Against Moral Responsibilisation of Health: Prudential Responsibility and Health Promotion.
In this article, we outline a novel approach to understanding the role of responsibility in health promotion. Efforts to tackle chronic disease have led to an emphasis on personal responsibility and the identification of ways in which people can 'take responsibility' for their health by avoiding risk factors such as smoking and over-eating. We argue that the extent to which agents can be considered responsible for their health-related behaviour is limited, and as such, state health promotion which assumes certain forms of moral responsibility should (in general) be avoided. This indicates that some approaches to health promotion ought not to be employed. We suggest, however, that another form of responsibility might be more appropriately identified. This is based on the claim that agents (in general) have prudential reasons to maintain their health, in order to pursue those things which make their lives go well-i.e. that maintenance of a certain level of health is (all-things-considered) rational for many agents, given their pleasures and plans. On this basis, we propose that agents have a self-regarding prudential responsibility to maintain their health. We outline the implications of a prudential responsibility approach to health promotion.


Solubilization and characterization of a guanine nucleotide-sensitive form of the calcitonin gene-related peptide receptor.
Calcitonin gene-related peptide (CGRP) receptors were solubilized from rat cerebellum membranes in an active, stable, and guanine nucleotide-sensitive form by using digitonin. Nearly 90% of membrane CGRP receptors and 50% of membrane protein were solubilized by digitonin treatment of cerebellum membranes. Binding of 125ICGRP to soluble receptors was specific, saturable, of high affinity, and reversible. Scatchard analysis of the saturation binding data revealed a homogeneous population of binding sites with a Kd of 178 +/- 42 pM and a Bmax of 201 +/- 17 fmol/mg of protein. Binding of 125ICGRP to soluble receptors was inhibited nearly 60% by guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) (100 microM), suggesting coupling of receptors with guanine nucleotide-binding proteins (G proteins) to form high affinity binding sites. Antiserum against the amino-terminal region of Gs alpha immunoprecipitated a significant portion of soluble CGRP receptors, indicating association of receptors with Gs alpha. In agreement with the saturation binding data, association kinetic studies with soluble receptors indicated binding of 125ICGRP to a single population of sites. Dissociation kinetic data, in contrast, demonstrated that 125ICGRP dissociated from labeled receptors with fast- and slow-dissociating components. GTP gamma S significantly accelerated dissociation of 125ICGRP from labeled receptors; however, dissociation still occurred from two distinct affinity components, with rate constants significantly different from those observed in the absence of GTP gamma S. These observations suggest that soluble CGRP receptors, like native membrane-bound receptors, exist in two distinct affinity states in both G protein-coupled and -uncoupled receptor states. Soluble receptors were retained specifically on a wheat germ lectin column, and affinity cross-linking of receptors specifically labeled with 125ICGRP demonstrated labeling of a 67-kDa protein, suggesting that the rat cerebellum CGRP receptor is a 67-kDa glycoprotein. This study is the first to report solubilization of CGRP receptors retaining the native ability of the receptor to undergo functional coupling with G proteins and to provide direct evidence for association of these receptors with Gs alpha.


Preparation and characterisation of dual-layer latex-coated columns for open-tubular capillary electrochromatographic preconcentration of cations combined in-line with their separation by capillary electrophoresis.
A dual-layer ion-exchange latex-coated column was prepared and characterised for on-capillary preconcentration of cations using an open-tubular ion-exchange CEC format. After preconcentration, the analyte cations were eluted with a transient isotachophoretic gradient and separated by CE. The latex double layer was established by first coating the negatively charged wall of the capillary with a layer of cationic quaternary ammonium anion-exchange Dionex AS5A latex particles (60 nm diameter), and then coating a layer of anionic sulphonated cation-exchange Dionex CS3 latex particles (300 nm diameter) onto the underlying AS5A layer. The adhesion of layers is based on electrostatic attractions. Several dual-layer capillaries were characterised for their EOF and ion-exchange capacity and this showed that coatings could be prepared reproducibly by a simple flushing procedure. The dual-layer columns exhibited a moderate, pH-independent EOF (ca. 26 x 10(-9 )m2V(-1)s(-1)) and an ion-exchange capacity of 57 microequiv./g (or 2.69 nequiv./column). Using an 8 cm length of coated capillary combined with a 72 cm length of untreated capillary, a method for on-line preconcentration and separation of monovalent organic bases, alkali metal ions and alkaline earth metal ions by CE was developed. Recoveries for the preconcentration step were 48% for 4-methylbenzylammonium, 43% for benzylammonium, 30-32% for alkali metal ions and 71-75% for alkaline earth cations. In all cases, recoveries were reproducible with RSDs being less than 6.2%. The influences of the ion-exchange selectivity coefficient of the analyte and the sample-loading rate on analyte recovery were also examined. The proposed method was utilised for the determination of alkaline earth cations and low microM detection limits were obtained.


Is diabetes mellitus an important risk factor for the antibiotic resistance in extraintestinal pathogenic Escherichia coli?
Escherichia coli is a major cause of extraintestinal infections in all age group. However, the infection becomes more severe when patients have some underlying condition such as Diabetes Mellitus. The aim of the study was to determine whether diabetic mellitus may act as an important risk factor for the E. coli to express drug resistance property. This descriptive study was carried out in a multi-specialty tertiary care hospital. One hundred and twenty-seven E. coli isolates from diabetic patients, and one hundred seventy-three isolates from nondiabetic patients were studied. Possession drug resistance genes were determined by multiplex polymerase chain reaction (PCR). Phylogenetic analysis was performed by triplex PCR. Antibiotic sensitivity testing was performed by Kirby-Bauer disk diffusion method. Among the study isolates from Diabetic patients maximum numbers were from phylogroup B2 (42.5%) and D (33%) similarly in case of nondiabetic patients B2 (29%) and D (38%) were the most common phylogroup. Presence of drug resistance genes among the diabetic and nondiabetic patient's isolates were as followed extended-spectrum beta-lactamase (70% and 70.5%) AmpC (9.5% and 14.5%) and NDM-1 ( 7% and 4.5%) and by disk diffusion methods susceptibility pattern were meropenem (94% and 94%), imipenem (92% and 92%), amikacin (76% and 74%), and ampicillin/sulbactam (68% and 69%), respectively. The proportion of diabetic patients strains with the drug resistance characteristics were not significantly different from that seen in nondiabetic patients strains, which indicating that in a predisposed host additional or subtraction bacterial aids for drug resistance property are not a necessity.


Evaluation of the role of the vaccinia virus uracil DNA glycosylase and A20 proteins as intrinsic components of the DNA polymerase holoenzyme.
The vaccinia virus DNA polymerase is inherently distributive but acquires processivity by associating with a heterodimeric processivity factor comprised of the viral A20 and D4 proteins. D4 is also an enzymatically active uracil DNA glycosylase (UDG). The presence of an active repair protein as an essential component of the polymerase holoenzyme is a unique feature of the replication machinery. We have shown previously that the A20-UDG complex has a stoichiometry of ∼1:1, and our data suggest that A20 serves as a bridge between polymerase and UDG. Here we show that conserved hydrophobic residues in the N' terminus of A20 are important for its binding to UDG. Our data argue against the assembly of D4 into higher order multimers, suggesting that the processivity factor does not form a toroidal ring around the DNA. Instead, we hypothesize that the intrinsic, processive DNA scanning activity of UDG tethers the holoenzyme to the DNA template. The inclusion of UDG as an essential holoenzyme component suggests that replication and base excision repair may be coupled. Here we show that the DNA polymerase can utilize dUTP as a substrate in vitro. Moreover, uracil moieties incorporated into the nascent strand during holoenzyme-mediated DNA synthesis can be excised by the viral UDG present within this holoenzyme, leaving abasic sites. Finally, we show that the polymerase stalls upon encountering an abasic site in the template strand, indicating that, like many replicative polymerases, the poxviral holoenzyme cannot perform translesion synthesis across an abasic site.


Discrete magnitude-squared channel modeling, equalization, and detection for volume holographic storage channels.
As storage density increases, the performance of volume holographic storage channels is degraded, because intersymbol interference and noise also increase. Equalization and detection methods must be employed to mitigate the effects of intersignal interference and noise. However, the output detector array in a holographic storage system detects the intensity of the incident light's wave front, leading to loss of sign information. This sign loss precludes the applicability of conventional equalization and detection schemes. We first address channel modeling under quadratic nonlinearity and develop an efficient model named the discrete magnitude-squared channel model. We next introduce an advanced equalization method called the iterative magnitude-squared decision feedback equalization (IMSDFE), which takes the channel nonlinearity into account. The performance of IMSDFE is quantified for optical-noise-dominated channels as well as for electronic-noise-dominated channels. Results indicate that IMSDFE is a good candidate for a high-density, high-intersignal-interference volume holographic storage channel.


Ultracold electron source for single-shot, ultrafast electron diffraction.
Ultrafast electron diffraction (UED) enables studies of structural dynamics at atomic length and timescales, i.e., 0.1 nm and 0.1 ps, in single-shot mode. At present UED experiments are based on femtosecond laser photoemission from solid state cathodes. These photoemission sources perform excellently, but are not sufficiently bright for single-shot studies of, for example, biomolecular samples. We propose a new type of electron source, based on near-threshold photoionization of a laser-cooled and trapped atomic gas. The electron temperature of these sources can be as low as 10 K, implying an increase in brightness by orders of magnitude. We investigate a setup consisting of an ultracold electron source and standard radio-frequency acceleration techniques by GPT tracking simulations. The simulations use realistic fields and include all pairwise Coulomb interactions. We show that in this setup 120 keV, 0.1 pC electron bunches can be produced with a longitudinal emittance sufficiently small for enabling sub-100 fs bunch lengths at 1% relative energy spread. A transverse root-mean-square normalized emittance of epsilon(x) = 10 nm is obtained, significantly better than from photoemission sources. Correlations in transverse phase-space indicate that the transverse emittance can be improved even further, enabling single-shot studies of biomolecular samples.


A Novel Technique of Fabricating a Modified Removable Provisional Prosthesis over an Autologous Bone Grafted Maxillary Anterior Edentulous Segment Prior to Implant Placement.
Implant dentistry has provided a lot of surgical as well as prosthetic techniques for improving the success of the implants. The surgical technique commonly followed now prior to implant placement is bone grafting procedure. One of the commonest techniques is the use of autologous block graft harvested from mandibular chin region. However, interference in healing as well as excessive bone resorption due to the use of removable provisional prosthesis over the bone grafted region has been commonly observed/reported. Hence now-a-days, fixed provisional prosthesis is preferred over removable provisional prosthesis for the added advantages of superior aesthetics and patient acceptance. This article highlights a new technique of fabricating removable provisional prosthesis, which is superior in aesthetics and strength, consumes less chair time and exerts zero pressure onto the grafted site.


Ankle dexterity is less impaired than muscle strength in incomplete spinal cord lesion.
Motor assessment after incomplete spinal cord injury (iSCI) currently consists of tests for muscle strength (manual muscle testing) and gait. The ability to adequately time a movement, an aspect of dexterity, is not tested. Thus, this study assessed the timing of ankle dorsiflexion in iSCI patients in the supine position and during gait and examined its relation to measures for muscle strength, corticospinal conductivity and gait speed. In 12 subjects with iSCI and 12 matched controls, timing of ankle dorsiflexion was tested by means of auditory-paced dorsi- and plantar-flexion movements at three frequencies in the supine position and by determining initiation and termination of dorsiflexion in swing during gait. In addition, maximal movement velocity (MMV) in the ankle task, maximal voluntary contraction (MVC), corticospinal conductivity (motor evoked potentials (MEP)) and gait speed (10 Meter Walk Test) were assessed. The groups did not significantly differ in timing of ankle dorsiflexion, neither in the supine position nor in gait. However, they significantly differed in MMV at all frequencies, MEP latency, MEP amplitude and gait speed. In contrast to ankle timing in the supine position, the onset of dorsiflexion in swing during gait significantly correlated to the dynamic MEP parameters. Although MMV and gait speed were significantly reduced, timing of ankle dorsiflexion, both in the supine position and during gait,was less impaired in iSCI patients. This indicates that the loss of strength, particularly of dynamic strength, is the major motor impairment in iSCI, which might be considered when assessing treatment interventions.


Erythro-myeloid progenitors can differentiate from endothelial cells and modulate embryonic vascular remodeling.
Erythro-myeloid progenitors (EMPs) were recently described to arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages. Questions remain, however, concerning whether EMPs differentiate directly from the endothelium or merely pass through. We provide the first evidence in vivo that EMPs can emerge directly from endothelial cells (ECs) and demonstrate a role for these cells in vascular development. We find that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein (AcLDL), as ECs do. When the endothelium is labelled with AcLDL before EMPs differentiate, EMPs and EMP-derived cells arise that are AcLDL+. If AcLDL is injected after the onset of EMP differentiation, however, the majority of EMP-derived cells are not double labelled. We find that cell division precedes entry of EMPs into circulation, and that blood flow facilitates the transition of EMPs from the endothelium into circulation in a nitric oxide-dependent manner. In gain-of-function studies, we inject the CSF1-Fc ligand in embryos and found that this increases the number of CSF1R+ cells, which localize to the venous plexus and significantly disrupt venous remodeling. This is the first study to definitively establish that EMPs arise from the endothelium in vivo and show a role for early myeloid cells in vascular development.


Nd:YAG ring laser with 213 W linearly polarized fundamental mode output power.
We present a high power fundamental mode ring oscillator with four longitudinally diode-pumped laser rods and effective birefringence compensation as a laser source for the next generation of gravitational wave detection. With this setup a linearly polarized output power of 213 W in a nearly diffraction limited beam with an M2 value of 1.15 was demonstrated.


Effect of initial immunosuppression on long-term kidney transplant outcome in immunological low-risk patients.
Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. Three regimes were used in over 200 patients: cyclosporine (CsA)/prednisolone (Pred) (n = 542), CsA/mycophenolate mofetil (MMF)/Pred (n = 857) and tacrolimus (TAC)/MMF/Pred (n = 811). Covariate-adjusted analysis revealed no significant differences in 10-year death-censored graft survival between patients on TAC/MMF/Pred therapy (79%) compared with patients on CsA/MMF/Pred (82%, P = 0.88) or CsA/Pred (79%, P = 0.21). However, 1-year rejection-free survival censored for death and failure unrelated to rejection was significantly higher for TAC/MMF/Pred (81%) when compared with CsA/MMF/Pred (67%, P < 0.0001) and CsA/Pred (64%, P < 0.0001). These results suggest that in immunological low-risk patients excellent long-term kidney graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (CsA or TAC; with or without MMF), despite differences in 1-year rejection-free survival.


Elevated expression of IFN-gamma in the HIV-1 infected brain.
We determined the extent of expression of three cytokines (IFN-gamma, IL-4, and TNF-alpha ) in brain tissue infected with human immunodeficiency virus-1 (HIV-1). The selections were IFN-gamma as a Th1 cytokine, IL- 4 as a Th2 cytokine, and TNF-alpha as a pro-inflammatory cytokine (and because of its prior implication in brain tissue damage due to HIV-1 infection). Based on current models for pathogenesis of HIV-1-associated dementia (HAD), in the periphery, Th1 cytokines are considered to be salutary, whereas Th2 cytokines are regarded as deleterious. However, we hypothesized that in the CNS these roles are reversed. Post-mortem temporal lobe tissue specimens from 16 HIV-1-seropositive patients and 11 HIV-1-seronegative controls were stained for IFN-gamma, IL-4, and TNF-alpha utilizing immunohistochemistry and alkaline phosphatase. HIV-1 infection causes alterations of brain cytokine expression that include increased IFN-gamma expression for HIV-1-seropositive vs. HIV-1-seronegative individuals. There was increased expression of IFN-gamma for HIV-1-seropositive individuals with or without HAD, with or without the broader category of neuropsychiatric impairment (NPI), and with or without opportunistic infections (OIs) compared to HIV-1-seronegatives. A significant inverse correlation between IFN-gamma vs. IL-4 in HIV-1-seropositives with HAD and in seronegative individuals was observed. There was an inverse correlation in seropositives between IFN-gamma vs. TNF-alpha, a positive trend with HAD, significant without HAD, significant with NPI and significant without OIs. Between IL-4 vs. TNF-alpha there was a correlation (trend) in seropositives, a trend with NPI, significant without NPI, and a trend without OI. Due to HIV-1 infection of the brain and neurological disease there is a prominent increased expression of IFN-gamma, an inverse expression of IFN-gamma vs. TNF-alpha, and TNF-alpha vs. IL-4. The inverse correlation between increased IFN-gamma and decreased IL-4 expression is consistent with the stimulation of activated macrophages, and T cells, greater toxicity in the HIV-1-infected brain, and is supportive of the significance of IFN-gamma in HIV-1-infected patients.


The Quality of Life as a Predictor of Social Support for Multiple Sclerosis Patients and Caregivers.
Coping with a diagnosis of multiple sclerosis (MS) is challenging. MS is one of the most common causes of nontraumatic disability in young adults, and patients may need assistance with daily life activities. This article explores the relation between quality of life (QOL) and the perceived available social support among patients with MS and their families. The study included 120 subjects (60 patient-caregiver dyads). The average age of the patients was 53.95 ± 10.19 years, and for caregivers, it was 50.8 ± 13.3 years. The study used 2 subscales of the Berlin Social Support Scale (perceived availability of social support and need for social support) and the World Health Organization Quality of Life questionnaire for the assessment of QOL. QOL in MS is lower compared with that of their caregivers in all dimensions except the social domain (P < .001, r = 0.54-0.64). A higher need for social support was experienced by caregivers. The need for support in this group is affected by 3 predictors: QOL in the environmental domain and in the physical domain as well as their subjective health. An improvement in QOL in all the domains is related to an increase of perceived available support, in both the group of patients and that of their caregivers (P < .05, ρ = 0.28-0.59). Perceived available support is of great importance for both patients and their caregivers to enable them to function better in the physical, mental, social, and environmental domains of their QOL, where social relationships play a predictive role.


The structure of an immunodominant loop on foot and mouth disease virus, serotype O1, determined under reducing conditions.
Residues 136-159 of VPI of foot and mouth disease virus (FMDV) comprise the G-H loop of the protein and form a prominent feature on the surface of virus particles. This sequence contains an immunodominant neutralizing epitope, which can be mimicked with synthetic peptides, and includes an Arg, Gly, Asp motif which has been implicated in the binding of the virus to cellular receptors. Crystallographic analysis of native virus particles failed to resolve the structure of this region due to its disordered state. However, reduction of a disulphide bond between cysteine residues 134 of VP1 and 130 of VP2 caused the G-H loop to collapse onto the surface of the virus particle and allowed its conformation to be determined.


Variation in anthropoid vertebral formulae: implications for homology and homoplasy in hominoid evolution.
Variation in vertebral formulae within and among hominoid species has complicated our understanding of hominoid vertebral evolution. Here, variation is quantified using diversity and similarity indices derived from population genetics. These indices allow for testing models of hominoid vertebral evolution that call for disparate amounts of homoplasy, and by inference, different patterns of evolution. Results are interpreted in light of "short-backed" (J Exp Zool (Mol Dev Evol) 302B:241-267) and "long-backed" (J Exp Zool (Mol Dev Evol) 314B:123-134) ancestries proposed in different models of hominin vertebral evolution. Under the long-back model, we should expect reduced variation in vertebral formulae associated with adaptively driven homoplasy (independently and repeatedly reduced lumbar regions) and the relatively strong directional selection presumably associated with it, especially in closely related taxa that diverged relatively recently (e.g., Pan troglodytes and Pan paniscus). Instead, high amounts of intraspecific variation are observed among all hominoids except humans and eastern gorillas, taxa that have likely experienced strong stabilizing selection on vertebral formulae associated with locomotor and habitat specializations. Furthermore, analyses of interspecific similarity support an evolutionary scenario in which the vertebral formulae observed in western gorillas and chimpanzees represent a reasonable approximation of the ancestral condition for great apes and humans, from which eastern gorillas, humans, and bonobos derived their unique vertebral profiles. Therefore, these results support the short-back model and are compatible with a scenario of homology of reduced lumbar regions in hominoid primates. Fossil hominin vertebral columns are discussed and shown to support, rather than contradict, the short-back model.


Predicting the status of axillary sentinel lymph nodes in 4351 patients with invasive breast carcinoma treated in a single institution.
Reliable predictors of metastatic involvement would enable a better selection of candidate patients for sentinel lymph node biopsy (SLNB) and possibly allow identification of patients with such a low risk of axillary sentinel lymph node (SLN) involvement to be even spared SLNB. The authors evaluated 4351 consecutive patients surgically treated for breast carcinoma who also underwent SLNB. Clinicopathologic features significantly associated with SLN metastases by univariate analysis were included in a multivariate model. By multivariate analysis, the prevalence of SLN metastases was associated directly with tumor size, multifocality, and with the occurrence of peritumoral vascular invasion (PVI; all P < 0.0001), and was associated inversely with a favorable histotype (P = 0.0007) and lack of progesterone receptors (P = 0.004). A predictive model based on the features more closely associated with SLN status documented that the patients with a favorable tumor type </= 1 cm in size and without PVI (n = 178 [4% of the population]) had the lowest risk of SLN metastases (9.5%) whereas patients with tumors > 2 cm and with PVI (n = 250 [5.7% of the population]) had the highest risk (77.2%) of SLN involvement. Tumor size and PVI emerged as the most powerful independent predictors of SLN metastases. Although no combination of features identified patients with a < 9.5% risk of SLN metastases, the current data may be used to tailor the management of patients with breast carcinoma with the aim of minimizing as much as possible the diagnostic and therapeutic procedures, thus improving the quality of life of the patients without any adverse effect on their survival rates.


2,4,5-Trihydroxy-3-methylacetophenone: A Cellulosic Chromophore as a Case Study of Aromaticity.
The title compound (2,4,5-trihydroxy-3-methylacetophenone, 1) was isolated as chromophore from aged cellulosic pulps. The peculiar feature of the compound is its weak aromatic system that can be converted into nonaromatic (quinoid or cyclic aliphatic) tautomers, depending on the conditions and reaction partners. In alkaline media, the participation of quinoid canonic forms weakens aromaticity, whereas in neutral and acidic media, the strong hydrogen bond between the 2-hydroxyl group and the acetyl moiety plays an important role in favoring quinoid tautomers. As a result, compound 1, with quinoid contributions being already "preset", is relatively stable toward oxidation and hardly undergoes alkylation or nitration at CH-6, whereas the 2,4,5-trimethoxyderivative, being "properly" aromatic and even more sterically hindered, is readily alkylated or nitrated. The lability of the aromatic system is best demonstrated by the unusual reaction of 1 with hydroxylamine, producing a tetroxime that is derived from its 2,4,5-triketo tautomer. The high oxidative stability and low reactivity of the compound hinder oxidative bleaching of this chromophore in cellulosic pulps and detection reactions for analytical purposes.


Muscle-specific signaling mechanism that links actin dynamics to serum response factor.
Myocardin and the myocardin-related transcription factors (MRTFs) MRTF-A and MRTF-B are coactivators for serum response factor (SRF), which regulates genes involved in cell proliferation, migration, cytoskeletal dynamics, and myogenesis. MRTF-A has been shown to translocate to the nucleus and activate SRF in response to Rho signaling and actin polymerization. Previously, we described a muscle-specific actin-binding protein named striated muscle activator of Rho signaling (STARS) that also activates SRF through a Rho-dependent mechanism. Here we show that STARS activates SRF by inducing the nuclear translocation of MRTFs. The STARS-dependent nuclear import of MRTFs requires RhoA and actin polymerization, and the actin-binding domain of STARS is necessary and sufficient for this activity. A knockdown of endogenous STARS expression by using small interfering RNA significantly reduced SRF activity in differentiated C2C12 skeletal muscle cells and cardiac myocytes. The ability of STARS to promote the nuclear localization of MRTFs and SRF-mediated transcription provides a potential muscle-specific mechanism for linking changes in actin dynamics and sarcomere structure with striated muscle gene expression.


Pergolide versus bromocriptine for levodopa-induced motor complications in Parkinson's disease.
To compare the efficacy and safety of adjunct pergolide therapy versus bromocriptine in patients with Parkinson's disease, already established on levodopa and suffering the long-term complications of therapy. Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Eli Lilly Company and Sandoz Limited. Randomised controlled trials of pergolide versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. Data was abstracted independently by each author and differences settled by discussion. Three short-term trials fulfilled the inclusion criteria for the review. Pergolide was superior to bromocriptine regarding UPDRS and NYPDS motor and NYPDS ADL scores in two trials. More patients recorded a 'marked' or 'moderate improvement' in clinician's global impression score with pergolide than bromocriptine in two studies. Insufficient evidence on fluctuations and dyskinesia was available to draw any conclusions. No significant differences between the agonists were seen in levodopa dose reduction, drop outs or adverse events. Although pergolide is superior to bromocriptine in reducing motor impairments and disability, no firm conclusions regarding levodopa-induced motor complications can be reached. Levodopa dose reduction, adverse events and withdrawals from treatment are similar for the two agonists. The small advantage of pergolide in efficacy does not take into account its additional cost compared with bromocriptine.


Secondary cytotoxic allograft responses in vitro. III. The immunogenicity of allogeneic membrane fragments.
The immunogenicity of murine membrane fragments was tested both in primary and in secondary in vitro cytotoxic allograft responses, and compared to that of intact allogeneic stimulator cells. Allogeneic membrane fragments induced poor proliferative and cytotoxic responses in normal splenic responder cells. However reexposure of immune responder T cells to allogeneic membrane fragments triggered the generation of highly reactive cytotoxic T lymphocytes (CTL). Moreover, the generation of secondary CTL as induced by allogeneic membrane fragments was preceded by only a marginal cell proliferation. The results obtained are compatible with the concept that serologically defined (SD) antigens alone are capable of triggering alloimmune T cells to differentiate highly reactive secondary CTL.


Construction of a recombinant vaccine expressing Nipah virus glycoprotein using the replicative and highly attenuated vaccinia virus strain LC16m8.
Nipah virus (NiV) is a highly pathogenic zoonotic virus that causes severe encephalitis and respiratory diseases and has a high mortality rate in humans (>40%). Epidemiological studies on various fruit bat species, which are natural reservoirs of the virus, have shown that NiV is widely distributed throughout Southeast Asia. Therefore, there is an urgent need to develop effective NiV vaccines. In this study, we generated recombinant vaccinia viruses expressing the NiV glycoprotein (G) or fusion (F) protein using the LC16m8 strain, and examined their antigenicity and ability to induce immunity. Neutralizing antibodies against NiV were successfully induced in hamsters inoculated with LC16m8 expressing NiV G or F, and the antibody titers were higher than those induced by other vaccinia virus vectors previously reported to prevent lethal NiV infection. These findings indicate that the LC16m8-based vaccine format has superior features as a proliferative vaccine compared with other poxvirus-based vaccines. Moreover, the data collected over the course of antibody elevation during three rounds of vaccination in hamsters provide an important basis for the clinical use of vaccinia virus-based vaccines against NiV disease. Trial Registration: NCT05398796.


Life Cycle of the pseudocolonial dinoflagellate Polykrikos kofoidii (Gymnodiniales, Dinoflagellata).
The athecate, pseudocolonial polykrikoid dinoflag-ellates show a greater morphological complexity than many other dinoflagellate cells and contain not only elaborate extrusomes but sulci, cinguli, flagellar pairs, and nuclei in multiple copies. Among polykrikoids, Polykrikos kofoidii is a common species that plays an important role as a grazer of toxic planktonic algae but whose life cycle is poorly known. In this study, the main life cycle stages of P. kofoidii were examined and documented for the first time. The formation of gametes, 2-zooid-1-nucleus stages very different from vegetative cells, was observed and the process of gamete fusion, isogamy, was recorded. Karyogamy followed shortly after completed plasmogamy. A complex reorganization of furrows (cinguli and sulci) and flagella followed zygote formation, resulting in a 4-zooid zygote with one nucleus. The fate of zygotes under different nutritional conditions was also investigated; well-fed zygotes were able to reenter the vegetative cycle via meiotic divisions as indicated by nuclear cyclosis. However, nuclear cyclosis was preceded by a presumably mitotic division of the primary zygote nucleus which by definition would imply that P. kofoidii has a diplohaplontic life cycle. Nuclear cyclosis in germlings hatched from spiny resting cysts indicate that these cysts are of zygote origin (hypnozygotes). Hypnozygote formation, cyst hatching, the morphology of the germling (a 1-zooid cell), and its development into a normal pseudocolony are documented here for the first time. There is evidence that P. kofoidii has a system of complex heterothallism.


Gene and protein expression associated with protein synthesis and breakdown in paraplegic skeletal muscle.
Spinal cord injury reduces the rate of skeletal muscle protein synthesis and increases protein breakdown, resulting in rapid muscle loss. The purpose of this study was to determine whether long-term paraplegia would eventually result in a downregulation of muscle mRNA and protein expression associated with both protein synthesis and breakdown. After 10 weeks of spinal cord transection, soleus muscle from 12 rats (6 sham-control, 6 paraplegic) was studied for mRNAs and proteins associated with protein synthesis and breakdown using real-time polymerase chain reaction and immunoblotting techniques. Protein kinase B (PKB/Akt), ribosomal S6 kinase 1 (S6K1), and myogenin mRNA were downregulated, whereas muscle ring finger 1 (MuRF1) and phospho-forkhead transcription factor 4 (FoxO4) protein were increased in paraplegic rats. We conclude that gene and protein expression of pathways associated with protein synthesis are reduced, whereas some markers of protein breakdown remain elevated following chronic paraplegia. Clinical interventions designed to increase muscle protein synthesis may be helpful in preventing excessive muscle loss during long-term paraplegia.


Extremity pain and refusal to walk in children with invasive meningococcal disease.
Early recognition of invasive meningococcal disease in children may be difficult. Extremity pain and refusal to walk (extremity symptoms) are uncommonly mentioned as clinical findings in children who present with this disease. We sought to determine 1) the frequency of extremity symptoms as part of the clinical presentation in children with invasive meningococcal disease and 2) whether these symptoms help identify children with otherwise unsuspected meningococcal disease. We reviewed the medical records of patients who were younger than 20 years and had invasive meningococcal disease from 1985 to 1996 at 3 pediatric referral centers. Children with extremity symptoms were identified and described. We compared clinical and laboratory findings and frequency of adverse outcomes between these children and those with invasive meningococcal disease without extremity symptoms. We identified 274 children with invasive meningococcal disease, 45 (16%) of whom had either history or physical examination evidence of extremity pain (31) or refusal to walk (14) as part of their clinical presentations. Five of the 45 patients had arthritis at the time of presentation. Patients with extremity symptoms at presentation were significantly older (77.9 +/- 62.2 vs 44.0 +/- 56.9 months), had lower temperatures (38.8 +/- 1.2 degrees C vs 39.2 +/- 1.2 degrees C), and had higher band counts (28.2 +/- 15.2% vs 18.1 +/- 12.4%) than did patients without extremity symptoms. There were no significant differences, however, between groups with regard to rash, white blood cell counts, coagulation parameters, prevalence of meningitis, or adverse outcomes. Seventy-three (27%) of the 274 patients had unsuspected disease, and 5 (7%) of these had extremity symptoms at the time of diagnosis. Sixteen percent of children with invasive meningococcal disease have extremity symptoms at the time of diagnosis. These symptoms may help to identify some patients with otherwise unsuspected invasive meningococcal disease.


Global warming and marine carbon cycle feedbacks on future atmospheric CO2
A low-order physical-biogeochemical climate model was used to project atmospheric carbon dioxide and global warming for scenarios developed by the Intergovernmental Panel on Climate Change. The North Atlantic thermohaline circulation weakens in all global warming simulations and collapses at high levels of carbon dioxide. Projected changes in the marine carbon cycle have a modest impact on atmospheric carbon dioxide. Compared with the control, atmospheric carbon dioxide increased by 4 percent at year 2100 and 20 percent at year 2500. The reduction in ocean carbon uptake can be mainly explained by sea surface warming. The projected changes of the marine biological cycle compensate the reduction in downward mixing of anthropogenic carbon, except when the North Atlantic thermohaline circulation collapses.


Stem cell therapy for heart failure: the science and current progress.
Cell therapy, particularly with stem cells, has created great interest as a solution to the fact that there are limited treatments for postischemic heart disease and none that can regenerate damaged heart cells to strengthen cardiac performance. From the first efforts with myoblasts to recent clinical trials with bone marrow-derived stem cells, early reports of cell therapy suggest improvement in cardiac performance as well as other clinical end points. Based on these exciting but tentative results, other stem cell types are being explored for their particular advantages as a source of adult stem cells. Autologous adipose-derived stem cells are multilinear and can be obtained relatively easily in large quantities from patients; cardiac-derived stem cells are highly appropriate for engraftment in their natural niche, the heart. Human umbilical cord blood cells are potentially forever young and allogenic adult mesenchymal stem cells appear not to evoke the graft versus host reaction. Human embryonic stem cells are effective and can be scaled up for supply purposes. The recent discovery of induced pluripotentcy in human adult stem cells, with only three transcription factor genes, opens a whole new approach to making autologous human pluripotent stem cells from skin or other available tissues. Despite the excitement, stem cells may have to be genetically modified with heme oxygenase, Akt or other genes to survive transplantation in a hypoxic environment. Homing factors and hormones secreted from transplanted stem cells may be more important than cells if they provide the necessary stimulus to trigger cardiac regrowth to replace scar tissue. As we await results from larger and more prolonged clinical trials, the science of stem cell therapy in cardiac disease keeps progressing.


Annual average indoor radon variations over two decades.
Long-term exposure to elevated radon (222Rn) concentrations has been linked to increased lung cancer risk. Year-long measurements of contemporary radon concentrations have been the "gold standard" for epidemiologists trying to reconstruct past radon exposures and for homeowners trying to estimate future radon exposure. Random variations and persistent temporal trends can affect remedial action decisions and risk coefficients derived from epidemiological studies. Temporal fluctuations are possible when changes occur in a home's structure, climate, environment, or occupants. The annual-average temporal radon behavior was studied at 196 sites in 98 Minnesota houses. Seventeen hundred year-long indoor radon measurements were made from 1983 to 2000 to determine year-to-year radon fluctuations and long-term temporal trends. Ten year-long measurements over a span of 13 years were made at the typical site. The median radon concentration was 120 Bq m-3. The median radon concentration of the group of houses showed little year-to-year variation and no persistent temporal trends. At individual sites, year-to-year radon variations ranged from 3 to 110%. The median variation was 26%. Climate, exposure to wind, and radon concentration affected year-to-year variation, but house age, construction, or measurement floor did not. Some individual sites showed significantly larger radon changes when modifications were made to the house structure and heating-ventilation systems. Year-long radon measurements on the first floor provided better estimates of cumulative radon exposure than screening measurements. The radon variations observed in this study provide uncertainty estimates for year-long measurements that could help improve remediation decision protocols and refine risk estimates from epidemiological studies.


The T antigen locus of Merkel cell polyomavirus downregulates human Toll-like receptor 9 expression.
Establishment of a chronic infection is a key event in virus-mediated carcinogenesis. Several cancer-associated, double-stranded DNA (dsDNA) viruses act via their oncoproteins to downregulate Toll-like receptor 9 (TLR9), a key receptor in the host innate immune response that senses viral or bacterial dsDNA. A novel oncogenic virus, Merkel cell polyomavirus (MCPyV), has been recently identified that causes up to 80% of Merkel cell carcinomas (MCCs). However, it is not yet known whether this oncogenic virus also disrupts immune-related pathways. We find that MCPyV large T antigen (LT) expression downregulates TLR9 expression in epithelial and MCC-derived cells. Accordingly, silencing of LT expression results in upregulation of mRNA TLR9 levels. In addition, small T antigen (sT) also appears to inhibit TLR9 expression, since inhibition of its expression also resulted in an increase of TLR9 mRNA levels. LT inhibits TLR9 expression by decreasing the mRNA levels of the C/EBPβ transactivator, a positive regulator of the TLR9 promoter. Chromatin immunoprecipitation reveals that C/EBPβ binding at a C/EBPβ response element (RE) in the TLR9 promoter is strongly inhibited by expression of MCPyV early genes and that mutation of the C/EBP RE prevents MCPyV downregulation of TLR9. A survey of BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), KI polyomavirus (KIPyV), MCPyV, simian virus 40 (SV40), and WU polyomavirus (WUPyV) early genes revealed that only BKPyV and MCPyV are potent inhibitors of TLR9 gene expression. MCPyV LT targeting of C/EBP transactivators is likely to play an important role in viral persistence and potentially inhibit host cell immune responses during MCPyV tumorigenesis.


A quantitative evaluation of the effect of enzyme complexes on the glycolytic rate in vivo: mathematical modeling of the glycolytic complex.
The cellular distribution of free and bound glycolytic enzymes in vivo was estimated by means of a model based on previously determined association constants for individual binding interactions and in vivo protein concentrations. The calculations revealed that a significant proportion of the enzymes would be either associated with F-actin, or bound in binary enzyme-enzyme complexes in vivo. An analysis of the relative concentration, and relative activity, of F-actin-bound enzymes suggested that a complete glycolytic complex, composed of all enzymatic steps from phosphofructokinase (PFK) to lactate dehydrogenase (LDH) does not exist. This was indicated by a very low concentration of F-actin-associated phosphoglycerate kinase (PGK) and by a very low activity of F-actin bound aldolase and PGK; this model showed that aldolase and PGK would be absent from any F-actin bound complex. An analysis of soluble enzyme-enzyme associations indicated that formation of binary enzyme complexes may lead to an increased overall flux through glyceraldehyde 3-phosphate dehydrogenase and LDH, but would serve to decrease flux through PFK and aldolase. A 1.4-fold activation of PFK, which occurs when the soluble enzyme binds to F-actin, suggested that reversible binding of PFK to F-actin may represent a novel cellular mechanism for controlling glycolytic flux during periods of increased metabolic demand by controlling the key regulatory enzyme of glycolysis.


Comprehension of an Elevated Amyloid Positron Emission Tomography Biomarker Result by Cognitively Normal Older Adults.
The goal of Alzheimer disease (AD) prevention together with advances in understanding the pathophysiology of AD have led to clinical trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Data are needed to inform the processes of describing AD biomarkers to cognitively normal adults and assessing their understanding of this knowledge. To determine the comprehension of an elevated amyloid positron emission tomographic (PET) biomarker result by cognitively unimpaired adults. The Study of Knowledge and Reactions to Amyloid Testing, a substudy of an AD prevention trial, involved 2 semistructured telephone interviews with 80 participants recruited from 9 study sites: 50 received elevated and 30 received not elevated amyloid PET scan results. Interviews were conducted 4 to 12 weeks after result disclosure and again 1 year later. Data presented here were collected from November 5, 2014, through December 10, 2015. The 50 participants included in this study were cognitively normal, aged 65 to 85 years, evenly distributed by gender, and had elevated amyloid PET results. Subsequent reports will examine persons with "not elevated" results and compare the influence of the different results. Participant comprehension of an elevated amyloid result was assessed by analyzing their responses to the following questions: "What was the result of your amyloid PET scan?" (followed by "Can you tell me in your own words what that means?" or "How would you explain it to a friend?"), "Was it the result you expected?" and "Did the result teach you anything or clarify anything for you?" Of the 50 participants aged 65 to 85 years, 49 (98%) were white, 40 (80%) reported a family history of AD, and 30 (60%) had a postgraduate educational level. Most participants (31 [62%]) understood that elevated amyloid conferred an increased but uncertain risk of developing AD. Some desired understanding of the term elevated other than its being a categorical result enabling trial entry eligibility; they wanted information regarding how elevated their amyloid was, how close to the study threshold they were, or percentages, numbers, or a scale to help them make sense of the result. Including an explanation of how and why a dimensional biomarker is converted to a categorical classification would enhance future AD biomarker clinical trials and educational materials.


Near-haploid acute lymphoblastic leukemia: a unique subgroup with a poor prognosis?
We describe two adolescent girls with acute lymphoblastic leukemia (ALL) whose leukemia cells were near-haploid. Their lymphoblasts stained in a block pattern with periodic acid Schiff and had "common ALL" surface markers confirmed by indirect immunofluorescence. Each patient had two populations of blasts, one near-haploid and one hyperdiploid, which was an exact doubling of the near-haploid karyotype. The first patient had a predominant population of cells with 26 chromosomes and a few with 52, while the second had a predominance of cells with 56 and a minority with 28. Flow cytometric analysis of DNA content initially detected the minor near-haploid population in the second patient, which was confirmed later by cytogenetic review of the marrow sample. In addition to our two patients, only four patients have been reported with near-haploid ALL. Of these six, five were girls, five were adolescents, and five had short survivals (median, 10 mo). All six had disomy of chromosome 21 with or without disomy for chromosomes 10, 14, 18, or X (four patients each). Thus, near-haploid ALL may represent a unique subgroup of ALL with a poor prognosis. To detect these and other possible subgroups, we have included cytogenetic analysis and flow cytometric analysis of DNA content in our initial evaluation of patients with ALL.


Endogenous human milk peptide release is greater after preterm birth than term birth.
Hundreds of naturally occurring milk peptides are present in term human milk. Preterm milk is produced before complete maturation of the mammary gland, which could change milk synthesis and secretion processes within the mammary gland, leading to differences in protein expression and enzymatic activity, thereby resulting in an altered peptide profile. This study examined differences in peptides present between milk from women delivering at term and women delivering prematurely. Nano-LC tandem mass spectrometry was employed to identify naturally occurring peptides and compare their abundances between term and preterm human milk samples at multiple time points over lactation. Term milk samples were collected from 8 mothers and preterm milk was collected from 14 mothers. The 28 preterm and 32 term human milk samples were divided into 4 groups based on day of collection (<14, 14-28, 29-41, and 42-58 d). Preterm milk peptide counts, ion abundance, and concentration were significantly higher in preterm milk than term milk. Bioinformatic analysis of the cleavage sites for peptides identified suggested that plasmin was more active in preterm milk than term milk and that cytosol aminopeptidase and carboxypeptidase B2 likely contribute to extensive milk protein breakdown. Many identified milk peptides in both term and preterm milk overlapped with known functional peptides, including antihypertensive, antimicrobial, and immunomodulatory peptides. The high protein degradation by endogenous proteases in preterm milk might attenuate problems because of the preterm infant's immature digestive system. This trial was registered at clinicaltrials.gov as NCT01817127.


Cross-band relative absorption technique for the measurement of molecular mixing ratios.
We describe a new method for the measurement of molecular mixing ratios called Cross-Band Relative Absorption (CoBRA). The proposed method is based on relative measurements in different molecular bands referenced to a band of O2 with properly selected wavelength combinations providing high level of cancelation in temperature sensitivities. The CoBRA approach is particularly promising for satellite based remote sensing of molecular mixing ratios of the atmospheric trace gases. Very low temperature sensitivities and the potential of achieving close weighting function matching for the measurement and reference wavelengths are the main advantages of the method. The effectiveness of CoBRA approach is demonstrated for the retrieval of CO2 mixing ratios (XCO2) with application to the ASCENDS mission.


Developing measures of patients' perceptions of orthognathic surgery.
Measurements of patients' perceptions of the benefits, costs, and risks of orthognathic treatment are needed to assess the utility of alternative treatments, and to assess and improve patient education to make informed decisions. A two-part study was conducted to develop and evaluate measures assessing patients' perceptions of the benefits and risks of orthognathic surgery in comparison to an orthodontics-only approach or no treatment. The first part of this study included 49 patients who had completed orthodontics and orthognathic surgery and 34 patients considering orthognathic surgery. All patients were asked to complete an open-ended telephone questionnaire about their perceptions of the benefits and risks of orthognathic surgery and of alternative options. Patients' answers were sorted into categories, and the second part of this study included a closed-form written questionnaire to assess the perceived likelihood of possible outcomes in each category. Reliability of the questionnaire was assessed using Cronbach's alpha coefficient of internal consistency reliability. Cronbach's alpha ranged from 0.74 to 0.91 when the instrument was used to assess either overall benefits or risks of orthognathic surgery, orthodontics only, or no treatment, indicating acceptable reliability for each of these uses. Subscales concerning more narrowly defined aspects of benefits and risks were less reliable than the overall scales.


Real-time functional magnetic resonance imaging (rt-fMRI) in patients with brain tumours: preliminary findings using motor and language paradigms.
Functional MRI (fMRI) shows areas of the brain that are active during a task, but the standard approach (offline analysis after the imaging has finished) precludes tailoring of the imaging to the individual patient, e.g. for assessing normal function around an individual lesion. The aims of the study were to explore the technical feasibility of acquiring functional images in real-time (rt-fMRI), develop the necessary software interfaces and protocols for image acquisition, and to compare images of functional activation acquired in real-time with the standard offline statistical parametric method in patients with solitary brain tumours. Patients with a solitary supratentorial lesion were studied. The rt-fMRI paradigms were sequential finger opposition, ankle movement and language function (correct recognition of grammatically violated sentences). Datasets were analysed using AFNI software (National Institute of Mental Health, Bethesda, Maryland, USA) for the real-time analysis and SPM99 (Functional Imaging Laboratory, University College, London, UK) for the offline analysis. From 11 patients, useful data were obtained in nine. The finger tapping task produced most consistent activation between real-time and offline analysis with good anatomic localization to the primary motor cortex contralateral to the tapping finger. Ankle movement produced weaker activation and correlation with real-time analysis. For the language task the offline analysis provided reproducible activation patterns, but the real-time method showed no activation at the chosen threshold of p = 0.001. Tumourous areas of brain did not show any activation with either method of analysis during any task. rt-fMRI is feasible and could be a valuable functional evaluation tool in the planning of surgery for tumours in motor regions of the brain. Further paradigm development is required for evaluation of language, and possibly other more complex executive functions.


Copper Selenidophosphates Cu4P2Se6, Cu4P3Se4, Cu4P4Se3, and CuP2Se, Featuring Zero-, One-, and Two-Dimensional Anions.
Five new compounds in the Cu/P/Se phase diagram have been synthesized, and their crystal structures have been determined. The crystal structures of these compounds comprise four previously unreported zero-, one-, and two-dimensional selenidophosphate anions containing low-valent phosphorus. In addition to two new modifications of Cu4P2Se6 featuring the well-known hexaselenidohypodiphosphate(IV) ion, there are three copper selenidophosphates with low-valent P: Cu4P3Se4 contains two different new anions, (i) a monomeric (zero-dimensional) selenidophosphate anion [P2Se4](4-) and (ii) a one-dimensional selenidophosphate anion [Formula: see text], which is related to the well-known gray-Se-like [Formula: see text] Zintl anion. Cu4P4Se3 contains one-dimensional [Formula: see text] polyanions, whereas CuP2Se contains the 2D selenidophosphate [Formula: see text] polyanion. It consists of charge-neutral CuP2Se layers separated by a van der Waals gap which is very rare for a Zintl-type phase. Hence, besides black P, CuP2Se constitutes a new possible source of 2D oxidized phosphorus containing layers for intercalation or exfoliation experiments. Additionally, the electronic structures and some fundamental physical properties of the new compounds are reported. All compounds are semiconducting with indirect band gaps of the orders of around 1 eV. The phases reported here add to the structural diversity of chalcogenido phosphates. The structural variety of this family of compounds may translate into a variety of tunable physical properties.


On the preparation of highly purified slow reacting substance of anaphylaxis (SRS-A) from biological extracts.
1 Very highly purified (greater than 100,000 u/mg) slow reacting substance of anaphylaxis (SRS-A) has been prepared by reversed phase high pressure liquid chromatographic (HPLC) techniques. 2 High resolution liquid chromatography suggests that SRS-A may exist in at least three distinct forms which are possible tautomeric. 3 SRS-A collected by antigen challenge in vivo and by calcium ionophore-induced release in vitro are chromatographically indistinguishable. 4 Treatment of SRS-A with diazomethane but not sodium borohydride results in a loss of biological activity but treatment of the methyl ester with base results in a partial recovery of activity. 5 Highly purified SRS-A was examined by infrared and ultra-violet spectroscopy, and found to have a benzene-aromatic and probably an amino acid.


Mitochondrial DNA Variants in Patients with Liver Injury Due to Anti-Tuberculosis Drugs.
Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid's metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT ≥5 times the upper limit of normal (ULN), or ALT ≥3 times the ULN with total bilirubin ≥2 times the ULN. In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I's NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. Variants in complex I's subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor.


The genus Anogeissus: A review on ethnopharmacology, phytochemistry and pharmacology.
The genus Anogeissus (axlewood tree, ghatti tree, button tree and chewing stick tree) belongs to Combretaceae, includes eight species that are distributed in Asia and Africa. Plants are used as an ethnomedicine in Asia and Africa to treat various ailments like diabetes, fever, diarrhoea, dysentery, tuberculosis, wound healing, skin diseases (eczema, psoriasis), snake and scorpion venom. Based on the traditional knowledge, different phytochemical and pharmacological activities have been at the focus of research. The aim of this review is to provide updated, comprehensive and categorized information on the ethnobotany, phytochemistry, pharmacological research and toxicity of Anogeissus species in order to identify their therapeutic potential and directs future research opportunities. The relevant data was searched by using the keyword "Anogeissus" in "Scopus", "Google Scholar", "Web of Science", "PubMed", and "ScienceDirect" databases. Plant taxonomy was validated by the databases "The Plant List" and A.J. Scott, 1979. This review discusses the current knowledge of the ethnobotany, phytochemistry and in vitro as well as in vivo pharmacological evaluations carried out on the extracts and isolated main active constituents of Anogeissus genus. Among eight species, most of the phytochemical and pharmacological studies were performed on four species. About 55 secondary metabolites are isolated from the genus. Stem bark, leaf, seed, fruit, root of the plants are used for the treatment of several health disorders such as diabetes, fever, diarrhoea, dysentery, tuberculosis, wound healing, skin diseases (eczema, psoriasis), snake and scorpion venom. Gum ghatti obtained from Anogeissus latifolia is used after delivery as tonic and in spermatorrhoea. Many phytochemical investigations on this genus confirmed that it is rich in phenolic compounds. Modern pharmacology research has confirmed that the crude extracts or the isolated active compounds of the genus Anogeissus possess antioxidant, antimicrobial, wound healing, antiulcer, anti-inflammation, anti-diabetics, hepatoprotective, hypolipidemic, antiparasitic and neuroprotective effects. This review confirms that some Anogeissus species have emerged as a good source of the traditional medicine for wound healing, inflammation, skin diseases, microbial infection and diabetes. Many traditional uses of Anogeissus species have now been validated by modern pharmacology research. Intensive investigations of all the species of Anogeissus regarding phytochemical and pharmacological properties, especially their mechanism of action, safety and efficacy could be the future research interests before starting clinical trials.


RpS3 translation is repressed by interaction with its own mRNA.
Ribosomal protein S3 (RpS3) is a well-known multi-functional protein mainly involved in protein biosynthesis as a member of the small ribosomal subunit. It also plays a role in repairing various DNA damage acting as a repair UV endonuclease. Most of the rpS3 pool is located in the ribosome while the minority exists in free form in the cytoplasm. We here report an additional function of rpS3 in which it represses its own translation by binding to its cognate mRNA. Through RT-PCR of the RNAs co-immunoprecipitated with ectopically expressed rpS3, rpS3 protein was found to interact with various RNAs-endogenous rpS3, 18S rRNA. The S3-C terminal domain was shown to be the major mRNA binding domain of rpS3, independent of the KH domain. This interaction was shown to occur in cytoplasmic fractions rather than ribosomal fractions, and then is involved in its own mRNA translational inhibition by in vitro translation. Furthermore, when Flag-tagged rpS3 was transiently transfected into 293T cells, the level of endogenous rpS3 gradually decreased regardless of transcription. These results suggest that free rpS3 regulates its own translation via a feedback mechanism.


Cannabidiol inhibits angiogenesis by multiple mechanisms.
Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.


Early Expression of Neuronal Dopaminergic Markers in a Parkinson's Disease Model in Rats Implanted with Enteric Stem Cells (ENSCs).
Parkinson's Disease (PD) is a common neurodegenerative disorder affecting the dopaminergic (DAergic) system. Replacement therapy is a promising alternative aimed at reconstructing the cytoarchitecture of affected brain regions in PD. Experimental approaches, such as the replacement of DAergic neurons with cells obtained from the Enteric Nervous System (ENS) has yet to be explored. To establish and characterize a cell replacement strategy with ENS Cells (ENSCs) in a PD model in rats. Since ENSCs can develop mature DAergic phenotypes, here we cultured undifferentiated cells from the myenteric plexus of newborn rats, establishing that they exhibit multipotential characteristics. These cells were characterized and further implanted in the Substantia nigra pars compacta (SNpc) of adult rats previously lesioned by a retrograde degenerative model produced by intrastriatal injection of 6-Hydroxydopamine (6-OHDA). DAergic markers were assessed in implants to validate their viability and possible differentiation once implanted. Cell cultures were viable, exhibited stem cell features and remained partially undifferentiated until the time of implant. The retrograde lesion induced by 6-OHDA produced DAergic denervation, reducing the number of fibers and cells in the SNpc. Implantation of ENSCs in the SNpc of 6-OHDAlesioned rats was tracked after 5 and 10 days post-implant. During that time, the implant increased selective neuronal and DAergic markers, Including Microtubule-Associated Protein 2 (MAP-2), Dopamine Transporter (DAT), and Tyrosine Hydroxylase (TH). Our novel results suggest that ENSCs possess a differentiating, proliferative and restorative potential that may offer therapeutic modalities to attenuate neurodegenerative events with the inherent demise of DAergic neurons.


Relativistic effects in earth-orbiting Doppler lidar return signals.
Frequency shifts of side-ranging lidar signals are calculated to high order in the small quantities (v/c), where v is the velocity of a spacecraft carrying a lidar laser or of an aerosol particle that scatters the radiation back into a detector (c is the speed of light). Frequency shift measurements determine horizontal components of ground velocity of the scattering particle, but measured fractional frequency shifts are large because of the large velocities of the spacecraft and of the rotating earth. Subtractions of large terms cause a loss of significant digits and magnify the effect of relativistic corrections in determination of wind velocity. Spacecraft acceleration is also considered. Calculations are performed in an earth-centered inertial frame, and appropriate transformations are applied giving the velocities of scatterers relative to the ground.


Risk factors for intra-abdominal hypertension and abdominal compartment syndrome among adult intensive care unit patients: a systematic review and meta-analysis.
Although intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are associated with substantial morbidity and mortality among critically ill adults, it remains unknown if prevention or treatment of these conditions improves patient outcomes. We sought to identify evidence-based risk factors for IAH and ACS in order to guide identification of the source population for future IAH/ACS treatment trials and to stratify patients into risk groups based on prognosis. We searched electronic bibliographic databases (MEDLINE, EMBASE, PubMed, and the Cochrane Database from 1950 until January 21, 2013) and reference lists of included articles for observational studies reporting risk factors for IAH or ACS among adult ICU patients. Identified risk factors were summarized using formal narrative synthesis techniques alongside a random effects meta-analysis. Among 1,224 citations identified, 14 studies enrolling 2,500 patients were included. The 38 identified risk factors for IAH and 24 for ACS could be clustered into three themes and eight subthemes. Large volume crystalloid resuscitation, the respiratory status of the patient, and shock/hypotension were common risk factors for IAH and ACS that transcended across presenting patient populations. Risk factors with pooled evidence supporting an increased risk for IAH among mixed ICU patients included obesity (four studies; odds ratio (OR) 5.10; 95% confidence interval (CI), 1.92 to 13.58), sepsis (two studies; OR 2.38; 95% CI, 1.34 to 4.23), abdominal surgery (four studies; OR 1.93; 95% CI, 1.30 to 2.85), ileus (two studies; OR 2.05; 95% CI, 1.40 to 2.98), and large volume fluid resuscitation (two studies; OR 2.17; 95% CI, 1.30 to 3.63). Among trauma and surgical patients, large volume crystalloid resuscitation and markers of shock/hypotension and metabolic derangement/organ failure were risk factors for IAH and ACS while increased disease severity scores and elevated creatinine were risk factors for ACS in severe acute pancreatitis patients. Although several IAH/ACS risk factors transcend across presenting patient diagnoses, some appear specific to the population under study. As our findings were somewhat limited by included study methodology, the risk factors reported in this study should be considered candidate risk factors until confirmed by a large prospective multi-centre observational study.


Role of fructose in glycation and cross-linking of proteins.
Incubation of carbohydrate-free human serum albumin (HSA) with fructose in an aqueous buffer at pH 7.4 resulted in glycation of epsilon-amino groups of lysyl residues. A recently developed procedure, involving analysis of hexitol amino acids by high-performance liquid chromatography of phenylthiocarbamyl derivatives, was used to show that 85% of the bound hexose was attached to protein via carbon 2 (C-2). The remainder was attached to protein via carbon 1 (C-1). When incubations were conducted with glucose under identical conditions, all the hexose was attached via C-1. Examination of human ocular lens proteins showed that the majority of the covalently bound hexose was connected to epsilon-amino groups of lysyl residues via C-1; this was attributed mainly to nonenzymatic glucosylation in vivo, which has already been documented. A significant proportion (10-20%) of the bound hexose was connected via C-2. In view of the HSA-hexose incubation results (above), this indicated that the lens proteins had reacted with endogenous fructose; i.e., they had undergone nonenzymatic fructosylation in vivo. The model protein bovine pancreatic ribonuclease A reacted with fructose and glucose at similar rates under physiological conditions. However, covalent, non-disulfide cross-linking, which could be inhibited by D-penicillamine, was induced 10 times more rapidly by fructose than by glucose. It is postulated that some of the protein cross-linking that occurs in vivo is fructose-induced. The possible significance of these processes in diabetic subjects is discussed.


The mitochondrial cytochrome c N-terminal region is critical for maturation by holocytochrome c synthase.
The covalent attachment of heme to mitochondrial cytochrome c is catalysed by holocytochrome c synthase (HCCS, also called heme lyase). How HCCS functions and recognises the substrate apocytochrome is unknown. Here we have examined HCCS recognition of a chimeric substrate comprising a short mitochondrial cytochrome c N-terminal region with the C-terminal sequence, including the CXXCH heme-binding motif, of a bacterial cytochrome c that is not otherwise processed by HCCS. Heme attachment to the chimera demonstrates the importance of the N-terminal region of the cytochrome. A series of variants of a mitochondrial cytochrome c with amino acid replacements in the N-terminal region have narrowed down the specificity determinants, providing insight into HCCS substrate recognition.


Analysis of tyrosine phosphorylation sites in signaling molecules by a phosphotyrosine-specific immonium ion scanning method.
Signal transduction pathways involve cascades of events, such as formation of second messengers and protein complexes that alter the activities of proteins. This can ultimately lead to changes in gene expression in response to the stimuli. Reversible phosphorylation of proteins is an important mechanism for activating or inhibiting enzymes and for the assembly of multiprotein complexes. Here, we describe a mass spectrometry-based phosphotyrosine-specific immonium ion scanning (PSI scanning) method for selective detection of tyrosine-phosphorylated peptides. Once the tyrosine-phosphorylated peptides are identified, they can be directly sequenced in the same experiment to localize the phosphorylation site. We provide protocols for isolation and preparation of samples for analysis, and detailed instructions for operation of a quadrupole time-of-flight (TOF) mass spectrometer for this method. Because of its simplicity and specificity, PSI scanning is likely to become an important tool in proteomic studies of pathways involving tyrosine phosphorylation.


The electric organ discharge of pulse gymnotiforms: the transformation of a simple impulse into a complex spatio-temporal electromotor pattern
An understanding of how the nervous system processes an impulse-like input to yield a stereotyped, species-specific electromotor output is relevant for electric fish physiology, but also for understanding the general mechanisms of coordination of effector patterns. In pulse gymnotids, the electromotor system is repetitively activated by impulse-like signals generated by a pacemaker nucleus in the medulla. This nucleus activates a set of relay cells whose axons descend along the spinal cord and project to electromotor neurones which, in turn, project to electrocytes. Relay neurones, electromotor neurones and electrocytes may be considered as layers of a network arranged with a lattice hierarchy. This network is able to coordinate a spatio-temporal pattern of postsynaptic and action currents generated by the electrocyte membranes. Electrocytes may be innervated at their rostral face, at their caudal face or at both faces, depending on the site of the organ and the species. Thus, the species-specific electric organ discharge patterns depend on the electric organ innervation pattern and on the coordinated activation of the electrocyte faces. The activity of equally oriented faces is synchronised by a synergistic combination of delay lines. The activation of oppositely oriented faces is coordinated in a precise sequence resulting from the orderly recruitment of subsets of electromotor neurones according to the 'size principle' and to their position along the spinal cord. The body of the animal filters the electric organ output electrically, and the whole fish is transformed into a distributed electric source.


Single cardiac ventricular myosins are autonomous motors.
Myosin transduces ATP free energy into mechanical work in muscle. Cardiac muscle has dynamically wide-ranging power demands on the motor as the muscle changes modes in a heartbeat from relaxation, via auxotonic shortening, to isometric contraction. The cardiac power output modulation mechanism is explored in vitro by assessing single cardiac myosin step-size selection versus load. Transgenic mice express human ventricular essential light chain (ELC) in wild- type (WT), or hypertrophic cardiomyopathy-linked mutant forms, A57G or E143K, in a background of mouse α-cardiac myosin heavy chain. Ensemble motility and single myosin mechanical characteristics are consistent with an A57G that impairs ELC N-terminus actin binding and an E143K that impairs lever-arm stability, while both species down-shift average step-size with increasing load. Cardiac myosin in vivo down-shifts velocity/force ratio with increasing load by changed unitary step-size selections. Here, the loaded in vitro single myosin assay indicates quantitative complementarity with the in vivo mechanism. Both have two embedded regulatory transitions, one inhibiting ADP release and a second novel mechanism inhibiting actin detachment via strain on the actin-bound ELC N-terminus. Competing regulators filter unitary step-size selection to control force-velocity modulation without myosin integration into muscle. Cardiac myosin is muscle in a molecule.


Interactions between injured workers and insurers in workers' compensation systems: a systematic review of qualitative research literature.
Work-related injury is a major public health problem and a worker's recovery can be shaped by their interactions with employers, healthcare providers and the workers' compensation system. Most research on the effects of compensation has concentrated on examining outcomes rather than considering the compensation process itself. There has been little attention paid to the interactions between stakeholders and only recently has the client's view been considered as worthy of investigation. This systematic review aimed to identify and synthesize findings from peer reviewed qualitative studies that investigated injured workers interactions with insurers in workers' compensation systems. A search of six electronic library databases revealed 1,006 articles. After screening for relevance, 18 articles were read in full and a search of those bibliographies revealed a further nine relevant articles. Quality assessment of the 27 studies resulted in a final 13 articles of medium and high quality being retained for data extraction. Included studies focused mainly on experiences of injured workers, many of whom had long term claims. Findings were synthesized using a meta-ethnographic approach. Six themes were identified which characterised the interactions between insurers and injured workers. The majority of interactions were negative and resulted in considerable psychosocial consequences for injured workers. Positive interactions were less frequently reported and included respectful, understanding and supportive communication and efficient service from insurers. Findings from this synthesis support the growing consensus that involvement in compensation systems contributes to poorer outcomes for claimants. Interactions between insurers and injured workers were interwoven in cyclical and pathogenic relationships, which influence the development of secondary injury in the form of psychosocial consequences instead of fostering recovery of injured workers. This review suggests that further research is required to investigate positive interactions and identify mechanisms to better support and prevent secondary psychosocial harm to injured workers.


Selective toxicity of TGF-alpha-PE40 to EGFR-positive cell lines: selective protection of low EGFR-expressing cell lines by EGF.
The sensitivity of human breast and lung cancer cell lines to TGF-alpha-PE40, a novel chimeric recombinant cytotoxin composed of two independent domains, (i) TGF-alpha and (ii) a 40 kDa segment of the Pseudomonas exotoxin protein, PE-40, was investigated. Toxicity varied widely, correlated with epidermal growth factor receptor (EGFR) levels (P = 0.01) and was greatly reduced by EGF, indicating that binding of TGF-alpha-PE40 to EGFR is important in mediating toxicity. Cell lines expressing low EGFR levels were most highly protected by EGF, indicating that normal (low EGFR-expressing) tissue may be selectively protected by EGF in vivo. P-glycoprotein did not confer resistance to TGF-alpha-PE40, and toxicity was unaffected by multidrug resistance-modulating agents (cyclosporin A, tamoxifen, verapamil), indicating a role for TGF-alpha-PE40 in the clinical management of drug-resistant tumours.


Exact classification of Landau-Majorana-Stückelberg-Zener resonances by floquet determinants.
Recent experiments have shown that Landau-Majorana-Stückelberg-Zener (LMSZ) interferometry is a powerful tool for demonstrating and exploiting quantum coherence not only in atomic systems but also in a variety of solid state quantum systems such as spins in quantum dots, superconducting qubits, and nitrogen vacancy centers in diamond. In this Letter, we propose and develop a general (and, in principle, exact) theoretical formalism to identify and characterize the interference resonances that are the hallmark of LMSZ interferometry. Unlike earlier approaches, our scheme does not require any approximations, allowing us to uncover important and previously unknown features of the resonance structure. We also discuss the experimental observability of our results.


Summative evaluation results and lessons learned from the Aligning Forces for Quality program.
To report summative evaluation results from the Aligning Forces for Quality (AF4Q) initiative, the Robert Wood Johnson Foundation's (RWJF's) signature effort to improve quality of care from 2005 to 2015. This was a longitudinal mixed methods program evaluation (ie, multiphase triangulated evaluation) of 16 grantee "alliances" from across the country, funded by RWJF as part of the AF4Q initiative. Grantees were selected in a nonexperimental manner and were charged with deploying interventions in 5 main programmatic areas to improve health and healthcare in their communities. Except for a small proportion of outcomes, there were no major differences in the rate of longitudinal improvement in AF4Q communities, compared with control communities, on quantitative outcomes related to the Triple Aim. Although the majority of the measures improved in both AF4Q and non-AF4Q communities, there were some exceptions to this improving trend, most noticeably in the cost of care and population health. There was also considerable heterogeneity across communities in terms of programmatic areas and the scale and scope of interventions in these areas. Although a number of AF4Q alliances implemented robust interventions in specific areas, often advancing strategies useful for others in the field, no AF4Q alliance pursued and aligned all 5 AF4Q programmatic areas in a robust way. In addition, whereas all alliances were able to garner the participation of multiple stakeholders initially, sustaining this participation and securing new sources of funding after RWJF support ended proved challenging for many alliances. Conclusion and Policy and Practice Implications: While the AF4Q program did not attain the ambitious community-level changes predicted by its sponsor at the program's outset, it did produce pockets of success on some dimensions for particular alliances. A number of factors explain the less-than-expected impact of the AF4Q initiative on community health and the observed variation in alliance sustainability and intervention strength. These include differing acceptance of the AF4Q initiative's theory of change, variation in the experience and capacity of the alliance communities selected for the program, differences in alliances' local healthcare market context, and the changing programmatic requirements for alliances participating in the AF4Q initiative. The variation in AF4Q program outcomes offers important lessons for those engaged in regional health improvement work.


Quantifying the protein-protein association rate in polymer solutions: crowding-induced diffusion and energy modifications.
A theoretical framework is developed to study protein-protein association in polymer solutions under diffusion-limited conditions. Starting from the basal association rate, two fundamental aspects concerning macromolecular crowding are particularly taken into account. One is the effect of microviscosity on protein diffusion. The length-scale dependent relations of translational and rotational diffusion coefficients are incorporated. Another is relevant to the crowding-induced effective interaction between the pair of proteins. The resultant energy modifications to the basal association rate are properly introduced, following an instructive classification with increasing crowder size: repulsive interaction dominant, repulsive and attractive interactions competitive, and attractive interaction prevailing. With specific energy modification terms, we are able to investigate the deviations of the association rate from the Stokes-Einstein (SE) behavior (i.e., the linear relationship with respect to the reciprocal of macroviscosity) in a quantitative manner. Our theory is applied to study the association of TEM1-β-lactamase (TEM) and the β-lactamase inhibitor protein (BLIP) in polyethylene glycol (PEG) solutions, with varying concentration and polymerization. We explicitly evaluate the relative association rate constant as a function of the solution macroviscosity. The theoretical results demonstrate very good agreement with the experimental data. Moreover, the complicated non-trivial deviations, either positive (slower than SE) or negative (faster than SE), are systematically rationalized. The precise role of energy modifications and the microviscosity effect on diffusion, in particular on rotational diffusion, are clearly unraveled.


Experimental evaluation of the relationship between lethal or non-lethal virulence and transmission success in malaria parasite infections.
Evolutionary theory suggests that the selection pressure on parasites to maximize their transmission determines their optimal host exploitation strategies and thus their virulence. Establishing the adaptive basis to parasite life history traits has important consequences for predicting parasite responses to public health interventions. In this study we examine the extent to which malaria parasites conform to the predicted adaptive trade-off between transmission and virulence, as defined by mortality. The majority of natural infections, however, result in sub-lethal virulent effects (e.g. anaemia) and are often composed of many strains. Both sub-lethal effects and pathogen population structure have been theoretically shown to have important consequences for virulence evolution. Thus, we additionally examine the relationship between anaemia and transmission in single and mixed clone infections. Whereas there was a trade-off between transmission success and virulence as defined by host mortality, contradictory clone-specific patterns occurred when defining virulence by anaemia. A negative relationship between anaemia and transmission success was found for one of the parasite clones, whereas there was no relationship for the other. Notably the two parasite clones also differed in a transmission phenotype (gametocyte sex ratio) that has previously been shown to respond adaptively to a changing blood environment. In addition, as predicted by evolutionary theory, mixed infections resulted in increased anaemia. The increased anaemia was, however, not correlated with any discernable parasite trait (e.g. parasite density) or with increased transmission. We found some evidence supporting the hypothesis that there is an adaptive basis correlating virulence (as defined by host mortality) and transmission success in malaria parasites. This confirms the validity of applying evolutionary virulence theory to biomedical research and adds support to the prediction that partially effective vaccines may select for increasingly virulent malaria parasite strains. By contrast, there was no consistent correlation between transmission and sub-lethal anaemia, a more common outcome of malaria infection. However, overall, the data are not inconsistent with the recent proposal that sub-lethal effects may impose an upper limit on virulence. Moreover, clone specific differences in transmission phenotypes linked to anaemia do suggest that there is considerable adaptive potential relating anaemia and transmission that may lead to uncertain consequences following intervention strategies.


Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus.
Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) played a role in the eating behavior and glucose and lipid metabolism. In this study we measured the serum BDNF levels in newly diagnosed female patients with type 2 diabetes mellitus (n = 24, aged 34-59 years) and female subjects with normal glucose tolerance (n = 7, aged 34-56 years). The serum BDNF level was found to significantly increase in diabetic patients in comparison to that in healthy subjects (P < .05). In these patients, the serum BDNF level showed positive correlation with the body mass index (r = 0.535, P < .01), the percentage of body fat (r = 0.552, P < .01), the subcutaneous fat area based on computed tomography scan (r = 0.480, P < .05), the triglyceride level (r = 0.470, P < .05), the fasting blood glucose level (r = 0.437, P < .05), and the homeostasis model assessment of insulin resistance score (r = 0.506, P < .05), whereas it showed a negative correlation with age (r = -0.486, P < .05). The partial correlation coefficients adjusted by age showed significant differences regarding the body mass index (r = 0.423, P < .05), percentage of body fat (r = 0.504, P < .05), and triglyceride level (r = 0.426, P < .05). These results provide the first evidence that an increased BDNF is associated with a prevalence of type 2 diabetes mellitus. In addition, the BDNF is related to the total and abdominal subcutaneous fat mass and energy metabolism in the newly diagnosed female patients with type 2 diabetes mellitus.


Fiber taper for dispersion management in a mode-locked ytterbium fiber laser.
We exploit the large anomalous dispersion in the waist of a fiber taper to offset the intracavity normal chromatic dispersion of an Yb-doped fiber laser. The fiber taper provides sufficient anomalous dispersion to ensure soliton operation of the mode-locked laser. With the taper removed from the cavity, the laser operates in a net normal dispersion regime.


Evidence of the efficacy of occupational therapy in different conditions: an overview of systematic reviews.
To summarize the research evidence available from systematic reviews of the efficacy of occupational therapy (OT) for practitioners, researchers, purchasing organizations and policy-makers. The search for systematic reviews was conducted in PubMed and the Cochrane Library (October 2004). The reviews included were those that utilized a systematic search for evidence with regard to OT for specific patient groups. Data were summarized for patient group, interventions, outcome domains, type of study designs included, method of data synthesis and conclusions. Fourteen systematic reviews were included. Three reviews related to rheumatoid arthritis, four reviewed stroke and four focused on elderly people. Reviews of Parkinson's disease, multiple sclerosis, Huntington's disease, cerebral palsy and mental illnesses were also identified. The reviews of rheumatoid arthritis, stroke and elderly people showed evidence of the efficacy of OT in increasing functional abilities. Positive results were presented for quality of life and social participation in elderly people and stroke respectively. The efficacy of OT in all other patient groups is unknown due to insufficient evidence. This summary shows that elderly people and people with stroke or rheumatoid arthritis can expect to benefit from comprehensive OT. Evidence of the efficacy of specific interventions is sparse and should be addressed in future research. The evidence that does exist should be incorporated into OT practice.


How experts are chosen to inform public policy: can the process be improved?
The ever-increasing complexity of the food supply has magnified the importance of ongoing research into nutrition and food safety issues that have significant impact on public health. At the same time, ethical questions have been raised regarding conflict of interest, making it more challenging to form the expert panels that advise government agencies and public health officials in formulating nutrition and food safety policy. Primarily due to the growing complexity of the interactions among government, industry, and academic research institutions, increasingly stringent conflict-of-interest policies may have the effect of barring the most experienced and knowledgeable nutrition and food scientists from contributing their expertise on the panels informing public policy. This paper explores the issue in some depth, proposing a set of principles for determining considerations for service on expert advisory committees. Although the issues around scientific policy counsel and the selection of advisory panels clearly have global applicability, the context for their development had a US and Canadian focus in this work. The authors also call for a broader discussion in all sectors of the research community as to whether and how the process of empaneling food science and nutrition experts might be improved.


The measurement of maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein improves the early prediction of preeclampsia.
In the present study we measured maternal plasma concentrations of two placental neurohormones, corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP), in 58 at-risk pregnant women consecutively enrolled between 28 and 29 wk of pregnancy to evaluate whether their evaluation may predict third trimester-onset preeclampsia (PE). The statistical significance was assessed by t test. The cut-off points for defining altered CRF and CRF-BP levels for prediction of PE were chosen by receiving operator characteristics curve analysis, and the probability of developing PE was calculated for several combinations of hormone testing results. CRF and CRF-BP levels were significantly (both P < 0.0001) higher and lower, respectively, in the patients (n = 20) who later developed PE than in those who did not present PE at follow-up. CRF at the cut-off 425.95 pmol/liter achieved a sensitivity of 94.8% and a specificity of 96.9%, whereas CRF-BP at the cut-off 125.8 nmol/liter combined a sensitivity of 92.5% and a specificity of 82.5% as single markers for prediction of PE. The probability of PE was 34.5% in the whole study population, 93.75% when both CRF and CRF-BP levels were changed, and 0% if both hormone markers were unaltered. The measurement of CRF and CRF-BP levels may add significant prognostic information for predicting PE in at-risk pregnant women.


Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.
Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/beta-catenin pathway through the phosphorylation of GSK3-beta. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/beta-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells.