1H and 31P magnetic resonance spectroscopy of the brain in degenerative cerebral disorders.

Proton and phosphorus magnetic resonance spectroscopy of the brain was performed in 35 patients with degenerative cerebral disorders: 24 patients had demyelinating (white matter) disorders and 11 patients had neuronal (gray matter) disorders. Four grades of demyelination and three grades of cerebral atrophy were distinguished by magnetic resonance imaging criteria. The spectroscopic data were compared with normal values previously obtained. With increasing degrees of demyelination, lower ratios of phosphodiesters to beta-ATP were found. This trend was statistically significant. Decreased phosphodiester-beta-ATP ratios occurred simultaneously with imaging abnormalities. The decrease in phosphodiester-beta-ATP ratio in demyelinated areas is attributed to white matter rarefaction. Increasing cerebral atrophy was accompanied by lower ratios of N-acetyl aspartate to creatine. This trend was statistically significant. The decrease in the N-acetyl aspartate-creatine ratio was demonstrated before the magnetic resonance images showed signs of cerebral atrophy in patients with neuronal disorders. As N-acetyl aspartate is located exclusively in neurons and their branches, a decrease of the N-acetyl aspartate-creatine ratio can be attributed to neuronal and axonal damage and loss.     

Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors

In the introductory section an overview is given of the strategies which have been proposed in the search for side-effect free antipsychotics. Special attention is paid to the role of predominant 5HT₂ receptor blockade over D₂ blockade. Whereas D₂ receptor blockade seems to be essential for the treatment of positive symptoms of schizophrenia, it also underlies the induction of extrapyramidal side effects (EPS). Predominant 5HT₂ receptor blockade may reduce the EPS liability and can ameliorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eight new antipsychotics that recently entered clinical trial, 5HT₂ and D₂ receptor binding affinity (K_i values) and the rank order in affinity for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the complete receptor binding profile (including 33 radioligand receptor binding and neurotransmitter uptake models) is reported. Furthermore, for a series of 120 compounds the relative affinity for D₂ receptors and D₃ receptors (a recently cloned new dopamine receptor subtype) is compared. Finally, original findings are reported for the new antipsychotic risperidone and for haloperidol and clozapine on the in vivo occupation of neurotransmitter receptors in various brain areas after systemic treatment of rats or guinea pigs. The receptor occupation by the drugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the test compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT₂ and D₂ receptor mediated effects. With risperidone a high degree of central 5HT₂ receptor occupation was achieved before other neurotransmitter receptors became occupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D₂ receptor-mediated effects was achieved at widely varying degrees of D₂ receptor occupancy, from just about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic effects may be achieved at a relatively low degree of D₂ receptor occupancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiation between the various D₂ receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patients.     

The role of life stress in fibromyalgia

This paper focuses on recent evidence of etiopathogenetic links between fibromyalgia and life stress. From an etiologic point of view, studies concerning the role of adverse life events, personality and lifestyle factors, post-traumatic stress, and negative childhood experiences are reviewed. From a pathogenetic point of view, neurobiologic links between stress and fibromyalgia symptoms, notably chronic pain and fatigue are highlighted. Finally, several method-ologic issues with regard to stress research on fibromyalgia, as well as the clinical relevance of the stress concept for fibromyalgia are discussed.     

Sensory deficits in mice hypomorphic for a mammalian homologue of unc-53

The migration of cells and the extension of cellular processes along pathways to their defined destinations are crucial in the development of higher organisms. Caenorhabditis elegans unc-53 plays an important role in cell migration and the outgrowth of cellular processes such as axons. To gain further insight into the biological function of unc53H2, a recently identified mammalian homologue of unc-53, we have generated mice carrying a mutation of unc53H2 and provide evidence that unc53H2 is involved in neuronal development and, more specifically, the development of different sensory systems. The unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation) which in case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve. We hypothesize that in analogy with its C. elegans homologue, unc53H2 may play a role in the processes of cellular outgrowth and migration.     

Toric phakic intraocular lens: European multicenter study

OBJECTIVE: To evaluate safety, efficacy, predictability, stability, complications, and patient satisfaction after implantation of Artisan toric phakic intraocular lenses (TPIOLs) for the correction of myopia or hyperopia with astigmatism. DESIGN: Prospective, nonrandomized, comparative (self-controlled) multicenter trial. PARTICIPANTS: Seventy eyes of 53 patients (mean, 35 years; range, 22-59 years) with preoperative spherical equivalent between +6.50 and -21.25 diopters (D) and cylinder between 1.50 and 7.25 D. METHODS: Seventy eyes underwent implantation of a TPIOL with an optical zone of 5.0 mm (Artisan, Ophtec, Groningen, The Netherlands). The dioptric power of the intraocular lens was calculated by considering refraction, keratometry, and anterior chamber depth. The follow-up was 6 months in all cases. Lenses were available in powers ranging from +12.0 D to -23.5 D (spherical equivalent) in 0.5-D increments, with additional cylinder from 1.0 D to 7.0 D, also in 0.5-D increments. MAIN OUTCOME MEASURES: The main parameters assessed were best spectacle-corrected visual acuity (BSCVA), uncorrected visual acuity (UCVA), refraction, endothelial cell count (ECC), intraocular pressure, slit-lamp biomicroscopy, indirect ophthalmoscopy, subjective complaints, and patient satisfaction. RESULTS: Eyes were divided into group A, myopia (n = 48), with an average preoperative spherical equivalent of -8.90 +/- 4.52 D, and group B, hyperopia (n = 22), with an average preoperative spherical equivalent of +3.25 +/- 1.98 D. No eyes in either group experienced a loss in BSCVA, and 46 eyes gained 1 or more lines of their preoperative BSCVA. In 62 eyes (88.6%), UCVA was 20/40 or better. There was a significant reduction in spherical errors and astigmatism in all cases after surgery. All eyes of both groups were within +/-1.00 D of target refraction, and 51 eyes (72.9%) were within +/-0.50 D of target refraction. There was a 4.5% mean total loss of ECC during the first 6 months. No serious complications were observed. Overall patient satisfaction was very high. CONCLUSIONS: Six-month clinical trial results demonstrate that implantation of the Artisan TPIOL safely, predictably, and effectively reduced or eliminated high ametropia and astigmatism with one procedure. The refractive effect was stable at 6 months after surgery.     

Iris-claw phakic intraocular lens for high myopia.

PURPOSE: To evaluate the efficacy, safety, predictability, and stability of implanting a polymethylmethacrylate (PMMA) phakic intraocular lens (PIOL) (the Artisan myopia lens) to correct high myopia. METHODS: An Artisan myopia lens was implanted in 78 consecutive eyes of 49 patients with preoperative myopia that ranged from -6.25 to -28.00 D. Mean patient age was 42.4 years. Mean follow-up was 10.7 months and all patients were followed for at least 6 months; 45 eyes had follow-up of 12 months, and 10 eyes had 24 months. The desired outcome was emmetropia in all eyes except for those eyes with preoperative myopia greater then -23.00 D. RESULTS: Fifty-three eyes (67.9%) had a postoperative refraction at the last follow-up examination within +/-1.00 D of emmetropia, and 39 eyes (50.0%) had a postoperative refraction +/- within 0.50 D of emmetropia. The postoperative refraction remained stable during the entire follow-up period. Mean spectacle-corrected visual acuity improved from 20/32 preoperatively to 20/25 postoperatively. Mean postoperative uncorrected visual acuity was 20/32. There was no significant change in endothelial cell density from baseline. We did not encounter major complications. CONCLUSION: Implantation of the Artisan myopia lens to correct high myopia resulted in a stable and fairly predictable refractive outcome. A significant endothelial cell change was not detected.