Noninvasive laser therapy for outpatients with chronic inflammatory disorders of cervix.

UNLABELLED: Chronic inflammation of the cervix can develop cervical stenosis with infertility and cervical congestion is related with the cervical cancer. We create a review of main etiological agents and methods of screening and diagnosis. We also make a brief review of modern therapeutic approach. CONCLUSIONS: We follow the utility of LLLT through the following aspects: evolution, indications, results of Babes-Papanicolau screening, cytology, clinical aspects. The results of the study will allow the complex system of treatment to be used in a large category of women. We appreciate that the procedure (used in our center also) will decrease the cervical pathology, the morbidity inside the treatment, the mortality through the evolution of cervical cancer. We propose the applicability for outpatients first and then as an integrated treatment method inside hospitals for a wide access.

Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias.

BACKGROUND: The aims of the present study were: i) to measure levels of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA) and precursor tryptophan, as well as the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and thiamine in the cerebrospinal fluid (CSF) of patients with Friedreich's ataxia (FA), olivopontocerebellar atrophy (OPCA), and the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSAC), as compared with sex- and age-matched control subjects. PATIENTS AND METHODS: CSF amine related compound levels and thiamine results were compared in 40 FA, 44 OPCA and nine ARSAC patients with those of 94 sex- and age-matched subjects. Neuroimaging (CT scans and single photon emission computed tomographies i.e. SPECT) were carried out in all patients and controls. Genetic studies were conducted on OPCA patients. CSF amine related compounds were measured by high performance liquid chromatography, whereas CSF thiamine levels were measured by a microbiological method. RESULTS: FA patients had significantly lower CSF HVA, 5HIAA and thiamine values than control patients and a trend for lower MHPG levels. In OPCA patients, CSF HVA, MHPG and thiamine values were markedly lower whereas CSF 5HIAA values showed only a trend towards lower levels; in ARSAC patients only thiamine and HVA CSF values were lower than those in control subjects. CONCLUSION: After presenting the relationships between neurochemical findings on one side, the degree of ataxia, the degree of cerebellar atrophy and the SPECT findings on the other, the authors concluded that replacement and neuroprotective clinical trials in these patients would have to include two or three drugs because the neurotransmitter deficiencies are multiple.

A severe frontal-parietal lobe syndrome following cerebellar damage.

We report a case study of a frontal and parietal lobe syndrome with memory loss after unilateral left-sided cerebellar damage caused by a stroke in a patient with right cerebellar unusual developmental agenesis. The syndrome consisted of severe deficits in planning an organized sequence of events, in visuo-constructive abilities and inappropriate jocularity. These changes are ascribed in part to cerebellar-pontine lesions with resulting frontal lobe diaschisis as documented by single-photon emission computed tomography in the absence of morphological damage to the neocortex.

Central serotonin system in Dystonia musculorum mutant mice: biochemical, autoradiographic and immunocytochemical data.

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways that lead to ataxia. To investigate possible changes in the central serotonin system of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-tryptamine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain regions and the spinal cord of wild type and dt(J)/dt(J) mutant mice. Also, 5-HT transporters were quantified by [(3)H]citalopram autoradiography in 72 brain regions, subregions, and nuclei, and the 5-HT innervation visualized by immunocytochemistry throughout the brain and spinal cord. In all brain regions measured for indoleamine content, there were no significant differences between the two genotypes. In the spinal cord, an increased tissue concentration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytryptophol (+21%), and 5-hydroxytryptophan (+45%) in dt(J)/dt(J) actually corresponded to the same total amount of each of these indoleamines in the entire spinal cord, when taking into account its reduced size in the mutants. Quantification of the binding to 5-HT transporters showed increases in the medial geniculate nucleus (+14%), medial (+24%) and lateral (+18%) hypothalamus, interpeduncular (+13%), vestibular (+22%), and deep cerebellar nuclei (+37%) of dt(J)/dt mice, and decreases in the ventral tegmental area (-13%), median and linear raphe nuclei (-20%), as well as in the solitary complex (-35%). There were no apparent differences in the distribution of 5-HT-immunostained fibers in these and other regions of brain and in the spinal cord of dt(J)/dt(J) compared to wild type mice. The bulk of these results indicates a relative sparing of the central 5-HT system in the dt(J)/dt(J) mice, even though alterations in 5-HT transporters could justify attempts at improving the sensorimotor dysfunction by administration of serotoninergic agents in these mice.

Amantadine hydrochloride treatment in olivopontocerebellar atrophy: a long-term follow-up study.

The efficacy of amantadine, a dopamine-releasing agent and antagonist of the N-methyl-D-aspartate glutamate receptor, was evaluated in patients with olivopontocerebellar atrophy. By contrast to an untreated control group whose terminal performance deteriorated on 8 of 8 measurements of reaction time and movement time, patients treated with amantadine for a mean duration of over 40 months had improved performances in 1 of 4 reaction time measurements and in 3 of 4 movement time measurements and remained stable on the others. These results demonstrate long-term benefits of amantadine in olivopontocerebellar atrophy-induced deficits of movement initiation and movement completion.

Serotonin innervation of Lurcher mutant mice: basic data and manipulation with a combination of amantadine, thiamine and L-tryptophan.

The Lurcher (Lc/+) mutant mouse is characterized by a considerable atrophy of the cerebellum due to a massive loss of cerebellar Purkinje and granule cells, as well as of neurons from the inferior olivary nucleus. In this study the effects of a therapeutic combination of amantadine, thiamine and L-tryptophan on the serotonin (5-HT) innervation was assessed in Lurcher mice by autoradiography, using [3H]citalopram to label 5-HT transporters. In wild type mice as well as in both saline-treated and drug-treated Lurcher mutants, [3H]citalopram binding remained unchanged in forebrain and brainstem regions. In the cerebellum, labelling of deep cerebellar nuclei (CBnuc) was about twofold higher than in the cortex (CBctx). In saline-treated Lurcher mutants compared to wild type mice, the densities of [3H]citalopram were 98% higher in CBctx, and 180% higher in CBnuc. In CBctx of drug-treated Lurcher mutants, transporter densities were 89% higher than in the wild type, but did not differ from the saline-treated Lurcher. In the CBnuc of the drug-treated Lurcher mutants, [3H]citalopram binding was 50% higher than in the saline-treated Lurcher group, and 320% higher than in wild type mice. The results show that 5-HT transporters, already upregulated in the CBnuc of Lurcher mutant mice, can be further increased by a pharmacological treatment, possibly altering the availability of 5-HT in some of its target areas.

The treatment of spinocerebellar ataxias: facts and hypotheses.

Actual therapeutic assays in spinocerebellar ataxias, i.e. in Friedreich's ataxia (FA) and olivopontocerebellar atrophy (OPCA) are discussed in relation to (i) the serotoninergic theory; (ii) the excitotoxic action of glutamate; and (iii) cerebrospinal fluid thiamine deficiency in ataxic patients. Data from the literature show that neurochemical deficiencies arising from cerebellar damage in both FA and OPCA patients are multiple. Assays of replacement and neuroprotective therapeutics with a single drug have produced controversial data or mildly effective results. Consequently, it is hypothesized that a drug cocktail, i.e. L-5-hydroxytryptophan, thiamine and amantadine hydrochloride, would be more beneficial. This cocktail proved to be useful in open studies, improving respiratory disorders in FA patients. More powerful inhibitors of N-methyl-D aspartate receptor channels should be tried initially in animal experiments.

Regional distribution of 5-HT transporters in the brain of wild type and 'Purkinje cell degeneration' mutant mice: a quantitative autoradiographic study with [3H]citalopram.

The neurological mutant 'Purkinje cell degeneration' (pcd) is characterized by a primary degeneration of Purkinje cells, as well as by retrograde and secondary partial degeneration of cerebellar granule cells and inferior olivary neurons, and can be considered as an animal model of human degenerative ataxias. The serotonin (5-HT) innervation was examined in wild type and pcd mice, by quantifying 5-HT uptake sites, or transporters, using [3H]citalopram binding autoradiography. In both wild type and pcd mutants, the highest densities of 5-HT transporters were in mesencephalic and rostral pontine regions, in limbic structures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling was found in cerebellum and brainstem reticular formation. In pcd mice, although [3H]citalopram labelling was higher in cerebellar cortex and deep cerebellar nuclei, when binding densities were corrected for surface area, the up-regulation of 5-HT transporters was present only in deep cerebellar nuclei. Also, higher labelling was found in nuclei raphe dorsalis and medialis, in ventral divisions of rostral neostriatum, caudal neostriatum, rostral globus pallidus, posteromedial amygdaloid nucleus, septum, olfactory tubercles, vertical limb of Broca's diagonal band, periventricular, latero-ventral and medio-ventral thalamic nuclei, medial geniculate nucleus, anterior hypothalamus and entorhinal cortex. The results indicate a relative integrity of the 5-HT innervation, but with a reorganization of serotoninergic terminals in the cerebellum, in particular in the deep cerebellar nuclei. This suggests that in progressive cerebellar degeneration, as found in the pcd mutant, the modified 5-HT system may still participate in motor functions by exerting an overall modulation of excitatory amino acid neurotransmission, but the availability of 5-HT may be altered in defined brain targets, as is the case for other spontaneous cerebellar mutants, in particular for the 'Lurcher' mutant mouse, a model of human olivopontocerebellar atrophy.

Brain dopamine and amino acid concentrations in Lurcher mutant mice.

Lurcher mutant mice are characterized by massive degeneration of the cerebellum, including Purkinje cells and granule cells, as well as for the loss of neurons from the inferior olive. Concentrations of dopamine and two of its metabolites and of several amino acid neurotransmitters were determined in the cerebellum and in other brain regions of these mutants. By comparison to wild-type mice of the same background strain, glutamate and taurine concentrations were reduced in the Lurcher cerebellum. No decrease was found for aspartate, gamma-aminobutyric acid (GABA), glycine, as well as dopamine and its metabolites. Moreover, no neurochemical alterations occurred in the brain stem, thalamus, or neostriatum of Lurcher mutants. A selective reduction of glutamate concentration was found in the hippocampus, while all amino acids measured were decreased in the entorhinal-piriform areas. These results indicate region-selective reductions of neurotransmitter concentrations in a mouse mutant with a defined cerebellar cortical pathology.

Diaschisis and neurobehavior.

We review forms of diaschisis and their relationship with neurobehavioral and neuropsychological findings. The following forms of diaschisis are discussed: (1) cortico-cerebellar diaschisis; (2) cerebello-cortical diaschisis; (3) transhemispheric diaschisis; (4) cortico-thalamic diaschisis; (5) thalamo-cortical diaschisis; and (6) basal ganglia-cortical diaschisis. For each form, the neurobehavioral and neuropsychological findings are discussed. Diaschisis can be classified from the behavioral point of view as follows: (1) forms in which the metabolic effect at distance is not followed by neurobehavioral impairment; (2) forms in which the remote metabolic impairment could induce neurobehavioral and neuropsychological disorders; and (3) forms in which the role of the lesion itself and its remote metabolic effects on the production of neurobehavioral and neuropsychological abnormalities cannot be disentangled.

Distribution of dopamine transporters in basal ganglia of cerebellar ataxic mice by [125I]RTI-121 quantitative autoradiography.

Dopamine (DA) uptake sites, or transporters, were examined with [125I]RTI-121 in mutant mice that exhibit motor control deficits, namely weaver, lurcher and dystonia musculorum. In lurcher mice, the distribution of [125I]RTI-121 binding was similar to controls, except for a decrease in the subthalamic nucleus. For dystonia musculorum mice, the labelling presented no differences between controls and mutants, except for decreases in the dorsal half of caudal neostriatum and in the ventral tegmental area. Moreover, in this mutant the left rostral neostriatum DA transporters were reduced, when compared to the right counterpart. In weaver heterozygote (wv/+) mice, the distribution and density gradients of [125I]RTI-121 labelling were similar as in their controls, except in caudal neostriatum, where binding was slightly higher. In contrast, the weaver homozygote (wv/wv) showed important decreases in labelling of the dorsal quadrant of rostral neostriatum as well as of the dorsal half of caudal neostriatum, where the reductions of binding densities were of 65% to 70%, respectively. There were also slight decreases in [125I]RTI-121 binding in olfactory tubercles as well as in subthalamic nucleus, but only in wv/wv mice. In substantia nigra pars compacta and ventral tegmental area of wv/wv mice the labelling was lower; however, while the 60% decrease in labelling in substantia nigra was highly significant, the 30% reduction in ventral tegmental area did not attain statistical significance. In summary, in the ataxic neurological mutant mice studied, important reductions of DA transporters were documented only for the weaver mice, the cerebellar mutant presenting, besides its cerebellar pathology, a known degeneration of mesencephalic dopaminergic neurons. The results rule out major alterations of the central DA systems in lurcher and dystonia musculorum, and are compatible with the hypothesis that the dopaminergic abnormalities of weaver mutants are not secondary to cerebellar atrophy, but may be a direct consequence of the abnormal weaver gene expressed by DA neurons leading to their apoptotic death.

Can we treat respiratory failure in Friedreich ataxia?

BACKGROUND: Neurochemical disorders associated with spinocerebellar ataxias are multiple. OBJECTIVE: To use replacement and neuroprotective therapy in a case of severe respiratory failure in Friedreich ataxia. PATIENT AND TREATMENT: A 44-year-old man with severe Friedreich ataxia displayed arduous periodic breathing associated with minor desaturation as well as obstructive or mixed apneas associated with severe desaturation during the night. He was given oxitriptan (5-hydroxy-L-tryptophan) (1500 mg/d), thiamine hydrochloride (100 mg/d), and amantadine hydrochloride (100 mg/d). The first sleep study was conducted during the night before treatment, whereas the second was performed during the night after 9 months of treatment. RESULTS: After treatment, striking clinical improvement of spastic dysphonia was accompanied by significant diminution in the time spent in periodic breathing and in the number of obstructive and mixed apneas during the night. Controlled studies are needed.

Olivopontocerebellar atrophy and Friedreich's ataxia: neuropsychological consequences of bilateral versus unilateral cerebellar lesions.

This chapter deals with neuropsychological disturbances in patients with bilateral cerebellar damage (BCD), i.e., epileptic patients chronically receiving phenytoin, patients with olivopontocerebellar atrophy (OPCA), and Friedreich's ataxia (FA) versus those with unilateral cerebellar damage (UCD), i.e., patients with cerebellar strokes. BCD patients showed: (i) impaired executive functions in planning and programming of daily activities, elaborating and using structures, and difficulty in abstract thinking, functions that are related to cerebello-frontal loops; (ii) deficits in visuospatial organization for a concrete task and deficient visual-spatial working memory, functions related to cerebello-parietal loops; (iii) lower general intellectual abilities than controls (especially those with OPCA); (iv) difficulties with memory retrieval, diminished global memory quotient, and reduced spatial working memory ability; and (v) slower speed of information processing, as measured by simple and multiple choice reaction time (RT). In UCD patients, neuropsychological and neurobehavioral abilities were deficient for 2-5 months; after this time period, their performances returned to normal. In both BCD and UCD patients, single photon emission computed tomography (SPECT) studies showed different degrees of "reverse" cerebellar-->basal ganglia-->frontoparietal diaschisis which may underlie permanent or transitory neuropsychological deficits. The relationships among neuropsychological findings, SPECT studies, and chemical neuroanatomy are discussed.

Amantadine hydrochloride treatment in heredodegenerative ataxias: a double blind study.

OBJECTIVE: A group of 27 patients with Friedreich's ataxia and another group of 30 patients with olivopontocerebellar atrophies were each randomly divided into two subgroups, one receiving placebo and the other amantadine hydrochloride (AH; 200 mg daily) for three to four months. METHODS: The effect of double blind treatment was evaluated by simple visual and auditory reaction time (RT) and movement time (MT) for both right and left hands. RESULTS: The subgroup with olivopontocerebellar atrophies receiving AH showed significant improvement on seven out of eight variables studied by analysis of covariance. In patients with Friedreich's ataxia, improvement was definitely less. Treatment remained contraindicated for those with cardiomyopathies or drug intolerance. CONCLUSION: The rationale of AH use in heredodegenerative ataxias can be explained by its replacement effect (dopamine release) and by direct involvement of N-methyl-D-aspartate (NMDA) in glutamate mediated neurotoxicity in cerebellar granular cells; memantine, an AH analogue, is a potent blocker of NMDA receptors.

Regional distribution of the 5-HT innervation in the brain of normal and lurcher mice as revealed by [3H]citalopram quantitative autoradiography.

The neurological cerebellar mutant lurcher is characterized by a primary degeneration of Purkinje cells as well as retrograde secondary partial degeneration of cerebellar granule cells and inferior olivary neurons. Since serotonin (5-HT) has been implicated in the modulation of excitatory amino acid systems of the cerebellum, the 5-HT innervation of the normal and lurcher mice was examined by quantifying uptake sites using [3H]citalopram autoradiography, and by biochemical assays of the indoles 5-HT, 5-hydroxy-L-tryptophan and 5-hydroxyindole-3-acetic acid using high-performance liquid chromatography. Comparable results were found between [3H]citalopram binding and 5-HT tissue concentrations in different brain regions. The highest [3H]citaslopram labelling was observed in defined structures of the mesencephalic and upper pontine regions, in limbic strutures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling of uptake sites was documented in cerebellum and brainstem reticular formation. In lurcher mutants, the histology confirmed cell degeneration and the reduction in width, leading to 65%, 45% and 25% atrophies of total cerebellum, deep nuclei and inferior olivary nucleus, respectively. The [3H]citalopram labelling corrected for surface loss was 45% and 20% higher to cerebellar deep nuclei and red nucleus, respectively, but remained unchanged in the cerebellar cortex and inferior olivary nucleus. Moreover, higher labelling was found in nucleus raphe dorsalis, ventral tegmental area, inferior colliculus, locus coeruleus, pontine central grey and anterior thalamic nuclei, areas known to be part of cerebellar afferent and efferent systems. The present results indicate that in such pathological conditions as described for the lurcher mutant, the 5-HT system may modulate motor function not only at the level of the cerebellum, but also in other forebrain structures functionally related to the motor system.

Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients.

The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.

Effects of an ectodermal microceptor preparation on motor coordination in cerebellar mutant mice.

Lurcher mutant mice, characterized by degeneration of the olivocerebellar system, and dystonia musculorum (dt) mutant mice, characterized by degeneration of spinocerebellar fibers, were treated with an ectodermal microceptor preparation (EMP), a compound containing natural substances derived from embryonic bovine ectodermal tissue, or with placebo, and evaluated in motor coordination tests. EMP-treated lurchers, but not dt mutants, were quicker to initiate movement than placebo-treated controls in the inclined beam test. No group differences were found in terms of distance travelled on the beam or in motor coordination assessed in a more challenging coat-hanger test. These results indicate that ectodermal microceptors may improve movement initiation of cerebellar-related disorders in animals, but that these effects are test and disease-specific.

Neuropsychological functioning in unilateral cerebellar damage.

A woman had a left superior cerebellar artery infarct associated with reduced hexamethylpropileneamine oxime uptake on SPECT scan of the basal ganglia and frontoparietal areas of the opposite hemisphere performed poorly in some neuropsychological tests indicating right hemisphere dysfunction. There was a lengthening of reaction and movement times with the hand ipsilateral to the lesion. These deficits were temporary. A unilateral cerebellar lesion can produce neuropsychological deficits, possibly because of hypoperfusion in contralateral frontoparietal regions, but spontaneous neuropsychological remissions may occur.

Exploration and motor coordination in dystonia musculorum mutant mice.

Dystonia musculorum (dt) mutant mice, characterized by degeneration of spinocerebellar tracts, were impaired in terms of horizontal and vertical motor activity, hole poking, exploration, and motor coordination. In tests of motor coordination, their deficits were more severe than those of previously tested mutant mice with degeneration of cerebellar cells. However, unlike other cerebellar mutants, dt mutants alternated above chance levels in a two-trial spontaneous alternation test, which is a test of inhibitory tendencies and spatial orientation, and so dt mutants may not be impaired in these functions.