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Biomedical subjects

M Zimmermann

Publications and source records attributed to M Zimmermann.

At least 55 records · Page 3Linked to original sources
PubMed2003

Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase.

To evaluate the clinical benefit of the prophylactic use of urate oxidase in children with non-Hodgkin's lymphoma (NHL), we analyzed the incidence and complications of tumor lysis syndrome (TLS) in children with B-cell acute lymphoblastic leukemia (B-ALL) or stage III/IV Burkitt's lymphoma and a lactate dehydrogenase (LDH) level > or =500 U/l before and after the introduction of a protocol amendment to use urate oxidase for the prophylaxis of TLS. Data from 1791 children with NHL enrolled in the two subsequent multicenter studies NHL-BFM 90 and 95 were evaluated. The presence of the side effects TLS, anuria, sepsis, and other complications during the first 2 weeks after admission were registered. Until March 1996, no urate oxidase was used (period 1). From November 1997 all children with B-ALL or stage III and IV B-NHL and LDH > or =500 U/l should receive urate oxidase prophylactically (period 3). In between (period 2), urate oxidase was given in a minority of hospitals therapeutically. Initial chemotherapy was identical. Altogether, 78 children (4.4%) developed a TLS. Patients with B-ALL had the highest risk to develop a TLS (26.4%) followed by B-ALL/Burkitt's lymphoma and a LDH > or =500 U/l (14.9%). In period 1, 16.1% and 9.2% of the latter children developed a TLS or anuria, respectively, compared to 12.3% and 6.2% in period 3 ( p=NS). The incidence of sepsis remained unchanged (5.0% vs 4.6%). In children with B-ALL the differences in the incidence of TLS and anuria between period 3 and period 1 were more pronounced, reaching significance for anuria (15.4% vs 3.8%, p=0.03). Our results suggest that patients with the highest risk to develop a TLS might benefit from the prophylactic use of urate oxidase.

Adolescent↗
PubMed2003

[Postoperative pain therapy in orthopedics].

Postoperative pain management adheres to the principles of a three-step routine according to the WHO recommendations. This routine suggests the combination of a basic non-opioid (step I) with an opioid of low potency (step II) or high potency (step III). Non-opioids are routinely administered prior to an opioid. While i.v. application is the treatment of choice in the immediate postoperative course, a switch to oral pain medication is preferred as early as possible. With oral opioid therapy preference should be given to slow release drugs. Intramuscular application of pain medication has little place in postoperative pain management. In order to lower the need for systemic pain medication, postoperative pain management is supplemented by regional anesthesia administered pre- or intraoperatively. Requirement for pain medication beyond normal or increasing with postoperative time is suggestive of a postsurgical complication. Among the numerous drugs available for postoperative pain management, the physician is advised to confine his selection of pain medication to a limited number in order to gain superior knowledge of effects and side effects of the drugs administered.

Administration, Oral↗
PubMed2003

Conservative (labyrinth-preserving) transpetrosal approach to the clivus and petroclival region--indications, complications, results and lessons learned.

OBJECTIVE: Tumours or vascular lesions of the clivus and juxtaclival region present a unique challenge to neurosurgeons and a variety of techniques, with a wide spectrum of complexity, have been advocated. This report presents the use of a conservative transpetrosal approach which combines partial removal of the postero-lateral petrous bone with preservation of the labyrinth, with particular focus on efficacy and the reduction of complications. PATIENTS AND METHODS: Over 9 years, 52 patients underwent a conservative combined supra-infratentorial, labyrinth-preserving transpetrosal approach. There were 32 women and 20 men; 33 had tumour lesions including 22 patients with a clival or petroclival meningioma. Among the 19 patients with a vascular lesion, 12 patients had a basilar artery trunk aneurysm, including one giant midbasilar aneurysm. 3 Patients had vertebro-basilar junction aneurysms, and 4 patients had a pontine cavernoma. Data on the clinical features, investigations and operative techniques were extracted from the patient's case records. Outcome was assessed by serial examinations of the patients or by telephone interview with the treating physician, and in survivors graded as excellent, good or poor. RESULTS: 52 patients, 23 patients (44%) had an excellent outcome, in 21 patients (41%) the outcome was good and in 7 patients (13%) the outcome was poor. One patient with a complex fusiform basilar trunk aneurysm, operated upon as an emergency, died in the postoperative period. Total resection was achieved, as demonstrated by follow-up MRI in 20 of 33 patients with a tumour, including 15 of 22 patients with clival or petro-clival meningiomas. All vascular lesions were treated effectively and in 14 patients with a basilar or vertebro-basilar junction aneurysm, clipping of the aneurysm was achieved. In one patient, a giant calcified vertebro-basilar junction aneurysm was resected. New cranial nerve deficits or an accentuation of a pre-existing deficit, occurred in 8 patients with a tumour and 4 patients with a vascular lesion. Complications included: temporary conductive hearing deficit in 4 patients, a minor laceration of the sigmoid/transverse sinus in 4 and transient post-operative CSF leakage in 12 patients. Temporary lumbar drainage resulted in sealing of the CSF leak in 8 patients, but in 3 patients a permanent ventriculo-peritoneal shunt had to be implanted. CONCLUSION: When based on adequate experience in skull base surgery, the combined supra-infratentorial, conservative transpetrosal approach, with preservation of the labyrinth, allows direct and wide exposure of a large variety of tumour and vascular lesions located along the supra- and infratentorial juxta-clival area; little or almost no retraction of neurovascular structures is needed and with adherence to important principles, complications related to the approach can be minimised.

Adult↗
PubMed2003

Difference in configuration of ruptured and unruptured intracranial aneurysms determined by biplanar digital subtraction angiography.

There is an ongoing discussion about the risk of bleeding from unruptured intracranial aneurysms. Management guidelines were developed recently and some of the recommendations for decision making are based on the anatomical configuration of the aneurysm. The common assumption is that the presence of multiple lobes or a daughter sac indicates a higher risk of rupture. We have investigated the anatomical configuration of ruptured and unruptured intracranial aneurysms using biplanar digital subtraction angiography (DSA). The objective was to determine, whether there was a difference between ruptured and unruptured aneurysms regarding lobulation, the presence of a daughter sac or the shape as measured by the height/neck ratio. Biplanar DSA images of 124 patients were retrospectively analyzed. A total of 53 unruptured and 94 ruptured aneurysms were found (=147 aneurysms in total). Aneurysms of less than 10 mm diameter accounted for 82% of all aneurysms. Overall, 10% of unruptured aneurysm showed a multilobular appearance on DSA compared with 20% of ruptured aneurysms (Fisher's exact test, p=0.10). In the 5-9 mm aneurysm group, multiple lobes were found significantly more frequent in ruptured aneurysms (26% vs. 4%, Fisher's exact test, p<0.05). A height/neck ratio of less than 1.5 was not found in unruptured aneurysms (0/26) but in 21% (12/57) of ruptured aneurysms (p<0.05). Our data provide scientific support for using morphological features for the decision making process in the management of unruptured intracranial aneurysms. An irregular multilobar appearance was significantly more common in aneurysms of 5-9 mm size that ruptured.

Aneurysm, Ruptured↗
PubMed2003

Long-term study of the clinical significance of loss of heterozygosity in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies in childhood, with a widely variable outcome. Differences in the behavior and prognosis of the leukemia suggest that ALL can be divided into several biologic subgroups. We analyzed the loss of heterozygosity (LOH) of 6q, 9p, 11q and 12p using 31 microsatellite sites to determine their overall frequency and clinical value. We have studied 244 primary ALL samples obtained from the Multicenter Trial ALL-BFM 90 of Childhood ALL group. These patients have now been followed clinically for over 8 years. LOH occurred in 169 (69%) individuals in the following frequencies: 6q, 49 patients (20%); 9p, 97 patients (40%); 11q, 29 patients (12%); 12p, 60 patients (25%). Clinical data showed that those with 6q LOH were younger (P = 0.01) and had lower WBC counts (P = 0.02); patients with 9p LOH more frequently had CNS involvement (P = 0.01) and T cell phenotype (P = 0.0001); individuals with 11q LOH had a good response to induction chemotherapy (P = 0.02); those with 12p LOH were younger (P = 0.005), frequently had precursor B ALL (P = 0.001), and had a longer event-free survival (P = 0.05). Taken together, these data confirm that LOH is a very frequent alteration in childhood ALL.

B-Lymphocytes↗
PubMed2003

Emerging therapeutic agents for transmissible spongiform encephalopathies: a review.

Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative disorders associated with misfolding of prion protein, from PrPC to PrPSc. Different types of experimental studies have resulted in a better understanding of the pathogenesis of the prion diseases. Genetic and molecular properties of PrP isoforms have been explained but the conformational conversion of the PrPC isoform to the PrPSc isoform has not yet been entirely elucidated. However, a number of possible therapeutic agents have been tried and some have proven to be effective against TSEs but most have limitations in terms of toxicity and pharmacokinetics. Congo red (CR), anthracyclines, and polyanionic dextran sulfate have limited ability to cross the blood-brain barrier and may be toxic. The efficacy of polyene antibiotics seems to be restricted to certain scrapie strains. Tetrapyrroles and tetracyclines with low toxicities and favorable pharmacokinetics could be useful in preventing PrPSc accumulation. Compounds like branched polyamines, Cp-60, analogs of CR, quinacrine and chlorpromazine, beta-sheet breaker peptides and inhibitory peptides, active immunization using recombinant PrP and passive immunization with anti-PrP antibodies, have potential use as therapeutic agents but would need further research and clinical trials.

Animals↗
PubMed2003

Distinction between atrioventricular reciprocating tachycardia and atrioventricular node re-entrant tachycardia in the adult population based on P wave location; should we reconsider the value of some ECG criteria according to gender and age?

AIMS: Distinction between atrioventricular node re-entrant tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT) is sometimes difficult using location of retrograde P waves on ECG. METHODS: P wave location was retrospectively determined in 137 anterior slow-fast AVNRT (85%) and 26 orthodromic AVRT (15%) with narrow QRS occurring in 161 successive patients without pre-excitation. Mechanism of arrhythmia was assessed by electrophysiological study and confirmed by the efficacy of radiofrequency ablation. P waves were classified as invisible, visible after the QRS, or as R' in V(1) and/or S in II. Correlations with arrhythmia mechanism were made according to gender and age (>or= or <65 years old). RESULTS: Mechanism was related to gender but not to age, with a higher proportion of AVNRT in women (89/97, 91%) than in men (48/66, 72%) (P=0.001). AVRT presented with visible P waves in 26/26 cases (100%) while AVNRT presented with invisible P waves in 36/137 (27%), R'V(1)/SII in 79/137 (57%) and visible P waves in 22/137 (16%). P wave location during AVNRT was related to age but not to gender, with a higher proportion of AVNRT with visible P waves in elderly than in younger patients: 8/27 (29%) vs 14/110 (12%) (P=0.03). Visible P wave during AVNRT was mainly caused by a delay in nodal retrograde conduction in 17/22 patients (77%). Mechanism of tachycardia with visible P waves was related to gender (AVNRT in 14/22 women (64%), AVRT in 18/26 men (70%), P =0.02) and to age, although non-significantly (AVNRT in 8/13 (62%) old vs 14/35 (40%) young patients, P=0.18). A visible P wave was predictive of AVNRT in 25% and in 60% of the men and women younger than 65 years old, and in 50% and in 71% of older men and women respectively (P=0.08 - borderline significance). CONCLUSIONS: Correct distinction between anterior slow-fast AVNRT and orthodromic AVRT can be reliably made regardless of gender or age in case of R'V(1)/SII or invisible P wave. AVRT as the expected mechanism should be reconsidered in the case of visible P waves in the elderly and in the female gender in the absence of pre-excitation.

Age Factors↗
PubMed2003

[Frame-less and frame-based stereotaxy? How to choose the appropriate procedure].

In recent years, additional tools for image guided surgery have been developed. Devices are now available for frameless punction and biopsy of intracerebral lesions and the indications for frameless and frame-based stereotaxy are increasingly overlapping. The objective of our paper was to analyse the most important factors that influence the decision on when to use frameless and when frame-based stereotaxy. Criteria such as application accuracy, image information and ergonomics were investigated for different lesions. Frameless and frame-based stereotaxy are complementary systems with different indications. They are different in terms of image information and ergonomics. Image guided surgery is the standard for continuous 3-dimensional topographical orientation. With high quality images (1 mm slice thickness) and bone marker registration, frameless stereotaxy may achieve an application accuracy comparable to frame-based systems. However, when using adhaesively mounted skin fiducials for patient registration, frameless stereotaxy is less accurate than framebased systems. Therefore, the size of the lesion should exceed 10 mm for punction and biopsy with a frameless system. Frame-based stereotaxy remains the gold standard for accurate targeting of lesions < 10 mm and for functional procedures.

Ergonomics↗
PubMed2002

Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses.

Latent inhibition (LI) is an important model for understanding cognitive deficits in schizophrenia. Disruption of LI is thought to result from an inability to ignore irrelevant stimuli. The study investigated LI in schizophrenic patients by using Pavlovian conditioning of electrodermal responses in a complete within-subject design. Thirty-two schizophrenic patients (16 acute, unmedicated and 16 medicated patients) and 16 healthy control subjects (matched with respect to age and gender) participated in the study. The experiment consisted of two stages: preexposure and conditioning. During preexposure two visual stimuli were presented. one of which served as the to-be-conditioned stimulus (CSp + ) and the other one was the not-to-be-conditioned stimulus (CSp - ) during the following conditioning ( = acquisition). During acquisition, two novel visual stimuli(CSn + and CSn - ) were introduced. A reaction time task was used as the unconditioned stimulus (US). LI was defined as the difference in response differentiation observed between preexposed and non-preexposed sets of CS + and CS - . During preexposure, the schizophrenic patients did not differ in electrodermal responding from the control subjects, neither concerning the extent of orienting nor the course of habituation. The exposure to novel stimuli at the beginning of the acquisition elicited reduced orienting responses in unmedicated patients compared to medicated patients and control subjects. LI was observed in medicated schizophrenic patients and healthy controls, but not in acute unmedicated patients. Furthermore LI was found to be correlated with the duration of illness: it was attenuated in patients who had suffered their first psychotic episode.

Adolescent↗
PubMed2002

Glioblastoma multiforme of the brain stem in a patient with acquired immunodeficiency syndrome.

Glioblastoma of the brain stem is rare and there is no description of such a lesion in patients suffering from acquired immunodeficiency syndrome. The majority of intracerebral mass lesions are due either to toxoplasmosis or primary central nervous system lymphomas so that it is usually not included in the differential diagnosis of enhancing lesions of the central nervous system in these patients. A 31-year-old human immunodeficiency virus (HIV) infected man presented with a four months history of slowly progressive deterioration of brainstem associated symptoms despite antitoxoplasmic therapy. Magnetic resonance imaging revealed a large ring enhancing lesion in the brainstem. Clinical and neuroradiological data could not establish a proper diagnosis and a stereotactic serial biopsy was undertaken. Histological examination of the specimen showed a glioblastoma multiforme (GBM) as the first reported case of GBM located in the brainstem in an acquired immunodeficiency syndrome (AIDS) patient. Patient management and effectiveness of stereotactic serial biopsy are discussed.

AIDS Dementia Complex↗
PubMed2002

Palliative occipito-cervical stabilization in patients with malignant tumors of the occipito-cervical junction and the upper cervical spine.

BACKGROUND: Occipital-cervical stability may be impaired in patients with primary malignant or metastatic tumors of the cranio-cervical junction and the upper cervical spine. The purpose of this study was to evaluate occipital-cervical fixation with pre-bent titanium-loops and sublaminar wiring in order to achieve a rigid and safe stabilisation of the occipito-cervical region in this group of patients. METHOD: 20 patients with severe impairment of occipito-cervical stability due to primary malignant or metastatic cervical bone involvement were included in this study. For palliation of symptoms, resulting from destructive instability, a stabilization procedure using Ransford Loops with sublaminar cable fixation was used in these patients as a palliative therapeutic concept. FINDINGS: Pain which was the major symptom in all patients treated, showed good and immediate response to the stabilization procedures. All 20 patients were either pain free or had good improvement with less intake of analgesic drugs. Signs of spinal cord compression like spasticity and quadraparesis were less likely to improve after surgery. However in 3 of 5 patients neurological function improved after surgery whereas in 2 patients no improvement was achieved. INTERPRETATION: In all patients with impaired occipito-cervical stability due to primary malignant or metastatic tumors of the occipito-cervical junction and the upper cervical spine, immediate stabilization resulting in an improvement of pain was achieved. Occipito-cervical stabilization using contoured Ransford loops is a promising palliative therapeutic concept in this group of patients.

Adult↗
PubMed2002

Effect of endothelin-converting enzyme inhibitors on big endothelin-1 induced contraction in isolated rat basilar artery.

INTRODUCTION: The aim of this study was to investigate whether blocking functional endothelin-converting enzyme (ECE) activity may offer a new approach to inhibit the development of cerebral vasopasm after subarachnoid hemorrhage (SAH) by preventing transformation of big Endothelin-1 (big ET-1) to vasoactive Endothelin-1 (ET-1). METHODS: In vitro, the effect of potential ECE inhibitors was determined by measurement of isometric contractions, induced by big ET-1, in isolated rat basilar arteries. Endothelium intact (E+) and de-endothelialized (E-) segments were examined after pre-incubated with the putative ECE inhibitors: Phosphoramidon (10(-4) M), Captopril (10(-3) M and 10(-4) M) and [(22)D-Val] big ET-1 (16-38) (10(-5) M and 10(-6) M). RESULTS: Application of 10(-4) M Phosphoramidon resulted in a statistically significant decrease in big ET-1 induced contraction in endothelium intact (E+) and de-endothelialized (E-) segments; 10(-3) M Captopril in E- segments caused a statistically significant inhibitory effect; 10(-4) M and 10(-3) M Captopril in E+ segments showed no statistically significant effect; 10(-5) M and 10(-6) M [(22)D-Val] big ET-1 (16-38) in E- segments produced no statistically significant effect. The application of 10(-6) M [(22)D-Val] big ET-1 (16-38) in E+ segments caused increased contractions as shown by the shift to the left of the concentration-effect curve (CEC). CONCLUSION: The present study indicates the existence of functional ECE activity in rat basilar artery, which is different in the endothelium and the smooth muscle layer. This ECE-activity could be inhibited by Captopril and Phosporamidon, suggesting a potency for prevention and therapy of cerebral vasospasm. However, the structural analogue of big ET-1, [(22)D-Val] big ET-1 (16-38), was ineffective in reducing big ET-1 induced vasoconstriction and rather increased contraction in E+ vessels. Therefore further studies of the biochemical nature of the functional relevant cerebrovascular ECE activity are required for better understanding and development of other efficient ECE inhibitors.

Animals↗
PubMed2002

Effect of three different doses of urapidil on blood glucose concentrations in the streptozotocin diabetic rat.

BACKGROUND AND OBJECTIVE: Diabetes mellitus associated with hypertension often causes perioperative complications. The alpha1-adrenoceptor antagonist/5-hydroxytryptamine-1A receptor agonist urapidil is an approved drug used in hypertension and hypertensive emergencies. 5-Hydroxytryptamine-1A (5-HT1A) receptor agonists impair glucose metabolism. To evaluate a possible dose-dependent hyperglycaemic effect of urapidil due to its 5-HT1A receptor agonistic properties, the effect of three doses of urapidil on hyperglycaemia in the streptozotocin diabetic rat was investigated. METHODS: Male Wistar-Kyoto rats were made diabetic by streptozotocin and randomly allocated to the following daily treatments for 7 days (n = 6 each): urapidil 6 mg kg(-1), urapidil 20 mg kg(-1), urapidil 60 mg kg(-1), insulin 4 IU kg(-1) subcutaneously. One diabetic group and one non-diabetic healthy group served as controls. RESULTS: Treatment for 7 days with urapidil 20 mg kg(-1) and urapidil 60 mg kg(-1) reduced mean glucose concentrations significantly (urapidil-20: 15.6 +/- 1.1 mmol L(-1), P = 0.023; urapidil-60: 15.8 +/- 0.8 mmol L(-1), P = 0.04) compared with diabetic controls (20.9 +/- 0.8 mmol L(-1)), whereas those after urapidil 6 mg kg(-1) were similar to diabetic controls. Insulin treatment normalized blood glucose concentrations. CONCLUSIONS: The alpha1-adrenoceptor antagonist/5-HT1A receptor agonist urapidil has no hyperglycaemic effect on experimental diabetes mellitus, even in high doses, despite its 5-HT1A receptor agonistic properties.

Adrenergic alpha-Antagonists↗
PubMed2002

Infant acute lymphoblastic leukemia - combined cytogenetic, immunophenotypical and molecular analysis of 77 cases.

We used karyotyping, fluorescence in situ hybridization (FISH), Southern blotting, and RT-PCR in order to analyze prospectively 77 infants (less than 1 year of age) with acute lymphoblastic leukemia for the occurrence of 11q23/MLL rearrangements and/or other cytogenetic abnormalities. Out of the 69 informative samples we found an 11q23/MLL rearrangement in 42 cases (61%). Regarding only pro-B ALL cases, the incidence of 11q23/MLL rearranged cases, however, reached more than 90% The infants were treated within the therapy studies ALL-BFM90, ALL-BFM95 and CoALL-05-92. For patients with an adequate follow-up of 4 years the event-free survival of the 11q23/MLL-positive and 11q23/MLL-negative group was 0.2 or 0.64, respectively (P = 0.024). The monoclonal antibody 7.1. (moab 7.1) does not react with normal hematopoetic precursors or mature blood cells but was shown to specifically react with leukemic cells bearing a rearrangement of chromosome 11q23 or the MLL gene, respectively. We, therefore, specifically addressed the question whether the reactivity of moab 7.1, as determined by flow cytometry, may substitute for molecular testing of an 11q23/MLL rearrangement in this cohort of infant ALLs. Reactivity of moab 7.1 indicated a 11q23/MLL rearrangement with a specificity of 100%. However, five of the 11q23/MLL-positive cases did not react with moab 7.1 indicating a sensitivity of 84% only. Three of these five moab 7.1-negative but 11q23/MLL-positive cases could be identified by their unique expression pattern of CD65s and/or CD15. Thus, 95% of all 11q23/MLL-positive ALL cases in infancy may be identified by flow cytometry based on their expression of CD15, CD65s and/or moab 7.1.

Antigens, CD↗
PubMed2001

Dielectric spectroscopy of Schizosaccharomyces pombe using electrorotation and electroorientation.

Two complementary AC electrokinetic techniques electrorotation (ER) and electroorientation (EO) enabled the dielectric characterization of the rod-shaped fission yeast Schizosaccharomyces pombe. The use of microstructured electrodes allowed both ER and EO measurements to be performed over wide ranges of field frequency and medium conductivity. Due to their layered structure, living S. pombe cells exhibited up to three well resolved peaks in their ER spectra and also two distinct orientations, i.e., parallel or perpendicular to the imposed linear field. Heat treatment and enzymatic protoplast isolation led to dramatic changes in the electrokinetic behavior of fission yeast. Application of the theoretical models linking the ER and EO spectra yielded the dielectric parameters of the major structural units of S. pombe cells (cell wall, plasma membrane and cytosol). The dielectric characterization of yeasts has an enormous impact in biotechnology and biomedicine, because electric field pulse techniques (electrofusion and electropermeabilization) are widely used for production of transgenic yeast strains of economic importance. The present study also showed that combined ER and EO measurements can be employed as a powerful diagnostic tool for analyzing changes in yeast structure and physiology upon exposure to various stress conditions.

Electric Conductivity↗
PubMed2001

Pathobiology of neuropathic pain.

This review deals with physiological and biological mechanisms of neuropathic pain, that is, pain induced by injury or disease of the nervous system. Animal models of neuropathic pain mostly use injury to a peripheral nerve, therefore, our focus is on results from nerve injury models. To make sure that the nerve injury models are related to pain, the behavior was assessed of animals following nerve injury, i.e. partial/total nerve transection/ligation or chronic nerve constriction. The following behaviors observed in such animals are considered to indicate pain: (a) autotomy, i.e. self-attack, assessed by counting the number of wounds implied, (b) hyperalgesia, i.e. strong withdrawal responses to a moderate heat stimulus, (c) allodynia, i.e. withdrawal in response to non-noxious tactile or cold stimuli. These behavioral parameters have been exploited to study the pharmacology and modulation of neuropathic pain. Nerve fibers develop abnormal ectopic excitability at or near the site of nerve injury. The mechanisms include unusual distributions of Na(+) channels, as well as abnormal responses to endogenous pain producing substances and cytokines such as tumor necrosis factor alpha (TNF-alpha). Persistent abnormal excitability of sensory nerve endings in a neuroma is considered a mechanism of stump pain after amputation. Any local nerve injury tends to spread to distant parts of the peripheral and central nervous system. This includes erratic mechano-sensitivity along the injured nerve including the cell bodies in the dorsal root ganglion (DRG) as well as ongoing activity in the dorsal horn. The spread of pathophysiology includes upregulation of nitric oxide synthase (NOS) in axotomized neurons, deafferentation hypersensitivity of spinal neurons following afferent cell death, long-term potentiation (LTP) of spinal synaptic transmission and attenuation of central pain inhibitory mechanisms. In particular, the efficacy of opioids at the spinal level is much decreased following nerve injury. Repeated or prolonged noxious stimulation and the persistent abnormal input following nerve injury activate a number of intracellular second messenger systems, implying phosphorylation by protein kinases, particularly protein kinase C (PKC). Intracellular signal cascades result in immediate early gene (IEG) induction which is considered as the overture of a widespread change in protein synthesis, a general basis for nervous system plasticity. Although these processes of increasing nervous system excitability may be considered as a strategy to compensate functional deficits following nerve injury, its by-product is widespread nervous system sensitization resulting in pain and hyperalgesia. An important sequela of nerve injury and other nervous system diseases such as virus attack is apoptosis of neurons in the peripheral and central nervous system. Apoptosis seems to induce neuronal sensitization and loss of inhibitory systems, and these irreversible processes might be in common to nervous system damage by brain trauma or ischemia as well as neuropathic pain. The cellular pathobiology including apoptosis suggests future strategies against neuropathic pain that emphasize preventive aspects.

Animals↗
PubMed2001

Effects of the opioid remifentanil on olfactory function in healthy volunteers.

The effects of opioids on human subjective olfactory function have rarely been investigated. This is despite the fact that opioid receptors are widely distributed throughout the olfactory systems. Using an established validated test of subjective olfactory function, olfactory threshold, odor discrimination and odor identification performance were tested in 16 healthy volunteers before opioid administration and at steady state after 3 hours remifentanil infusion. Each one man and one women were assigned randomly to one out of eight predefined remifentanil target plasma concentrations: 0, 1.2, 1.8, 2.4, 3, 3.6, 4.8, and 6 ng/ml. In the thirteen subjects that had completed the tests, olfactory thresholds were elevated with increasing remifentanil dose, and this correlated statistically significant with the remifentanil dose. Remifentanil plasma concentrations were linearly related to changes in olfactory thresholds. In contrast, effects of remifentanil on odor discrimination and identification were not statistically significant. However, remifentanil target plasma concentrations were also significantly correlated with the subjects' ratings of tiredness and drowsiness, although only drowsiness was significantly correlated with the differences in odor thresholds. We conclude that opioid administration leads to impaired olfactory function expressed in raised olfactory thresholds. This is compatible with previously reported opioidergic effects at the level of the olfactory bulb.

Adult↗