The effects of impaired cerebral circulation on Alzheimer's disease pathology: evidence from animal studies.

Persistent systemic hypoxia, a direct consequence of alterations in vascular function, can compromise the brain by increasing the risk of developing dementias such as Alzheimer’s disease (AD). Vascular contributions to cognitive impairment and AD in aged individuals are common, and several vascular risk factors for AD are linked to hypoxia. Clinical evidence confirms that structural and functional changes characteristic of AD pathology also occur following hypoxic-ischemic events such as stroke and traumatic brain injury. Studies with transgenic and non-transgenic mouse models reliably show that hypoxia increases the levels of amyloid- peptides that form the characteristic plaques in AD brains. Moreover, some studies suggest that vascular lesions also promote tau phosphorylation, modulate apolipoprotein E expression, and have more profound in effects in aged animals, but additional evidence is needed to establish these findings. Although the mechanisms underlying hypoxia-related effects remain unclear, controlled animal studies continue to reveal mechanistic aspects of the relationship between hypoxia and AD pathology that are necessary for therapeutic developments. The present review summarizes evidence from rodent studies regarding the effects of hypoxia on AD-related pathology and evaluates its impact on understanding human disease.Persistent systemic hypoxia, a direct consequence of alterations in vascular function, can compromise the brain by increasing the risk of developing dementias such as Alzheimer’s disease (AD). Vascular contributions to cognitive impairment and AD in aged individuals are common, and several vascular risk factors for AD are linked to hypoxia. Clinical evidence confirms that structural and functional changes characteristic of AD pathology also occur following hypoxic-ischemic events such as stroke and traumatic brain injury. Studies with transgenic and non-transgenic mouse models reliably show that hypoxia increases the levels of amyloid- peptides that form the characteristic plaques in AD brains. Moreover, some studies suggest that vascular lesions also promote tau phosphorylation, modulate apolipoprotein E expression, and have more profound in effects in aged animals, but additional evidence is needed to establish these findings. Although the mechanisms underlying hypoxia-related effects remain unclear, controlled animal studies continue to reveal mechanistic aspects of the relationship between hypoxia and AD pathology that are necessary for therapeutic developments. The present review summarizes evidence from rodent studies regarding the effects of hypoxia on AD-related pathology and evaluates its impact on understanding human disease

Decision Models and Technology Can Help Psychiatry Develop Biomarkers

Why is psychiatry unable to define clinically useful biomarkers? We explore this question from the vantage of data and decision science and consider biomarkers as a form of phenotypic data that resolves a well-defined clinical decision. We introduce a framework that systematizes different forms of phenotypic data and further introduce the concept of decision model to describe the strategies a clinician uses to seek out, combine, and act on clinical data. Though many medical specialties rely on quantitative clinical data and operationalized decision models, we observe that, in psychiatry, clinical data are gathered and used in idiosyncratic decision models that exist solely in the clinician's mind and therefore are outside empirical evaluation. This, we argue, is a fundamental reason why psychiatry is unable to define clinically useful biomarkers: because psychiatry does not currently quantify clinical data, decision models cannot be operationalized and, in the absence of an operationalized decision model, it is impossible to define how a biomarker might be of use. Here, psychiatry might benefit from digital technologies that have recently emerged specifically to quantify clinically relevant facets of human behavior. We propose that digital tools might help psychiatry in two ways: first, by quantifying data already present in the standard clinical interaction and by allowing decision models to be operationalized and evaluated; second, by testing whether new forms of data might have value within an operationalized decision model. We reference successes from other medical specialties to illustrate how quantitative data and operationalized decision models improve patient care

Clinical relevance assessment of animal preclinical research (RAA) tool: development and explanation

Background Only a small proportion of preclinical research (research performed in animal models prior to clinical trials in humans) translates into clinical benefit in humans. Possible reasons for the lack of translation of the results observed in preclinical research into human clinical benefit include the design, conduct, and reporting of preclinical studies. There is currently no formal domain-based assessment of the clinical relevance of preclinical research. To address this issue, we have developed a tool for the assessment of the clinical relevance of preclinical studies, with the intention of assessing the likelihood that therapeutic preclinical findings can be translated into improvement in the management of human diseases. / Methods We searched the EQUATOR network for guidelines that describe the design, conduct, and reporting of preclinical research. We searched the references of these guidelines to identify further relevant publications and developed a set of domains and signalling questions. We then conducted a modified Delphi-consensus to refine and develop the tool. The Delphi panel members included specialists in evidence-based (preclinical) medicine specialists, methodologists, preclinical animal researchers, a veterinarian, and clinical researchers. A total of 20 Delphi-panel members completed the first round and 17 members from five countries completed all three rounds. / Results This tool has eight domains (construct validity, external validity, risk of bias, experimental design and data analysis plan, reproducibility and replicability of methods and results in the same model, research integrity, and research transparency) and a total of 28 signalling questions and provides a framework for researchers, journal editors, grant funders, and regulatory authorities to assess the potential clinical relevance of preclinical animal research. / Conclusion We have developed a tool to assess the clinical relevance of preclinical studies. This tool is currently being piloted

Immunolocalization of the short neuropeptide F receptor in queen brains and ovaries of the red imported fire ant (Solenopsis invicta Buren)

<p>Abstract</p> <p>Background</p> <p>Insect neuropeptides are involved in diverse physiological functions and can be released as neurotransmitters or neuromodulators acting within the central nervous system, and as circulating neurohormones in insect hemolymph. The insect short neuropeptide F (sNPF) peptides, related to the vertebrate neuropeptide Y (NPY) peptides, have been implicated in the regulation of food intake and body size, and play a gonadotropic role in the ovaries of some insect species. Recently the sNPF peptides were localized in the brain of larval and adult <it>Drosophila</it>. However, the location of the sNPF receptor, a G protein-coupled receptor (GPCR), has not yet been investigated in brains of any adult insect. To elucidate the sites of action of the sNPF peptide(s), the sNPF receptor tissue expression and cellular localization were analyzed in queens of the red imported fire ant, <it>Solenopsis invicta </it>Buren (Hymenoptera), an invasive social insect.</p> <p>Results</p> <p>In the queen brains and subesophageal ganglion about 164 cells distributed in distinctive cell clusters (C1-C9 and C12) or as individual cells (C10, C11) were immuno-positive for the sNPF receptor. Most of these neurons are located in or near important sensory neuropils including the mushroom bodies, the antennal lobes, the central complex, and in different parts of the protocerebrum, as well as in the subesophageal ganglion. The localization of the sNPF receptor broadly links the receptor signaling pathway with circuits regulating learning and feeding behaviors. In ovaries from mated queens, the detection of sNPF receptor signal at the posterior end of oocytes in mid-oogenesis stage suggests that the sNPF signaling pathway may regulate processes at the oocyte pole.</p> <p>Conclusions</p> <p>The analysis of sNPF receptor immunolocalization shows that the sNPF signaling cascade may be involved in diverse functions, and the sNPF peptide(s) may act in the brain as neurotransmitter(s) or neuromodulator(s), and in the ovaries as neurohormone(s). To our knowledge, this is the first report of the cellular localization of a sNPF receptor on the brain and ovaries of adult insects.</p

Improving the coverage of the PMTCT programme through a participatory quality improvement intervention in South Africa

<p>Abstract</p> <p>Background</p> <p>Despite several years of implementation, prevention of mother-to-child transmission (PMTCT) programmes in many resource poor settings are failing to reach the majority of HIV positive women. We report on a data driven participatory quality improvement intervention implemented in a high HIV prevalence district in South Africa.</p> <p>Methods</p> <p>A participatory quality improvement intervention was implemented consisting of an initial assessment undertaken by a team of district supervisors, workshops to assess results, identify weaknesses and set improvement targets and continuous monitoring to support changes.</p> <p>Results</p> <p>The assessment highlighted weaknesses in training and supervision. Routine data revealed poor coverage of all programme indicators except HIV testing. Monthly support to all facilities took place including an orientation to the PMTCT protocol, review of local data and identification of bottlenecks to optimal coverage using a continuous quality improvement approach. One year following the intervention large improvements in programme indicators were observed. Coverage of CD4 testing increased from 40 to 97%, uptake of maternal nevirapine from 57 to 96%, uptake of infant nevirapine from 15 to 68% and six week PCR testing from 24 to 68%.</p> <p>Conclusion</p> <p>It is estimated that these improvements in coverage could avert 580 new infant infections per year in this district. This relatively simple participatory assessment and intervention process has enabled programme managers to use a data driven approach to improve the coverage of this important programme.</p

Management of giant pseudomeningoceles after spinal surgery

<p>Abstract</p> <p>Background</p> <p>Pseudomeningoceles are a rare complication after spinal surgery, and studies on these complex formations are few.</p> <p>Methods</p> <p>Between October 2000 and March 2008, 11 patients who developed symptomatic pseudomeningoceles after spinal surgery were recruited. In this retrospective study, we reported our experiences in the management of these complex, symptomatic pseudomeningoceles after spinal surgery. A giant pseudomeningocele was defined as a pseudomeningocele >8 cm in length. We also evaluated the risk factors for the formation of giant pseudomeningoceles.</p> <p>Results</p> <p>All patients were treated successfully with a combined treatment protocol of open revision surgery for extirpation of the pseudomeningoceles, repair of dural tears, and implantation of a subarachnoid catheter for drainage. Surgery-related complications were not observed. Recurrence of pseudomeningocele was not observed for any patient at a mean follow-up of 16.5 months. This result was confirmed by magnetic resonance imaging.</p> <p>Conclusions</p> <p>We conclude that a combined treatment protocol involving open revision surgery for extirpation of pseudomeningoceles, repair of dural tears, and implantation of a subarachnoid catheter for drainage is safe and effective to treat giant pseudomeningoceles.</p

Soil Respiration in Relation to Photosynthesis of Quercus mongolica Trees at Elevated CO2

Knowledge of soil respiration and photosynthesis under elevated CO2 is crucial for exactly understanding and predicting the carbon balance in forest ecosystems in a rapid CO2-enriched world. Quercus mongolica Fischer ex Ledebour seedlings were planted in open-top chambers exposed to elevated CO2 (EC = 500 µmol mol−1) and ambient CO2 (AC = 370 µmol mol−1) from 2005 to 2008. Daily, seasonal and inter-annual variations in soil respiration and photosynthetic assimilation were measured during 2007 and 2008 growing seasons. EC significantly stimulated the daytime soil respiration by 24.5% (322.4 at EC vs. 259.0 mg CO2 m−2 hr−1 at AC) in 2007 and 21.0% (281.2 at EC vs. 232.6 mg CO2 m−2 hr−1 at AC) in 2008, and increased the daytime CO2 assimilation by 28.8% (624.1 at EC vs. 484.6 mg CO2 m−2 hr−1 at AC) across the two growing seasons. The temporal variation in soil respiration was positively correlated with the aboveground photosynthesis, soil temperature, and soil water content at both EC and AC. EC did not affect the temperature sensitivity of soil respiration. The increased daytime soil respiration at EC resulted mainly from the increased aboveground photosynthesis. The present study indicates that increases in CO2 fixation of plants in a CO2-rich world will rapidly return to the atmosphere by increased soil respiration

Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis

Accumulation of M2 macrophages in the liver, within the context of a strong Th2 response, is a hallmark of infection with the parasitic helminth, Schistosoma mansoni, but the origin of these cells is unclear. To explore this, we examined the relatedness of macrophages to monocytes in this setting. Our data show that both monocyte-derived and resident macrophages are engaged in the response to infection. Infection caused CCR2-dependent increases in numbers of Ly6Chi monocytes in blood and liver and of CX3CR1+ macrophages in diseased liver. Ly6Chi monocytes recovered from liver had the potential to differentiate into macrophages when cultured with M-CSF. Using pulse chase BrdU labeling, we found that most hepatic macrophages in infected mice arose from monocytes. Consistent with this, deletion of monocytes led to the loss of a subpopulation of hepatic CD11chi macrophages that was present in infected but not naïve mice. This was accompanied by a reduction in the size of egg-associated granulomas and significantly exacerbated disease. In addition to the involvement of monocytes and monocyte-derived macrophages in hepatic inflammation due to infection, we observed increased incorporation of BrdU and expression of Ki67 and MHC II in resident macrophages, indicating that these cells are participating in the response. Expression of both M2 and M1 marker genes was increased in liver from infected vs. naive mice. The M2 fingerprint in the liver was not accounted for by a single cell type, but rather reflected expression of M2 genes by various cells including macrophages, neutrophils, eosinophils and monocytes. Our data point to monocyte recruitment as the dominant process for increasing macrophage cell numbers in the liver during schistosomiasis

Perceptions about data-informed decisions: an assessment of information-use in high HIV-prevalence settings in South Africa

BACKGROUND: Information-use is an integral component of a routine health information system and essential to influence policy-making, program actions and research. Despite an increased amount of routine data collected, planning and resource-allocation decisions made by health managers for managing HIV programs are often not based on data. This study investigated the use of information, and barriers to using routine data for monitoring the prevention of mother-to-child transmission of HIV (PMTCT) programs in two high HIV-prevalence districts in South Africa. METHODS: We undertook an observational study using a multi-method approach, including an inventory of facility records and reports. The performance of routine information systems management (PRISM) diagnostic ‘Use of Information’ tool was used to assess the PMTCT information system for evidence of data use in 57 health facilities in two districts. Twenty-two in-depth interviews were conducted with key informants to investigate barriers to information use in decision-making. Participants were purposively selected based on their positions and experience with either producing PMTCT data and/or using data for management purposes. We computed descriptive statistics and used a general inductive approach to analyze the qualitative data. RESULTS: Despite the availability of mechanisms and processes to facilitate information-use in about two-thirds of the facilities, evidence of information-use (i.e., indication of some form of information-use in available RHIS reports) was demonstrated in 53% of the facilities. Information was inadequately used at district and facility levels to inform decisions and planning, but was selectively used for reporting and monitoring program outputs at the provincial level. The inadequate use of information stemmed from organizational issues such as the lack of a culture of information-use, lack of trust in the data, and the inability of program and facility managers to analyze, interpret and use information. CONCLCUSIONS: Managers’ inability to use information implied that decisions for program implementation and improving service delivery were not always based on data. This lack of data use could influence the delivery of health care services negatively. Facility and program managers should be provided with opportunities for capacity development as well as practice-based, in-service training, and be supported to use information for planning, management and decision-making