Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma.

BACKGROUND: Bronchial thermoplasty (BT) is a non-pharmacological intervention for severe asthma whose mechanism of action is not completely explained by a reduction of airway smooth muscle (ASM). In this study we analyzed the effect of BT on nerve fibers and inflammatory components in the bronchial mucosa at 1 year. METHODS: Endobronchial biopsies were obtained from 12 subjects (mean age 47 ± 11.3 years, 50% male) with severe asthma. Biopsies were performed at baseline (T0) and after 1 (T1), 2 (T2) and 12 (T12) months post-BT, and studied with immunocytochemistry and microscopy methods. Clinical data including Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores, exacerbations, hospitalizations, oral corticosteroids use were also collected at the same time points. RESULTS: A statistically significant reduction at T1, T2 and T12 of nerve fibers was observed in the submucosa and in ASM compared to T0. Among inflammatory cells, only CD68 showed significant changes at all time points. Improvement of all clinical outcomes was documented and persisted at the end of follow up. CONCLUSIONS: A reduction of nerve fibers in epithelium and in ASM occurs earlier and persists at one year after BT. We propose that nerve ablation may contribute to mediate the beneficial effects of BT in severe asthma. TRIAL REGISTRATION: Registered on April 2, 2013 at ClinicalTrials.gov Identifier: NCT01839591 .

Comparative in vitro study of the pro-apolipoprotein A-I to apolipoprotein A-I converting activity between normal and Tangier plasma.

We examined the ability of the plasma of a 52-yr-old male Tangier patient to effect the conversion of radiolabeled pro-apolipoprotein A-I (apo A-I), isolated from hepatoma cell culture media, into mature apo A-I. The conversion was assessed by amino-terminal sequence analysis, isoform patterns with two-dimensional gel electrophoresis, and a rapid assay based on the different solubilities of intact pro-apo A-I and its hexapeptide prosegment in 10% trichloroacetic acid. We found that the converting activity of Tangier plasma was comparable to that exhibited by control normolipidemic plasma and that in both cases pro-apo A-I was correctly processed at the Gln-Asp bond. After ultracentrifugal fractionation of Tangier plasma at d = 1.21 g/ml, the pro-apo A-I-to-mature apo A-I converting activity was mainly recovered in the middle fraction of d = 1.225 g/ml and was at least 10-fold more effective than the top and bottom fractions. In contrast, in normal plasma the activity was only present in the top and bottom fractions. It has been previously established that in Tangier plasma the pro-apo A-I/apo A-I ratio is significantly higher than normal (1 vs. 0.02). Our studies suggest that this abnormal ratio is not the result of a reduced converting enzyme activity and may relate to differences in turnover rates between Tangier and normal plasma apolipoproteins.

Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region.

Mutations in the ryanodine receptor type 1 (RYR1) gene are associated with Malignant Hyperthermia (MH) and Central Core Disease (CCD). We report here on the molecular analysis of the RYR1 gene in Italian families referred as potential cases of MH or in patients with CCD or multicore/minicore myopathy. Of a total of 20 individuals with mutations in the RYR1 gene, 14 were part of a group of 47 MH susceptible (MHS) patients, 4 of 34 individuals diagnosed as MH equivocal (MHE), and 2 were patients diagnosed with minicore myopathy and CCD, respectively. Mutations were found to segregate with the MHS or MHE phenotype within the families of the probands. A discordance between phenotype and genotype was observed in a family where a mutation detected in an MHS proband was also found in the father who had been diagnosed MH normal (MHN) at the IVCT. In addition to known mutations, seven novel mutations were found, five of which occurred in exons encoding the C-terminal region of RYR1. These results indicate that the C-terminal region of RYR1 represents an additional hot spot for mutations in patients with MH, similar to what has been reported for patients with CCD.

Precocious loss of physiological sleep in a case of Creutzfeldt Jakob disease: a serial polygraphic study.

Creutzfeldt-Jakob disease (CJD) is a prion-related subacute encephalopathy producing widespread neuronal degeneration and spongiform pathological changes, especially in the neocortex. Progressive dementia, motor signs and electroencephalographic (EEG) alterations characterize the full stage of the disease. A series of eight 24-hour polygraphic recordings were carried out in the last 3 months of life of a 68-year-old female patient affected by CJD that was confirmed neuropathologically. Genetic classification demonstrated this patient to have a sporadic form of the disease. The polygraphic recordings demonstrated three types of EEG findings, as follows: 1) sustained pseudoperiodic discharges (SPD), characterized by long-lasting diffuse sequences of slow sharp waves or di- or triphasic slow waves recurring at 0.5- to 1.5-second intervals; 2) discontinuous pseudoperiodic discharges (DPD), consisting of runs of pseudoperiodic discharges (PD)(phase A) cyclically replaced at about 1-minute intervals with semi-rhythmic theta-delta activities (phase B); 3) non-rapid eye movement (NREM) sleep-like pattern, with dominant 0.5- to 4-Hz activities, less rhythmic than the EEG of phase B. Only these three EEG patterns occurred spontaneously during the repeated polygraphic sessions. The NREM sleep-like pattern was found only in the first recording, whereas the following polygraphic sessions were occupied exclusively by SPD or by a DPD pattern. SPD was associated with either a relatively high level of vigilance (along the first three recordings) or a state of alert-appearing silent immobility (following the fourth recording). During DPD, the patient was unable to accomplish any voluntary movement and fluctuated between levels of greater arousal (phase A) and lesser arousal (phase B). Just as in stage 2 coma, the fluctuations between phases A and B of DPD were synchronous with phasic modifications of muscle activity and neurovegetative functions. In particular, reinforcement of muscle tone and myoclonic spasms coincided with phase A, whereas heart rate deceleration and respiratory pauses or decrease in flow were synchronous with phase B. As EEG evolved toward the disappearance of DPD and finally to flatness, the phase-locked coordination among arousal, somatic and vegetative activities was progressively impaired and was replaced with an uncontrolled exaggeration of cardiorespiratory activity. The genetic, neuropathological and polysomnographic differences between CJD and another prion disease, fatal familial insomnia, are discussed.

Clinical and molecular studies of 73 Italian families with autosomal dominant cerebellar ataxia type I: SCA1 and SCA2 are the most common genotypes.

We clinically and genetically evaluated 73 Italian families with autosomal dominant cerebellar ataxia (ADCA) type I. Spinocerebellar ataxia (SCA) type 1 was the most common genotype (SCA1), accounting for 41% of cases (30 families), SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. In SCA1 and SCA2 families there was a significant inverse correlation between expansion size and age at onset. Analysis of triplet repeat numbers in parent-offspring pairs showed greater meiotic instability, which was associated with an earlier onset of the disease in SCA2 families than in SCA1 families.

Creutzfeldt-Jakob disease presenting as Wernicke-Korsakoff syndrome.

A 47-year-old man began to suffer from progressive truncal ataxia and mental alterations typical of Wernicke-Korsakoff syndrome. He showed confusional state, hallucinations, delirium of jealousy and a serious impairment of recent memory. The symptomatology lasted 13 months, but only in the last weeks was it complicated by myoclonias. Triphasic pseudoperiodic sharp-waves characterized the EEG-recordings only in the final stage. Macroscopic examination of the brain showed marked atrophy of the mammillary bodies and superior vermis. However, the histological features were consistent with Creutzfeldt-Jakob disease (CJD) with focal accentuation of the changes in the latter structures. This case supports the hypothesis that CJD-changes begin focally in the CNS and, subsequently, spread along neuronal pathways, probably via central axons. Only in the final stage does the pathological process involve most parts of the gray matter. A focal accentuation of the CJD process in the cerebello-mammillo-thalamic system caused in this case a Wernicke-Korsakoff-like syndrome.

Tangier disease: central nervous system impairment in a case of syringomyelia-like syndrome.

A neuroradiological investigation of the central nervous system (CNS) in a case of Tangier disease presenting as a syringomyelia-like syndrome is reported. No syringomyelinic cavities were found. However, MRI showed cervical spinal cord atrophy and scattered foci of greater density with T2 weighted images in the white matter of the frontal, parietal and occipital lobes. Cerebral and cervical spinal cord involvement in the course of Tangier disease is now shown for the first time. The authors postulate that the MRI detected alterations are related to the underlying illness.

Panencephalopathic type of Creutzfeldt-Jakob disease with neuropathologic features similar to Pick's disease.

The panencephalopathic type of Creutzfeldt-Jakob disease is characterized by a serious degeneration of the white matter in addition to the other pathological features of the classic Creutzfeldt-Jakob disease. The clinical and neuropathological findings of a new case are described in a woman aged 62, who died after a year of illness. The brain appeared seriously affected by atrophy and white matter degeneration. Microscopically, it showed a marked cortical spongiosis, with gemistocytic astrogliosis and degeneration of the white matter of both hemispheres. Although a serious loss of nerve cells was evident, some residual neurons with a ballooned aspect were found in the fronto-temporal cortex. Other neurons presented argyrophilic inclusions similar to Pick bodies. By means of immunohistochemical techniques and monoclonal antineurofilaments antibodies some neurons with swollen cytoplasm and enlargement of the first tract of the neurites were detected in the basal layers of the frontal and temporal cortex. These abnormal features were due to the accumulation of phosphorylated 200 Kd neurofilaments. The relations between Creutzfeldt-Jakob and Pick's diseases are analyzed on the basis of the neuropathological findings. There is evidence from the immunohistochemical data of an interference in the axonal transport of neurofilaments.

Megalencephaly with formation of Rosenthal fibers in symmetric subependymal gliomatous proliferations: clinicopathologic report.

Clinical and neuropathologic observations are reported concerning a girl with retarded psychomotor development accompanied with a steady increase in the volume of the cranium and brain, tetraparesis, and a serious epileptic syndrome resulting in death at the age of 13 years. The neuropathologic study revealed a marked megalencephaly and the presence of two bilateral and symmetric areas of atypical glial proliferation, corresponding with the optostriatal groove, with endoventricular protrusion: in this region the histologic findings gave evidence of a tapetum of Rosenthal fibers. Discussion is focused on the observed neuropathologic aspects in relation to the various diagnostic hypotheses: Alexander's disease, primary megalencephaly associated with astrocytomas or reactive gliosis, or megalencephaly associated with subependymal hamartomas.

[Fabry's disease and familial lymphedema. Description of 2 cases]. / Malattia di Fabry e linfedema familiare. Descrizione di due casi.

Two cases of Fabry's disease (FD) with lymphedema of the lower limbs are reported. On the basis of lymphographic investigations showing lymphatic aplasia, the hypothesis of an inborn error in the development of the lymphatic system of the lower limbs--Familial Lymphedema--controlled by a gene associated with FD gene on the same chromosome, is suggested.

Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial.

BACKGROUND: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]). METHODS: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15). RESULTS: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009. CONCLUSIONS: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.

On the variability of the human flocculus and paraflocculus accessorius.

42 human cerebelli were examined macroscopically in order to ascertain the general morphological, conformation of the flocculus and accessory paraflocculus, as well as their variability. The flocculus had a mean number of 14.2 +/- 0.3 (s.e.) folia and 7.0 +/- 0.4 (s.e.) subfolia arranged in a rosette-like cluster of relatively constant shape. The coefficient of variability of the number of folia and subfolia was respectively 22.1% and 47.4%. The accessory paraflocculus had a mean number of 4.2 +/- 0.2 (s.e.) folia and 2.0 +/- 0.2 (s.e.) subfolia, with a variability coefficient of respectively 50.2% and 102.8% which was more than double that of the flocculus. In fact the conformation of the accessory paraflocculus varied from a single small flattened lamella to a rosette-like cluster of folia similar in shape and size to those of the flocculus. There was no correlation between the variability of the flocculus and accessory paraflocculus. The possible reason for this marked variability is discussed in the light of the phylogenetic evolution of the structures examined.

Recovery from herpes simplex encephalitis: selective impairment of specific semantic categories with neuroradiological correlation.

The clinical, neuropsychological and neuroradiological features of two patients affected by herpes simplex virus type 1 (HSV-1) encephalitis are described. An experimental study for the assessment of naming, recognition and description displayed in one patient a persistent significant impairment in naming living things. The other patient showed a failing "semantic memory" for the same categories, although a significant impairment emerged only for plants. In both patients, the late neuroradiological sequelae were localised mainly in the inferior and middle gyri of the left temporal lobe and in the left-side insula. In one patient, the right-side insula was also involved. The selective cerebral damage induced by HSV-1 is stressed and a correlation between the neuroradiological and neuropsychological findings is attempted. The stereotyped anatomical and neuropsychological changes lead to the belief that the virus may recognise, within the limbic system, particular cellular "strains" on the basis of their molecular specificity.

Acute confusional migraine attacks resolved by sleep: lack of significant abnormalities in post-ictal polysomnograms.

We observed acute confusional migraine (ACM) attacks in two adolescents, and in both cases the episodes ended when the patients fell asleep spontaneously. Laboratory and neuroradiologic examinations were unremarkable. The post-ictal polysomnograms displayed a regular quality and duration of the physiologic components of sleep. Random posterior slow waves occurred only during the nocturnal awakenings and REM periods. The observation that sleep may resolve migraine attacks is emphasized. ACM is characterized by peculiar and relatively quickly reversible clinical manifestations and EEG abnormalities. The lack of significant abnormalities in post-ictal polysomnograms corresponds to a functional integrity of the brainstem structures involved in the global organization of sleep and may represent a useful laboratory feature in the diagnosis of ACM.

Orthochromatic leukodystrophy with pigmented glial cells. An adult case with clinical-anatomical study.

The case history is reported of a woman who died at the age of 36, at the conclusion of 11 years progressive neurological and psychiatric symptomatology. The anatomical and histological examination demonstrated an orthochromatic leukodystrophy with pigmented glial cells. Attention is drawn to the difficulty of finding these cells, which serve to differentiate between the unusual and the "simple" form of the disease. In the reported patient the pigmented cells were found around the vessels and only in specific cerebral locations. It is emphasized that the form is extremely rare (this is the tenth case so far reported). The significance of whether the iron content should be considered as an incidental or necessary finding is discussed. Systematic research for pigmented casts of this kind is taken to be important for all brains presenting a diffuse sclerosis after a protracted clinical course, mainly in adult patients.

[Intracranial and spinal dermo-epidermoid tumours. Anatomoclinical study (author's transl)]. / Tumori dermo-epidermoidi cranio-spinali. Studio anatomo clinico di un caso.

The authors review the previous report of intracranial or spinal dermo-epidermoid tumours, in concern with both nosographical and biological problems. They report their clinical and anatomical findings on a patient who presented the same tumours within the skull and in the vertebral canal. The authors underscore the rarity of such finding, the length of the course. albeit a few symptoms and no positive neuroradiological findings had been remarked, and the quite atypical eventual troubles.

Adult metachromatic leucodystrophy: clinicopathological report of two familial cases with slow course.

Two cases of adult metachromatic leucodystrophy in one family are reported. The main clinical features in both were predominantly psychiatric with alcoholism and an extremely long duration of the illness. Neuropathological examination revealed a similar distribution of the lesions in both, and scanty metachromatic accumulation in the CNS and not at all elsewhere. The great variability of the lengths of the courses is stressed. The duration in no way seems to be linked to the age of onset, except in the typical infantile form. The authors argue that different lengths of history correlate with distinct neuropathological findings, and may possibly be related to qualitative differences in the involved enzyme disturbance. Therefore, the authors suggest that the classification based on the age of onset be enlarged with a further one distinguishing between 'rapid' and 'slow' course types.

Anderson-Fabry's disease: neuropathological and neurochemical investigation.

A clinical, neuropathological and neurochemical study of a case of Anderson-Fabry's disease is described. The clinical course mainly consisted of repeated ictus with major involvement of the CNS. The neuropathological examination is dominated by severe alterations in the cerebral vessels due to glycolipid deposits on the walls, with reduction or occlusion of the lumen. This is correlated with secondary ischaemic foci scattered throughout the cortex as well as through the white matter. In addition, the cells of the cerebral cortex, thalamus, basal ganglia, amygdala, cerebellar and olivary nuclei show a marked accumulation of lipofuscin. Biochemical examination reveals a threefold increase in galactolipids due to the specific alpha-galactosidase deficiency. Cholesterol is reduced secondarily to ischaemic myelin damage. Glycosaminoglycans uronic acid is increased in cytosol and membrane-bound fractions which could be related to reactive gliosis. Glycoprotein sugars show a decrease in N-acetyl-neuraminic acid and fucose as well as an increase in hexosamines and hexoses in membrane-bound fraction, while in cytosol fraction all sugars are increased. This suggests that the alpha-galactosidase deficiency can alter not only the glycolipid but also the glycoprotein metabolism, resulting in a higher presence of hexosamines and hexoses-rich glycoproteins.