Correlates of local cerebral blood flow (CBF) in normal pressure hydrocephalus patients before and after shunting--A retrospective analysis of [(15)O]H(2)O PET-CBF studies in 65 patients

OBJECTIVES: Findings in local cerebral blood flow (rCBF) in Normal pressure hydrocephalus (NPH) have always been challenged by the variable and inconsistent relation to clinical symptoms before and after shunt treatment. [(15)O]H(2)O PET data from a consecutive cohort of 65 idiopathic NPH patients were retrospectively analyzed questioning whether the functional status before and after shunt treatment might correlate with local blood flow. PATIENTS AND METHODS: Using statistical parametric mapping (SPM99, Wellcome Department of Cognitive Neurology, London), the [(15)O]H(2)O uptake was correlated with the preoperative clinical scores, graded according to a modified Stein and Langfitt score. Furthermore, differences in the uptake in the pre-and post-shunt treatment study after seven to 10 days in patients with and without clinical improvement were studied. RESULTS: A higher clinical score significantly correlated with a reduced tracer uptake in mesial frontal (k=1,239 voxel, Z=4.41) and anterior temporal (k=469, Z=4.07) areas. In the mesial frontal areas, tracer uptake showed significant reciprocal changes in the clinically improved vs. the unimproved patients. CONCLUSION: Matched with the existing literature, the regional blood flow alterations are suggested relevant to the NPH syndrome and to post-treatment functional changes. The present rCBF findings warrant prospective studies on the accuracy of neuroimaging studies as they may provide a more specific insight into disease mechanisms.     

Balancing respect for autonomy with competing values with the use of principle-based ethics

Psychologists sometimes find themselves in situations in which they need to balance respect for patient autonomy with other competing values and neither the laws nor ethics codes provide clear direction on how they are to do so. With the use of a model from principle-based ethics, this article recommends a strategy for resolving those dilemmas in a manner that promotes patient autonomy as much as possible, even when respect for autonomy may be temporarily trumped by other values. (PsycINFO Database Record (c) 2010 APA, all rights reserved).     

The amygdala regulates the antianxiety sensitization effect of flumazenil during repeated chronic ethanol or repeated stress

BACKGROUND: The benzodiazepine receptor antagonist flumazenil reduces anxiety-like behavior and sensitization of anxiety-like behavior in various models of ethanol withdrawal in rodents. The mechanism and brain region(s) that account for this action of flumazenil remain unknown. This investigation explored the potential role of several brain regions (amygdala, raphe, inferior colliculus, nucleus accumbens, and paraventricular hypothalamus) for these actions of flumazenil. METHODS: Rats were surgically implanted with guide cannulae directed over the brain region of interest and then treated with an ethanol diet for three 7-day dietary cycles (5 days on ethanol diet followed by 2 days on control diet). At approximately 4 hours, flumazenil was administered intracranially into each of the first 2 withdrawals. Examinations of anxiety-like behavior followed 1 week later during a third withdrawal. In other animals, restraint stress sessions or intra-amygdala DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) injections, preceded by intraperitoneal flumazenil injections, were substituted for the first 2 ethanol treatment cycles to assess the potential anxiety-sensitizing action of stress or a benzodiazepine receptor inverse agonist, respectively. RESULTS: Flumazenil treatment of the amygdala during the first 2 withdrawals blocked the development of sensitized anxiety seen during a third withdrawal. Similar actions of flumazenil were found when stress sessions substituted for the first 2 cycles of ethanol exposure and withdrawal. Amygdala treatment with DMCM magnified the anxiety response to the single subthreshold chronic ethanol treatment, and prophylactic flumazenil blocked this effect. CONCLUSIONS: Intra-amygdala flumazenil inhibits the development of anxiety sensitized by repeated ethanol withdrawal, stress/ethanol withdrawal, or DMCM/ethanol withdrawal. These actions suggest that site-specific and persistent effects of flumazenil on gamma-aminobutyric acid-modulatory processes in this brain region are relevant to sensitized behavioral effects seen in alcoholism.     

A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases

Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333'531, a PKCbeta inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333'531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients.     

Resources for mental health: scarcity, inequity, and inefficiency

Resources for mental health include policy and infrastructure within countries, mental health services, community resources, human resources, and funding. We discuss here the general availability of these resources, especially in low-income and middle-income countries. Government spending on mental health in most of the relevant countries is far lower than is needed, based on the proportionate burden of mental disorders and the availability of cost-effective and affordable interventions. The poorest countries spend the lowest percentages of their overall health budgets on mental health. Most care is now institutionally based, and the transition to community care would require additional funds that have not been made available in most countries. Human resources available for mental health care in most low-income and middle-income countries are very limited, and shortages are likely to persist. Not only are resources for mental health scarce, they are also inequitably distributed-between countries, between regions, and within communities. Populations with high rates of socioeconomic deprivation have the highest need for mental health care, but the lowest access to it. Stigma about mental disorders also constrains use of available resources. People with mental illnesses are also vulnerable to abuse of their human rights. Inefficiencies in the use of available resources for mental health care include allocative and technical inefficiencies in financing mechanisms and interventions, and an overconcentration of resources in large institutions. Scarcity of available resources, inequities in their distribution, and inefficiencies in their use pose the three main obstacles to better mental health, especially in low-income and middle-income countries.     

Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration

Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease.     

White paper of the European Association of Nuclear Medicine (EANM) and the European Society of Radiology (ESR) on multimodality imaging

Introduction New multimodality imaging systems bring together anatomical and molecular information and require the competency and accreditation of individuals from both nuclear medicine and radiology. Aim This paper sets out the positions and aspirations of the European Association of Nuclear Medicine (EANM) and the European Society of Radiology (ESR) working together on an equal and constructive basis for the future benefit of both specialties. Discussion EANM and ESR recognise the importance of coordinating working practices for multimodality imaging systems and that undertaking the nuclear medicine and radiology components of imaging with hybrid systems requires different skills. It is important to provide adequate and appropriate training in the two disciplines in order to offer a proper service to the patient using hybrid systems. Training models are proposed with the overall objective of providing opportunities for acquisition of special competency certification in multimodality imaging. Both organisations plan to develop common procedural guidelines and recognise the importance of coordinating the purchasing and management of hybrid systems to maximise the benefits to both specialties and to ensure appropriate reimbursement of these examinations. European multimodality imaging research is operating in a highly competitive environment. The coming years will decide whether European research in this area manages to defend its leading position or whether it falls behind research in other leading economies. Since research teams in the Member States are not always sufficiently interconnected, more European input is necessary to create interdisciplinary bridges between research institutions in Europe and to stimulate excellence. EANM and ESR will work with the European Institute for Biomedical Imaging Research (EIBIR) to develop further research opportunities across Europe. Recommendation European Union grant-funding bodies should allocate funds to joint research initiatives that encompass clinical research in diagnostic imaging in conjunction with research in mechanical and electronic engineering, informatics and biostatistics, and epidemiology. This paper is a result of working party negotiations of ESR and EANM delegations throughout the period from October 2005 to February 2007. All authors contributed equally to the production of this paper. This paper was approved by the executive council of the ESR, the general assembly of the European Association of Radiology (EAR), the executive committee of the EANM and the executive committees of the UEMS sections of radiology and nuclear medicine. The document was presented at the EANM strategy committee meeting held in London in February 2007. It was also presented at both the EANM advisory council meeting and the EANM extraordinary delegates’ meeting that took place in Vienna in March 2007.Authors are listed in alphabetical order. Authors on behalf of the EANM are: Angelika Bischof Delaloye, Ignasi Carrió, Alberto Cuocolo and Wolfram Knapp. Authors on behalf of the ESR are: Nicholas Gourtsoyiannis, Iain McCall, Maximilian Reiser and Bruno Silberman. An editorial relating to this paper is available at .     

Long-term prescribing of antidepressants in the older population: a qualitative study

Background

High rates of long-term antidepressant prescribing have been identified in the older population.

Aims

To explore the attitudes of older patients and their GPs to taking long-term antidepressant therapy, and their accounts of the influences on long-term antidepressant use.

Design of study

Qualitative study using in-depth semi-structured interviews.

Setting

One primary care trust in North Bradford.

Method

Thirty-six patients aged ≥75 years and 10 GPs were interviewed. Patients were sampled to ensure diversity in age, sex, antidepressant type, and home circumstances.

Results

Participants perceived significant benefits and expressed little apprehension about taking long-term antidepressants, despite being aware of the psychological and social factors involved in onset and persistence of depression. Barriers to discontinuation were identified following four themes: pessimism about the course and curability of depression; negative expectations and experiences of ageing; medicine discontinuation perceived by patients as a threat to stability; and passive (therapeutic momentum) and active (therapeutic maintenance) decisions to accept the continuing need for medication.

Conclusion

There is concern at a public health level about high rates of long-term antidepressant prescribing, but no evidence was found of a drive for change either from the patients or the doctors interviewed. Any apprehension was more than balanced by attitudes and behaviours supporting continuation. These findings will need to be incorporated into the planning of interventions aimed at reducing long-term antidepressant prescribing in older people.     

Chest compressions before defibrillation for out-of-hospital cardiac arrest: A meta-analysis of randomized controlled clinical trials

Background

Current 2005 guidelines for advanced cardiac life support strongly recommend immediate defibrillation for out-of-hospital cardiac arrest. However, findings from experimental and clinical studies have indicated a potential advantage of pretreatment with chest compression-only cardiopulmonary resuscitation (CPR) prior to defibrillation in improving outcomes. The aim of this meta-analysis is to evaluate the beneficial effect of chest compression-first versus defibrillation-first on survival in patients with out-of-hospital cardiac arrest.

Methods

Main outcome measures were survival to hospital discharge (primary endpoint), return of spontaneous circulation (ROSC), neurologic outcome and long-term survival. Randomized, controlled clinical trials that were published between January 1, 1950, and June 19, 2010, were identified by a computerized search using SCOPUS, MEDLINE, BIOS, EMBASE, the Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts database, and Web of Science and supplemented by conference proceedings. Random effects models were used to calculate pooled odds ratios (ORs). A subgroup analysis was conducted to explore the effects of response interval greater than 5 min on outcomes.

Results

A total of four trials enrolling 1503 subjects were integrated into this analysis. No difference was found between chest compression-first versus defibrillation-first in the rate of return of spontaneous circulation (OR 1.01 [0.82-1.26]; P = 0.979), survival to hospital discharge (OR 1.10 [0.70-1.70]; P = 0.686) or favorable neurologic outcomes (OR 1.02 [0.31-3.38]; P = 0.979). For 1-year survival, however, the OR point estimates favored chest compression first (OR 1.38 [0.95-2.02]; P = 0.092) but the 95% CI crossed 1.0, suggesting insufficient estimate precision. Similarly, for cases with prolonged response times (> 5 min) point estimates pointed toward superiority of chest compression first (OR 1.45 [0.66-3.20]; P = 0.353), but the 95% CI again crossed 1.0.

Conclusions

Current evidence does not support the notion that chest compression first prior to defibrillation improves the outcome of patients in out-of-hospital cardiac arrest. It appears that both treatments are equivalent. However, subgroup analyses indicate that chest compression first may be beneficial for cardiac arrests with a prolonged response time.