Visualizing the trigeminovagal complex in the human medulla by combining ex-vivo ultra-high resolution structural MRI and polarized light imaging microscopy.

A trigeminovagal complex, as described in some animals, could help to explain the effect of vagus nerve stimulation as a treatment for headache disorders. However, the existence of a trigeminovagal complex in humans remains unclear. This study, therefore investigated the existence of the trigeminovagal complex in humans. One post-mortem human brainstem was scanned at 11.7T to obtain structural (T1-weighted) and diffusion magnetic resonance images ((d)MR images). Post-processing of dMRI data provided track density imaging (TDI) maps to investigate white matter at a smaller resolution than the imaging resolution. To evaluate the reconstructed tracts, the MR-scanned brainstem and three additional brainstems were sectioned for polarized light imaging (PLI) microscopy. T1-weighted images showed hyperintense vagus medullar striae, coursing towards the dorsomedial aspect of the medulla. dMRI-, TDI- and PLI-images showed these striae to intersect the trigeminal spinal tract (sp5) in the lateral medulla. In addition, PLI images showed that a minority of vagus fibers separated from the vagus trajectory and joined the trigeminal spinal nucleus (Sp5) and the sp5. The course of the vagus tract in the rostral medulla was demonstrated in this study. This study shows that the trigeminal- and vagus systems interconnect anatomically at the level of the rostral medulla where the vagus fibers intersect with the Sp5 and sp5. Physiological and clinical utility of this newly identified interconnection is a topic for further research.

Transport and health--a five-country perspective.

Devolution in the UK has, inadvertently, provided a natural experiment for comparing the impact of different approaches to policy and practice on populations that are broadly similar by most criteria. Realizing the potential gold mine that this presents for comparing policy and practice in the field of public health, the UK Public Health Association has established a Devolution Strategic Interest Group to explore and capitalize on this. From the start, the Group has included the Republic of Ireland in its purview to add an extra dimension of diversity and innovation. Having previously looked at the organization of health care and public health, and at policy and practice on food, nutrition and obesity, the Group opted to look at transport and health this year. Here, the links between separate relevant policy streams are less obvious and clearly less developed than those for food, nutrition and obesity. Also, the perceived need to raise the issue up the public health agenda provides a new challenge to campaigning action for the Group.

An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM).

BACKGROUND: The randomized clinical trial of implantable drug delivery systems (IDDS) plus comprehensive medical management (CMM) versus CMM alone showed better clinical success at 4 weeks for IDDS patients. This 'as treated' analysis assessed if improvements in pain control, drug toxicity and survival were maintained over time. PATIENTS AND METHODS: We compared those who received IDDS with those who did not receive IDDS (non-IDDS). All patients had Visual Analogue Scores (VAS) for pain > or =5/10 on at least 200 mg morphine or equivalent daily. RESULTS: At 4 weeks, 46 of 52 (88.5%) IDDS patients achieved clinical success compared with 65 of 91 (71.4%; P=0.02) non-IDDS patients, and more often achieved > or =20% reduction in both pain VAS and toxicity [35 of 52 (67.3%) versus 33 of 91 patients (36.3%); P=0.0003]. By 12 weeks, 47 of 57 (82.5%) IDDS patients had clinical success compared with 35 of 45 (77.8%; P=0.55) non-IDDS patients, and more often had a > or =20% reduction in both pain VAS and toxicity [33 of 57 (57.9%) versus 15 of 45 patients (33.3%); P=0.01]. At 12 weeks the IDDS VAS pain scores decreased from 7.81 to 3.89 (47% reduction) compared with 7.21 to 4.53 for non-IDDS patients (42% reduction; P=0.23). The 12 week drug toxicity scores for IDDS patients decreased from 6.68 to 2.30 (66% reduction), and for non-IDDS patients from 6.73 to 4.13 (37% reduction; P=0.01). All individual drug toxicities improved with IDDS at both 4 and 12 weeks. At 6 months, only 32% of the group randomized to CMM and who did not cross over to IDDS were alive, compared with 52%-59% for patients in those groups who received IDDS. CONCLUSIONS: IDDS improved clinical success, reduced pain scores, relieved most toxicity of pain control drugs, and was associated with increased survival for the duration of this 6 month trial.

Safety, tolerability, and efficacy of orally administered cannabinoids in MS.

The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression.

Spinal drug delivery.

Clinicians currently base decisions regarding the use of intrathecal drug therapy for chronic pain on reports from uncontrolled and retrospective studies that fail to rely on standardized outcome measures. In this article, we summarize what is known about currently administered intrathecal therapies, including opioids, gamma-aminobutyric acid agonists, alpha-2 adrenoreceptor agonists, local anesthetics (sodium channel antagonists), calcium channel antagonists, miscellaneous agents, and drug combination therapy. In addition, we offer a brief look at novel approaches that may revolutionize intrathecal drug delivery.

Development and validation of the Observation List for early signs of Dementia (OLD).

OBJECTIVE: Development and validation of a short Observation List of possible early signs of Dementia (OLD) for use in general practice. DESIGN: Stepwise development using reviews of publications and expert consensus. Field study for evaluation of reliability. Validation study (interviews, family forms) using existing valid and reliable measures. Use of data reduction techniques to construct a short version. Setting of field study Twenty-two GPs in 19 Dutch practices. PARTICIPANTS: The first two patients seen on 15 working days (n = 470) were observed. Inclusion: age > 75, without a known diagnosis of dementia. Exclusion: psychiatric treatment, severe depression, acute illness with confusion. Division of patients into three groups with no, intermediate, and the most signs (total of interviewed patients, n = 60; family forms, n = 39). Outcome measures Reliability (Cronbach's alpha and factor-analysis). Convergent validity using the Cognitive Screening Test (CST), the Word Learning Test (WLT, total and retention), the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), the Groningen Activities Restriction Scale (GARS), and an IADL scale. Discriminant validity using the geriatric depression scale (GDS). Construct validity using a Principal Component Analysis (PRINCALS). Incremental validity using the intuitive opinion of the GP (McNemar test). RESULTS: Reliability in the total group 0.88, first factor explained variance 42.5%. Convergent validity (two-way ANOVA) results: CST (p = 0.00), WLT-total (p = 0.001), WLT retention (p = 0.00), IQCODE (p = 0.09). No statistically significant differences for GARS and IADL. GDS (p = 0.30) not different. PRINCALS first factor explained 48% of variance. The OLD added to the GP opinion (McNemar p = 0.00). Reliability short version 0.89 (interviewed group), 0.86 (total group). CONCLUSIONS: The OLD is a valid and reliable method to detect early signs of dementia in general practice that can indicate when it may be useful to employ existing screening instruments.

[Indicators of early Alzheimer dementia in family practice. Development and validation of the Observation List of Early Symptoms of Dementia (OLD)]. / Signalering van beginnende Alzheimer-dementie in de huisartspraktijk. Ontwikkeling en validering van de Observatie Lijst voor vroege symptomen van Dementie (OLD).

UNLABELLED: Aim of the study was the development and validation of a short observation list of possible early signs of dementia (OLD) for use in general practice. A stepwise development was carried out using reviews of publications and expert consensus. Experimental observations were carried out by 22 general practitioners in 19 Dutch practices. A field study (with interviews and family forms) was conducted out afterwards, to evaluate reliability and validity. Data reduction techniques were used to construct a short version. The first two patients seen on 15 working days (N = 470) were observed. INCLUSION CRITERIA: age > 75, without a known diagnosis of dementia. Exclusion: psychiatric treatment, severe depression, acute illness with confusion. The patients were divided into three groups with no, intermediate, and the most signs (total of interviewed patients n = 60; family forms n = 39). Cronbach's alpha and factor-analysis were used to evaluate the reliability. The Cognitive Screening Test (CST), the Word Learning Test (WLT; total and retention), the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), the Groningen Activities Restriction Scale (GARS), and an IADL scale were used to evaluate convergent validity. The Geriatric Depression Scale (GDS) was used to evaluate discriminant validity. Construct validity was evaluated using PRINCALS. Incremental validity was evaluated using the intuitive opinion of the GP (McNemar test). The reliability in the total group was 0.88, the first factor explained 42.5% of the variance. Convergent validity (2-side ANOVA) results: CST (p = 0.00), WLT-total (p = 0.001), WLT retention (p = 0.00), IQCODE (p = 0.09). No statistically significant differences were found for GARS and IADL. The GDS (p = 0.30) showed no difference. The first factor of PRINCALS explained 48% of the variance. The OLD added to the GP opinion (McNemar p = 0.00). Reliability of the short version (12 items) was 0.89 (interviewed group), and 0.86 (total group). The conclusion is that the OLD is a valid and reliable method to detect early signs of dementia in general practice. (Partly adapted from: Hopman-Rock M, Tak ECPM, Staats PGM. Development and validation of the Observation List for early signs of Dementia (OLD). Int J Geriatr Psychiatry 2001 (in press)).

Effects of the nitric oxide/cGMP system compared with the cAMP system on airway mucus secretion in the rat.

Mucus secretion of the airways is under the control of a variety of intracellular second messenger systems. Cyclic nucleotides such as cGMP, coupled to the recently discovered nitric oxide system, and cAMP are of outstanding interest in this respect. The present study used the modified Ussing chamber technique and mucins labelled with (35)SO(4) to investigate mucus secretion in the rat trachea to clarify the contribution of these different second messenger systems to the control of mucin secretion.A variety of drugs affecting either the generation or the breakdown of the respective cyclic nucleotides were used. Neither drugs interfering with nitric oxide synthase nor the phosphodiesterase isoenzyme responsible for cGMP breakdown nor cGMP analogues were able to affect mucus secretion. In contrast, stimulation of adenylate cyclase or inhibition of the respective phosphodiesterase resulted in a potent increase of mucus secretion. In conclusion, we failed to show the involvement of the nitric oxide/cGMP system, whereas the cAMP system seems to be a very efficient regulator of mucus secretion in the rat trachea.

The additive impact of anxiety and a placebo on pain.

OBJECTIVE: We investigated the effects of pain anxiety and a placebo/nocebo/neutral intervention on ice water-induced pain. DESIGN: We divided 72 volunteers into high- and low-anxiety groups before randomly assigning them to experimental and control subgroups. METHOD: Participants completed preimmersion tests of pain anxiety, pain worry, and mood. We scored first immersion pain behavior, experience, and intensity. Each subgroup then received an instruction designed to elicit a positive (placebo), negative (nocebo), or neutral response. After repeating the pain worry test, we gathered second immersion pain scores, and participants repeated the mood test, completed the treatment credibility measure, and were debriefed. OUTCOME MEASURES: We used the Pain Anxiety Symptom Scale; self-rating Likert-type scales for pain worry, pain intensity, and pain-coping; the Multiple Affect Adjective Checklist (mood); timed measurements for pain threshold and pain tolerance; and a treatment credibility scale. RESULTS: Pain anxiety and the placebo interventions significantly altered participants' pain scores, with best-to-worse scores reported by the low pain-anxiety/placebo, high anxiety/placebo, low anxiety/neutral, low anxiety/nocebo, high anxiety neutral, and high anxiety/nocebo groups. The high pain-anxiety group demonstrated the greatest response to the placebo/nocebo intervention in the expected directions in pain, worry, and anxious mood scores and in decreased self-confidence in managing pain (this was also negatively affected by the nocebo in each pain-anxiety group). CONCLUSION: This study demonstrates that the interaction of the personality variable of pain anxiety with the placebo/nocebo response has an impact on pain, worry, and mood.

The effects of alcohol celiac plexus block, pain, and mood on longevity in patients with unresectable pancreatic cancer: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: This additional analysis of data from a previously reported prospective trial comparing the effect of intraoperative alcohol or saline placebo neurolytic block in patients with pancreatic cancer was conducted in response to the development of a new theory, which explores the relationship of negative mood states to pain, pain-related behavior, and ultimately, longevity. METHODS: The original study used a double-blind procedure to randomly assign 139 patients with histologically proven, unresectable pancreatic cancer to receive either an alcohol or a saline block. Data on visual analog pain, mood, and interference with activity were collected preoperatively and every 2 months postoperatively until death. The current analysis was conducted on the complete data sets received from 130 patients. Demographic data were submitted to chi-square analysis and to univariate and multivariate analysis of variance. Univariate and multivariate analyses of variance also compared 1) the effect of alcohol versus saline on pain, mood, interference of pain with activities, and longevity and 2) the impact of mood on pain with longevity as the dependent variable. Correlation and regression analyses examined the impact of mood on life expectancy. RESULTS: The alcohol intervention had a significant positive effect on life duration and mood scores. High negative mood states correlated significantly with an increase in visual analog pain, the rating of pain intensity at its worse, and pain interference with patients' activities. CONCLUSION: In these subjects, the neurolytic block, as compared with medical management alone, improved pain, elevated mood, reduced pain interference with activity, and was associated with an increase in life expectancy.

Long-term intrathecal ziconotide therapy: a case study and discussion.

This case study describes the therapeutic result of intrathecal administration of ziconotide, a new synthetic neurotoxin derived from the venom of the Philippine marine snail, Conus Magus, to a 48-year-old male with chronic, and previously untreatable, neuropathic pain of an undeterminable etiology. The patient suffered tactile allodynia and reported his baseline pain intensity to be 80 mm on the 100 mm Visual Analog Scale for Pain Intensity. After responding affirmatively to treatment in a blinded placebo-controlled trial, the patient enrolled in a long-term, open-label trial. Currently, the patient rates his pain at 16 mm and enjoys an improved quality of life. This result suggests that treatment with ziconotide may provide outstanding relief to patients with chronic pain while sparing them the unpleasant side effects associated with other treatments.

Biochemical characterization of the mitochondrial permeability transition in isolated forebrain mitochondria.

Induction of the mitochondrial permeability transition (PT) has been proposed to contribute to neuronal cell death. Nearly all studies of the biochemistry of PT induction, however, have been conducted in isolated liver mitochondria. To better understand PT induction in brain mitochondria, we used Ficoll gradients to purify nonsynaptosomal mitochondria from the forebrains of male Fischer 344 rats. Incubation of these mitochondria with Ca(2+) was associated with a loss of absorbance. Inorganic phosphate enhanced this loss of absorbance, and the PT inhibitor cyclosporin A reduced it, especially in conjunction with ADP. These findings suggest that Ca(2+)-mediated loss of absorbance resulted from PT induction. Na(+), which enhances mitochondrial Ca(2+) efflux, but stimulates mitochondrial free radical production, had no effect on PT induction. These data confirm the existence of tissue-specific differences in the nature of PT induction.

The effects of a psychomotor activation programme for use in groups of cognitively impaired people in homes for the elderly.

OBJECTIVES: To test the effects of the Psychomotor Activation Programme (PAP) on the behaviour and cognition of demented elderly people. DESIGN: Randomized controlled trial with an experimental group and a control group. Post-test after 6 months. SETTING: Group care projects for demented elderly people living in 11 different homes for the elderly in The Netherlands. PARTICIPANTS: One hundred and thirty-four subjects entered the study (72 in the experimental group and 62 in the control group), 42 of whom dropped out (27 in the experimental group and 15 in the control group). MEASUREMENTS: Individual behaviour and group behaviour were scored using two Dutch scales (BIP and SIPO respectively) developed and validated for use in psychogeriatric populations. Cognition was measured with the short and the long versions of the Cognitive Screening Test (CST-14 and CST-20). Disability was measured with the Barthel Index. Medicine use, falls, other accidents and life events were registered. RESULTS: The PAP had a beneficial effect on cognition (CST-14, F = 2.63, p < or = 0.05, effect size 0.4) (CST-20, F = 3.77, p < or = 0.05, effect size 0.5) and increased positive group behaviour in participants with relatively mild cognitive problems (SIPO, F = 4.46 p < or = 0.05). CONCLUSIONS: The PAP stabilizes cognitive performance and has some beneficial effects on behaviour. Positive findings were supported by a simultaneously conducted process evaluation.

Management of chronic pain.

Chronic pain is a common condition for which patients seek care from various health-care providers. This type of pain causes much suffering and disability and is frequently mistreated or undertreated. Patients who present for evaluation for chronic pain should undergo a careful assessment before therapy. Patients with chronic pain commonly experience depression, sleep disturbance, fatigue, and decreased overall physical and mental functioning. They frequently require an interdisciplinary model of care to allow care givers to address the multiple components of the patient's pain experience. After a careful evaluation, therapy may include medication, nerve blocks, active physical therapy, behavioural interventions, and assistance with vocational evaluation and training. Less frequently therapy may include placement of implantable devices to alter the pain experience. These patients suffer from a chronic condition and often require long-term care, with frequent reassessment and adjustment of therapy. Although cure is possible, it is also infrequent. Therefore, therapy is provided with the aim of decreasing pain and suffering while improving physical and mental functioning.