Heterogeneity in 5-HT-induced contractile and proliferative responses in rat pulmonary arterial bed.

AIMS: 5-Hydroxytryptamine (5-HT) is a potent vasoconstrictor and mitogen in the pulmonary vascular bed which exhibits phenotypical and functional heterogeneity according to size of the vessels. METHODS: We thus investigated both contractile response and smooth muscle cell (SMC) proliferation in response to 5-HT in rat main extrapulmonary artery (MPA) and intrapulmonary arteries of the first and second order (IPA1 and IPA2). RESULTS: The contractile effect of 5-HT was higher in IPA1 and IPA2 compared to MPA. 5-HT2 receptor antagonists like ketanserin and ritanserin and a 5-HT(1B/D) receptor antagonist, GR127935, partially inhibited the contraction. alpha-Methyl-5-HT, a 5-HT2 receptor agonist, induced a higher contraction in MPA than in IPA and inversely 5-carboxamidotryptamine, a 5-HT1 receptor agonist, induced a higher contraction in IPA2 than in MPA and IPA1. Nitrendipine reduced the contraction, whereas the addition of thapsigargin, an inhibitor of the sarcoplasmic reticulum Ca-ATPases, had an additive blocking effect only in IPA1. The residual contraction to 5-HT was abolished by Y-27632, a rho kinase inhibitor. Finally, SMC proliferation in response to 5-HT was higher in MPA than in IPA2. CONCLUSION: Our results demonstrate regional differences in SMC proliferation as well as in the functional role of 5-HT receptors and the sarcoplasmic reticulum in the contraction.

Lumbar puncture and the risk of herniation: when should we first perform CT?

Death following lumbar puncture (LP) is feared by physicians. Many opinions are found in literature on the question whether computed cranial tomography (CT) should be performed before LP, to prevent herniation. These opinions are mainly based on retrospective studies and pathophysiological reasoning. In this review the difficulties in the decision whether we should perform CT before LP are discussed. It is explained that the concept of "raised intracranial pressure" is confusing, and that the less ambiguous terms "brain shift" and "raised CSF pressure" should be used instead. Brain shift is a contraindication to LP, whether CSF pressure is raised or not, and whether papilloedema is present or not. Subsequently, recommendations are offered for indications to perform CT before LP, grouped according to the safety and clinical utility of LP.

Early diagnosis of dementia: which tests are indicated? What are their costs?

Dementia is reversible in a minority of patients, and these should be diagnosed but without subjecting the majority with irreversible disease to an excessive set of investigations. Should a battery of ancillary investigations be performed routinely in dementia? Or can these tests be carried out as clinically indicated? Three arguments are important to answer this question. (a) Reversible dementia is rare: about 1% of cases. (b) If the clinical criteria for diagnosing primary degenerative disease are used consistently, the results of investigations can be predicted with sufficient accuracy, except those of blood tests. (c) Treatment of reversible dementia has the best results in its most frequent causes: depression and drug intoxication; however, treatment of medical and surgical causes of dementia may also be effective. Based on these three considerations, we propose the following guideline in the setting of a memory clinic: to perform blood tests in every patient with dementia, but also to perform other tests, such as electroencephalography (EEG) and computed tomography (CT), as clinically indicated.

[Revised consensus 'Diagnosis of the dementia syndrome']. / Herziening consensus 'Diagnostiek bij het dementiesyndroom'.

Dementia is a clinical syndrome and is diagnosed on clinical grounds. Various types can be distinguished: the Alzheimer-type, frontal lobe dementia and subcortical dementia syndromes. Neuropsychological examination can contribute to the clinical diagnosis. Differentiation from delirium and depression, which may co-exist with dementia, is necessary. Once a dementia syndrome has been diagnosed its cause has to be ascertained. Alzheimer's disease is the most common cause and can often be diagnosed clinically. The clinical suspicion of vascular dementia has to be confirmed by imaging methods. Drug intoxication may cause or contribute to dementia. Blood tests should be performed routinely, but EEG, CT or MRI, SPECT and genetic tests can be carried out on clinical indication. Subsequently the need for care of the patient has to be established, as well as the ability of the carers to meet it. Regular follow-up is necessary. A definite diagnosis can only be made post-mortem when neuropathological examination has been performed. The organisation of diagnosis in the dementia syndrome should preferably take place in specialised multidisciplinary teams.

Synthesis and biological evaluation of monoindolyl and indolocarbazolyl oxazolones and imidazolones.

Eight compounds structurally related to protein kinase C inhibitor MDL 27032 and substituted with indole moieties were synthesized. Their activities towards protein kinase C (PKC) and protein kinase A (PKA) were determined. Their effect on PKC-mediated contraction of rat tracheal smooth muscle, their antiproliferative activity on two murine tumor cell lines, melanoma B16 and leukemia P388 and their antimicrobial activity on a gram-positive bacterium Bacillus cereus were also examined. The mammalian and bacterial cell antiproliferative activity, as well as vasorelaxant effect, observed for some of them could not be correlated to PKC or PKA inhibition. Only bulky bis-indolyl compounds exhibited biological activity in these experiments. Rigid indolocarbazoles had the strongest antiproliferative activity.

Symptomatic treatment of elderly patients with early Alzheimer's disease at a memory clinic.

It is widely accepted that excess disability (treatable coexisting physical disorders and psychiatric phenomena) is common in demented patients, and should be looked for carefully and treated properly, as it may result in improvement. This idea, however, does not state what investigations should be performed and what kind of improvement can be expected. Therefore, we studied prospectively in elderly outpatients with early Alzheimer's disease the prevalence of excess disability, the results of medication treatment, and the added value of investigations for diagnosis, treatment, and outcome after clinical examination. Outcome was assessed clinically and clinimetrically (using instruments with regard to cognition, disability in daily functioning, behavior, and caregiver burden). Excess disability was present in 66% of patients. Medication treatment was effective with regard to target symptoms, but (partial) reversal of dementia did not occur. Only blood tests produced unexpected results with consequences for treatment and outcome. Positive treatment effects often resulted from clinical examination only. We recommend blood tests in all patients; other investigations can be performed on clinical indication.

Reversible dementia in elderly patients referred to a memory clinic.

Dementia has a reversible cause in some cases, and these should be diagnosed without over-investigating the many patients with irreversible disease. We prospectively studied the prevalence of reversible dementia in a memory clinic, determined the added value of investigations compared with clinical examination and assessed the outcome of treatment of potentially reversible causes by measuring (1) cognition, (2) disability in daily functioning, (3) behavioural changes and (4) caregiver burden. Two hundred patients aged 65 years and over were examined, using the CAMDEX-N. If they were demented, the probable cause was diagnosed clinically and confirmed or excluded by a standard set of investigations, which were done in all patients. Of the patients, 170 (mean age 79.2 years) were demented; 31 were treated for potentially reversible causes. At follow-up after 6 months, no patients showed complete reversal of dementia. Five patients improved on clinical impression, but only one on clinical measurement. Thirty patients were cognitively impaired, but not demented; seven were treated. Judged clinically, three patients improved, but on assessment only one did so; she recovered completely. Blood tests often produced diagnostic results that were not expected clinically, but electroencephalography and computed tomography of the brain did not. None of the investigations had an effect on outcome of dementia after treatment. We conclude that in elderly patients referred to a memory clinic, the prevalence of reversible dementia is of the order of 1%, if outcome after treatment is assessed by a standardized measurement. We recommend blood tests in all patients, to detect not only metabolic causes of dementia but also co-morbidity possibly worsening the dementia. Other investigations can be performed on clinical indication. Clinical evaluation remains the mainstay of diagnosis in dementia.

Human and rat airway smooth muscle responsiveness after ozone exposure in vitro.

We previously reported that NO2 and acrolein administered ex vivo to the lung altered the subsequent responsiveness of airway smooth muscle. The aim of this study was to determine the dose-response relationship for O3 in both human isolated bronchi and rat tracheae and to investigate the mechanisms underlying O3-induced airway responsiveness. Exposure to 1 ppm O3 for 15 min significantly increased the maximal response to carbachol of rat tracheal rings to 149.6 +/- 5.4% of the reference response to acetylcholine (ACh) compared with that of unexposed rings (131.3 +/- 2.4%, n = 6, P < 0.05). The change in maximal airway responsiveness to carbachol, when plotted against the product of exposure concentration and exposure time to O3, a surrogate for the dose, formed a bell-shaped curve. The peak of this dose-response curve was shifted to the right for human bronchi (50 ppm x min, n = 5) compared with that of rat tracheae (15 ppm x min, n = 6). In the rat trachea, responses to KCl were not altered by O3, whereas those to 5-hydroxytryptamine hydrochloride (5-HT) were significantly increased. Finally, in the absence of external Ca2+, O3 exposure still potentiated the maximal response to carbachol from 73.6 +/- 13.9 to 137.0 +/- 6.0% and that to 5-HT from 21.5 +/- 5.5 to 38.7 +/- 2.2% of the reference ACh response. These results indicate that O3 alters the subsequent in vitro airway responsiveness depending on 1) the dose, 2) the nature of the agonist, and 3) the species investigated. Because in vitro exposure to O3 increases responses to agonists that release intracellular Ca2+ and since this effect is maintained in Ca(2+)-free solution, the mechanism of O3-induced increase in airway smooth muscle responsiveness is likely to involve an enhancement in intracellular Ca2+ release.

[Variation in chemonucleolysis as treatment in herniated intervertebral disk]. / Variatie bij chemonucleolyse als behandeling van hernia nuclei pulposi.

OBJECTIVE: To measure the variation of chemonucleolysis in the management of lumbosacral intervertebral disk herniation in the Netherlands. DESIGN: Descriptive. SETTING: Academic Medical Centre, Amsterdam, the Netherlands. METHOD: The use of chymopapain per specialist from 1987 to 1995 was determined by dividing the amount of chymopapain sold, as given by the pharmaceutical company, by the number of specialists as recorded by the specialist associations. Subsequently, variation of chemonucleolysis in time, between specialists and in place was calculated. RESULTS: Between 1987 and 1995 the number of chemonucleolysis treatments decreased gradually from 2084 to 538. Most neurosurgeons, orthopaedic surgeons and neurologists did not treat patients with herniation of a lumbosacral intervertebral disk with chemonucleolysis. Within the group of specialists which did treat patients with chemonucleolysis, a minority accounted for the majority of treatments. Chemonucleolysis was mainly performed in non-academic hospitals outside urban western Holland. CONCLUSIONS: Variation of chemonucleolysis in the management of lumbosacral intervertebral disk herniation in the Netherlands is considerable. Different preferences of specialists are probably the underlying cause.

[Computer-assisted education in problem-solving in neurology; a randomized educational study]. / Computerondersteund onderwijs voor het leren oplossen van neurologische problemen; een gerandomiseerd onderwijskundig onderzoek.

OBJECTIVE: To determine the effect of computer-based medical teaching (CBMT) as a supplementary method to teach clinical problem-solving during the clerkship in neurology. DESIGN: Randomized controlled blinded study. SETTING: Academic Medical Centre, Amsterdam, the Netherlands. METHOD: 103 Students were assigned at random to a group with access to CBMT and a control group. CBMT consisted of 20 computer-simulated patients with neurological diseases, and was permanently available during five weeks to students in the CBMT group. The ability to recognize and solve neurological problems was assessed with two free-response tests, scored by two blinded observers. RESULTS: The CBMT students scored significantly better on the test related to the CBMT cases (mean score 7.5 on a zero to 10 point scale; control group 6.2; p < 0.001). There was no significant difference on the control test not related to the problems practised with CBMT. CONCLUSION: CBMT can be an effective method for teaching clinical problem-solving, when used as a supplementary teaching facility during a clinical clerkship. The increased ability to solve problems learned by CBMT had no demonstrable effect on the performance with other neurological problems.

Reversible dementia: more than 10% or less than 1%? A quantitative review.

Dementia is reversible in some cases and these should be diagnosed without over-investigating the many others with irreversible disease. To estimate how often dementia can be reversed, we carried out a quantitative review of studies reported between 1972 and 1994 in which reversible dementia was diagnosed and outcome after treatment was assessed. We found 16 studies comprising 1551 patients. The percentages of reversed dementia varied widely: from 0 to 23% for partial and from 0 to 10% for full reversal. Depression and drug intoxication were the most frequent causes of reversible dementia, followed by metabolic and neurosurgical disorders. The percentage of both partial and full reversal of dementia has fallen in recent years, to less than 1% for both in the four most recent studies. This decrease could be associated with the change from an inpatient to an outpatient setting and the use of stricter diagnostic methods. We conclude that reversible dementia is very rare in an outpatient setting when using strict diagnostic methods. This has important implications for the diagnostic strategy in patients with dementia: major procedures should be performed selectively. In patients with clinical characteristics of Alzheimer's disease, CT of the brain is unlikely to detect a treatable cause of dementia.

Role of protein kinase C in nonsensitized and passively sensitized human isolated bronchial smooth muscle.

To examine the role of protein kinase C (PKC) activation in the control of the mechanical activity of human isolated bronchial smooth muscle obtained at thoracotomy, the effect of the phorbol ester phorbol 12,13-dibutyrate (PDB) was evaluated. PDB produced slowly developing and sustained contractions that were reduced 1) by the PKC inhibitor staurosporine and 2) after long-term (12 h) exposure to PDB, which downregulates PKC. Moreover, the inactive phorbol ester 4 alpha-phorbol 12,13 didecanoate had no contractile effect. Removal of external Ca2+ or addition of the Ca(2+)-channel antagonist verapamil reduced the PDB-induced contraction. Passive sensitization of human isolated bronchial rings, i.e., incubation overnight of tissues in serum from atopic asthmatic patients, decreased the maximal response to PDB to 28.9 +/- 8% of the maximal response to acetylcholine (ACh) when compared with that of paired nonsensitized rings, i.e., tissues incubated overnight in serum from normal subjects (46.7 +/- 9.4% of the maximal response to ACh, n = 5, P < 0.05). The decrease in the response to PDB induced by either long-term preexposure to PDB or passive sensitization was reversed when both types of tissues were allowed to recover unstimulated for 3 h before PDB application. These results show that 1) PKC activation induces maintained contractions in human isolated airway smooth muscle that are largely dependent on extracellular calcium; 2) passive sensitization alters the PKC-mediated response in a way similar to that induced by prolonged stimulation of PKC.

[The use of protocols in a neurological department]. / Het gebruik van protocollen op een neurologische afdeling.

OBJECTIVE: To assess the use of protocols in a neurological department. DESIGN: Prospective study. SETTING: Academic Medical Centre, Amsterdam. METHOD: Protocols were drafted by residents and staff members, criticised in protocol meetings and amended if necessary. During 6 months it was ascertained in each newly admitted patient (n = 317), whether a protocol was available, whether it was used and if not, why not. RESULTS: During the period before the introduction of the protocol for brain infarction and TIA (the largest category), protocols were available for 20% of the patients and used in 61% of those patients. After introduction of the brain infarction/TIA protocol, these percentages rose to 46 and 82, respectively. Protocols were not used if doctors were not aware of them or forgot to use them or if they were not applicable to individual patients. CONCLUSION: Writing and implementing protocols are feasible in neurological departments.