on the path of anaerobic pentose fermentation to ethanol because it does not regenerate NAD+. The deletion of the gene ZWF1 (which codes for glucose-6-phosphate dehydrogenase), in combination with overexpression of GDP1 further stimulated D-xylose fermentation with respect to rate and yield. Through genetic engineering of the redox reactions, the yeast strain was converted from a strain that produced mainly xylitol and CO2 from D-xylose to a strain that produced mainly ethanol under anaerobic conditions.


The equilibrium structure of self-assembled protein nano-cages.
Understanding how highly symmetric, robust, monodisperse protein nano-cages self-assemble can have major applications in various areas of bio-nanotechnology, such as drug delivery, biomedical imaging and gene therapy. We develop a model to investigate the assembly of protein subunits into the structures with different sizes and symmetries. Using Monte Carlo simulation, we obtain global minimum energy structures. Our results suggest that the physical properties including the spontaneous curvature, flexibility and bending rigidity of coat proteins are sufficient to predict the size, symmetry and shape selectivity of the assembly products. Further, on a thermodynamic basis, we discuss the polymorphism of nano-cages observed in assembly experiments.


Recurrence and poor prognosis following resection of small hepatitis B-related hepatocellular carcinoma lesions are associated with aberrant tumor expression profiles of glypican 3 and osteopontin.
Early detection and following appropriate treatments of hepatocellular carcinoma (HCC) is still the gold standard for favored outcome of HCC patients; nevertheless, a small portion of hepatitis B virus (HBV)-related small HCC (<5 cm) patients got poor prognosis. Furthermore, the study for small HBV-HCC was limited. Therefore, the aim of this study was to explore the potential genetic signature for HBV-related small HCC as novel prognostic factors. We examined expression profiles of HBV-related small HCC using an Affymetrix U133A GeneChip, evaluated differential gene expression by quantitative real-time polymerase chain reaction (qRT-PCR), and finally validated these expression patterns by immunohistochemistry (IHC). A total of 57 genes were differentially expressed between tumor and normal parts (n = 20 pairs) using Affymetrix U133A chip, and 16 genes were further evaluated by qRT-PCR. The result was compatible with the finding of oligonucleotide microarray (Pearson's correlation, r = 0.87). Furthermore, the expression pattern in HCC tissue by IHC in another group of small HBV-HCC (n = 100) showed overexpression of either osteopontin (OPN) or glypican 3 (GPC3) is an independent prognostic factor for disease-free survival (DFS) in HBV-positive small HCC (P < 0.01 and 0.03, respectively). Long-term DFS and overall survival (OS) for small HBV-HCC patients with high risk (both elevated GPC3(+)/OPN(+)) were DFS 0%, OS 0%, respectively; on the other hand, DFS and OS in patients with moderate (only 1 gene elevated) or low (OPN(-)/GPC3(-)) risk were 35.0 and 46.5%, respectively. Elevation of both OPN and GPC3 may act as an adverse indicator for HBV-related small HCC patients after curative resection.


Virus-induced Gene Silencing in Streptocarpus rexii (Gesneriaceae).
Many members of the family Gesneriaceae are cultivated as ornamental plants, including Cape primrose (Streptocarpus) species. The range of plant architecture found in this genus has also made it a model to study leaf and meristem development and their evolution. However, the lack of tools to study gene functions through reverse genetics in Streptocarpus has limited the exploitation of its genetic potential. To aid functional genomic studies in Streptocarpus rexii, we sought to investigate virus-induced gene silencing (VIGS). Using the broad host range Tobacco Rattle Virus (TRV) to target the PHYTOENE DESATURASE (PDS) gene of S. rexii, we show that infection with sap from Nicotiana benthamiana triggered VIGS efficiently. VIGS was most effective in the seedling leaves 8 weeks after sowing, but was limited in duration and systemic spread. This study reports the first successful use of VIGS in Streptocarpus and in the family Gesneriaceae. The inoculation of viral sap derived from N. benthamiana was able to overcome the difficulties of standard Agrobacterium-mediated transformation in this genus. Irrespective of its transient effect, this VIGS system will be useful to assess gene function at the cellular level and represent an important tool for further understanding molecular mechanisms in Streptocarpus.


Social media in disaster risk reduction and crisis management.
This paper reviews the actual and potential use of social media in emergency, disaster and crisis situations. This is a field that has generated intense interest. It is characterised by a burgeoning but small and very recent literature. In the emergencies field, social media (blogs, messaging, sites such as Facebook, wikis and so on) are used in seven different ways: listening to public debate, monitoring situations, extending emergency response and management, crowd-sourcing and collaborative development, creating social cohesion, furthering causes (including charitable donation) and enhancing research. Appreciation of the positive side of social media is balanced by their potential for negative developments, such as disseminating rumours, undermining authority and promoting terrorist acts. This leads to an examination of the ethics of social media usage in crisis situations. Despite some clearly identifiable risks, for example regarding the violation of privacy, it appears that public consensus on ethics will tend to override unscrupulous attempts to subvert the media. Moreover, social media are a robust means of exposing corruption and malpractice. In synthesis, the widespread adoption and use of social media by members of the public throughout the world heralds a new age in which it is imperative that emergency managers adapt their working practices to the challenge and potential of this development. At the same time, they must heed the ethical warnings and ensure that social media are not abused or misused when crises and emergencies occur.


Glassiness of thermotropic liquid crystals across the isotropic-nematic transition.
The orientational dynamics of thermotropic liquid crystals across the isotropic-nematic phase transition have traditionally been investigated at long times or low frequencies using frequency domain measurements. The situation has now changed significantly with the recent report of a series of interesting transient optical Kerr effect (OKE) experiments that probed orientational relaxation of a number of calamitic liquid crystals (which consist of rod-like molecules) directly in the time domain, over a wide time window ranging from subpicoseconds to tens of microseconds. The most intriguing revelation is that the decay of the OKE signal at short to intermediate times (from a few tens of picoseconds to several hundred nanoseconds) follows multiple temporal power laws. Another remarkable feature that has emerged from these OKE measurements is the similarity in the orientational relaxation behavior between the isotropic phase of calamitic liquid crystals near the isotropic-nematic transition and supercooled molecular liquids, notwithstanding their largely different macroscopic states. In this article, we present an overview of the understanding that has emerged from recent computational and theoretical studies of calamitic liquid crystals across the isotropic-nematic transition. Topics discussed include (a) single-particle as well as collective orientational dynamics at a short-to-intermediate time window, (b) heterogeneous dynamics in orientational degrees of freedom diagnosed by a non-Gaussian parameter, (c) fragility, and (d) temperature-dependent exploration of underlying energy landscapes as calamitic liquid crystals settle into increasingly ordered mesophases upon cooling from the high-temperature isotropic phase. A comparison of our results with those of supercooled molecular liquids reveals an array of analogous features in these two important classes of soft matter systems. We further find that the onset of growth of the orientational order in the parent nematic phase induces translational order, resulting in smectic-like layers in the potential energy minima of calamitic systems if the parent nematic phase is sandwiched between the high-temperature isotropic phase and the low-temperature smectic phase. We discuss implications of this startling observation. We also discuss recent results on the orientational dynamics of discotic liquid crystals that are found to be rather similar to those of calamitic liquid crystals.


Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer.
Myeloid-derived suppressor cells (MDSC) are believed to play a role in immune suppression and subsequent failure of T cells to mount an efficient anti-tumor response, by employing both direct T-cell inhibition as well as induction of regulatory T cells (Tregs). Investigating the frequency and function of immune suppressive cell subsets in the peripheral blood of 41 patients with prostate cancer (PC) and 36 healthy donors (HD) showed a significant increase in circulating CD14(+) HLA-DR(low/neg) monocytic MDSC (M-MDSC) and Tregs in patients with PC compared to HD. Furthermore, M-MDSC frequencies correlated positively with Treg levels. In vitro proliferation assay with autologous T cells confirmed M-MDSC-mediated T-cell suppression, and intracellular staining of immune suppressive enzyme iNOS revealed a higher expression in M-MDSC from patients with PC. Increased frequencies of M-MDSC correlated with known negative prognostic markers in patients with PC including elevated levels of lactate dehydrogenase and prostate-specific antigen. Accordingly, high levels of M-MDSC were associated with a shorter median overall survival. Our data strongly suggest that M-MDSC, possibly along with Tregs, play a role in establishing an immune suppressive environment in patients with PC. Moreover, correlation of M-MDSC frequency with known prognostic markers and the observed impact on OS could reflect a possible role in tumor progression. Further insight into the generation and function of MDSC and their interplay with Tregs and other cell types may suggest ways to tackle their induction and/or function to improve immunological tumor control.


Anticonvulsant properties of Euterpe oleracea in mice.
Açai (Euterpe oleracea Mart.), a highly consumed fruit in Amazon, is from a common palm with remarkable antioxidant properties. Because oxidative stress and seizures are intimately linked, this study investigated the potential neuroprotective and anticonvulsant effects of commercial clarified açai juice (EO). EO did not alter spontaneous locomotor activity. Four doses of EO were sufficient to increase latencies to both first myoclonic jerk and first generalized tonic-clonic seizure and significantly decrease the total duration of tonic-clonic seizures caused by pentylenetetrazol administration. Also, electrocortical alterations provoked by pentylenetetrazol were prevented, significantly decreasing amplitude of discharges and frequencies above 50 Hz. EO was also able to completely prevent lipid peroxidation in the cerebral cortex, showing a potent direct scavenging property. These results demonstrate for the first time that E. oleracea significantly protects against seizures and seizure-related oxidative stress, indicating an additional protection for humans who consume this fruit.


Active Brownian filaments with hydrodynamic interactions: conformations and dynamics.
The conformational and dynamical properties of active self-propelled filaments/polymers are investigated in the presence of hydrodynamic interactions by both, Brownian dynamics simulations and analytical theory. Numerically, a discrete linear chain composed of active Brownian particles is considered, analytically, a continuous linear semiflexible polymer with active velocities changing diffusively. The force-free nature of active monomers is accounted for-no Stokeslet fluid flow induced by active forces-and higher order hydrodynamic multipole moments are neglected. Hence, fluid-mediated interactions are assumed to arise solely due to intramolecular forces. The hydrodynamic interactions (HI) are taken into account analytically by the preaveraged Oseen tensor, and numerically by the Rotne-Prager-Yamakawa tensor. The nonequilibrium character of the active process implies a dependence of the stationary-state properties on HI via the polymer relaxation times. In particular, at moderate activities, HI lead to a substantial shrinkage of flexible and semiflexible polymers to an extent far beyond shrinkage of comparable free-draining polymers; even flexible HI-polymers shrink, while active free-draining polymers swell monotonically. Large activities imply a reswelling, however, to a less extent than for non-HI polymers, caused by the shorter polymer relaxation times due to hydrodynamic interactions. The polymer mean square displacement is enhanced, and an activity-determined ballistic regime appears. Over a wide range of time scales, flexible active polymers exhibit a hydrodynamically governed subdiffusive regime, with an exponent significantly smaller than that of the Rouse and Zimm models of passive polymers. Compared to simulations, the analytical approach predicts a weaker hydrodynamic effect. Overall, hydrodynamic interactions modify the conformational and dynamical properties of active polymers substantially.


A human monoclonal macroglobulin with specificity for alpha(2----8)-linked poly-N-acetyl neuraminic acid, the capsular polysaccharide of group B meningococci and Escherichia coli K1, which crossreacts with polynucleotides and with denatured DNA.
We have described an IgM antibody from a patient with macroglobulinemia specifically reacting with poly-alpha(2----8)N-acetyl neuraminic acid (NeuNAc) the capsular polysaccharide of two important human pathogens, group B meningococcus and E. coli K1. This antibody has a narrowly defined specificity in its interactions with polysaccharides, being unable to bind poly-alpha(2----9)NeuNAc or alternating poly-alpha(2----8)alpha(2----9)NeuNAc. However, it shows interesting crossreactivity with seemingly unrelated polynucleotides and denatured DNA, supporting the hypothesis that charged groups with a given spacing may determine the specificity of antigen-antibody interactions on otherwise dissimilar molecular structures. Despite the crossreactivity with denatured DNA and polynucleotides, the antibody does not appear to have adverse effects in the patient. The antibody protects newborn rats against E. coli K1 infection, as well as the standard horse antiserum H46, and one would expect it to prove useful in humans as an adjunct to antibiotic therapy in infections with group B meningococcus and E. coli K1. We have attempted to clone the antibody-producing cells from peripheral blood, and have shown that the relevant cells are present and can be cultured.


Improving the quality of hospital care for children by supportive supervision: a cluster randomized trial, Kyrgyzstan.
To determine whether periodic supportive supervision after a training course improved the quality of paediatric hospital care in Kyrgyzstan, where inappropriate care was common but in-hospital postnatal mortality was low. In a cluster, randomized, parallel-group trial, 10 public hospitals were allocated to a 4-day World Health Organization (WHO) course on hospital care for children followed by periodic supportive supervision by paediatricians for 1 year, while 10 hospitals had no intervention. We assessed prospectively 10 key indicators of inappropriate paediatric case management, as indicated by WHO guidelines. The primary indicator was the combination of the three indicators: unnecessary hospitalization, increased iatrogenic risk and unnecessary painful procedures. An independent team evaluated the overall quality of care. We prospectively reviewed the medical records of 4626 hospitalized children aged 2 to 60 months. In the intervention hospitals, the mean proportion of the primary indicator decreased from 46.9% (95% confidence interval, CI: 24.2 to 68.9) at baseline to 6.8% (95% CI: 1.1 to 12.1) at 1 year, but was unchanged in the control group (45.5%, 95% CI: 25.2 to 67.9, to 64.7%, 95% CI: 43.3 to 86.1). At 1 year, the risk ratio for the primary indicator in the intervention versus the control group was 0.09 (95% CI: 0.06 to 0.13). The proportions of the other nine indicators also decreased in the intervention group (P < 0.0001 for all). Overall quality of care improved significantly in intervention hospitals. Periodic supportive supervision for 1 year after a training course improved both adherence to WHO guidelines on hospital care for children and the overall quality of paediatric care.


Probabilistic modeling of an injectable aqueous crystalline suspension using influence networks.
Probabilistic modeling using influence networks is an efficient, intuitive, and easy to communicate strategy in the development of complex pharmaceutical products. This study was aimed to use a risk-based approach to explore the complex interactions between product and process design parameters affecting size and shape of the particles in injectable aqueous crystalline suspensions (ACS). Based on a risk assessment, a design of experiments (DOE) was applied to evaluate the most important parameters, i.e., four critical material attributes and two critical process parameters. A model hydrophobic drug (carbamazepine) was milled and homogenized in a multistep process (dispersion and milling steps). The final formulations were characterized with automated at-line image analysis of thousands of individual particles. The particle size and shape distributions were summarized with descriptive parameters, and the relationship of these parameters and the DOE was modeled using influence networks (INs). This approach was compared and contrasted with a classical modeling approach based on multivariate linear regression (MVLR). INs had a superior visual interpretation capability of the complex and multivariate ACS system making the risk-based decision making more accessible. The probability and causality were included in the IN, i.e., the relationships between size and shape. Moreover, IN allowed to incorporate prior knowledge in a systematic way by implementing a 'black and white list'. An IN based model was created with the following model performance: a mean absolute percentage error of 1.7% and 1.1% for the size and 6.2% and 5.0% for the shape, respectively for dispersed and milled ACS. Parameters with the highest and lowest probability to control the critical quality attributes of ACS could be identified. Consequently, the parameter settings giving the optimum particle size and shape could be predicted using a Monte Carlo simulation to calculate the probability of success including the uncertainty of the model. The cubic MVLR model for the size of milled ACS was comparable to the IN in terms of the mean absolute percentage error, i.e., 1.1%. However, IN was more efficient in visualizing the complex and multivariate data set, including all the critical quality attributes and formulation/process parameters of the ACS at the same time. Moreover, the prior knowledge used in probabilistic modeling of IN could be systematically documented.


The impact of ethnicity and obesity on the course of colonic diverticulitis.
Little research has been performed on the impact of race/ethnicity and obesity on the course of diverticulitis. To determine whether patients of different racial/ethnic backgrounds and patients who are obese have disparate courses of disease with regard to complications, recurrence rates, and need for surgery. We conducted a retrospective review of the charts of 347 patients with confirmed diverticulitis in 2 university teaching hospitals at Bronx, NY. African Americans were more likely [odds ratio (OR), 2.28, 95% confidence interval (CI), 1.04-5.00, P = 0.04] and Hispanics were less likely than other racial/ethnic groups (OR, 0.47; 95% CI, 0.22-0.97; P = 0.04) to require surgery for recurrent diverticulitis after at least 1 medically managed hospital admission for diverticulitis. Caucasians were less likely than other racial/ethnic groups to suffer a recurrence of diverticulitis (OR, 0.48; 95% CI, 0.27-0.86; P = 0.01). Obese patients [ body mass index (BMI) >30] were more likely than nonobese patients to experience a recurrent episode of diverticulitis (OR, 1.69; 95% CI, 1.08-2.64; P = 0.02). The odds of requiring surgery on the initial presentation of diverticulitis were not significantly different among the various races/ethnicities nor was the likelihood of surgery influenced by BMI. Complication rates did not differ significantly when patients were stratified by age, sex, race, BMI, or number of prior episodes of diverticulitis. Surgery for diverticulitis after at least 1 medically managed hospital admission for diverticulitis is more frequently needed in African Americans and less frequently needed in Hispanics. Caucasians are less likely than other races/ethnicities to suffer a recurrence of diverticulitis. Finally, obesity is a risk factor for recurrent diverticulitis, but not for surgical therapy of diverticulitis.


TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization.
The miR-143/145 cluster is highly expressed in smooth muscle cells (SMCs), where it regulates phenotypic switch and vascular homeostasis. Whether it plays a role in neighboring endothelial cells (ECs) is still unknown. To determine whether SMCs control EC functions through passage of miR-143 and miR-145. We used cocultures of SMCs and ECs under different conditions, as well as intact vessels to assess the transfer of miR-143 and miR-145 from one cell type to another. Imaging of cocultured cells transduced with fluorescent miRNAs suggested that miRNA transfer involves membrane protrusions known as tunneling nanotubes. Furthermore, we show that miRNA passage is modulated by the transforming growth factor (TGF) β pathway because both a specific transforming growth factor-β (TGFβ) inhibitor (SB431542) and an shRNA against TGFβRII suppressed the passage of miR-143/145 from SMCs to ECs. Moreover, miR-143 and miR-145 modulated angiogenesis by reducing the proliferation index of ECs and their capacity to form vessel-like structures when cultured on matrigel. We also identified hexokinase II (HKII) and integrin β 8 (ITGβ8)-2 genes essential for the angiogenic potential of ECs-as targets of miR-143 and miR-145, respectively. The inhibition of these genes modulated EC phenotype, similarly to miR-143 and miR-145 overexpression in ECs. These findings were confirmed by ex vivo and in vivo approaches, in which it was shown that TGFβ and vessel stress, respectively, triggered miR-143/145 transfer from SMCs to ECs. Our results demonstrate that miR-143 and miR-145 act as communication molecules between SMCs and ECs to modulate the angiogenic and vessel stabilization properties of ECs.


Frequency of skeletal metastases in nasopharyngeal carcinoma after initiation of therapy: should bone scans be used for follow-up?
Previous reports have indicated a relatively high incidence of distant metastases in patients with nasopharyngeal carcinoma (NPC), one of the most common sites being the skeleton. Although bone scintigraphy offers the advantage of whole-body imaging in patients with cancer by providing useful information about disease spread, its value in patients with NPC is not well defined because of cost-effectiveness considerations. In this study, we assessed the value of follow-up bone scintigraphy for the evaluation of skeletal metastases in patients with different stages of NPC. Between 1994 and 2001, 230 patients with histologically proven NPC were admitted to the Department of Radiation Oncology. Out of 230 patients, 171 were examined for skeletal metastases with bone scintigraphy prior to therapy and at 1 year intervals. Bone scintigraphy detected increased uptake in 29 patients, which was reported as suggestive of metastases or equivocal. Twenty-six of these were true-positive, confirmed by radiography or clinical follow-up. Bone pain was present in 67% of these patients and serum lactate dehydrogenase and alkaline phosphatase were elevated in 35% and 37%, respectively. The incidence of bone metastases correlated with the extent of lymph node involvement, which were detected after a median time of 10.5 months following the diagnosis of the primary disease. No correlation was observed between the metastatic status and local T stage, histological differentiation age or gender of the patient. We can therefore recommend that bone scintigraphy be used in determining the presence of bone metastases, but its utilization should be preserved for those with nodal involvement.


Emerging cytokine networks in colorectal cancer.
Cytokine networks are crucial aspects of tumour immunology, particularly for colorectal cancer (CRC), in which inflammation and antitumour immunity are key determinants of disease progression. In this Review, we highlight new insights into the functions of well-known cytokines in CRC, describe recently discovered roles for a growing number of novel players, and emphasize the complexity and therapeutic implications of the cytokine milieu. We also discuss how cancer mutations and epigenetic adaptations influence the oncogenic potential of cytokines, a relatively unexplored area that could yield crucial insights into tumour immunology and facilitate the effective application of cytokine-modulatory therapies for CRC.


Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease.
The biological functions of the BCL2 gene were investigated in transgenic mice harboring human BCL2 cDNA under the control of an immunoglobulin heavy chain enhancer (E mu). Mice of a representative transgenic strain, E mu-bcl-2-22, had a great excess of B lymphocytes, immunoglobulin-secreting cells, and serum immunoglobulins, attributable to increased longevity of B-lineage cells. Pre-B and plasma cells as well as B cells exhibited prolonged survival in culture. Immunized animals produced an amplified and protracted antibody response. Within the first year of life, most mice spontaneously produced antibodies to nuclear antigens, and 60% developed kidney disease, diagnosed as immune complex glomerulonephritis. Thus E mu-bcl-2-22 mice constitute a transgenic model for a systemic autoimmune disease resembling the human disorder systemic lupus erythematosus.


Fast calibration of high-order adaptive optics systems.
We present a new method of calibrating adaptive optics systems that greatly reduces the required calibration time or, equivalently, improves the signal-to-noise ratio. The method uses an optimized actuation scheme with Hadamard patterns and does not scale with the number of actuators for a given noise level in the wavefront sensor channels. It is therefore highly desirable for high-order systems and/or adaptive secondary systems on a telescope without a Gregorian focal plane. In the latter case, the measurement noise is increased by the effects of the turbulent atmosphere when one is calibrating on a natural guide star.


miR-151-5p, targeting chromatin remodeler SMARCA5, as a marker for the BRCAness phenotype.
In recent years, the assessment of biomarkers useful for "precision medicine" has been a hot topic in research. The involvement of microRNAs in the pathogenesis of breast cancer has been highly investigated with the aim of being able to molecularly stratify this highly heterogeneous disease. Our aim was to identify microRNAs targeting DNA repair machinery, through Affymetrix GeneChip miRNA Arrays, in a cohort of BRCA-related and sporadic breast cancers. Moreover, we analyzed microRNA expression taking into account our previous results on the expression of PARP1, because of its importance in targeted therapy. miR-361-5p and miR-151-5p were found to be overexpressed in PARP1-upregulating BRCA-germline mutated and sporadic breast tumors. Pathway enrichment analysis was performed to identify potential target genes to be analyzed in the validation step in an independent cohort. Our results confirmed the overexpression of miR-151-5p and, interestingly, its role in the targeting of SMARCA5, a chromatin remodeler. This result was also confirmed in vitro, both through luciferase assay and by analyzing endogenous levels of SMARCA5 in MCF-7 cell lines using miR-151-5p mimic and inhibitor. In conclusion, our data showed the possibility of considering the overexpression of PARP1 and miR-151-5p as biomarkers useful to correctly treat sporadic breast cancers, which eventually could be considered as BRCAness tumors, with PARP-inhibitors.


An assessment of the preregistration year experience.
All 115 graduates qualifying at Liverpool University Medical School in one year were sent a questionnaire in the final week of their preregistration year to assess the experience they had gained. Of the 105 graduates (92%) who replied, 99 (94%) considered the supervision that they had received to be adequate, 89 (85%) received most of their teaching from other junior doctors, and only 47 believed that they had learnt a considerable amount from their consultant colleagues. Half of the doctors received little or no training in terminal care. Although 100 (95%) felt competent in dealing with various medical emergencies, cardiopulmonary resuscitation skills were less developed; only 71 (68%) were confident in using a defibrillator, and 37 (35%) considered themselves to be competent in dealing with cardiac arrhythmias. A fifth of the doctors found interviewing relatives stressful. Of the 105 doctors who replied, 77 (73%) thought that their preregistration experience had had little or no effect on their choice of career.


Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.
A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ(9)-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose-response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB1 receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184).


Safety and efficacy of inspiratory muscle training for preventing adverse outcomes in patients at risk of prolonged hospitalisation.
The early institution of inspiratory muscle training on hospitalised patients with no established respiratory deficits could prevent in-hospital adverse outcomes that are directly or indirectly associated to the loss of respiratory muscle mass inherent to a prolonged hospital stay. The objective of the clinical trial is to assess the impact of inspiratory muscle training on hospital inpatient complications. This is a double-blind randomised controlled trial. Subjects in the intervention group underwent an inspiratory muscle training loaded with 50% maximum inspiratory pressure twice daily for 4 weeks from study enrolment. Patients were randomly assigned to an inspiratory muscle training group or a sham inspiratory muscle training group. All patients received conventional physiotherapy interventions. Baseline and post-intervention respiratory and peripheral muscle strength, functionality (performance of activities of daily living), length of hospital stay, and death were evaluated. Clinical outcomes were assessed until hospital discharge. This study was approved by the Institutional Hospital Ethics Committee (03/2014). Thirty-one patients assigned to the inspiratory muscle training group and 34 to the sham inspiratory muscle training group were analysed. Patients in the inspiratory muscle training group had a shorter mean length of hospital stay (35.3 ± 2.7 vs. 41.8 ± 3.5 days, p < 0.01) and a lower risk of endotracheal intubation (relative risk (RR) = 0.36; 95% confidence interval (CI) 0.27-0.97; p = 0.03) as well as muscle weakness (RR = 0.36; 95% CI 0.19-0.98; p = 0.02) and mortality (RR = 0.23; 95% CI 0.2-0.94; p = 0.04). The risk of adverse events did not differ significantly between groups. Inspiratory muscle training was a protective factor against endotracheal intubation, muscle weakness, and mortality. ClinicalTrials.gov, ID: NCT02459444 . Registered on 19 May 2015.


MAP1981c, a Putative Nucleic Acid-Binding Protein, Produced by Mycobacterium avium subsp. paratuberculosis, Induces Maturation of Dendritic Cells and Th1-Polarization.
Mycobacterium avium subsp. paratuberculosis (MAP) is the causative pathogen of chronic granulomatous enteropathy (Johne's disease) in animals, and has been focused on its association with various autoimmune diseases in humans, including Crohn's disease. The discovery of novel mycobacterial antigens and exploring their role in host immunity can contribute to the advancement of effective defense strategies including vaccines and diagnostic tools. In a preliminary study, we identified cellular extract proteins of MAP that strongly react with the blood of patients with Crohn's disease. In particular, MAP1981c, a putative nucleic acid-binding protein, showed high expression levels and strong reactivity to IgG and IgM in the sera of patients. Here, we investigated the immunological features of MAP1981c and focused on its interaction with dendritic cells (DCs), confirming its immunomodulatory ability. MAP1981c was shown to recognize Toll-like receptor (TLR) 4, and induce DC maturation and activation by increasing the expression of co-stimulatory (CD80 and CD86) and MHC class I/II molecules and the secretion of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in DCs. This DC activation by MAP1981c was mediated by downstream signaling of TLR4 via MyD88- and TRIF-, MAP kinase-, and NF-κB-dependent signaling pathways. In addition, MAP1981c-treated DCs activated naïve T cells and induced the differentiation of CD4+ and CD8+ T cells to express T-bet, IFN-γ, and/or IL-2, but not GATA-3 and IL-4, thus indicating that MAP1981c contributes to Th1-type immune responses both in vitro and in vivo. Taken together, these results suggest that MAP1981c is a novel immunocompetent antigen that induces DC maturation and a Th1-biased response upon DC activation, suggesting that MAP1981c can be an effective vaccine and diagnostic target.


Cognitive changes in conjunctive rule-based category learning: An ERP approach.
When learning rule-based categories, sufficient cognitive resources are needed to test hypotheses, maintain the currently active rule in working memory, update rules after feedback, and to select a new rule if necessary. Prior research has demonstrated that conjunctive rules are more complex than unidimensional rules and place greater demands on executive functions like working memory. In our study, event-related potentials (ERPs) were recorded while participants performed a conjunctive rule-based category learning task with trial-by-trial feedback. In line with prior research, correct categorization responses resulted in a larger stimulus-locked late positive complex compared to incorrect responses, possibly indexing the updating of rule information in memory. Incorrect trials elicited a pronounced feedback-locked P300 elicited which suggested a disconnect between perception, and the rule-based strategy. We also examined the differential processing of stimuli that were able to be correctly classified by the suboptimal single-dimensional rule ("easy" stimuli) versus those that could only be correctly classified by the optimal, conjunctive rule ("difficult" stimuli). Among strong learners, a larger, late positive slow wave emerged for difficult compared with easy stimuli, suggesting differential processing of category items even though strong learners performed well on the conjunctive category set. Overall, the findings suggest that ERP combined with computational modelling can be used to better understand the cognitive processes involved in rule-based category learning.


Inheritance and maintenance of small RNA-mediated epigenetic effects.
Heritable traits are predominantly encoded within genomic DNA, but it is now appreciated that epigenetic information is also inherited through DNA methylation, histone modifications, and small RNAs. Several examples of transgenerational epigenetic inheritance of traits have been documented in plants and animals. These include even the inheritance of traits acquired through the soma during the life of an organism, implicating the transfer of epigenetic information via the germline to the next generation. Small RNAs appear to play a significant role in carrying epigenetic information across generations. This review focuses on how epigenetic information in the form of small RNAs is transmitted from the germline to the embryos through the gametes. We also consider how inherited epigenetic information is maintained across generations in a small RNA-dependent and independent manner. Finally, we discuss how epigenetic traits acquired from the soma can be inherited through small RNAs.


Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney.
Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage.


Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.
Chronic lung disease (CLD) occurs frequently in preterm infants. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increased compliance and tidal volume and decreased pulmonary resistance have been documented with the use of bronchodilators in infants with CLD. Therefore, bronchodilators might have a role in the prevention and treatment of CLD. To determine the effect of bronchodilators given as prophylaxis or as treatment for CLD on mortality and other complications of preterm birth in infants at risk for or identified as having CLD. On 2016 March 7, we used the standard strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE (from 1966), Embase (from 1980) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982). We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We applied no language restrictions. Randomised and quasi-randomised controlled trials involving preterm infants were eligible for inclusion. Initiation of bronchodilator therapy for prevention of CLD had to occur within two weeks of birth. Treatment of patients with CLD had to be initiated before discharge from the neonatal unit. The intervention had to include administration of a bronchodilator by nebulisation, by metered dose inhaler (with or without a spacer device) or by intravenous or oral administration versus placebo or no intervention. Eligible studies had to include at least one of the following predefined clinical outcomes: mortality, CLD, number of days on oxygen, number of days on ventilator, patent ductus arteriosus (PDA), pulmonary interstitial emphysema (PIE), pneumothorax, intraventricular haemorrhage (IVH) of any grade, necrotising enterocolitis (NEC), sepsis and adverse effects of bronchodilators. We used the standard method described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors extracted and assessed all data provided by each study. We reported risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) with 95% confidence interval (CI) for dichotomous outcomes and mean difference (MD) for continuous data. We assessed the quality of the evidence by using the GRADE approach. For this update, we identified one new randomised controlled trial investigating effects of bronchodilators in preterm infants. This study, which enrolled 73 infants but reported on 52 infants, examined prevention of CLD with the use of aminophylline. According to GRADE, the quality of the evidence was very low. One previously included study enrolled 173 infants to look at prevention of CLD with the use of salbutamol. According to GRADE, the quality of the evidence was moderate. We found no eligible trial that studied the use of bronchodilator therapy for treatment of individuals with CLD. Prophylaxis with salbutamol led to no statistically significant differences in mortality (RR 1.08, 95% CI 0.50 to 2.31; RD 0.01, 95% CI -0.09 to 0.11) nor in CLD (RR 1.03, 95% CI 0.78 to 1.37; RD 0.02, 95% CI -0.13 to 0.17). Results showed no statistically significant differences in other complications associated with CLD nor in preterm birth. Investigators in this study did not comment on side effects due to salbutamol. Prophylaxis with aminophylline led to a significant reduction in CLD at 28 days of life (RR 0.18, 95% CI 0.04 to 0.74; RD -0.35, 95% CI -0.56 to -0.13; NNTB 3, 95% CI 2 to 8) and no significant difference in mortality (RR 3.0, 95% CI 0.33 to 26.99; RD 0.08, 95% CI -0.07 to 0.22), along with a significantly shorter dependency on supplementary oxygen in the aminophylline group compared with the no treatment group (MD -17.75 days, 95% CI -27.56 to -7.94). Tests for heterogeneity were not applicable for any of the analyses, as each meta-analysis included only one study. Data are insufficient for reliable assessment of the use of salbutamol for prevention of CLD. One trial of poor quality reported a reduction in the incidence of CLD and shorter duration of supplementary oxygen with prophylactic aminophylline, but these results must be interpreted with caution. Additional clinical trials are necessary to assess the role of bronchodilator agents in prophylaxis or treatment of CLD. Researchers studying the effects of bronchodilators in preterm infants should include relevant clinical outcomes in addition to pulmonary mechanical outcomes. We identified no trials that studied the use of bronchodilator therapy for treatment of CLD.


Easy come easy go: surfaces containing immobilized nanoparticles or isolated polycation chains facilitate removal of captured Staphylococcus aureus by retarding bacterial bond maturation.
Adhesion of bacteria is a key step in the functioning of antimicrobial surfaces or certain types of on-line sensors. The subsequent removal of these bacteria, within a ∼ 10-30 min time frame, is equally important but complicated by the tendency of bacterial adhesion to strengthen within minutes of initial capture. This study uses Staphylococcus aureus as a model bacterium to demonstrate the general strategy of clustering adhesive surface functionality (at length scales smaller than the bacteria themselves) on otherwise nonadhesive surfaces to capture and retain bacteria (easy come) while limiting the progressive strengthening of adhesion. The loose attachment facilitates bacteria removal by moderate shearing flow (easy go). This strategy is demonstrated using surfaces containing sparsely and randomly arranged immobilized amine-functionalized nanoparticles or poly-l-lysine chains, about 10 nm in size. The rest of the surface is backfilled with a nonadhesive polyethylene glycol (PEG) brush that, by itself, repels S. aureus. The nanoparticles or polymer chains cluster cationic functionality, providing small regions that attract negatively charged S. aureus cells. Compared with surfaces of nearly uniform cationic character where S. aureus adhesion quickly becomes strong (on a time scale less than 5 min), placement of cationic charge in small clusters retards or prevents processes that increase bacteria adhesion on a time scale of ∼ 30 min, providing "easy go" surfaces.


Reducing the use of physical restraints in nursing homes: will it increase costs?
Reducing the widespread use of physical restraints in nursing homes is a primary goal of the federal nursing home reforms enacted as part of the Omnibus Budget Reconciliation Act of 1987. However, some nursing home operators assert that reducing restraint use could be prohibitively expensive, costing payors perhaps as much as $1 billion annually. We investigated whether nursing home residents free from physical restraint require more care and resources than similar residents who are restrained. We examined the major component of nursing home costs--staff time--and its allocation among residents who were physically restrained and those who were not restrained. The multivariate analysis used staff-time-study data on the care of 11,932 nursing home residents in 276 facilities in seven states. The analyses indicate that, when differences in impairment and care needs are controlled for, residents who are physically restrained require more nursing care than other residents. Higher levels of nursing-assistant time were consistently provided to restrained residents. Residents free of restraints are less costly to care for than restrained residents. The 1987 federal requirements concerning restraint use, which are aimed at improving quality of care and quality of life, can be implemented without engendering a major increase in care costs.


Mott transition in VO2 revealed by infrared spectroscopy and nano-imaging.
Electrons in correlated insulators are prevented from conducting by Coulomb repulsion between them. When an insulator-to-metal transition is induced in a correlated insulator by doping or heating, the resulting conducting state can be radically different from that characterized by free electrons in conventional metals. We report on the electronic properties of a prototypical correlated insulator vanadium dioxide in which the metallic state can be induced by increasing temperature. Scanning near-field infrared microscopy allows us to directly image nanoscale metallic puddles that appear at the onset of the insulator-to-metal transition. In combination with far-field infrared spectroscopy, the data reveal the Mott transition with divergent quasi-particle mass in the metallic puddles. The experimental approach used sets the stage for investigations of charge dynamics on the nanoscale in other inhomogeneous correlated electron systems.


Enhancing the modularity of the modular polyketide synthases: transacylation in modular polyketide synthases catalyzed by malonyl-CoA:ACP transacylase.
Selective incorporation of extender units in modular polyketide synthases is primarily controlled by acyl transferase (AT) domains. The AT domains catalyze transacylation of the extender unit from acyl-CoA to the phosphopantetheine arm of an acyl carrier protein (ACP) domain in the same module. New methods that can modulate the extender unit specificity of individual modules with minimal structural or kinetic perturbations in the engineered module are desirable for the efficient biosynthesis of novel natural product analogues. We have demonstrated that transacylation of malonyl groups onto an AT-null form of a mutant modular polyketide synthase by malonyl-CoA:ACP transacylase is an effective strategy for the engineered biosynthesis of site specifically modified polyketides. Using this strategy, 6-deoxyerythronolide B synthase was engineered to exclusively produce 2-desmethyl-6-deoxyerythronolide B. The productivity of the modified system was comparable to that of the wild-type synthase in vitro and in vivo.


A new look at water transport regulation in plants.
Plant function requires effective mechanisms to regulate water transport at a variety of scales. Here, we develop a new theoretical framework describing plant responses to drying soil, based on the relationship between midday and predawn leaf water potentials. The intercept of the relationship (Λ) characterizes the maximum transpiration rate per unit of hydraulic transport capacity, whereas the slope (σ) measures the relative sensitivity of the transpiration rate and plant hydraulic conductance to declining water availability. This framework was applied to a newly compiled global database of leaf water potentials to estimate the values of Λ and σ for 102 plant species. Our results show that our characterization of drought responses is largely consistent within species, and that the parameters Λ and σ show meaningful associations with climate across species. Parameter σ was ≤1 in most species, indicating a tight coordination between the gas and liquid phases of water transport, in which canopy transpiration tended to decline faster than hydraulic conductance during drought, thus reducing the pressure drop through the plant. The quantitative framework presented here offers a new way of characterizing water transport regulation in plants that can be used to assess their vulnerability to drought under current and future climatic conditions.


Isolation, characterization, and mapping of two human potassium channels.
Two novel human genes encoding putative potassium channels, kH1 and kH2, were identified from a human fetal brain cDNA library. Sequence analysis showed that kH1 and kH2 are homologous to rat IK8 and rat K13, respectively. The kH1 encodes a polypeptide of 495 amino acids, which shares 88% and 95% identity to IK8 at the nucleotide and amino acid level, respectively. The kH2 encodes a polypeptide of 515 amino acids with 86% and 92% identity to K13 at the nucleotide and amino acid level, respectively. Northern blot studies revealed that one mRNA species, approximately 5kb, of the kH1 was expressed abundantly in tissues examined, including the heart, skeletal muscle, and less abundant in the brain, liver, kidney, and pancreas. Interestingly, an alternative spliced form of 2.4 kb mRNA species of the kH1 was also found in the brain. Unlike kH1, 2.4 kb of kH2 was expressed predominantly in the brain, placenta, and the skeletal muscle where it shared a differently spliced form of the kH2 mRNA, approximately 2.0 kb. Fluorescence in situ hybridization localized kH1 to the human chromosome 2p25 and kH2 to the human chromosome 20q13.


Effect of pindolol on endocrine and temperature responses to buspirone in healthy volunteers.
Ten healthy subjects received buspirone (30 mg orally) with and without pre-treatment with the 5-HT1A receptor antagonist, pindolol (80 mg over 3 days). Following pindolol treatment the growth hormone and hypothermic responses to buspirone were significantly decreased. There was also a delay in the onset of the prolactin response to buspirone but the total amount of prolactin secretion, calculated as area under the curve, was not significantly reduced. The data suggest that the growth hormone and hypothermic responses to buspirone in humans are mediated by 5-HT1A receptors, but an explanation founded on pharmacokinetic factors cannot presently be excluded. Both this latter possibility and the lack of selectivity of pindolol for 5-HT receptors indicate the need for the further neuroendocrine studies of the mode of action of buspirone, preferably with more selective 5-HT1A receptor antagonists.


Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus.
Serum IgA class reticulin autoantibody test was performed prospectively once a year on 238 children and adolescents with insulin dependent diabetes mellitus (IDDM). At the initial testing, within one year after onset of IDDM, five were positive and 233 were negative. During follow up a further 11 of the initially antibody negative children became positive (6.7%). Jejunal biopsy was performed at the appearance of the autoantibodies and silent coeliac disease was shown in nine (3.8%). One of these children showed on initial biopsy after the onset of IDDM to have normal jejunal mucosal architecture deteriorating later to a flat lesion. Jejunal immunohistochemical studies of another of the patients positive for reticulin autoantibodies but normal on routine biopsy showed an increased density of intraepithelially located gamma/delta T cells and aberrant HLA-DR expression in the crypts pointing to ongoing mucosal inflammation and potential coeliac disease. This study shows that in IDDM patients, reticulin autoantibody negative subjects become antibody positive, which may be followed by coeliac disease. Repeated serological screening and rebiopsy should be considered to detect late developing clinically silent coeliac disease among patients with IDDM.


Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis.
The morbidity related to long-term steroid therapy has led to continued interest in withdrawal of steroids from immunosuppressant regimens after renal transplantation. A number of recent trials have provided long-term information regarding the risks and benefits of steroid avoidance or withdrawal (SAW). A literature search was performed using Ovid Medline, Embase, the Cochrane Library, and the Transplant Library. Randomized controlled trials comparing a maintenance steroid group with complete avoidance or withdrawal of steroids were selected. All studies were assessed for methodological quality. Trials were pooled by meta-analysis to provide summary effects (relative risk [RR] or weighted mean difference) with 95% confidence intervals (CI). Thirty-four studies including 5,637 patients met the inclusion criteria. SAW regimens significantly increased the risk of acute rejection (AR) over maintenance steroids (RR 1.56, CI 1.31-1.87, P<0.0001). No significant differences in corticosteroid resistant AR, patient survival, or graft survival were observed. Serum creatinine was increased and creatinine clearance was reduced with SAW. Cardiovascular risk factors including incidence of hypertension (RR 0.90, CI 0.85-0.94, P<0.0001), new onset diabetes (RR 0.64, CI 0.50-0.83, P=0.0006), and hypercholesterolemia (RR 0.76, CI 0.67-0.87, P<0.0001) were reduced significantly by SAW. Despite an increase in the risk of AR with SAW protocols, there is only a small effect on graft function with no measurable effect on graft or patient survival. There are significant benefits in cardiovascular risk profiles after SAW. SAW protocols would seem justified with current immunosuppressive protocols in low-risk recipients.


Reconstruction of the lateral ankle ligaments with bone-patellar tendon graft in patients with chronic ankle instability: a preliminary report.
Unsatisfactory long-term results have been reported after use of a Broström repair for patients with chronic ankle ligament insufficiency. Repair or reconstruction of both the anterior talofibular and calcaneofibular ligaments is essential for normal kinematics of the ankle-hindfoot. Case series. Thirteen patients with chronic instability of the ankle were found at operation to have injuries of both the anterior talofibular and calcaneofibular ligaments, with a lack of healthy ligament margins suitable for suturing. Reconstruction of the ligaments was performed with bone-patellar tendon graft. The score devised by Good et al. was used to assess the patients' clinical condition before the operation and at final follow-up. Before the operation, six patients had a grade 3 clinical condition and seven had a grade 4 condition. At a mean follow-up of 26.5 months, all patients had a grade 1 condition. The average talar tilt of the patients was improved from 18.4 degrees +/- 5.5 degrees to 4.9 degrees +/- 2.6 degrees, and the average anterior drawer sign was improved from 9.1 +/- 2.6 mm to 5.8 +/- 1.6 mm. In cases of combined injuries, short-term results of reconstruction of the anterior talofibular and calcaneofibular ligaments using bone-split patellar tendon graft were good, with a low frequency of complications.