Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: a literature review.
Acromegaly is a rare disease with a multifaceted clinical presentation. In 90-95% of patients with acromegaly, the disease is caused by a growth hormone (GH)-secreting pituitary adenoma with elevated GH levels that ultimately induce excessive hepatic secretion of insulin-like growth factor-1 (IGF-1). Somatostatin receptor ligands (SRLs) are considered the standard medical choice for the treatment of acromegaly, and normalization of GH and IGF-1 is attainable with effective therapy. This review aims to summarize the literature relative to SRL dose escalation therapy in patients with acromegaly. A United States National Library of Medicine PubMed search of SRL's was conducted using the following search terms: ((((LAR) OR ATG) OR octreotide) OR lanreotide Autogel) AND acromegaly. Related articles in non peer-reviewed journals were excluded. The rationale and benefits of SRL dose optimization therapy were investigated with emphasis on describing the clinical recognition, treatment, and management of patients with acromegaly. We found that dose escalation could provide additional biochemical control of acromegaly in patients who are inadequately controlled with conventional starting doses of octreotide LAR and lanreotide Autogel(®). Furthermore, patients should routinely have their GH and IGF-1 levels closely monitored and their SRL dose increased or decreased thereafter according to individual response.


Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors.
Telomeres are essential for cell survival and have been implicated in the mitotic control. The telomeric protein Pin2/TRF1 controls telomere elongation and its expression is tightly regulated during cell cycle. We previously reported that overexpression of Pin2/TRF1 affects mitotic progression. However, the role of Pin2/TRF1 at the interface between cell division and cell survival remains to be determined. Here we show that overexpression of Pin2 induced apoptosis in cells containing short telomeres, but not in cells with long telomeres. Furthermore, before entering apoptosis, Pin2-expressing cells first accumulated in mitosis and strongly stained with the mitosis-specific MPM2 antibody. Moreover, Pin2-induced apoptosis is potentiated by arresting cells in mitosis, but suppressed by accumulating cells in G1. In addition, overexpression of Pin2 also resulted in activation of caspase-3, and its proapoptotic activity was significantly reduced by inhibition of caspase-3. These results indicate that up-regulation of Pin2/TRF1 can specifically induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. Significantly, we also found that, out of 51 human breast cancer tissues and 10 normal controls examined, protein levels of Pin2/TRF1 in tumors were significantly lower than in normal tissues, as detected by immunoblotting analysis and immunocytochemistry. Since down-regulation of Pin2/TRF1 allows cells to maintain long telomeres, these results suggest that down-regulation of Pin2/TRF1 may be important for cancer cells to extend their proliferative potential.


A colorimetric and NIR fluorescent probe for ultrafast detecting bisulfite and organic amines and its applications in food, imaging, and monitoring fish freshness.
Herein, for the first time, we have successfully constructed a novel near-infrared (NIR) emission fluorescent probe Dpyt for ultrafast detecting (within 5 s) bisulfate and organic amines based on a 1,2-dihydrocyclopenta[b]chromene-barbiturate conjugation system. Upon addition of bisulfate or organic amines, Dpyt displayed a distinct color change from blue to colorless or from purple to blue, respectively, suggesting that the Dpyt can be used to detect two analytes by the naked eye. Based on quantum chemistry calculations, the fluorescence quenching of Dpyt after the addition of HSO3- is caused by the photoinduced electron transfer (PET) process of the adduct Dpyt-HSO3-. The fluorescence enhancement of Dpyt caused by most organic amines is due to the enhanced intramolecular charge transfer (ICT) process of deprotonated Dpyt. Notably, Dpyt can be applied for detecting HSO3- in actual food samples such as red wine and sugar, as well as for imaging of HSO3- and representative propylamine in living cells. And more importantly, indicator labels constructed by filter paper loaded with Dpyt can visually monitor the freshness of salmon in real-time by daylight and fluorescence dual-mode. The comparison with national standard method of China manifests that indicator labels are a valid tool to assess the freshness of seafood.


Use of standardized terminologies in clinical practice: A scoping review.
To explore the use and impact of standardized terminologies (STs) within nursing and midwifery practice. The standardization of clinical documentation creates a potential to optimize patient care and safety. Nurses and midwives, who represent the largest proportion of the healthcare workforce worldwide, have been using nursing-specific and multidisciplinary STs within electronic health records (EHRs) for decades. However, little is known regarding ST use and impact within clinical practice. A scoping review of the literature was conducted (2019) across PubMed, CINAHL, Embase and CENTRAL in collaboration with the Five Country Nursing and Midwifery Digital Leadership Group (DLG). Identified studies (n = 3547) were reviewed against a number of agreed criterion, and data were extracted from included studies. Studies were categorized and findings were reviewed by the DLG. One hundred and eighty three studies met the inclusion criteria. These were conducted across 25 different countries and in various healthcare settings, utilising mainly nursing-specific (most commonly NANDA-I, NIC, NOC and the Omaha System) and less frequently local, multidisciplinary or medical STs (e.g., ICD). Within the studies, STs were evaluated in terms of Measurement properties, Usability, Documentation quality, Patient care, Knowledge generation, and Education (pre and post registration). As well as the ST content, the impact of the ST on practice depended on the healthcare setting, patient cohort, nursing experience, provision of education and support in using the ST, and usability of EHRs. Employment of STs in clinical practice has the capability to improve communication, quality of care and interoperability, as well as facilitate value-based healthcare and knowledge generation. However, employment of several different STs and study heterogeneity renders it difficult to aggregate and generalize findings.


Multigenerational Exposure to Uranium Changes Sperm Metabolome in Rats.
Male infertility is a major public health issue that can be induced by a host of lifestyle risk factors such as environment, nutrition, smoking, stress, and endocrine disruptors. Regarding the human population exposed to uranium, it is necessary to explore these effects on male reproduction in multigenerational studies. The sensitivity of mass spectrometry (MS)-based methods has already proved to be extremely useful in metabolite identification in rats exposed to low doses of uranium, but also in human sperm. We applied this method to rat sperm over three generations (F0, F1 and F2) with multigenerational uranium exposure. Our results show a significant content of uranium in generation F0, and a reduction in the pregnancy rate only in generation F1. Based on principal component analysis (PCA), we observed discriminant profiles between generations. The partial least squares discriminant analysis (PLS-DA) of the 48 annotated variables confirmed that parental exposure of generation F0 (during both the preconceptional and prenatal periods) can have metabolic effects on spermatozoa for the next two generations. Metabolomics applied to epididymal spermatozoa is a novel approach to detecting the multigenerational effects of uranium in an experimental model, but could be also recommended to identify potential biomarkers evaluating the impact of uranium on sperm in exposed infertile men.


Test-retest reliability of automated whole body and compartmental muscle volume measurements on a wide bore 3T MR system.
To measure the test-retest reproducibility of an automated system for quantifying whole body and compartmental muscle volumes using wide bore 3 T MRI. Thirty volunteers stratified by body mass index underwent whole body 3 T MRI, two-point Dixon sequences, on two separate occasions. Water-fat separation was performed, with automated segmentation of whole body, torso, upper and lower leg volumes, and manually segmented lower leg muscle volumes. Mean automated total body muscle volume was 19·32 L (SD9·1) and 19·28 L (SD9·12) for first and second acquisitions (Intraclass correlation coefficient (ICC) = 1·0, 95% level of agreement -0·32-0·2 L). ICC for all automated test-retest muscle volumes were almost perfect (0·99-1·0) with 95% levels of agreement 1.8-6.6% of mean volume. Automated muscle volume measurements correlate closely with manual quantification (right lower leg: manual 1·68 L (2SD0·6) compared to automated 1·64 L (2SD 0·6), left lower leg: manual 1·69 L (2SD 0·64) compared to automated 1·63 L (SD0·61), correlation coefficients for automated and manual segmentation were 0·94-0·96). Fully automated whole body and compartmental muscle volume quantification can be achieved rapidly on a 3 T wide bore system with very low margins of error, excellent test-retest reliability and excellent correlation to manual segmentation in the lower leg. Sarcopaenia is an important reversible complication of a number of diseases. Manual quantification of muscle volume is time-consuming and expensive. Muscles can be imaged using in and out of phase MRI. Automated atlas-based segmentation can identify muscle groups. Automated muscle volume segmentation is reproducible and can replace manual measurements.


Inflammatory Bowel Disease [IBD] and Physical Activity: A Study on the Impact of Diagnosis on the Level of Exercise Amongst Patients With IBD.
Inflammatory bowel disease [IBD] can impair patients' functional capacity with significant negative effects on their quality of life. Our aim was to determine the impact of IBD diagnosis on fitness levels and to assess the levels of engagement in physical activity and fatigue in IBD patient before and after diagnosis. A prospective multi-centre cross-sectional study was performed. Patients diagnosed with IBD in the previous 18 months were recruited. Inclusion criteria included clinical remission and/or no treatment changes within the previous 6 months. Physical exercise levels were assessed by the Godin score and fatigue levels was assessed by the functional assessment of chronic illness therapy [FACIT] score. In total, 158 patients (100 Crohn's disease [CD]) were recruited. Mean age was 35.1 years (95% confidence interval [CI] ± 2.0). Gender distribution was approximately equal [51.3% male]. The Mean Harvey Bradshaw and Simple Clinical Colitis Activity indices were 2.25 [95% CI ± 0.40] and 1.64 [95% CI ± 0.49], respectively. The mean Godin score difference before and after IBD diagnosis was 6.94 [p = 0.002]. Patients with ulcerative colitis [UC] [41.8%] were more likely than patients with CD [23.0%] to reduce their exercise levels [p = 0.04]. FACIT scores were lower in patients who had experienced relapses [p = 0.012] and had severe disease [p = 0.011]. Approximately one-third of patients reduced their activity level following IBD diagnosis. Patients were significantly less physically active after a diagnosis of IBD and this was more apparent in UC. Identification of the risk factors associated with loss of fitness levels would help to address the reduced patient quality of life.


Homocysteine concentrations in subclinical hypothyroidism.
Hyperhomocysteinemia is considered to be an independent risk factor for atherosclerotic heart disease, including coronary artery disease (CAD). It is already known that overt hypothyroidism gives rise to a slight hyperhomocysteinemia. However, the effects of subclinical hypothyroidism on the levels of homocysteine are not known. In this study, we have evaluated homocysteine levels and the effect of L-thyroxine treatment in patients with subclinical hypothyroidism. For the purpose of the study, we selected 33 women patients with the diagnosis of subclinical hypothyroidism but without clinical CAD. After a euthyroidism development period of almost four months, a further study was done on patients who had been treated with thyroid hormone. The patient group was compared with 25 healthy control female subjects who were of similar age. In the patient group, homocysteine levels prior to treatment were significantly higher than in the control group (P < 0.001). After L-thyroxine treatment, homocysteine levels were reduced significantly. In summary, we found that homocysteine levels were in the normal range in subclinical hypothyroidism. However, when compared with the healthy control group, the difference between them was significant. On the other hand, therapy to produce euthyroidism caused a significant reduction in homocysteine levels.


Directional wetting in anisotropic inverse opals.
Porous materials display interesting transport phenomena due to restricted motion of fluids within the nano- to microscale voids. Here, we investigate how liquid wetting in highly ordered inverse opals is affected by anisotropy in pore geometry. We compare samples with different degrees of pore asphericity and find different wetting patterns depending on the pore shape. Highly anisotropic structures are infiltrated more easily than their isotropic counterparts. Further, the wetting of anisotropic inverse opals is directional, with liquids filling from the side more easily. This effect is supported by percolation simulations as well as direct observations of wetting using time-resolved optical microscopy.


Clinical studies with megakaryocyte growth and development factor (Mpl-ligand).
The haemopoietic growth factor mpl-ligand (also known as thrombopoietin, and Megakaryocyte Growth and Development Factor [MGDF] is a recently cloned and characterized megakaryocyte-active factor. Administration of MGDF to humans was associated with a dose-related increase in the platelet count with maximum levels observed between days 12-18. Platelets had normal appearance and functioned normally in assays of platelet aggregation and ATP-release. There was no evidence of platelet activation as assessed by platelet surface markers. The earliest detectable effect of MGDF was an increase in early (reticulated) platelets by day 3-4. MGDF also hastened recovery from thrombocytopenia when given after myelosuppressive chemotherapy. MGDF caused mobilisation into the blood of progenitor cells of multiple haemopoietic lineages, and was synergistic with G-CSF in this action after chemotherapy. MGDF was well tolerated with no adverse effects directly attributable to its administration. Further clinical evaluation is on-going.


The role of machine perfusion in liver xenotransplantation.
To review the role of machine perfusion in advancing the study and clinical application of liver xenotransplantation to liver transplantation. Recent multicenter trial has shown the benefits of normothermic machine perfusion (NMP) in the assessment and selection of suitable allografts for liver transplantation, especially marginal liver allografts. Advances in ex-vivo therapeutic intervention with proof-of-concept studies demonstrating successful ex-vivo genetic modification of donor allografts and blockade of gene expression with siRNA. Xenotransplantation and NMP are two of the most exciting and eagerly anticipated technologies in organ transplantation. Since the emergence of clinical transplantation, clinicians and researchers have attempted to manipulate xenografts for clinical use or to develop devices that could provide physiologic support of donor organs ex vivo. The past decade has seen significant progress in NMP with recent emergence of devices suitable for use in clinical practice. Following discovery of novel gene-editing techniques, xenotransplantation has also developed rapidly with encouraging outcomes in preclinical studies. Xenotransplantation is now currently poised to advance into the clinical realm. NMP can not only assist in the development of other novel technologies by providing a unique environment to safely study organ function and assess organ suitability but may also improve outcomes following hepatic xenotransplantation. In this review, we describe the current use of NMP in xenotransplantation research and also discuss the potential roles for NMP in xenotransplantation research and future clinical practice.


An Improved Protocol for the Matrigel Duplex Assay: A Method to Measure Retinal Angiogenesis.
Neovascular diseases of the retina, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), are proliferative retinopathies involving the growth of new blood vessels on the retina, which in turn causes impairment and potential loss of vision. A drawback of conventional angiogenesis assays is that they are not representative of the angiogenic processes in the retina. In the retina, the new blood vessels grow (from pre-existing blood vessels) and migrate into a non-perfused region of the eye including the inner limiting membrane of the retina and the vitreous, both of which contribute to vision loss. The Matrigel Duplex Assay (MDA) measures the migration of angiogenic capillaries from a primary Matrigel layer to a secondary Matrigel layer, which resembles the pathological angiogenesis in AMD and DR. The methodology of MDA is comprised of two steps. In the first step, the human retinal microvascular endothelial cells (HRMECs) are mixed with phenol red-containing Matrigel (in a 1:1 ratio) and seeded in the center of an 8-well chamber slide. After 24 h, a second layer of phenol red-free Matrigel is overlaid over the first layer. Over the course of the next 24 h, the HRMECs invade from the primary Matrigel layer to the secondary layer. Subsequently, the angiogenic sprouts are visualized by brightfield phase contrast microscopy and quantified by ImageJ software. The present manuscript measures the angiogenesis-inhibitory activity of the Src kinase inhibitor PP2 in primary HRMECs using the MDA. The MDA may be used for multiple applications like screening anti-angiogenic drugs, measuring the pro-angiogenic activity of growth factors, and elucidating signaling pathways underlying retinal angiogenesis in normal and disease states.


Changes in free amino acid and sugar levels of dried figs during aflatoxin B1 production by Aspergillus flavus and Aspergillus parasiticus.
An aqueous slurry of gamma-irradiated sterilized dried figs was inoculated with toxigenic strains of Aspergillus flavus and Aspergillus parasiticus. During incubation at 28 degrees C, pH, fructose, glucose, and free amino acids were determined by high-performance liquid chromatography and liquid chromatography (LC)/mass spectrometry, respectively, over 13 time points (1-20 days). At the same 13 time points using a LC/time-of-flight mass spectrometry screening method, aflatoxin B 1 and other secondary metabolites were simultaneously monitored. During the course of incubation, the pH significantly decreased and aflatoxin B 1 formation correlated with a reduction in proline content for both fungi. Of the 22 free amino acids that were monitored, only proline and cystine were found to be critical in supporting aflatoxin production. Levels of fructose and glucose steadily declined during incubation, until glucose was almost exhausted after 21 days. These time-course experiments confirmed the need for carbon and nitrogen sources for aflatoxin production in dried figs, and the favorable composition of figs as a fungal growth medium.


The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture.
TMEM175 is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability in lysosomes. It contains two homologous copies of a six-transmembrane-helix (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels. The prokaryotic TMEM175 channel, which is present in a subset of bacteria and archaea, contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 channel from Chamaesiphon minutus, CmTMEM175, the architecture of which represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family.


[Reflections on the excessive rates of cesareans in Brazil and the empowerment of women].
The medicalization of childbirth as an outcome of social medicalization has been described as a complex sociocultural process that transforms the experiences, suffering and pain - which were formerly managed in the family or community settings - into medical needs. The scope of this paper is to reflect upon the excessive number of cesarean sections in Brazil from a critical and objective standpoint. Data on caesarean section statistics and studies on women's preference on the manner of delivery are discussed in order to contribute to the discussion on the empowerment of the health system consumers. Medicalization is a cultural change that influences the empowerment to cope with the experience of giving birth, as it involves excessive dependency on and abuse of cesarean sections. Furthermore, social networks and movements are discussed as possible facilitators of women's empowerment, as they enable mutual support, sharing of experiences and a contribution to the construction of more balanced relations between women and health professionals. Participation of these networks fosters the collective mobilization of women to insist on their rights from society as a whole.


Functional maturation of the executive system during adolescence.
Adolescence is characterized by rapid development of executive function. Working memory (WM) is a key element of executive function, but it is not known what brain changes during adolescence allow improved WM performance. Using a fractal n-back fMRI paradigm, we investigated brain responses to WM load in 951 human youths aged 8-22 years. Compared with more limited associations with age, WM performance was robustly associated with both executive network activation and deactivation of the default mode network. Multivariate patterns of brain activation predicted task performance with a high degree of accuracy, and also mediated the observed age-related improvements in WM performance. These results delineate a process of functional maturation of the executive system, and suggest that this process allows for the improvement of cognitive capability seen during adolescence.


Evidence suggesting digenic inheritance of Waardenburg syndrome type II with ocular albinism.
Waardenburg syndrome (WS) is a series of auditory-pigmentary disorders inherited in an autosomal dominant manner. In most patients, WS2 results from mutations in the MITF gene. MITF encodes a basic helix-loop-helix transcription factor that activates transcription of tyrosinase and other melanocyte proteins. The clinical presentation of WS is highly variable, and we believe that Tietz syndrome and WS2 with ocular albinism (OA) are likely two variations of WS2 due to the presence of modifiers. One family with a molecular diagnosis of WS2 co-segregating with OA has previously been reported. A digenic mutation mechanism including both a MITF mutation and the TYR(R402Q) hypomorphic allele was proposed to be the cause of OA in this family. Here, we present a second WS2 family with OA and provide evidence suggesting the TYR(R402Q) allele does not cause OA in this family. We hypothesize the presence of a novel OCA3 mutation together with the MITF del p.R217 mutation account for the OA phenotype in this family. Since MITF is a transcription factor for pigmentation genes, a mutation in MITF plus a heterozygous mutation in OCA3 together provide an adverse effect crossing a quantitative threshold; therefore, WS2 with OA occurs. We have hypothesized previously that the clinical spectrum and mutation mechanism of OCA depend on the pigmentation threshold of an affected individual. This unique family has provided further evidence supporting this hypothesis. We suggest that by studying OCA patients alongside WS patients with various pigmentation profiles we can facilitate further understanding of the pigmentation pathway.


Sealing SU-8 microfluidic channels using PDMS.
A simple method of irreversibly sealing SU-8 microfluidic channels using PDMS is reported in this paper. The method is based on inducing a chemical reaction between PDMS and SU-8 by first generating amino groups on PDMS surface using N(2) plasma treatment, then allowing the amino groups to react with the residual epoxy groups on SU-8 surface at an elevated temperature. The N(2) plasma treatment of PDMS can be conducted using an ordinary plasma chamber and high purity N(2), while the residual epoxy groups on SU-8 surface can be preserved by post-exposure baking SU-8 at a temperature no higher than 95 °C. The resultant chemical bonding between PDMS and SU-8 using the method create an interface that can withstand a stress that is greater than the bulk strength of PDMS. The bond is permanent and is long-term resistant to water. The method was applied in fabricating SU-8 microfluidi-photonic integrated devices, and the obtained devices were tested to show desirable performance.


Limits to the early increase in free cytoplasmic calcium concentration during the mitogenic stimulation of lymphocytes.
Three aspects of the calcium hypothesis we have proposed previously [Metcalfe, Pozzan, Smith & Hesketh (1980) Biochem. Soc. Symp. 45, 1-26] for the control of mitogenic stimulation of lymphocytes are examined in studies on the mitogenic action of the Ca2+ ionophore A23187 and its effect on cap formation. (1) Pig lymphocytes that were mitogenically stimulated by continuous incubation with 3H-labelled A23187 for 48 h contained between 3 and 15 amol of ionophore per cell. Lymphocytes exposed to 3H-labelled A23187 for 2h before washing the cells and resuspending them in ionophore-free medium were only stimulated mitogenically at 48h if the residual ionophore associated with the cells after washing was in the concentration range 3-15 amol per cell. When the cells were washed repeatedly after 2h incubation with ionophore to reduce the cell-associated ionophore below the critical concentration range, no mitogenic stimulation occurred as a result of short-term exposure to any ionophore concentration. Re-addition of ionophore to within the indicated range of cell-associated concentrations restored mitogenic stimulation at 48h. We conclude that large, short-term Ca2+ fluxes into the cells induced by the ionophore cannot generate a mitogenic signal that commits the cells to enter the cell cycle. (2) Further experiments with the ionophore showed that detectable mitogenic stimulation at 48h required a minimum of 3h exposure to optimal ionophore concentrations, and that maximal stimulation required at least 20h exposure. This is consistent with the view that a prolonged increase in the free cytoplasmic calcium concentration is required to stimulate the maximum proportion of the cells into the cell cycle. (3) Mouse splenic lymphocytes treated for short periods with very high ionophore concentrations (30 microM) in the presence of various external Ca2+ concentrations showed significant inhibition of cap formation of surface immunoglobulin receptors in the range 1-10 microM-Ca2+ in normal or depolarizing medium. We conclude that mitogens at optimal concentrations for the stimulation of lymphocytes do not cause any early increase in the free cytoplasmic Ca2+ concentration above 10 microM.


Purification and characterization of osteopontin from human milk.
Osteopontin (OPN) is expressed in many organs and tissues and has different biological properties related to different molecular forms in respect to size and posttranslational modifications. However, a purification procedure for authentic intact OPN as well as fragments of OPN from an accessible biological source is missing. A four-step procedure was used to purify OPN from human milk, based on its crystal growth inhibitory activity, including anion exchange chromatography, the elimination of casein, hydroxyapatite chromatography, and negative affinity chromatography. Purified OPN was further separated into its different molecular forms by means of a two-step procedure, involving size exclusion chromatography and reverse phase chromatography. A rabbit polyclonal antibody was raised to purified intact OPN and high M(r) OPN components; the immunoreactivity of both forms was almost equal when investigated by enzyme immunoassay (EIA). The procedures facilitate the purification of intact OPN and OPN fragments for purposes of standardization, preparation of monospecific antibodies, and functional studies.


Interprofessional education and social interaction: The use of automated external defibrillators in team-based basic life support.
Automated external defibrillators are pervasive computing devices designed for the treatment and management of acute sudden cardiac arrest. This study aims to explain users' actual use behavior in teams formed by different professions taken after a short time span of interaction with automated external defibrillator. Before the intervention, all the participants were certified with the American Heart Association Basic Life Support for healthcare providers. A statistically significant difference was revealed in mean individual automated external defibrillator technical skills between uniprofessional and interprofessional groups. The technical automated external defibrillator team scores were greater for groups with interprofessional than for those with uniprofessional education. The nontechnical automated external defibrillator skills of interprofessional and uniprofessional teams revealed differences in advantage of interprofessional teams. Students positively accept automated external defibrillators if well-defined and validated training opportunities to use them expertly are available. Uniprofessional teams were successfully supported by their members and, thereby, used automated external defibrillator effectively. Furthermore, the interprofessional approach resulted in as much effective teamwork as the uniprofessional approach.


DEFORMED FLORAL ORGAN1 (DFO1) regulates floral organ identity by epigenetically repressing the expression of OsMADS58 in rice (Oryza sativa).
Floral organ identity in plants is controlled by floral homeotic A/B/C/D/E-class genes. In Arabidopsis thaliana, several epigenetic repressors that regulate these floral organ identity genes have been characterized. However, the roles of epigenetic factors in rice floral development have not been explored in detail. Here, we report the identification and functional characterization of a rice epigenetic repressor, DEFORMED FLORAL ORGAN1 (DFO1) gene, which causes abnormal floral morphology when mutated. We isolated dfo1 by mapping, and confirmed its function by rescue experiments, combined with genetic, cytological and molecular biological analysis. We showed that DFO1 is constitutively expressed and encodes a nuclear-localized protein. Mutation of DFO1 causes the ectopic expression of C-class genes in the dfo1-1 mutant, and overexpression of OsMADS58, a C-class gene, phenocopies the dfo1 mutants. In vitro and in vivo experiments demonstrated that DFO1 interacts with the rice polycomb group (PcG) proteins (OsMSI1 and OsiEZ1). Remarkably, trimethylation of histone H3 lysine 27, a mark of epigenetic repression, is significantly reduced on OsMADS58 chromatin in the dfo1-1 mutant. Our results suggest that DFO1 functions in maintaining rice floral organ identity by cooperating with PcG proteins to regulate the H3K27me3-mediated epigenetic repression on OsMADS58.


Is the onset of disabling chronic conditions in later childhood associated with exposure to social disadvantage in earlier childhood? A prospective cohort study using the ONS Longitudinal Study for England and Wales.
The aetiology of disabling chronic conditions in childhood in high income countries is not fully understood, particularly the association with socio-economic status (SES). Very few studies have used longitudinal datasets to examine whether exposure to social disadvantage in early childhood increases the risk of developing chronic conditions in later childhood. Here we examine this association, and its temporal ordering, with onset of all-cause disabling chronic later childhood in children reported as free from disability in early childhood. The study comprised a prospective cohort study, using data from the Office for National Statistics Longitudinal Study (ONSLS) for England and Wales. The study sample included 52,839 children with complete data born between 1981-1991 with no disabling chronic condition/s in 1991. Index cases were children with disability recorded in 2001. Comparison cases were children with no recorded disability in 1991. A socio-economic disadvantage index (SDI) was constructed from data on social class, housing tenure and car/van access. Associations were explored with logistic regression modelling controlling sequentially for potentially confounding factors; age, gender, ethnicity and lone parenthood. By 2001, 2049 (4%) had at least one disability. Socio-economic disadvantage, age, gender and lone parenthood but not ethnicity were significantly associated with onset of disabling chronic conditions. The SDI showed a finely graded association with onset of disabling chronic conditions in the index group (most disadvantaged OR 2·11 [CI 1·76 to 2·53]; disadvantaged in two domains OR 1·45 [CI 1·20 to 1·75]; disadvantaged in one domain OR 1·14 [CI 0·93 to 1·39] that was unaffected by age, gender and ethnicity and slightly attenuated by lone parenthood. To our knowledge, this is the first study to identify socio-economic disadvantage in earlier childhood as a predisposing factor for onset of all-cause disabling chronic conditions in later childhood. Temporal ordering and gradation of the response indicate socio-economic disadvantage may play a causal role. This suggests that targeting preventative efforts to reduce socio-economic disadvantage in early childhood is likely to be an important public health strategy to decease health inequalities in later childhood and early adulthood.


Joint modeling of linkage and association using affected sib-pair data.
There has been a growing interest in developing strategies for identifying single-nucleotide polymorphisms (SNPs) that explain a linkage signal by joint modeling of linkage and association. We compare several existing methods and propose a new method called the homozygote sharing transmission-disequilibrium test (HSTDT) to detect linkage and association or to identify SNPs explaining the linkage signal on chromosome 6 for rheumatoid arthritis using 100 replicates of the Genetic Analysis Workshop (GAW) 15 simulated affected sib-pair data. Existing methods considered included the family-based tests of association implemented in FBAT, a transmission-disequilibrium test, a conditional logistic regression approach, a likelihood-based approach implemented in LAMP, and the homozygote sharing test (HST). We compared the type I error rates and power for tests classified into three categories according to their null hypotheses: 1) no association in the presence of linkage (i.e., a SNP explains none of the linkage evidence), 2) no linkage adjusting for the association (i.e., a SNP explains all linkage evidence), and 3) no linkage and no association. For testing association in the presence of linkage, we found similar power among all tests except for the homozygote sharing test that had lower power. When testing linkage adjusting for association, similar power was observed between LAMP and HST, but lower power for the conditional logistic regression method. When testing linkage or association, the conditional logistic regression method was more powerful than FBAT.


Engagement of signaling pathways of protease-activated receptor 2 and μ-opioid receptor in bone cancer pain and morphine tolerance.
Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer. Using a rat model of bone cancer, recent findings suggest that proteinase-activated receptor 2 (PAR2) signaling pathways contribute to neuropathic pain and blocking PAR2 amplifies antinociceptive effects of systemic morphine. The purpose of our study was to examine the underlying mechanisms responsible for the role of PAR2 in regulating bone cancer-evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of PAR2 and its downstream pathways (protein kinases namely, PKCε and PKA) and transient receptor potential vanilloid 1 (TRPV1) were amplified in the dorsal horn of the spinal cord of bone cancer rats compared to control rats. Blocking spinal PAR2 by using FSLLRY-NH2 significantly attenuated the activities of PKCε/PKA signaling pathways and TRPV1 expression as well as mechanical and thermal hyperalgesia. Also, inhibition of PKCε/PKA and TRPV1 significantly diminished the hyperalgesia observed in bone cancer rats. Additionally, blocking PAR2 enhanced the attenuations of PKCε/PKA and cyclic adenosine monophosphate induced by morphine and further extended analgesia of morphine via μ-opioid receptor (MOR). Our data revealed specific signaling pathways, leading to bone cancer pain, including the activation of PAR2, downstream PKCε/PKA, TRPV1 and resultant sensitization of MOR. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of bone cancer pain often observed in clinics.


Interactions of coenzyme A with the aminoglycoside acetyltransferase (3)-IIIb and thermodynamics of a ternary system.
In this work, the binding of coenzyme A (CoASH) to the aminoglycoside acetyltransferase (3)-IIIb (AAC) is studied by several experimental techniques. These data represent the first thermodynamic and kinetic characterization of interaction of a cofactor with an enzyme that modifies the 2-deoxystreptamine ring (2-DOS) common to all aminoglycoside antibiotics. Acetyl coenzyme A (AcCoA) was the preferred substrate, but propionyl and malonyl CoA were also substrates. CoASH associates with two different sites on AAC as confirmed by ITC, NMR, and fluorescence experiments: one with a high-affinity, catalytic site and a secondary, low-affinity site that overlaps with the antibiotic binding pocket. The binding of CoASH to the high-affinity site occurs with a small, unfavorable enthalpy and a favorable entropy. Binding to the second site is highly exothermic and is accompanied by an unfavorable entropic contribution. The presence of an aminoglycoside alters the binding of CoASH to AAC dramatically such that the binding occurs with a favorable enthalpy (DeltaH < 0) and an unfavorable entropy (TDeltaS < 0). This is irrespective of which aminoglycoside is the cosubstrate and occurs without a significant change in the affinity of CoASH for AAC. Also, antibiotics eliminate binding of CoASH to the second site. These data allowed the enthalpies of all six equilibria present in a ternary system (AAC-antibiotic-coenzyme) to be determined for the first time for an aminoglycoside-modifying enzyme. NMR experiments also shed light on the dynamic nature of AAC as fast, slow, and intermediary exchanges between apoenzyme- and coenzyme-bound forms were observed.


Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity.
Young cystic fibrosis (CF) patients' airways are mainly colonized by Staphylococcus aureus, while Pseudomonas aeruginosa predominates in adults. However, the mechanisms behind this infection switch are unclear. Here, we show that levels of type-IIA-secreted phospholipase A2 (sPLA2-IIA, a host enzyme with bactericidal activity) increase in expectorations of CF patients in an age-dependent manner. These levels are sufficient to kill S. aureus, with marginal effects on P. aeruginosa strains. P. aeruginosa laboratory strains and isolates from CF patients induce sPLA2-IIA expression in bronchial epithelial cells from CF patients (these cells are a major source of the enzyme). In an animal model of lung infection, P. aeruginosa induces sPLA2-IIA production that favours S. aureus killing. We suggest that sPLA2-IIA induction by P. aeruginosa contributes to S. aureus eradication in CF airways. Our results indicate that a bacterium can eradicate another bacterium by manipulating the host immunity.


Health advocacy organizations and the pharmaceutical industry: an analysis of disclosure practices.
Health advocacy organizations (HAOs) are influential stakeholders in health policy. Although their advocacy tends to closely correspond with the pharmaceutical industry's marketing aims, the financial relationships between HAOs and the pharmaceutical industry have rarely been analyzed. We used Eli Lilly and Company's grant registry to examine its grant-giving policies. We also examined HAO Web sites to determine their grant-disclosure patterns. Only 25% of HAOs that received Lilly grants acknowledged Lilly's contributions on their Web sites, and only 10% acknowledged Lilly as a grant event sponsor. No HAO disclosed the exact amount of a Lilly grant. As highly trusted organizations, HAOs should disclose all corporate grants, including the purpose and the amount. Absent this disclosure, legislators, regulators, and the public cannot evaluate possible conflicts of interest or biases in HAO advocacy.


Fractal propagation method enables realistic optical microscopy simulations in biological tissues.
Current simulation methods for light transport in biological media have limited efficiency and realism when applied to three-dimensional microscopic light transport in biological tissues with refractive heterogeneities. We describe here a technique which combines a beam propagation method valid for modeling light transport in media with weak variations in refractive index, with a fractal model of refractive index turbulence. In contrast to standard simulation methods, this fractal propagation method (FPM) is able to accurately and efficiently simulate the diffraction effects of focused beams, as well as the microscopic heterogeneities present in tissue that result in scattering, refractive beam steering, and the aberration of beam foci. We validate the technique and the relationship between the FPM model parameters and conventional optical parameters used to describe tissues, and also demonstrate the method's flexibility and robustness by examining the steering and distortion of Gaussian and Bessel beams in tissue with comparison to experimental data. We show that the FPM has utility for the accurate investigation and optimization of optical microscopy methods such as light-sheet, confocal, and nonlinear microscopy.


Addiction to elevated insulin-like growth factor I receptor and initial modulation of the AKT pathway define the responsiveness of rhabdomyosarcoma to the targeting antibody.
Insulin-like growth factor I receptor (IGF-IR) and its ligands are overexpressed by tumors, mediating proliferation and protecting against stress-induced apoptosis. Accordingly, there has been a considerable amount of interest in developing therapeutic agents against IGF-IR. IGF-IR is believed to be ubiquitously expressed without detectable mutation or amplification in cancer. We explored the determinants of cellular response to a humanized anti-IGF-IR antibody. Our results showed a large variation in IGF-IR levels in rhabdomyosarcoma tumor specimens that were comparable with those in rhabdomyosarcoma cell lines. In vitro analysis revealed a direct and very significant correlation between elevated IGF-IR levels and antiproliferative effects of the antibody and defined a receptor number that would predict sensitivity. Our data further suggested a strong dependence on IGF-IR for AKT signaling in cells with elevated IGF-IR. The sensitivity of the high IGF-IR-expressing cells was blocked with a constitutively active AKT. The extracellular signal-regulated kinase pathway was not affected by the antibody. In vivo studies showed that anti-IGF-IR had single-agent antitumor activity; furthermore, predictions of responses based on IGF-IR levels were accurate. In vivo biomarker analysis suggested that h7C10 down-regulated both IGF-IR and p-AKT initially, concordant with antitumor activity. Subsequent progression of tumors was associated with reactivation of p-AKT despite sustained suppression of IGF-IR. These results identified the first predictive biomarker for anti-IGF-IR therapies in cancer.


[Correlation and association of income and educational level with health and nutritional conditions among the morbidly obese].
This article seeks to investigate the relationship between income and educational level and health and nutritional conditions among the morbidly obese. A cross-sectional study was conducted with 79 patients at first appointment, with Body Mass Index (BMI) ≥ 35 kg/m2 and age ≥ 20 years. The following data was collected: demographic, socioeconomic, anthropometric, lifestyle, biochemical and food intake data. Average BMI was 48.3 ± 6.9 kg/m2. There was a significant negative correlation between education level and the variables of weight (r = -0.234) and BMI (r = -0.364) and per capita family income with daily consumption of leafy vegetables (r = -0.263). After multivariate analysis, higher per capita family income was associated with the absence of heart disease (PR: 0.51, CI95%: 0.32-0.81), higher daily consumption of leafy vegetables (PR: 1.79, CI95%: 1.16-2.75) and candy (PR: 3.12, CI95%: 1.21-8.04). In the morbidly obese, per capita household income was associated with absence of heart disease and higher consumption of leafy vegetables and candy. On the other hand, education level was not associated with health and nutrition conditions.


NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview.
Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers.


Increased epidermal growth factor receptor expression at the invasive margin is a negative prognostic factor in colorectal cancer.
The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is often expressed in solid malignant tumours, and the expression has been correlated to disease progression. Multiple new agents targeted against the EGFR have been developed during the last decade, but treatment selecting criteria are still not clear. This immunohistochemical study includes 386 colorectal cancer patients and focuses on EGFR expression variations within the tumour, comparing central parts to the invasive margin. Positive immunostaining for EGFR was evident in the central part in 176/386 (46%) of analyzed primary tumours. The invasive margin was positive in 222/386 (58%). A similar expression in both the central part and the invasive front was evident in 286/386 (74%). An increased score at the invasive margin compared to central parts (EGFR(i) ) was evident in 97/386 (25%) of the tumours. Moreover, the results show a significant survival disadvantage for the EGFR(i) group, both in potentially curatively resected colon cancer patients (n = 170, p = 0.01) and in potentially curatively resected colon and rectal cancer patients combined (n = 273, p = 0.013). Multivariate survival analysis adjusted for age, gender, bowel localisation, grade, stage and tumour type showed an increased risk of cancer death for EGFR(i) tumours (HR, 1.53; 95% CI, 1.04-2.23; p = 0.029). A significant correlation between EGFR expression at the invasive margin and the presence of budding was seen (p = 0.0001). This investigation of a large patient material implies that EGFR immunohistochemical analysis still has a role in risk evaluation of colorectal cancer patients.


An open trial of self-help behaviours of clients with eating disorders in an online programme.
The aim of this study was to evaluate the self-help behaviour of individuals with eating disorders in an Internet-based self-help programme developed in the Asia-Pacific region and to determine their compliance with the programme. Eating disorders represent a growing health problem affecting both Western and Asian countries. Without timely and adequate treatment, individuals with eating disorders are at risk of premature death. Self-help approaches for treating eating disorders offer therapeutic promise. An open trial design was used. This study, conducted from August 2006-July 2011, included 280 participants recruited from outpatient eating disorder clinics and treatment units and through a university student newspaper and Internet websites. This open trial evaluated an Internet-based self-help programme, which included components on healthy eating, family education, health assessment, motivation enhancement, self-help strategies, and psychological health promotion. The progress of participants was followed up via monthly e-mails. A tracking system was implemented to determine their compliance with the programme. A small majority of the participants (56·9%) were already undergoing treatment for their eating disorders. About 63% (n = 176) demonstrated self-help behaviour, as manifested by their completion of health assessment questionnaires, involvement in motivation enhancement exercises, or the use of self-help strategies such as monitoring, normalizing eating behaviour, and stress management. Improvements were observed in their eating disorder psychopathology, motivational stage of change and psychological health from baseline to the 1-month follow up. Internet-based self-help programmes for eating disorders are helpful adjuncts to professional treatment.


The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep.
Daytime sleepiness is common in patients with sleep-disordered breathing. Although respiratory events during sleep are associated with the occurrence of daytime sleepiness, the differential impact of these events during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep on daytime sleepiness has not been well characterized. To determine the effect of respiratory events during REM sleep and NREM sleep on daytime sleepiness, as assessed by the multiple sleep latency test (MSLT). Cross-sectional study. University-based sleep disorders laboratory. Patients referred for polysomnography and daytime MSLT (n=1,821). N/A. The study sample was initially divided into quartiles based on the level of the apnea-hypopnea index (AHI) during NREM sleep. Within the first NREM-AHI quartile (NREM-AHI < 8.3 events/hr), the association between REM-related respiratory events and daytime sleepiness was examined using the method of Kaplan-Meier analysis and Cox proportional hazards regression. After adjusting for age, gender, body mass index, and the duration of NREM and REM sleep, REM-AHI was not associated with daytime sleepiness (Relative Risk: 1.01; 95%CI: 0.94-1.10). Similarly, no significant association was observed between REM-AHI and the MSLT in patients within the second through fourth NREM-AHI quartiles. In contrast, increasing severity of disordered breathing during NREM sleep was associated with daytime sleepiness. For a 10-point increase in NREM-AHI, the adjusted relative risks for daytime sleepiness in the second through fourth NREM-AHI quartile were 1.21 (95%CI: 1.01-1.46), 1.20 (95%CI: 1.05-1.37), and 1.10 (95%CI: 1.04-1.16), respectively. Sleep-disordered breathing during NREM sleep, but not REM sleep, is associated with increased risk of daytime sleepiness.


Widespread paleopolyploidy in model plant species inferred from age distributions of duplicate genes.
It is often anticipated that many of today's diploid plant species are in fact paleopolyploids. Given that an ancient large-scale duplication will result in an excess of relatively old duplicated genes with similar ages, we analyzed the timing of duplication of pairs of paralogous genes in 14 model plant species. Using EST contigs (unigenes), we identified pairs of paralogous genes in each species and used the level of synonymous nucleotide substitution to estimate the relative ages of gene duplication. For nine of the investigated species (wheat [Triticum aestivum], maize [Zea mays], tetraploid cotton [Gossypium hirsutum], diploid cotton [G. arboretum], tomato [Lycopersicon esculentum], potato [Solanum tuberosum], soybean [Glycine max], barrel medic [Medicago truncatula], and Arabidopsis thaliana), the age distributions of duplicated genes contain peaks corresponding to short evolutionary periods during which large numbers of duplicated genes were accumulated. Large-scale duplications (polyploidy or aneuploidy) are strongly suspected to be the cause of these temporal peaks of gene duplication. However, the unusual age profile of tandem gene duplications in Arabidopsis indicates that other scenarios, such as variation in the rate at which duplicated genes are deleted, must also be considered.


Expression of angiotensin II receptor subtypes AT(1A) and AT(1B) in enriched fractions of dispersed rat pituitary cells.
Differential evaluation of angiotensin II (Ang II) receptors (AT1A, AT1B and AT2) expression was performed in dispersed adenohypophyseal cells fractionated by unit gravity sedimentation. Binding of [125I-Sar1-Ile8]-Ang II and its displacement by specific nonpeptidic AT1 (DuP753) and AT2 (PD123319) antagonists was monitored throughout the gradient. Quantification of mRNA levels corresponding to both AT1 receptor subtypes (AT1A and AT1B) was achieved by reverse transcriptase polymerase chain reaction (RT-PCR) amplification in the presence of an AT1 receptor mutant cRNA as internal standard. Fractions were characterised by radioimmunoassay for the five major anterior pituitary hormones and by counting immunocytochemically labelled cells. Quantification of AT1 receptor subtype mRNA levels was also performed in four hypophyseal cell lines secreting prolactin, growth hormone, corticotropin and a gonadotropin subunit. As already described for the whole pituitary, AT1B receptor mRNA is predominantly expressed (80% of total AT1A + AT1B receptor mRNA content), whereas AT1A is expressed at lower level (20%) in dispersed pituitary cells. Most AT1 receptor mRNA and binding co-elute with fractions enriched in lactotropes and corticotropes. In contrast to AT1B, AT1A receptor mRNA is not present in heavier populations of lactotropes or in somatomammotropes. Low AT1B mRNA levels are detected in GH4C1 and in GC cells, two clones which secrete respectively prolactin and growth hormone. In contrast, no AT1 receptor mRNA expression was found in two other cell lines, AtT20 and alphaT3-1, which produce pro-opiomelanocortin and gonadotropin. It is concluded that expression of AT1 receptor subtypes is heterogeneous in different populations of lactotropes and corticotropes.


[Preparation and identification of monoclonal antibody against human spermine oxidase].
To prepare mouse anti-human spermine oxidase (anti-hSMO) monoclonal antibody (mAb) and testify its application in the biological techniques including Western blotting and immunohistochemistry. Plasmid pET-15b/SMO was first transferred into BL21 (DE3), and then SMO recombinant protein with 6×His tag was induced to express by IPTG and purified by Ni-NTA resin. The purified recombinant SMO was used to immunize BALB/c mouse. The spleen cells from the immunized mouse were harvested and hybridized with Sp2/0 myeloma cells to obtain a hybridoma cell line that could efficiently synthesize and secret anti-SMO mAb. The titer and antigen specificity of this antibody were identified by ELISA, Western blotting and immunohistochemistry. We successfully obtained the hybridoma cell line which could stably secret anti-SMO mAb. The mAb was of a high titer and antigen specificity and could be used in ELISA, Western blotting, and immunohistochemistry for SMO. The mouse anti-hSMO mAB with a high antigen specificity has been prepared successfully and used for a variety of bio-analytical techniques.


Mitochondrial injury: a hot spot for parkinsonism and Parkinson's disease?
The recent identification of genes (parkin, DJ-1, and PINK1) involved in recessive autosomal parkinsonism, and the indications that these proteins may have protective effects on the mitochondria, has led to the reemergence of the notion that mitochondrial dysfunction might play a central role in the etiology of sporadic Parkinson's disease (PD). This idea has previously been supported by biochemical analyses showing reduced mitochondrial activity in PD patients and in animal models of PD generated by the selective inhibition of mitochondria activity. However, the involvement of DJ-1 or PINK1 loss of function in classical idiopathic PD, characterized by pathological inclusions composed of aggregated alpha-synuclein protein, has still not been evaluated. More detailed studies of the possible interactions between parkin, DJ-1, PINK1, and alpha-synuclein and their effects on mitochondria are needed to more adequately define the biological pathways that may convergently or independently lead to parkinsonism.


Stress, allostatic load, catecholamines, and other neurotransmitters in neurodegenerative diseases.
As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple interacting effectors regulated by homeostatic comparators-"homeostats." Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholamines in the neuronal cytoplasm are autotoxic and that catecholamines from storage visicles leak into the cytoplasm continuously during life. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time.


An essential role for diet in exercise-mediated protection against dyslipidemia, inflammation and atherosclerosis in ApoE⁻/⁻ mice.
Diet and exercise promote cardiovascular health but their relative contributions to atherosclerosis are not fully known. The transition from a sedentary to active lifestyle requires increased caloric intake to achieve energy balance. Using atherosclerosis-prone ApoE-null mice we sought to determine whether the benefits of exercise for arterial disease are dependent on the food source of the additional calories. Mice were fed a high-fat diet (HF) for 4.5 months to initiate atherosclerosis after which time half were continued on HF while the other half were switched to a high protein/fish oil diet (HP). Half of each group underwent voluntary running. Food intake, running distance, body weight, lipids, inflammation markers, and atherosclerotic plaque were quantified. Two-way ANOVA tests were used to assess differences and interactions between groups. Exercised mice ran approximately 6-km per day with no difference between groups. Both groups increased food intake during exercise and there was a significant main effect of exercise F((1,44) = 9.86, p<0.01) without interaction. Diet or exercise produced significant independent effects on body weight (diet: F(1,52) = 6.85, p = 0.012; exercise: F(1,52) = 9.52, p<0.01) with no significant interaction. The combination of HP diet and exercise produced a greater decrease in total cholesterol (F(1, 46) = 7.9, p<0.01) and LDL (F(1, 46) = 7.33, p<0.01) with a large effect on the size of the interaction. HP diet and exercise independently reduced TGL and VLDL (p<0.05 and 0.001 respectively). Interleukin 6 and C-reactive protein were highest in the HF-sedentary group and were significantly reduced by exercise only in this group. Plaque accumulation in the aortic arch, a marker of cardiovascular events was reduced by the HP diet and the effect was significantly potentiated by exercise only in this group resulting in significant plaque regression (F1, 49 = 4.77, p<0.05). In this model exercise is beneficial to combat dyslipidemia and protect from atherosclerosis only when combined with diet.


[Bacteria of the genus Aeromonas as the causative agents of saprophytic infection].
The bacteriological study of feces from 458 patients with acute enteric diseases revealed that in 3.2% of cases (in summer in 8.1% of cases) the disease was caused by Aeromonas. In Aeromonas strains isolated from river water in the Volga delta, from fish and from raw meat the same pathogenicity factors occurred as in strains isolated from patients (hemolysin, DNA-ase, protease, lecithinase, amylase, adhesins, capacity of binding Congo red).


False positive screen test for mucopolysaccharidoses in healthy female newborns.
In total, 930 urine samples obtained on 2nd and 3rd day from birth have been analyzed for the early diagnosis of Mucopolysaccharidoses. Dimethylmethylene blue (DMB) assay and one-dimensional electrophoresis were performed in all urine samples. Agarose gel electrophoresis, before and after treatment with chondroitinase ABC and heparinases, was used for a comprehensive characterization. Out of 930 urine samples 7 showed anomalous electrophoretic pattern; 5 of them had high GAG levels by DMB test. Atypical samples (n = 7) were analyzed by agarose gel electrophoresis. After enzymatic digestion, some slow bands were still visible. A second urine sample of the above 7 newborns was analyzed at the age of 1 month, demonstrating both a normal pattern and normal GAG levels. Additional urine and vaginal mucus samples from 10 term neonates with vaginal bleeding showed the same electrophoretic pattern observed in the 7 false positive samples. The altered electrophoretic pattern may be due to the presence of glycoproteins and not to specific GAGs, due to high levels of maternal hormones exposure during pregnancy. To our knowledge, this is the first time maternal estrogen hormones are proposed as a likely cause of false-positive urinary glycosaminoglycan screen test in healthy newborns.


Clinical and Radiographic Features of Knee Osteoarthritis of Elderly Patients.
Knee osteoarthritis is a common pathology, characterized by a prevalence that increases with age. Absence of anatomo-clinical correlation is a complex management, particularly in a geriatric setting where it is not well studied. The aim of the present study is to investigate the epidemio-clinical profile, functional impairment and radiographic features of knee osteoarthritis in the old patients versus younger patients (<65 years). Cross-sectional study includes patients who were monitored for 6 months at a rheumatology department for knee osteoarthritis. Epidemio-clinical, anthropometric and radiographic data were gathered. A comparison was made of these various characteristics between patients of over 65 years of age (group1; n=56) and those under 65 (group2; n=56). The mean age of the group 1 patients was 71±5 with a clear feminine predominance. Comorbidity was observed in two thirds of cases. More than half of them were overweight. Gonalgia had been evolving for approximately 8.4±9.2 years and was bilateral in 82.6% of the cases and of mechanical type in 94.6% of the cases. The patients experienced an average pain scale of 65.2mm. Pain had an anterior site in major of cases. An axial deviation of the lower limbs were observed in 60.7% of the cases and a limited mobility of the knees in 48.2% of the cases. The mean value of Lequesne index was 11.02±4.8. The walking distance was not limited in 37.5% of the cases. Radiographically, knee osteoarthritis was bilateral in all cases and stage 4 was observed in 50% of the cases. Comparative study showed that elderly patients had a smaller waist size (p=0.003), a longer course of gonalgia (p<0.0001), a widespread site of pain (p=0.004), and a more frequent limitation of walking distance (p<0.0001) as well as more axial deviation (p<0.0001) and joint mobility limitation (p=0.005). Gonalgia manifesting during rest was more frequent in elderly patients (p=0.001). In addition, impaired functioning (p=0.001) and the stage of radiographic damage (p=0.02) were more advanced in elderly patients. The present study shows that knee osteoarthritis is more severe in the elderly patients in terms of clinical presentation and functional impairment.


Early intraocular pressure rise after trabeculectomy.
Intraocular pressure (IOP) was measured 4 to 6 hours after surgery and on the first postoperative day in 35 eyes of 35 consecutive patients undergoing initial trabeculectomy. In 27 eyes, the anterior chamber was re-formed at the completion of surgery with balanced salt solution, and in eight eyes it was reformed with hyaluronate sodium. A total of six eyes (17%) had an IOP of 40 mm Hg or greater 4 to 6 hours after surgery. Patients who received hyaluronate to maintain the depth of the anterior chamber had a significantly greater chance of experiencing a marked postoperative IOP rise, both at 4 to 6 hours (P = .005) and on the first postoperative day (P = .0038). There was no correlation between the postoperative IOP rise and the patient's age, sex, glaucoma diagnosis, preoperative IOP, use of 5-fluorouracil, or the number of sutures used to close the scleral flap. Hyaluronate may contribute to an early increase in IOP that could result in further visual field loss in eyes with severe glaucomatous damage. We recommend early monitoring of IOP after trabeculectomy and avoiding the routine use of hyaluronate.


Platelet-derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3-kinase and sterol regulatory element-binding proteins.
We analyzed the transcriptional program elicited by stimulation of normal human fibroblasts with platelet-derived growth factor (PDGF) using cDNA microarrays. 103 significantly regulated transcripts that had not been previously linked to PDGF signaling were identified. Among them, a cluster of genes involved in fatty acid and cholesterol biosynthesis, including stearoyl-CoA desaturase (SCD), fatty acid synthase, and hydroxymethylglutaryl-CoA synthase (HMGCS), was up-regulated by PDGF after 24 h of treatment, and their expression correlated with increased membrane lipid production. These genes are known to be controlled by sterol regulatory element-binding proteins (SREBP). PDGF increased the amount of mature SREBP-1 and regulated the promoters of SCD and HMGCS in an SREBP-dependent manner. In line with these results, blocking SREBP processing by addition of 25-hydroxycholesterol blunted the effects of PDGF on lipogenic enzymes. SREBP activation was dependent on the phosphatidylinositol 3-kinase (PI3K) pathway, as judged from the effects of the inhibitor LY294002 and mutation of the PDGFbeta receptor tyrosines that bind the PI3K adaptor subunit p85. Fibroblast growth factors (FGF-2 and FGF-4) and other growth factors mimicked the effects of PDGF on NIH3T3 and human fibroblasts. In conclusion, our results suggest that growth factors induce membrane lipid synthesis via the activation SREBP and PI3K.


Effectiveness of video-based health promotion: A systematic review and meta-analysis.
Although health promotion scholars and practitioners frequently employ video-based promotion, its effectiveness remains uncertain due to mixed findings. Nuanced details regarding content and design also remain under-explored. We conducted a comprehensive search across nine databases to identify relevant empirical research articles. Our systematic review included a total of 54 studies, with 38 studies eligible for meta-analysis. Findings highlight the promising potential of video messaging strategies in promoting health behaviors. Future research should focus on designing video content that targets detection behaviors within an appropriate length, guided by robust theoretical frameworks to maximize the efficacy of video promotion. More substantial evidence is needed to assess whether video promotion can achieve similar persuasive effectiveness across diverse cultural, political, and economic circumstances. Factors related to the audience (e.g., distinct psychological and personality influences) and message characteristics (e.g., length, credibility) should be further explored to better elucidate the relationship between video-based health promotion and health outcomes. Health practitioners and organizations should incorporate video-based messages in interventions as supplement or alternative means to educate audiences of positive prevention methods, establish accurate attitude and intentions toward prevention behaviors, and increase their vigilance toward risky behaviors.


Physical Inactivity and Sedentarism during and after Admission with Community-Acquired Pneumonia and the Risk of Readmission and Mortality: A Prospective Cohort Study.
Bed rest with limited physical activity is common during admission. The aim was to determine the association between daily step count and physical activity levels during and after admission with community-acquired pneumonia (CAP) and the risk of readmission and mortality. A prospective cohort study of 166 patients admitted with CAP. Step count and physical activity were assessed with accelerometers during and after admission and were categorised as sedentary, light, or moderate-vigorous physical activity. Linear regression was used to assess the association between step count and length of stay. Logistic regression was used to assess the association between step count, physical activity level, and risk of readmission and mortality. Patients admitted with CAP were sedentary, light physically active, and moderate-to-vigorous physically active 96.4%, 2.6%, and 0.9% of their time, respectively, with 1356 steps/d. For every 500-step increase in daily step count on day 1, the length of stay was reduced by 6.6%. For every 500-step increase in daily step count during admission, in-hospital and 30-day mortality was reduced. Increased light and moderate-to-vigorous physical activity during admission were associated with reduced risk of in-hospital and 30-day mortality. After discharge, patients increased their daily step count to 2654 steps/d and spent more time performing light and moderate-to-vigorous physical activity. For every 500-step increase in daily step count after discharge, the risk of readmission was reduced. Higher moderate-to-vigorous physical activity after discharge was associated with a reduced risk of readmission. Increased physical activity during admission was associated with a reduced length of stay and risk of mortality, whereas increased physical activity after discharge was associated with a reduced risk of readmission in patients with CAP. Interventions focusing on increasing physical activity levels should be prioritised to improve the prognosis of patients admitted with CAP.


Effects of manufacturing errors on diffraction efficiency for multilayer diffractive optical elements.
The effect of manufacturing errors on diffraction efficiency for multilayer diffractive optical elements (MLDOEs) used in imaging optical systems is discussed in this paper. The relationship of diffraction efficiency and depth-scaling errors are analyzed for two different cases: the two relative depth-scaling errors change in the same sign and in the opposite sign. For the first condition, the corresponding diffraction efficiency decreases more slowly. The effect of periodic width errors on diffraction efficiency is also evaluated. When the two major manufacturing errors coexist, the magnitude of the decrease of diffraction efficiency is analyzed for MLDOEs. The result can be used for analyzing the effects of the manufacturing errors on diffraction efficiency for MLDOEs.


Postsurgical complications and their clinical management.
Thus, we have briefly touched upon several sources of potential postsurgical complications. When these various conditions arise, they most often interfere with the overall healing process or total recovery period. In addition to causing aggravation and concern to the surgeon, they frequently complicate the operative impressions of the patient. The basic prevention techniques discussed should provide a substantial decrease in postsurgical complications. In summary, proper medical history and physical examination, vascular evaluation, biomechanical, radiographic, and laboratory studies are important. To employ good surgical preparation and sterile technique is also an important preventive measure. Plan your site of incision to maximize the approach to the bone correction while minimizing trauma to the underlying soft tissue structures. Always be prepared with adequate and back up instrumentation, including new surgical blades, burs, or Brophies. Use the instrumentation that best accomplishes the work proposed or contemplated. Good tissue handling and dissection along with adequate flushing of the wound site with sterile saline solutions are necessary. The well-informed patient can also reduce or prevent postoperative complications by the fact that they have been educated and informed about the pre-, intra-, and postoperative course of events. In conclusion, we have presented the most common postsurgical complications, their possible etiology, prevention, and management. Hopefully, these subjects will stimulate the practitioner to be more aware of such complications and therefore recognize and treat these less than desirable events appropriately.


Essential role of microRNA-650 in the regulation of B-cell CLL/lymphoma 11B gene expression following transplantation: A novel mechanism behind the acute rejection of renal allografts.
Kidney transplantation is an effective final therapeutic procedure for patients with end-stage kidney failure. Although advanced immunosuppressive therapy is administered following transplantation, certain patients still suffer from acute allograft rejection. MicroRNAs (miRs) have a potential diagnostic and therapeutic value for acute renal allograft rejection; however, their underlying mechanism of action is largely unknown. In the present study, an increased level of miR-650 was identified to be associated with the downregulation of B-cell CLL/lymphoma 11B (BCL11B) expression in acute renal allograft rejection. Furthermore, in vitro study using human renal glomerular endothelial cells (HRGECs) transfected with a miR-650 mimic revealed that key characteristics of acute renal allograft rejection were observed, including apoptosis, the release of cytokines and the chemotaxis of macrophages, while the effects were reduced in HRGECs transfected with a miR-650 inhibitor. The existence of a conserved miR-650 binding site on the 3'-untranslated region of BCL11B mRNA was predicted by computational algorithms and confirmed by a luciferase reporter assay. Knockdown of BCL11B with small interfering RNA (siRNA) significantly increased the apoptotic rate and significantly decreased the proliferation ability of HRGECs compared with the negative control group. HRGECs transfected with a combination of BCL11B siRNA and the miR-650 mimic demonstrated a significant increase in the rate of apoptosis compared with the control. These results suggest that the upregulation of miR-650 contributes to the development of acute renal allograft rejection by suppression of BCL11B, which leads to apoptosis and inflammatory responses. Thus, miR-650 and BCL11B may represent potential therapeutic targets for the prevention of acute renal allograft rejection.


Three-dimensional geometric morphometrics applied to the study of children with cleft lip and/or palate from the North East of England.
This prospective cross-sectional, case-controlled morphometric study investigated three-dimensional facial morphological variation among and between 8- and 12-year-old children [40 with a unilateral cleft lip and palate (UCLP), 23 with a unilateral cleft lip and alveolus (UCLA), 19 with a bilateral cleft lip and palate (BCLP), and 21 with an isolated cleft palate (ICP)]. Eighty gender- and age-matched individuals comprised the control group. The mean shape of each group was computed using generalized Procrustes analysis (GPA). Differences in shape between group means were assessed using multivariate analysis of variance and permutation tests, and shape differences were visualized for interpretation using warpings of the grand mean shape and transformation grids computed using thin plate splines (TPA). Statistically significant differences between the mean facial shapes and forms (shape plus size) of all groups were found. The greatest difference was in the BCLP group and the second greatest in the UCLP group. The study of asymmetry indicated different degrees and differences in the nature of asymmetry that characterize different cleft lip and palate (CLP) deformities. Principal component analyses (PCA) of form space and of means, plus reflected means, were informative with respect to the differences in facial size and shape and asymmetry between these groups. The results highlight differences in the aetiology of ICP and CLP groups and underline the potential value of statistical shape analysis in assessing the outcomes of CLP treatment.


Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon.
By exposing human blood-derived macrophages and alveolar macrophages in vitro to dexamethasone, we showed in these studies that glucocorticoids markedly suppress the antimicrobial activity of macrophages but not macrophage activation by lymphokines. As little as 2.5 X 10(-8) mol/liter of dexamethasone prevented macrophages from inhibiting germination of Aspergillus spores or from eliminating ingested bacteria such as Listeria, Nocardia, or Salmonella. Damage to macrophage function was inhibited by progesterone and appeared to be receptor-mediated. In accordance with in vivo observations, dexamethasone required 24-36 h to suppress antimicrobial activity. While glucocorticoids interfered with base-line activity of macrophages, dexamethasone concentrations comparable to drug levels in patients had no effect on macrophage activation. Proliferating lymphocytes and gamma-interferon thus increased the antimicrobial activity of phagocytes exposed to glucocorticoids over that of control cells. Macrophage activation and correction of the dexamethasone effect by gamma-interferon, however, was dependent on the pathogen. The lymphokine enhanced the antimicrobial activity of dexamethasone-treated macrophages against Listeria and Salmonella but not against Aspergillus or Nocardia. Dexamethasone-induced damage to the antimicrobial activity of human macrophages in vitro parallels observations that glucocorticoids render laboratory animals susceptible to listeriosis and aspergillosis by damaging resident macrophages. Suppression of macrophage antimicrobial activity should thus be considered when treating patients with glucocorticoids; its prevention by gamma-interferon might be beneficial for some but not all pathogens.


The osteoblast to osteocyte transition: epigenetic changes and response to the vitamin D3 hormone.
Osteocytes are derived from osteoblast lineage cells that become progressively embedded in mineralized bone. Development of the osteocytogenic cell line IDG-SW3 has enabled a temporal and mechanistic investigation of this process. Through RNA-sequencing analyses, we show that although substantial changes in gene expression occur during the osteoblast to osteocyte transition, the majority of the transcriptome remains qualitatively osteoblast like. Genes either up-regulated or expressed uniquely in the osteocyte include local and systemic factors such as Sost and Fgf23 as well as genes implicated in neuronal, muscle, vascular, or regulatory function. As assessed by chromatin immunoprecipitation coupled to high-throughput sequencing, numerous changes in epigenetic histone modifications also occur during osteocytogenesis; these are largely qualitative rather than quantitative. Specific epigenetic changes correlate with altered gene expression patterns that are observed during the transition. These genomic changes likely influence the highly restricted transcriptomic response to 1,25(OH)(2)D(3) that occurs during differentiation. VDR binding in osteocytes revealed an extensive cistrome co-occupied by retinoid X receptor and located predominantly at sites distal to regulated genes. Although sites of VDR binding were apparent near many 1,25(OH)(2)D(3)-regulated genes, the expression of others adjacent to VDR-binding sites were unaffected; lack of VDR binding was particularly prevalent at down-regulated genes. Interestingly, 1,25(OH)(2)D(3) was found to induce the Boc and Cdon coreceptors that are active in hedgehog signaling in osteocytes. We conclude that osteocytogenesis is accompanied by changes in gene expression that may be driven by both genetic and epigenetic components. These changes are likely responsible for the osteocyte phenotype and may contribute to reduced sensitivity to 1,25(OH)(2)D(3).


Vitamin B12 absorption studies using radioactive vitamin B12: comparison of whole body retention and urinary excretion after flushing dose (Schilling's test).
Vitamin B-12 absorption of 12 healthy young male subjects was determined by using labelled vitamin B-12 by Schilling's test and whole body retention test. The whole body retention test was performed first using low energy Co57 isotope and a week later, Schilling's test was performed. Whole body retention showed a mean absorption of 56.5% while Schilling's test showed mean absorption of 16.9% in the same subjects. Data supports the whole body retention test being more accurate.


Embryonic stem cell research: one small step for science or one giant leap back for mankind?
At the forefront of modern debate over the ethical use of biotechnology is embryonic stem cell research. In this poignant analysis of its legitimacy, the author examines the history of this research in light of the United States' policy favoring the protection of human beings over scientific progress. Stem cells, which can divide in culture to create specialized cells in the human body, possess significant potential for curing disease, particularly when taken from human embryos. However, as evidenced by the research atrocities committed under the Nazi regime, the benefits of human research do not come without a cost to humanity. Recognizing this, the later trial of these scientists produced the Nuremberg Code, a set of natural law principles guiding future research on humans that continues to influence health policy decisions. Drawing on this background, the author first considers the appropriate legal status for a human embryo. Biologically, the characteristics of a human embryo place it between human tissue and a constitutional person. Judicially, the answer is even less clear. The author analyzes case law in the context of abortion and in vitro fertilization, as well as classifications by the common law, state legislation, and the National Bioethics Advisory Commission, to conclude that a human embryo should be subject to the same legal and ethical restrictions as any other "human subject." Accordingly, the author argues that embryonic stem cell research violates the ethical standards and purposes of the Nuremberg Code and should be banned by federal legislation. Such a prohibition will fulfill the societal policy choice of protecting potential life and vulnerable human subjects.


Calcitonin gene-related peptide (CGRP) in the developing mouse limb.
The mitogenic effects of neuropeptides and their localization to developing tissues suggest an important role for these peptides during gestation. We examined the expression and action of the neuropeptide calcitonin gene-related peptide (CGRP) in the developing mouse limb bud, an excellent model system for studying musculoskeletal development. CGRP immunoreactivity (CGRP-ir) was detected in the developing limb at day 16.5 of gestation (E 16.5) and was limited to nerve fibers surrounding blood vessels, within the developing muscle or in close proximity to the developing cartilaginous skeleton. Although CGRP-ir was not observed until E 16.5, limb buds were responsive to CGRP as early as E 11.5. Within 5 min of exposure to CGRP (10(-8) to 10(-7) M) a 2--3-fold increase in cyclic AMP (cAMP) levels was observed. This CGRP-induced increase in cAMP was abolished by the addition of human CGRP8-37, a CGRP receptor antagonist. This result suggests that the effect on cAMP was mediated by the interaction of CGRP with CGRP receptors. Our findings indicate that mouse limbs are responsive to CGRP when they are composed of primarily undifferentiated mesenchyme and that CGRP-ir appears at a later stage of development in association with cartilage and muscle differentiation.


Endothelium-specific amyloid precursor protein deficiency causes endothelial dysfunction in cerebral arteries.
The exact physiological function of amyloid-β precursor protein (APP) in endothelial cells is unknown. Endothelium-specific APP-deficient (eAPP-/-) mice were created to gain new insights into the role of APP in the control of vascular endothelial function. Endothelium-dependent relaxations to acetylcholine were significantly impaired in basilar arteries of global APP knockout (APP-/-) and eAPP-/- mice ( P < 0.05). In contrast, endothelium-independent relaxations to nitric oxide (NO)-donor diethylamine-NONOate were unchanged. Western blot analysis revealed that protein expression of endothelial nitric oxide synthase (eNOS) was significantly downregulated in large cerebral arteries of APP-/- mice and eAPP-/- mice as compared to respective wild-type littermates ( P < 0.05). Furthermore, basal levels of cyclic guanosine monophosphate (cGMP) were also significantly reduced in large cerebral arteries of APP-deficient mice ( P < 0.05). In contrast, protein expression of prostacyclin synthase as well as levels of cyclic adenosine monophosphate (cAMP) was not affected by genetic inactivation of APP in endothelial cells. By using siRNA to knockdown APP in cultured human brain microvascular endothelial cells we also found a significant downregulation of eNOS mRNA and protein expressions in APP-deficient endothelium ( P < 0.05). These findings indicate that under physiological conditions, expression of APP in cerebral vascular endothelium plays an important protective function by maintaining constitutive expression of eNOS .


Suicidal Ideation of the Elderly According to Their Involvement in Grandchild Care.
The purpose of the present study was to examine the severity of suicidal ideation of the older adults according to the amount of involvement in grandchild care. Data for this research were drawn from a cross-sectional study conducted on community-dwelling adults aged 65 years or older. The 922 participants were divided into three groups according to their involvement in grandchild care: 18.5% had provided daily care, 12.4% had provided occasional care, and 69.1% had never cared for their grandchildren. ANCOVA analysis showed that the scores for depression was significantly lower in the group which took care of their grandchildren occasionally compared to the other two groups. The scores for suicidal ideation was significantly higher in the group which had never taken care of their grandchildren compared to the other two groups. Current study suggests that grandparenting may have a positive effect on suicidal ideation of the older adults.


The dangers of widespread nitric oxide screening for primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is underdiagnosed and requires complex testing at specialist diagnostic centres. Measurement of nasal nitric oxide (nNO) has good sensitivity and specificity screening for PCD, but is currently usually measured at PCD centres rather than prior to referral. Proposals to include NO testing for asthma diagnoses could widen access to PCD screening if nasal mode analysers are available. Data from 282 consecutive referrals to our PCD diagnostic centre (31 PCD positive) were used to model predictive values for nNO testing with varying pretest probability and showed that predictive values were good in the referral population, but extending screening to more general populations would result in excessive false positives that may overwhelm diagnostic services. Although nNO remains a useful test, a 'normal' result with classical clinical history should still be considered for further testing.


ARPC1/Arc40 mediates the interaction of the actin-related protein 2 and 3 complex with Wiskott-Aldrich syndrome protein family activators.
The actin-related protein 2 and 3 (Arp2/3) complex is a seven-subunit protein complex that nucleates actin filaments at the cell cortex. Despite extensive cross-linking, crystallography, genetic and biochemical studies, the contribution of each subunit to the activity of the complex remains largely unclear. In this study we characterized the function of the 40-kDa subunit, ARPC1/Arc40, of the yeast Arp2/3 complex. We showed that this subunit is indeed a stable component of the Arp2/3 complex, but its highly unusual electrophoretic mobility eluded detection in previous studies. Recombinant Arc40 bound the VCA domain of Wiskott-Aldrich syndrome protein family activators at a K(d) of 0.45 mum, close to that of the full complex with VCA (0.30 microm), and this interaction was dependent on the conserved tryptophan at the COOH terminus of VCA. Using a newly constructed Delta arc40 yeast strain, we showed that loss of Arc40 severely reduced the binding affinity of the Arp2/3 complex with VCA as well as the nucleation activity of the complex, suggesting that Arc40 contains an important contact site of the Arp2/3 complex with VCA. The Delta arc40 cells exhibited reduced growth rate, loss of actin patches, and accumulation of cables like actin aggregates, phenotypes typical of other subunit nulls, suggesting that Arc40 functions exclusively within the Arp2/3 complex.


Light field analysis for modeling image formation.
Image formation is traditionally described by a number of individual models, one for each specific effect in the image formation process. However, it is difficult to aggregate the effects by concatenating such individual models. In this paper, we apply light transport analysis to derive a unified image formation model that represents the radiance along a light ray as a 4-D light field signal and physical phenomena such as lens refraction and blocking as linear transformations or modulations of the light field. This unified mathematical framework allows the entire image formation process to be elegantly described by a single equation. It also allows most geometric and photometric effects of imaging, including perspective transformation, defocus blur, and vignetting, to be represented in both 4-D primal and dual domains. The result matches that of traditional models. Generalizations and applications of this theoretic framework are discussed.


Pretranslational regulation of Na-K-ATPase in cultured canine kidney cells by low K+.
Long-term upregulation of the sodium pump [Na-K-adenosine triphosphatase (Na-K-ATPase)] entails an increase in the number of enzyme molecules. We incubated Madin-Darby canine kidney (MDCK) cells in low K+ medium and studied the time course and magnitude of change in the relative abundance of the two Na-K-ATPase subunits (alpha and beta), in the synthesis rate of the subunits, and in the relative abundance of alpha- and beta-mRNA. When cells were incubated in medium containing 0.25 mM K+, intracellular Na+ increased from 25.2 +/- 0.9 (SE) mmol/l cell H2O to 69.8 +/- 9.6 at 4 h and 132 +/- 6 at 16 h. Cell K+ fell from 146 +/- 4 mmol/l cell H2O to 105 +/- 9 at 4 h and 42.3 +/- 4.7 at 16 h. The relative abundance of Na-K-ATPase subunits, measured with immunoblots of cell homogenates, increased such that after 24 h alpha was 1.71 +/- 0.33 and beta was 1.67 +/- 0.22 times control. After 8 h of K+ depletion, alpha-synthesis rate, measured by immunoprecipitation of pulse-labeled cells, increased to 2.30 +/- 0.50 and beta increased to 2.07 +/- 0.42 times control. The alpha- and beta-subunit mRNA abundance, measured by hybridizing alpha- and beta-cDNA probes to total RNA, increased within 30 min to 1.93 +/- 0.24 and 2.29 +/- 0.64 times control, respectively. We conclude that regulatory adjustments of Na-K-ATPase abundance involve an increase in translation after a rapid and coordinate increase in the concentrations of alpha- and beta-subunit mRNA.


Prevalence and risk of violence and the physical, mental, and sexual health problems associated with human trafficking: systematic review.
There is very limited evidence on the health consequences of human trafficking. This systematic review reports on studies investigating the prevalence and risk of violence while trafficked and the prevalence and risk of physical, mental, and sexual health problems, including HIV, among trafficked people. We conducted a systematic review comprising a search of Medline, PubMed, PsycINFO, EMBASE, and Web of Science, hand searches of reference lists of included articles, citation tracking, and expert recommendations. We included peer-reviewed papers reporting on the prevalence or risk of violence while trafficked and/or on the prevalence or risk of any measure of physical, mental, or sexual health among trafficked people. Two reviewers independently screened papers for eligibility and appraised the quality of included studies. The search identified 19 eligible studies, all of which reported on trafficked women and girls only and focused primarily on trafficking for sexual exploitation. The review suggests a high prevalence of violence and of mental distress among women and girls trafficked for sexual exploitation. The random effects pooled prevalence of diagnosed HIV was 31.9% (95% CI 21.3%-42.4%) in studies of women accessing post-trafficking support in India and Nepal, but the estimate was associated with high heterogeneity (I² = 83.7%). Infection prevalence may be related as much to prevalence rates in women's areas of origin or exploitation as to the characteristics of their experience. Findings are limited by the methodological weaknesses of primary studies and their poor comparability and generalisability. Although limited, existing evidence suggests that trafficking for sexual exploitation is associated with violence and a range of serious health problems. Further research is needed on the health of trafficked men, individuals trafficked for other forms of exploitation, and effective health intervention approaches.