Spread of dystonia in patients with idiopathic adult-onset laryngeal dystonia.

BACKGROUND AND PURPOSE: Adult-onset laryngeal dystonia (LD) can be isolated or can be associated with dystonia in other body parts. Combined forms can be segmental at the onset or can result from dystonia spread to or from the larynx. The aim of this study was to identify the main clinical and demographic features of adult-onset idiopathic LD in an Italian population with special focus on dystonia spread. METHODS: Data were obtained from the Italian Dystonia Registry (IDR) produced by 37 Italian institutions. Clinical and demographic data of 71 patients with idiopathic adult-onset LD were extracted from a pool of 1131 subjects included in the IDR. RESULTS: Fifty of 71 patients presented a laryngeal focal onset; the remaining subjects had onset in other body regions and later laryngeal spread. The two groups did not show significant differences of demographic features. 32% of patients with laryngeal onset reported spread to contiguous body regions afterwards and in most cases (12 of 16 subjects) dystonia started to spread within 1 year from the onset. LD patients who remained focal and those who had dystonia spread did not show other differences. CONCLUSIONS: Data from IDR show that dystonic patients with focal laryngeal onset will present spread in almost one-third of cases. Spread from the larynx occurs early and is directed to contiguous body regions showing similarities with clinical progression of blepharospasm. This study gives a new accurate description of LD phenomenology that may contribute to improving the comprehension of dystonia pathophysiology.

TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course.

The 43-kD transactive response (TAR)-DNA-binding protein (TARDBP) mutations have been demonstrated to be causative of sporadic and familial forms of amyotrophic lateral sclerosis. More recently, these mutations have been reported in cases of frontotemporal lobar degeneration (FTLD). The aim of this study was to evaluate the role of TARDBP genetic variations in a large sample of consecutive patients with FTLD. A total of 252 FTLD patients were investigated. Each subject had a clinical and neuropsychological evaluation and a brain imaging study. The clinical diagnosis was confirmed by at least 1 year of follow up. The entire TARDBP gene, the intronic flaking regions, and the 5'-untranslated region (5'-UTR) were screened. Six genetic variations were identified in patients with behavioral variant frontotemporal dementia (FTD) and FTD with motor neuron disease phenotypes. Two of these mutations, namely N267S and M359V, lead to amino acid changes within exon 6. We further identified three genetic variations, i.e., Y214Y, IVS-IV + 45C/T, and 5'-UTR G/A, that could potentially affect the normal splicing process as predicted by in silico analyses. None of these genetic variations was found in healthy age-matched controls. Moreover, we identified a previously described benign variant, A66A, in 5 patients. Our study has confirmed and extended the list of pathogenetic mutations in the TARDBP gene in both apparently sporadic and familial FTLD patients. This work further supports the need for TARDBP screening in FTLD. Also intronic splicing that affects mutations should be considered as well.

Cognitive and behavioral assessment in the early stages of neurodegenerative extrapyramidal syndromes.

Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration Syndrome (CBDS) are the most common neurodegenerative extrapyramidal syndromes. Beyond motor symptoms, cognitive dysfunctions and behavioral disturbances are reported. Neuropsychological and neuropsychiatry features in the early stages, however, are under-investigated, and few comparison studies are available yet. The aim of the present study was to evaluate the cognitive and behavioral profile in the early stages of neurodegenerative extrapyramidal syndromes. Thirty-nine PD, 27 DLB, 16 CBDS, and 24 PSP were recruited. Groups were matched for global cognitive and motor impairment. The overall sample showed a common neuropsychological core characterized by visuospatial deficits. Although in the early stage of the disease, a high presence of behavioral disturbances was detected, depression and anxiety were the most common disorders, followed by apathy and sleep disturbances. The observation of overlapping clinical entities points the attention on the need of adjunctive diagnostic markers for early differential diagnosis.

Is Tolosa-Hunt syndrome a limited form of Wegener's granulomatosis? Report of two cases with anti-neutrophil cytoplasmic antibodies.

Two patients with recurrent painful ophthalmoplegia due to granulomatous involvement of the intracavernous sinus (Tolosa-Hunt syndrome) had circulating anti-neutrophil cytoplasmic antibodies with a granular cytoplasmic immunofluorescence pattern during a flare-up of the disease. The presence of these antibodies suggests that Tolosa-Hunt syndrome might be regarded as a localized form of Wegener's granulomatosis.

ANG II- or AVP-induced increases in protein synthesis are not dependent on autocrine secretion of PDGF-AA.

Previous studies have demonstrated that angiotensin II (ANG II) and arginine vasopressin (AVP) stimulate increased protein synthesis and cellular hypertrophy in cultured rat aortic smooth muscle cells (SMC). The aim of this study was to explore the hypothesis that ANG II- and/or AVP-induced increases in protein synthesis are mediated by autocrine secretion of platelet-derived growth factor (PDGF)-AA. Results demonstrated that ANG II or AVP increased expression of PDGF-A, but not -B, chain mRNA. Additionally, conditioned media from ANG II- and AVP-treated SMC had increased mitogenic activity for Swiss 3T3 cells, which could be inhibited with a neutralizing antibody to PDGF-AA. However, PDGF-AA-neutralizing antibodies did not inhibit ANG II- or AVP-induced increases in protein synthesis, and exogenous PDGF-AA did not stimulate increased protein synthesis. Furthermore, no PDGF-alpha receptors were evident based on 125I-labeled PDGF-AA binding studies. In summary, results indicate that ANG II- or AVP-induced increases in protein synthesis were not dependent on autocrine secretion of PDGF-AA.

Reaction time responses in parkinsonian and hemiparkinsonian patients.

Twenty-one normal subjects, 32 bilateral parkinsonian patients (BPs) and 29 hemiparkinsonian patients (HP) were submitted to separate or sequentially associated motor tasks that included simple reaction times (RT), choice RTs, directional RTs, and movement RTs. The results showed that simple RTs, directional RTs, and movement times (MT) were slower in BPs as compared to normal subjects; for choice RTs there was no difference. Response patterns were similar in normal controls and BPs. In both groups RTs became more prolonged as sequentially programmed operations increased. If movement occurred at the end of the sequence, they prolonged the RTs of the preceding operations, but MTs per se did not vary. In HPs the same results were observed on the "bad" hand side versus normal controls and versus the healthy side, but a significant statistical level was reached mainly when the "bad" hand was the right one.

Vascular responsiveness to protein kinase C activators in mineralocorticoid-hypertensive rats.

This study characterizes vascular reactivity to protein kinase C activators, 12-O-tetradecanoylphorbol-13-acetate (TPA) and mezerein, in normotensive sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Mesenteric arteries were excised, cut helically into strips and placed in a muscle bath for measurement of isometric force generation. Cumulative addition of TPA or mezerein to the bath caused an increase in tension in arteries from hypertensive and normotensive rats. Threshold values for TPA and mezerein (dose that produced a 5 mN/mm2 response) were lower in arteries from DOCA-salt rats (TPA, 0.24 x 10(-8) mol/l; mezerein, 0.32 x 10(-8) mol/l) than in control arteries (TPA, 2.82 x 10(-8) mol/l; mezerein, 2.34 x 10(-8) mol/l). Contractions to TPA in arteries from DOCA hypertensive rats were inhibited by the calcium-channel antagonist verapamil (10(-6) mol/l) to a greater degree than normotensive values. Arteries from rats undergoing DOCA-salt treatment for 5-7 days and from DOCA-treated rats drinking tap water for 4-6 weeks were less responsive to TPA than were arteries from the DOCA-salt hypertensive rats after 4-6 weeks of treatment. Furthermore, responsiveness to TPA in arteries from untreated rats was reduced compared with that in arteries from normotensive rats maintained on high-salt drinking water. Threshold responses to TPA did not differ between arteries incubated with 10(-6) mol/l deoxycorticosterone and those incubated with the vehicle (ethanol). This study demonstrates that arteries from DOCA-salt hypertensive rats are more responsive to the contractile effects of TPA and mezerein than those from normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of angiotensin II- and arginine vasopressin-induced increases in protein synthesis and content in cultured rat aortic smooth muscle cells. Evidence for selective increases in smooth muscle isoactin expression.

Previous studies from this laboratory have demonstrated that angiotensin II (Ang II) and arginine vasopressin (AVP) are potent hypertrophic agents in cultured rat aortic smooth muscle cells. The present study identified major proteins that accumulate in Ang II-induced and AVP-induced hypertrophic cells and initiated studies of the mechanisms that contribute to their accumulation. Smooth muscle cell hypertrophy induced by Ang II and/or AVP (1 microM each) was associated with widespread increases in the content of many cellular proteins that were resolved by one- and two-dimensional gel electrophoresis. However, increases were also selective in nature, with increases in certain individual proteins, including actin (twofold to threefold), vimentin (2.5-fold to sevenfold), tropomyosin (threefold to sixfold), and myosin heavy chain, far exceeding overall increases in cellular protein content (20-40%). Increases in actin content were due largely to increased expression of smooth muscle alpha-actin (3.6- to 7.5-fold), as opposed to nonmuscle beta-actin (1.7- to 2.5-fold). Increases in smooth muscle alpha-actin were accompanied by a fivefold to eightfold increases in smooth muscle alpha-actin mRNA, indicating that these changes were not due exclusively to translational controls. Results demonstrate that contractile agonist-induced hypertrophy in cultured smooth muscle cells is due, in part, to increased expression of smooth muscle contractile proteins. Furthermore, the fact that Ang II and AVP induced selective increases in smooth muscle alpha-actin suggests that these agonists may not only regulate growth of vascular smooth muscle but may also promote expression of smooth muscle-specific contractile proteins during differentiation of vascular smooth muscle.

Calcium and contractile responses to phorbol esters and the calcium channel agonist, Bay K 8644, in arteries from hypertensive rats.

This study examined the calcium dependency of contractions in arteries from rats made hypertensive by aortic coarctation and in rats with genetic hypertensive (stroke-prone spontaneously hypertensive rats). Mesenteric artery and aortic strips were suspended in tissue baths for isometric force recording and contractions to two drugs were characterized: 1) a phorbol ester, TPA (12-O-tetrade-canoylphorbol-13-acetate), and 2) the calcium channel agonist, Bay K 8644. Thoracic aortae and mesenteric arteries from hypertensive rats were more sensitive to the contractile properties of the protein kinase C activator TPA than comparable arteries from normotensive rats. In thoracic aortae from coarcted rats, the contractile activity of Bay K 8644 was potentiated compared to normotensive values. In the presence of 19.2 mmol/L KCl, responses to Bay K 8644 in thoracic aortae from normotensive rats were potentiated and did not differ from coarcted values. In contrast, contractions to Bay K 8644 and TPA in abdominal aortae obtained below the coarctation were not different from normotensive values. Upon exposure to 26.2 mmol/L KCl, contractions to Bay K 8644 in abdominal aortae were potentiated and those in aortae from coarcted rats did not differ from sham values. Contractile responses to both drugs were blocked by nifedipine and verapamil and responses were attenuated in calcium-free solution. We conclude that calcium channel function and its regulation by protein kinase C contribute to altered vascular reactivity in hypertension. Further, these abnormalities have a pressure dependency, because they did not occur in abdominal aortae from coarcted rats.

Vascular responsiveness to phorbol esters in coarctation-hypertensive rats.

Recent observations suggest that a phospholipid-sensitive, calcium-dependent protein kinase affects the contractile responses of vascular smooth muscle. Protein kinase C activators such as the tumor-promoting phorbol esters have been used as tools to study protein kinase C function in various intact cells. The present study characterizes vascular reactivity to protein kinase C activation in rats made hypertensive by coarctation of the abdominal aorta. Thoracic aortic strips from hypertensive rats developed greater force than arteries from normotensive rats in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). Thoracic aortae from hypertensive rats were more responsive (lower threshold dose) to the phorbol ester than those from normotensive rats. Additionally, arteries from hypertensive rats were more responsive to the contractile effects of mezerein, a non-phorbol ester activator of protein kinase C. Removal of the endothelium did not eliminate the difference in responsiveness to TPA in thoracic aortae from normotensive and hypertensive rats. The threshold dose of TPA in abdominal aortae from hypertensive rats was not different from that in normotensive rats. However, the maximal response to 10(-6) mol/l TPA after 60 min in abdominal aortae from hypertensive rats was significantly less than that in aortae from normotensive rats. Thus, contractile responses to TPA appear to be influenced by arterial pressure per se. The inhibitory effects of the calcium antagonist, verapamil, in thoracic aortae from hypertensive rats were greater than in those from normotensive rats. Verapamil inhibited TPA-induced contractions in abdominal aortae from hypertensive rats to the same extent as in those from normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of Madopar HBS plus Madopar standard in patients with fluctuating Parkinson's disease: two years of follow-up.

Clinical response to a new galenic formulation of levodopa plus benserazide, Madopar HBS, was studied in 25 fluctuating parkinsonians. This open study was planned in two phases. In the first phase, the administering of HBS alone resulted in a surprisingly high number of dropouts. In the second phase, Madopar standard in association with Madopar HBS, the follow-up period was 24 months. A stable long-lasting improvement in predictable fluctuations and their severity was maintained for the whole period without any change in drug dose. Nocturnal and early morning akinesia improved too. The study shows that Madopar HBS plus Madopar standard is effective in producing a prolonged and stable response in parkinsonian fluctuating patients.

Augmented phosphoinositide metabolism in aortas from genetically hypertensive rats.

Recent studies suggest that serotonergic receptor activation is coupled to phospholipase C-mediated phosphoinositide hydrolysis, which results in the release of intracellular second messengers. The purpose of this study was to determine whether altered phosphoinositide metabolism is the basis for augmented vascular responsiveness to serotonin in genetic hypertension. Thoracic aortic segments isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto normotensive rats (WKY) were labeled with myo-[3H]inositol and stimulated with serotonin in the presence of LiCl. Accumulation of [3H]inositol phosphates was then quantitated by column chromatography. Basal inositol phosphate accumulation and basal incorporation of myo-[3H]inositol into aortic cell membranes from SHRSP was not significantly different from WKY values. At 2.6 x 10(-7) to 2.6 x 10(-4) M serotonin, phosphoinositide metabolism was significantly augmented in aortae from SHRSP compared with WKY. Depolarization (100 mM KCl) did not increase phosphoinositide hydrolysis above basal levels in SHRSP or WKY. 2-Nitro-4-carboxyphenyl-N,N-diphenyl carbamate (NCDC), an inhibitor of phospholipase C, prevented the serotonin-induced phosphoinositide metabolism. NCDC also partially inhibited phasic contractions (responses in calcium-free solution) to serotonin in aortas from SHRSP and WKY. In conclusion, abnormal phosphoinositide metabolism may be one mechanism responsible for the characteristic increase in vascular reactivity to serotonin in hypertension.

Lateralization of visual attention in patients with classic migraine and unilateral prodromes.

The present study is aimed to investigate whether and how mechanisms of visual attention are changed into conditions of monohemispheric disorders. For this purpose, Posner's paradygm was applied to classic migraine patients with prodromal phenomena localized in one hemisphere. The subjects were examined in acute phase (within 24 h of the episode end) and after a week or more from the episode (interparoxysmal phase). The patients in interparoxysmal phase behaved as normal subjects. In acute phase, we observed a selective involvement of attentional behaviour in migraineurs with left hemispheric symptoms. A possible explanation might be based on the well-known tendency of this hemisphere to prevail in performing attentive tasks.

Enhanced vascular reactivity to protein kinase C activators in genetically hypertensive rats.

Recent studies suggest that phospholipid-sensitive, Ca2+-dependent protein kinase C participates in contractile responses of vascular smooth muscle. This study characterizes vascular reactivity to protein kinase C activators in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Helical strips of mesenteric arteries were mounted in organ chambers for measurement of isometric contractions (responses were normalized as a percentage of maximal force in response to 100 mM KCl; in SHRSP, 350 +/- 16 mg; in WKY, 335 +/- 21 mg). Arteries from SHRSP contracted faster and developed greater force than arteries from WKY (168 +/- 9% vs 143 +/- 3%) in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. Arteries from SHRSP (0.6 X 10(-8) M) were more sensitive to the phorbol ester than those from WKY (2.2 X 10(-8) M), as indicated by the dose of the phorbol ester required to produce 50% of the maximal response to KCl. Additionally, SHRSP arteries were more sensitive to the contractile effects of mezerein, a non-phorbol ester activator of protein kinase C. Ca2+-free solution (1.0 mM EGTA) and verapamil (10(-7) M) caused relaxation (approximately -60%) of contractions in response to the phorbol ester (10(-6) M). Addition of 10(-6) M of the phorbol ester to arteries that were preincubated in Ca2+-free solution (1.0 mM EGTA for 30 minutes) elicited submaximal contractions (in SHRSP, 26 +/- 4%; in WKY, 38 +/- 7%). Upon addition of 1.6 mM Ca2+, arteries from SHRSP contracted faster (t1/2 = 2.7 +/- 0.6 minutes) than those from WKY (8.2 +/- 0.5 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Immediate rebound followed by deterioration of regional left ventricular function with coronary reperfusion.

The immediate and early effects of coronary artery reperfusion initiated 1 and 3 hours after coronary artery occlusion were evaluated by two-dimensional echocardiographic measurements of overall and regional left ventricular function. A total of 29 anesthetized open chest dogs underwent one of the following: 1 hour occlusion followed by reperfusion (Group I, n = 9), 3 hour occlusion followed by reperfusion (Group II, n = 12) or 5 hour occlusion without reperfusion (Group III, n = 8). Serial two-dimensional echocardiography was performed at baseline; at 1, 3 and 5 hours of coronary occlusion; within 5 minutes of reperfusion; and at 2 hours of reperfusion. After occlusion, all groups manifested significant (p less than 0.01) increases in left ventricular diastolic and systolic area and decreases in left ventricular area ejection fraction. With coronary reperfusion, there was no improvement in these global variables in Groups I and II. However, immediately after reperfusion, there was improvement in the regional extent of dysfunction (Group I, 138 +/- 35 to 66 +/- 62 degrees, p less than 0.05; Group II, 156 +/- 51 to 85 +/- 77 degrees, p less than 0.05) as well as improvement in the regional degree of dyskinesia (p less than 0.05). These regional improvements were transient and resolved by 2 hours of coronary reperfusion. This immediate rebound of function was not associated with the duration of coronary occlusion, hemodynamic variables or ultimate infarct size. Thus, in the anesthetized open chest dog model, coronary artery reperfusion at 1 or 3 hours produces an immediate but transient improvement in regional systolic myocardial function.

Loss of calmodulin activity in cardiac sarcoplasmic reticulum after ischemia.

Experiments were designed to evaluate whether cardiac ischemia affected the subcellular distribution of calmodulin activity. Major cellular fractions (nuclei, mitochondria, sarcoplasmic reticulum and cytosol) were isolated from globally ischemic hearts by differential centrifugation. Ischemia did not affect calmodulin activity in cell fractions other than sarcoplasmic reticulum, which showed a consistent and complete loss of activity. This site-specific loss of calmodulin activity may be one mechanism by which ischemia induces contractile dysfunction.