Cardiac output in idiopathic normal pressure hydrocephalus: association with arterial blood pressure and intracranial pressure wave amplitudes and outcome of shunt surgery

<p>Abstract</p> <p>Background</p> <p>In patients with idiopathic normal pressure hydrocephalus (iNPH) responding to shunt surgery, we have consistently found elevated intracranial pressure (ICP) wave amplitudes during diagnostic ICP monitoring prior to surgery. It remains unknown why ICP wave amplitudes are increased in these patients. Since iNPH is accompanied by a high incidence of vascular co-morbidity, a possible explanation is that there is reduced vascular compliance accompanied by elevated arterial blood pressure (ABP) wave amplitudes and even altered cardiac output (CO). To investigate this possibility, the present study was undertaken to continuously monitor CO to determine if it is correlated to ABP and ICP wave amplitudes and the outcome of shunting in iNPH patients. It was specifically addressed whether the increased ICP wave amplitudes seen in iNPH shunt responders were accompanied by elevated CO and/or ABP wave amplitude levels.</p> <p>Methods</p> <p>Prospective iNPH patients (29) were clinically graded using an NPH grading scale. Continuous overnight minimally-invasive monitoring of CO and ABP was done simultaneously with ICP monitoring; the CO, ABP, and ICP parameters were parsed into 6-second time windows. Patients were assessed for shunt surgery on clinical grade, Evan's index, and ICP wave amplitude. Follow-up clinical grading was performed 12 months after surgery.</p> <p>Results</p> <p>ICP wave amplitudes but not CO or ABP wave amplitude, showed good correlation with the response to shunt treatment. The patients with high ICP wave amplitude did not have accompanying high levels of CO or ABP wave amplitude. Correlation analysis between CO and ICP wave amplitudes in individual patients showed different profiles [significantly positive in 10 (35%) and significantly negative in 16 (55%) of 29 recordings]. This depended on whether there was also a correlation between ABP and ICP wave amplitudes and on the average level of ICP wave amplitude.</p> <p>Conclusions</p> <p>These results gave no evidence that the increased levels of ICP wave amplitudes seen in iNPH shunt responders prior to surgery were accompanied by elevated levels of ABP wave amplitudes or elevated CO. In the individual patients the correlation between CO and ICP wave amplitude was partly related to an association between ABP and ICP wave amplitudes which can be indicative of the state of cerebrovascular pressure regulation, and partly related to the ICP wave amplitude which can be indicative of the intracranial compliance.</p

Experiences of the implementation of a tool for lifestyle intervention in primary health care: a qualitative study among managers and professional groups

<p>Abstract</p> <p>Background</p> <p>In recent years there has been increasing interest in transferring new knowledge into health care practices, a process often referred to as implementation. The various subcultures that exist among health care workers may be an obstacle in this process. The aim of this study was to explore how professional groups and managers experienced the implementation of a new tool for lifestyle intervention in primary health care (PHC). The computer-based tool was introduced with the intention of facilitating the delivery of preventive services.</p> <p>Methods</p> <p>Focus group interviews with staff and individual interviews with managers at six PHC units in the southeast of Sweden were performed 9 months after the introduction of the new working tool. Staff interviews were conducted in groups according to profession, and were analysed using manifest content analysis. Experiences and opinions from the different staff groups and from managers were analysed.</p> <p>Results</p> <p>Implementation preconditions, opinions about the lifestyle test, and opinions about usage were the main areas identified. In each of the groups, managers and professionals, factors related to the existing subcultures seemed to influence their experiences of the implementation. Managers were visionary, GPs were reluctant, nurses were open, and nurse assistants were indifferent.</p> <p>Conclusion</p> <p>This study indicates that the existing subcultures in PHC influence how the implementation of an innovation is perceived by managers and the different professionals. In PHC, an organization with several subcultures and an established hierarchical structure, an implementation strategy aimed at all groups did not seem to result in a successful uptake of the new method.</p

Protective Immunity to Listeria Monocytogenes Infection Mediated by Recombinant Listeria innocua Harboring the VGC Locus

In this study we propose a novel bacterial vaccine strategy where non-pathogenic bacteria are complemented with traits desirable for the induction of protective immunity. To illustrate the proof of principle of this novel vaccination strategy, we use the model organism of intracellular immunity Listeria. We introduced a, low copy number BAC-plasmid harbouring the virulence gene cluster (vgc) of L. monocytogenes (Lm) into the non-pathogenic L. innocua (L.inn) strain and examined for its ability to induce protective cellular immunity. The resulting strain (L.inn::vgc) was attenuated for virulence in vivo and showed a strongly reduced host detrimental inflammatory response compared to Lm. Like Lm, L.inn::vgc induced the production of Type I Interferon's and protection was mediated by Listeria-specific CD8+ T cells. Rational vaccine design whereby avirulent strains are equipped with the capabilities to induce protection but lack detrimental inflammatory effects offer great promise towards future studies using non-pathogenic bacteria as vectors for vaccination

Quantification of Visual Field Loss in Age-Related Macular Degeneration

Background An evaluation of standard automated perimetry (SAP) and short wavelength automated perimetry (SWAP) for the central 10–2 visual field test procedure in patients with age-related macular degeneration (AMD) is presented in order to determine methods of quantifying the central sensitivity loss in patients at various stages of AMD. Methods 10–2 SAP and SWAP Humphrey visual fields and stereoscopic fundus photographs were collected in 27 eyes of 27 patients with AMD and 22 eyes of 22 normal subjects. Results Mean Deviation and Pattern Standard Deviation (PSD) varied significantly with stage of disease in SAP (both p<0.001) and SWAP (both p<0.001), but post hoc analysis revealed overlap of functional values among stages. In SWAP, indices of focal loss were more sensitive to detecting differences in AMD from normal. SWAP defects were greater in depth and area than those in SAP. Central sensitivity (within 1°) changed by −3.9 and −4.9 dB per stage in SAP and SWAP, respectively. Based on defect maps, an AMD Severity Index was derived. Conclusions Global indices of focal loss were more sensitive to detecting early stage AMD from normal. The SWAP sensitivity decline with advancing stage of AMD was greater than in SAP. A new AMD Severity Index quantifies visual field defects on a continuous scale. Although not all patients are suitable for SWAP examinations, it is of value as a tool in research studies of visual loss in AMD

rBCG Induces Strong Antigen-Specific T Cell Responses in Rhesus Macaques in a Prime-Boost Setting with an Adenovirus 35 Tuberculosis Vaccine Vector

BACKGROUND: BCG vaccination, combined with adenoviral-delivered boosts, represents a reasonable strategy to augment, broaden and prolong immune protection against tuberculosis (TB). We tested BCG (SSI1331) (in 6 animals, delivered intradermally) and a recombinant (rBCG) AFRO-1 expressing perfringolysin (in 6 animals) followed by two boosts (delivered intramuscullary) with non-replicating adenovirus 35 (rAd35) expressing a fusion protein composed of Ag85A, Ag85B and TB10.4, for the capacity to induce antigen-specific cellular immune responses in rhesus macaques (Macaca mulatta). Control animals received diluent (3 animals). METHODS AND FINDINGS: Cellular immune responses were analyzed longitudinally (12 blood draws for each animal) using intracellular cytokine staining (TNF-alpha, IL-2 and IFN-gamma), T cell proliferation was measured in CD4(+), CD8alpha/beta(+), and CD8alpha/alpha(+) T cell subsets and IFN-gamma production was tested in 7 day PBMC cultures (whole blood cell assay, WBA) using Ag85A, Ag85B, TB10.4 recombinant proteins, PPD or BCG as stimuli. Animals primed with AFRO-1 showed i) increased Ag85B-specific IFN-gamma production in the WBA assay (median >400 pg/ml for 6 animals) one week after the first boost with adenoviral-delivered TB-antigens as compared to animals primed with BCG (<200 pg/ml), ii) stronger T cell proliferation in the CD8alpha/alpha(+) T cell subset (proliferative index 17%) as compared to BCG-primed animals (proliferative index 5% in CD8alpha/alpha(+) T cells). Polyfunctional T cells, defined by IFN-gamma, TNF-alpha and IL-2 production were detected in 2/6 animals primed with AFRO-1 directed against Ag85A/b and TB10.4; 4/6 animals primed with BCG showed a Ag85A/b responses, yet only a single animal exhibited Ag85A/b and TB10.4 reactivity. CONCLUSION: AFRO-1 induces qualitatively and quantitatively different cellular immune responses as compared with BCG in rhesus macaques. Increased IFN-gamma-responses and antigen-specific T cell proliferation in the CD8alpha/alpha+ T cell subset represents a valuable marker for vaccine-take in BCG-based TB vaccine trials

Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease:A randomized controlled trial

Objective: The aim of the study is to determine the effect of lutein combined with vitamin and mineral supplementation on contrast sensitivity in people with age-related macular disease (ARMD). Design: A prospective, 9-month, double-masked randomized controlled trial. Setting: Aston University, Birmingham, UK and a UK optometric clinical practice. Subjects: Age-related maculopathy (ARM) and atrophic age-related macular degeneration (AMD) participants were randomized (using a random number generator) to either placebo (n = 10) or active (n=15) groups. Three of the placebo group and two of the active group dropped out. Interventions: The active group supplemented daily with 6 mg lutein combined with vitamins and minerals. The outcome measure was contrast sensitivity (CS) measured using the Pelli-Robson chart, for which the study had 80% power at the 5% significance level to detect a change of 0.3log units. Results: The CS score increased by 0.07 ± 0.07 and decreased by 0.02 ± 0.18 log units for the placebo and active groups, respectively. The difference between these values is not statistically significant (z = 0.903, P = 0.376). Conclusion: The results suggest that 6 mg of lutein supplementation in combination with other antioxidants is not beneficial for this group. Further work is required to establish optimum dosage levels

Probing the Role of Protein Surface Charge in the Activation of PrfA, the Central Regulator of Listeria monocytogenes Pathogenesis

Listeria monocytogenes is a food-borne intracellular bacterial pathogen capable of causing serious human disease. L. monocytogenes survival within mammalian cells depends upon the synthesis of a number of secreted virulence factors whose expression is regulated by the transcriptional activator PrfA. PrfA becomes activated following bacterial entry into host cells where it induces the expression of gene products required for bacterial spread to adjacent cells. Activation of PrfA appears to occur via the binding of a small molecule cofactor whose identity remains unknown. Electrostatic modeling of the predicted PrfA cofactor binding pocket revealed a highly positively charged region with two lysine residues, K64 and K122, located at the edge of the pocket and another (K130) located deep within the interior. Mutational analysis of these residues indicated that K64 and K122 contribute to intracellular activation of PrfA, whereas a K130 substitution abolished protein activity. The requirement of K64 and K122 for intracellular PrfA activation could be bypassed via the introduction of the prfA G145S mutation that constitutively activates PrfA in the absence of cofactor binding. Our data indicate that the positive charge of the PrfA binding pocket contributes to intracellular activation of PrfA, presumably by facilitating binding of an anionic cofactor

The CRE1 carbon catabolite repressor of the fungus Trichoderma reesei: a master regulator of carbon assimilation

<p>Abstract</p> <p>Background</p> <p>The identification and characterization of the transcriptional regulatory networks governing the physiology and adaptation of microbial cells is a key step in understanding their behaviour. One such wide-domain regulatory circuit, essential to all cells, is carbon catabolite repression (CCR): it allows the cell to prefer some carbon sources, whose assimilation is of high nutritional value, over less profitable ones. In lower multicellular fungi, the C2H2 zinc finger CreA/CRE1 protein has been shown to act as the transcriptional repressor in this process. However, the complete list of its gene targets is not known.</p> <p>Results</p> <p>Here, we deciphered the CRE1 regulatory range in the model cellulose and hemicellulose-degrading fungus <it>Trichoderma reesei </it>(anamorph of <it>Hypocrea jecorina</it>) by profiling transcription in a wild-type and a delta-<it>cre1 </it>mutant strain on glucose at constant growth rates known to repress and de-repress CCR-affected genes. Analysis of genome-wide microarrays reveals 2.8% of transcripts whose expression was regulated in at least one of the four experimental conditions: 47.3% of which were repressed by CRE1, whereas 29.0% were actually induced by CRE1, and 17.2% only affected by the growth rate but CRE1 independent. Among CRE1 repressed transcripts, genes encoding unknown proteins and transport proteins were overrepresented. In addition, we found CRE1-repression of nitrogenous substances uptake, components of chromatin remodeling and the transcriptional mediator complex, as well as developmental processes.</p> <p>Conclusions</p> <p>Our study provides the first global insight into the molecular physiological response of a multicellular fungus to carbon catabolite regulation and identifies several not yet known targets in a growth-controlled environment.</p