Prevalence of small intestinal bacterial overgrowth in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with gastrointestinal motility abnormalities that could favor the occurrence of small intestinal bacterial overgrowth. The aim of the study was to assess the prevalence of small intestinal bacterial overgrowth in PD patients. METHODS: Consecutive PD patients were enrolled. The controls were subjects without PD. All patients and controls underwent the glucose breath test to assess small intestinal bacterial overgrowth. RESULTS: Forty-eight PD patients and 36 controls were enrolled. The prevalence of small intestinal bacterial overgrowth was significantly higher in PD patients than in controls (54.17% vs 8.33%; P < .0001; OR, 2.24; 95% CI, 3.50-48.24). Multivariate analysis showed Hoehn and Yahr stage (OR, 3.07; 95% CI, 1.14-8.27) and Unified PD Rating score (OR, 1.12; 95% CI, 1.02-1.23) were significantly associated with small intestinal bacterial overgrowth in PD patients. CONCLUSIONS: Small intestinal bacterial overgrowth is highly prevalent in PD. Gastrointestinal motility abnormalities might explain this association.

Cephalometric findings in facioscapulohumeral muscular dystrophy patients with obstructive sleep apneas.

PURPOSES: The purposes of the study are: (1) to establish if cephalometry and upper airway examination may provide tools for detecting facioscapulohumeral (FSHD) patients at risk for obstructive sleep apnea syndrome (OSAS); and (2) to correlate cephalometry and otorhinolaryngologic evaluation with clinical and polysomnographic features of FHSD patients with OSAS. METHODS: Patients were 13 adults affected by genetically confirmed FSHD and OSAS, 11 men, with mean age 47.1 ± 12.8 years (range, 33-72 years). All underwent clinical evaluation, Manual Muscle Test, Clinical Severity Scale for FSHD, Epworth Sleepiness Scale, polysomnography, otorhinolaryngologic evaluation, and cephalometry. RESULTS: Cephalometric evidence of pharyngeal narrowing [posterior airways space (PAS) < 10 mm] was present in only one patient. The mandibular planus and hyoid (MP-H) distance ranged from 6.5 to 33.1 mm (mean, 17.5 ± 7.8 mm). The mean length of soft palate (PNS-P) was 31.9 ± 4.8 mm (range, 22.2 to 39.7 mm). No patient presented an ANB angle > 7°. There was no significant correlation between cephalometric measures, clinical scores, and PSG indexes. PAS and MP-H were not related to the severity of the disease. CONCLUSIONS: Upper airway morphological evaluation is of poor utility in the clinical assessment of FSHD patients and do not allow to predict the occurrence of sleep-related upper airway obstruction. This suggests that the pathogenesis of OSAS in FSHD is dependent on the muscular impairment, rather than to the anatomy of upper airways.

Long-term motor cortex stimulation for amyotrophic lateral sclerosis.

BACKGROUND: Motor cortex stimulation has been proposed for treatment of amyotrophic lateral sclerosis (ALS) and preliminary studies have reported a slight reduction of disease progression using both invasive and noninvasive repetitive stimulation of the motor cortex. OBJECTIVE: The aim of this proof of principle study was to investigate the effects of motor cortex stimulation performed for a prolonged period (about 2 years) on ALS progression. METHODS: Two patients were included in the study; the first patient was treated with monthly cycles of repetitive transcranial magnetic stimulation (rTMS) and the second one was treated with chronic epidural motor cortex stimulation. The rate of progression of the disease before and during treatment was compared. RESULTS: The treatments were well tolerated by the patients. Both patients deteriorated during treatment; however, the patient treated with rTMS showed a slight reduction in deterioration rate. CONCLUSIONS: Although we cannot be sure whether the effects observed in the patient treated with rTMS can be attributed to this form of stimulation, our study set the groundwork for possible future studies investigating the effects of rTMS, for a prolonged period, on a larger group of ALS patients.

Decreased nocturnal movements in patients with facioscapulohumeral muscular dystrophy.

STUDY OBJECTIVES: Reduced mobility during sleep characterizes a variety of movement disorders and neuromuscular diseases. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy in the general population, and people with FSHD have poor sleep quality. The aims of the present study were to evaluate nocturnal motor activity in patients with FSHD by means of videopolysomnography and to verify whether activity was associated with modifications in sleep structure. METHODS: We enrolled 32 adult patients affected by genetically confirmed FSHD (18 women and 14 men, mean age 45.1 +/- 13.4 years) and 32 matched control subjects, (18 women and 14 men, mean age 45.5 +/- 11.4 years). Major body movements (MBM) were scored in videopolygraphic recordings in accordance with established criteria. An MBM index was calculated (number of MBM per hour of sleep). RESULTS: The FSHD group showed a decrease in the MBM index (FSHD: 1.2 +/- 1.1; control subjects: 2.3 +/- 1.2, analysis of variance F = 13.672; p = 0.008). The sleep pattern of patients with FSHD, as compared with that of controls, was characterized by longer sleep latencies, shorter sleep durations, an increased percentage of wake during sleep, and a decreased percentage of rapid eye movement sleep. In the patient group, the MBM index was inversely correlated with severity of disease (Spearman test: r30 = -0.387; p < 0.05). CONCLUSIONS: The present findings suggest that patients with FSHD have a reduced number of nocturnal movements, which is related to disease severity. Reduced movement in bed may contribute to the sleep modifications observed in these patients.

CD8(+)Foxp3(+) T cells in peripheral blood of relapsing-remitting multiple sclerosis patients.

A defect of CD4(+) regulatory T cells (Treg) seems to be involved in the pathogenesis of multiple sclerosis (MS). Besides Treg, CD8(+) T cells also can suppress the immune response. Forkhead box p3 (Foxp3) is known to program the acquisition of suppressive capacities in CD4(+) T cells and recent studies showed that in vitro antigen activation leads to Foxp3 expression in CD8(+) T cells, gaining of suppressive activity. By flow cytometry we found a lower percentage of circulating CD8(+)Foxp3(+) T cells in relapsing than in remitting patients with MS and in controls. No significant differences were observed in CD8(+)Foxp3(+) T cell percentage between healthy subjects and patients in remission. Our data suggest that peripheral CD8(+)Foxp3(+) T cells may play a role in the maintenance of tolerance in MS.

Increased aging in primary muscle cultures of sporadic inclusion-body myositis.

Ageing is thought to participate to the pathogenesis of sporadic inclusion-body myositis (s-IBM). Although the regenerative potential of s-IBM muscle is reduced in vivo, age-related abnormalities of satellite cells possibly accounting for the decline of muscle repair have not been demonstrated. Here we show that proliferation rate and clonogenicity of s-IBM myoblasts are significantly lower and doubling time is longer than normal age-matched controls, indicating that proliferative capacity of s-IBM muscles becomes exhausted earlier. Telomere shortening is detected in s-IBM cells suggesting premature senescence. Differently from controls, s-IBM myoblasts show increased active beta-catenin mainly localized within myonuclei, indicating active Wnt stimulation. After many rounds of muscle growth, only s-IBM myoblasts accumulate congophilic inclusions and immunoreactive Abeta(1-40) deposits. Therefore, s-IBM myoblasts seem to have a constitutively impaired regenerative capacity and the intrinsic property, upon sufficient aging in vitro, to accumulate Abeta. Our results might be valuable in understanding molecular mechanisms associated with muscle aging underlying the defective regeneration of s-IBM muscle and provide new clues for future therapeutic strategies.

Motor cortex stimulation for ALS: a double blind placebo-controlled study.

Preliminary data suggest that repetitive transcranial magnetic stimulation (rTMS) of the brain may produce a modest slowing of disease progression in amyotrophic lateral sclerosis (ALS). The present study was designed to test the hypothesis that rTMS given as continuous theta burst stimulation (cTBS), repeated monthly for one year, would affect ALS progression. We performed a double blind, placebo-controlled trial. Twenty patients with ALS were randomly allocated to blinded real or placebo stimulation. cTBS of the motor cortex was performed for five consecutive days every month for one year. Primary outcome was the rate of decline as evaluated with the revised ALS functional rating scale (ALSFRS-R). Treatment was well tolerated. There was no significant difference in the ALSFRS-R score deterioration between patients treated with real or placebo stimulation. ALSFRS-R mean scores declined from 32.0 (SD 7.1) at study entry to 23.1 (SD 6.3) at 12 months in patients receiving real cTBS and from 31.3 (SD 6.9) to 21.2 (SD 6.0) in those receiving placebo stimulation. Although cTBS proved a safe procedure, on the basis of the present findings a larger randomized confirmatory trial seems unjustified in ALS patients, at least in advanced stage of the disease.

Sleep disordered breathing in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent forms of muscular dystrophy. The aims of this study were: 1) to evaluate the prevalence of sleep disordered breathing (SDB) in patients with FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients with SDB; and 3) to find the clinical predictors of SDB. Fifty-one consecutive FSHD patients were enrolled, 23 women, mean age 45.7+/-12.3 years (range: 26-72). The diagnosis of FSHD was confirmed by genetic tests. All patients underwent medical and neurological evaluations, subjective evaluation of sleep and full-night laboratory-based polysomnography. Twenty patients presented SDB: 13 presented obstructive apneas, four presented REM related oxygen desaturations and three showed a mixed pattern. Three patients needed positive airways pressure. SDB was not related to the severity of the disease. Body mass index, neck circumference and daytime sleepiness did not allow prediction of SDB. In conclusion, the results suggest a high prevalence of SDB in patients with FSHD. The presence of SDB does not depend on the clinical severity of the disease. SDB is often asymptomatic, and no clinical or physical measure can reliably predict its occurrence. A screening of SDB should be included in the clinical assessment of FSHD.

Regulatory T cells fail to suppress CD4T+-bet+ T cells in relapsing multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and a defect in the regulatory T-cell subset seems to be involved in the pathogenesis of the disease. Foxp3 is a transcription factor that is selectively expressed in CD4+ CD25+ regulatory T cells and is required for their development and function. T-bet is a key transcription factor for the development of T helper 1 (Th1) cells. We found that both the percentage of circulating CD4+ CD25+ Foxp3+ cells and Foxp3 expression were lower in relapsing-remitting (RR) MS patients during relapses than during remission. Otherwise, the percentage of CD4+ T-bet+ T cells and T-bet expression in CD4+ T cells were higher in relapsing than in remitting RRMS patients. CD4+ CD25+ T cells both from relapsing and from remitting RRMS patients showed significantly less capacity than corresponding cells from healthy subjects to suppress autologous CD4+ CD25(-) T-cell proliferation, despite a similar Foxp3 expression level. CD4+ CD25+ T cells from healthy subjects and patients in remission clearly reduced T-bet mean fluorescence intensity (MFI) in CD4+ CD25(-) T cells up to a ratio of 1:10, whereas CD4+ CD25+ T cells from patients in relapse were able to reduce T-bet expression only at a high ratio. Our data indicate that the increased number of regulatory T (T-reg) cells and the increased Foxp3 expression in circulating CD4+ CD25+ T cells may contribute to the maintenance of tolerance in the remission phase of MS. Moreover, the inhibitory capacity of CD4+ CD25+ T cells seems to be impaired in relapsing patients under inflammatory conditions, as shown by the high levels of T-bet expression in CD4+ T cells.

Transient global amnesia during transoesophageal echocardiogram.

Transient global amnesia (TGA) is a common paroxysmal disorder of episodic memory. The aetiology of TGA is still unknown. Brain ischaemia, migraine, epileptic seizure, venous congestion and psychological disturbances have been proposed as pathological mechanisms. Moreover, different precipitating events are recognised in most TGA patients including physical activity, severe emotional stress, painful experiences, immersion in cold water and sexual intercourse. We describe a 54-year-old woman who presented a TGA immediately after right-left shunt of saline contrast during the execution of transoesophageal echocardiography. Aetiopathological considerations for this uncommon presentation are discussed.

Hyposialylation of neprilysin possibly affects its expression and enzymatic activity in hereditary inclusion-body myopathy muscle.

Autosomal recessive hereditary inclusion-body myopathy (h-IBM) is caused by mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene, a rate-limiting enzyme in the sialic acid metabolic pathway. Previous studies have demonstrated an abnormal sialylation of glycoproteins in h-IBM. h-IBM muscle shows the abnormal accumulation of proteins including amyloid-beta (Abeta). Neprilysin (NEP), a metallopeptidase that cleaves Abeta, is characterized by the presence of several N-glycosylation sites, and changes in these sugar moieties affect its stability and enzymatic activity. In the present study, we found that NEP is hyposialylated and its expression and enzymatic activity reduced in all h-IBM muscles analyzed. In vitro, the experimental removal of sialic acid by Vibrio Cholerae neuraminidase in cultured myotubes resulted in reduced expression of NEP. This was most likely because of a post-translational modification consisting in an abnormal sialylation of the protein that leads to its reduced stability. Moreover, treatment with Vibrio Cholerae neuraminidase was associated with an increased immunoreactivity for Abeta mainly in the form of distinct cytoplasmic foci within myotubes. We hypothesize that, in h-IBM muscle, hyposialylated NEP has a role in hampering the cellular Abeta clearing system, thus contributing to its abnormal accumulation within vulnerable fibers and possibly promoting muscle degeneration.

Functional evaluation of cerebral cortex in dementia with Lewy bodies.

Neurochemical investigations have demonstrated central cholinergic dysfunction in patients with dementia with Lewy bodies (DLB). Central cholinergic circuits of the human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation of the contralateral motor cortex. This test, named short latency afferent inhibition has been shown in healthy subjects to be sensitive to the blockage of muscarinic acetylcholine receptors and it is impaired in patients with Alzheimer disease (AD), a cholinergic form of dementia, while it is normal in non-cholinergic forms of dementia such as fronto-temporal dementia. We evaluated short latency afferent inhibition in a group of patients with DLB and compared the data with that from a group of AD patients and a control group of age-matched healthy individuals. Short latency afferent inhibition was significantly reduced in DLB and AD patients. The findings suggest that this method can be used as a non-invasive test for the assessment of cholinergic pathways in patients with dementia and may represent a useful additional tool for discriminating between cholinergic and non-cholinergic forms of dementia.

The Facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure.

BACKGROUND: The homologous 4q and 10q subtelomeric regions include two distinctive polymorphic arrays of 3.3 kb repeats, named D4Z4. An additional BlnI restriction site on the 10q-type sequence allows to distinguish the chromosomal origin of the repeats. Reduction in the number of D4Z4 repeats below a threshold of 10 at the 4q locus is tightly linked to Facioscapulohumeral Muscular Dystrophy (FSHD), while similar contractions at 10q locus, are not pathogenic. Sequence variations due to the presence of BlnI-sensitive repeats (10q-type) on chromosome 4 or viceversa of BlnI-resistant repeats (4q-type) on chromosome 10 are observed in both alleles. RESULTS: We analysed DNA samples from 116 healthy subiects and 114 FSHD patients and determined the size distributions of polymorphic 4q and 10q alleles, the frequency and the D4Z4 repeat assortment of variant alleles, and finally the telomeric sequences both in standard and variant alleles. We observed the same frequency and types of variant alleles in FSHD patients and controls, but we found marked differences between the repeat arrays of the 4q and 10q chromosomes. In particular we detected 10q alleles completely replaced by the 4q subtelomeric region, consisting in the whole set of 4q-type repeats and the distal telomeric markers. However the reciprocal event, 10q-type subtelomeric region on chromosome 4, was never observed. At 4q locus we always identified hybrid alleles containing a mixture of 4q and 10q-type repeats. CONCLUSIONS: The different size distribution and different structure of 10q variant alleles as compared with 4q suggests that these loci evolved in a different manner, since the 4q locus is linked to FSHD, while no inheritable disease is associated with mutations in 10qter genomic region. Hybrid alleles on chromosome 4 always retain a minimum number of 4q type repeats, as they are probably essential for maintaining the structural and functional properties of this subtelomeric region. In addition we found: i) several instances of variant alleles that could be misinterpreted and interfere with a correct diagnosis of FSHD; ii) the presence of borderline alleles in the range of 30-40 kb that carried a qA type telomere and were not associated with the disease.

Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression.

Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling-Wnt, Notch, and BMP-are progressively induced or repressed in the natural history of DMD.

Dystonia gravidarum: a new case with a long follow-up.

We report a case of cervical dystonia occurring in a 33-year-old without personal history of movement disorder but with family history of essential tremor, primigravid, primiparous woman at 1 weeks' amenorrhea, resolved completely after delivery in the course of 3 months. Dystonia never recurred in the following 5 years. Several neurological disorders are known to occur or worsen during pregnancy. As far as we know, this is the second reported case of dystonia occurring during pregnancy, thus confirming that dystonia gravidarum represents a new entity and should be considered in women of reproductive age affected by dystonia, especially when presenting with rapid-onset cervical dystonia.

Chronic GM2 gangliosidosis type Sandhoff associated with a novel missense HEXB gene mutation causing a double pathogenic effect.

We identified a novel c.1556A>G transition in exon 12 of the HEXB gene associated with chronic Sandhoff's disease, changing a conserved aspartic acid to glycine at position 494 of the Hex beta-subunit; moreover, RT-PCR showed aberrant exon 12 skipping, causing a frame-shift and premature stop codon, consequent to the disruption of an exonic splicing enhancer motif by the mutation. These data suggest that the c.1556 A>G transition would affect both HEXB mRNA processing and biochemical properties of the beta-subunit.

Prevalence of spinocerebellar ataxia type 2 mutation among Italian Parkinsonian patients.

We evaluated the prevalence of the SCA2 mutation among 224 Italian patients affected by typical Parkinsonism, including 145 sporadic and 79 familial forms. Pink1, Parkin, and LRRK2 gene mutations had been excluded previously. Molecular testing for the CAG expansion at the SCA 2 locus was performed on leukocyte DNA. Cloning and sequencing of the expanded allele was performed in patients positive for the SCA2 expansion. A 38 CAG expansion was detected in 1 of 79 families studied. The proband, a male age 67, and his sister, age 69, were both affected by a benign form of L-dopa-responsive Parkinsonism not associated with cerebellar signs. The inheritance was autosomal dominant. The CAG expansion was stable through meiotic transmission: sequence analysis showed that the CAG stretch was interrupted by 3 CAA. Our study shows that CAG expansion at the SCA 2 locus may represent a genetic cause of familial L-dopa-responsive Parkinsonism among Italian patients. The stability of the pathological CAG expansion detected in this family was related to the presence of CAA interruptions. These findings, together with literature data, suggest that the molecular intrinsic structure of the expanded allele may modulate the phenotypic expression of the SCA2 mutation.