Different mechanisms by which anti-DNA MoAbs bind to human endothelial cells and glomerular mesangial cells.

The mechanisms by which anti-DNA MoAbs derived from MRL-lpr/lpr mice, bind to human umbilical vein endothelial cells (HUVEC) and glomerular mesangial cells were studied using a cellular ELISA. DNAse-treatment of either the MoAb or HUVEC followed by reconstitution with DNA and/or histones was performed to determine whether DNA and histones mediated such binding. It was found that MoAb410 bound to HUVEC and mesangial cells in the form of preformed DNA/anti-DNA immune complex, and such binding was facilitated by histones. In contrast, MoAb 152 bound directly to cell membrane-associated DNA, and adding DNA to MoAb 152 reduced its cellular binding. DNA binds endothelial cell surface and histones enhance the binding of both MoAb 410 and MoAb 152 to HUVEC by increasing cell membrane-associated DNA. Finally, the degree of MoAb binding to HUVEC is critically influenced by the relative concentrations of antibody, DNA, and histones.     

Fluoroscopic peroperative cholangiography: technique and associated radiation hazards

The techniques specific to peroperative fluorocholangiography are discussed based on an experience of 632 cholangiograms and an estimation has been made of the associated radiation doses to staff and patients. Rapid and accurate information can be obtained during fluorocholangiography using appropriate techniques with acceptably low radiation hazards.     

Ethical issues in clinical neuroscience research: A patient’s perspective

A patient-centered paradigm for clinical research and medical care is presented as a solution to the problem of declining innovation and increasing costs and development time in the pipeline for new therapies. Fundamental differences in values and motivations among scientists, clinicians, industry sponsor, and patients in neurotherapeutics provide a framework for analysis of ethical conflicts and the loss of public confidence in medical research. Parkinson advocates’ views on clinical trial participation, perceived risks and benefits, placebo controls, and sham surgery are presented. These views reflect the sense of urgency and the unique perspective that comes from living with this progressive, debilitating condition full time. A patient-centered paradigm that includes authentic voices of patients as collaborators at every stage of development will help to resolve conflicts, build trust, recruit trial participants, and accelerate new therapies. Key elements are adaptive clinical trial methods and the development of information technology for the assessment of outcomes and surveillance of safety over the life cycle of a medical product. Supported by the Parkinson’s Disease Foundation, the Parkinson Pipeline Project is a grassroots group of Parkinson’s patients whose goal is to represent an authentic voice for patients in the treatment development process. This group promotes education and communication between members of the Parkinson’s community and active stakeholders in medical research, industry, and regulatory agencies. Its members are an example of a new breed of knowledgeable consumers, armed with first-hand access to research findings and reinforced by on-line connections to like-minded peers throughout the world.     

Fifteen-year follow-up of 92 hospitalized adults with Down's syndrome: incidence of cognitive decline, its relationship to age and neuropathology

Background The clinical and neuropathological features associated with dementia in Down’s syndrome (DS) are not well established. Aims To examine clinico‐pathological correlations and the incidence of cognitive decline in a cohort of adults with DS. Method A total of 92 hospitalized persons with DS were followed up from 1985 to December 2000. At outset, 87 participants were dementia‐free, with a median age of 38 years. Assessments included the Prudhoe Cognitive Function Test (PCFT) and the Adaptive Behavior Scale (ABS), to measure cognitive and behavioural deterioration. Dementia was diagnosed from case records and caregivers’ reports. Results Eighteen (21%) patients developed dementia during follow‐up, with a median age of onset 55.5 years (range 45–74). The PCFT demonstrated cognitive decline among those with a less severe intellectual disability (mild and moderate) but not among the profoundly disabled people (severe and profound). Clinical dementia was associated with neuropathological features of Alzheimer’s disease, and correlated with neocortical neurofibrillary tangle densities. At the age of 60 years and above, a little more than 50% of patients still alive had clinical evidence of dementia. Conclusions Clinical dementia associated with measurable cognitive and functional decline is frequent in people with DS after middle age, and can be readily diagnosed among less severely intellectually disabled persons using measures of cognitive function such as the PCFT and behavioural scales such as the ABS. In the more profoundly disabled people, the diagnosis of dementia is facilitated by the use of behavioural and neurological criteria. In this study, the largest prospective DS series including neuropathology on deceased patients, the density of neurofibrillary tangles related more closely to the dementia of DS than senile plaques. In people with DS surviving to middle and old age, the development of dementia of Alzheimer type is frequent but not inevitable, and some people with DS reach old age without clinical features of dementia.     

Delayed Nociceptive Response Following Cold-Water Swim in the Formalin Test: Possible Mechanisms of Action

Exposure of animals to aversive events produces stress-induced analgesia. A common method of producing stress in animals is the cold-water swim (CWS). The present series of experiments examines the effect of CWS on tonic pain, as measured by the formalin test, and explores possible mechanisms of action. Experiment 1 demonstrates that a 3.5-min swim in 2°C water produces a delayed nociceptive response (DNR), characterized by a prolonged period of no formalin responding which then begins and continues during the time when control animals, which have not received the CWS, are finished responding. The delayed response begins at 50–60 min postformalin injection, peaks at 80 min, and is still present at 120 min. Experiment 2 indicates that paw temperature effects are not responsible for the DNR, although core body temperature effects are a possible mechanism. However, systematic delays in the formalin injection following the CWS (Experiment 3) drastically altered the DNR even though core body temperature remained unchanged, suggesting that a decrease of core body temperature is insufficient to account for the DNR. Experiment 4 demonstrates that the NMDA antagonist MK-801 administered prior to the CWS dramatically reduces the DNR. The present experiment is the first study that reports a delay as long as 60 min in pain responding. It is concluded that the delayed response to formalin injection is the result of complex interactions involving peripheral mechanisms and central neuronal plasticity in which activity initiated by a noxious input persists after the cessation of the input as a consequence of a stressful event such as the cold-water swim.