Preserved brain functional plasticity after upper limb task-oriented rehabilitation in progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Limited research has been dedicated to upper limb (UL) rehabilitation in progressive multiple sclerosis (PMS). The objective in this pilot study was to investigate the effect of task-oriented UL rehabilitation in PMS and to perform explorative analyses of the magnetic resonance imaging (MRI) correlates of changes in motor performance. METHODS: Twenty-six PMS patients with mild UL impairment were prospectively enrolled and randomized into two groups: an active treatment group (ATG, n = 13) and a passive treatment group (PTG, n = 13). At baseline and after training, patients underwent MRI scans with structural and functional imaging and were evaluated with the action research arm test, the nine-hole peg test, the ABILHAND scale and the modified fatigue impact scale (MFIS). Measures of motor finger performance were obtained by engineered glove measuring. RESULTS: After rehabilitation, the ATG improved in several finger motor tasks (0.001 ≤ P ≤ 0.03, 0.72 ≤ Cohen's d ≤ 1.22) and showed reduced MFIS scores compared with the PTG (P = 0.03). The ATG showed increased functional connectivity within the cerebellar and thalamic resting state networks compared with the PTG (P < 0.05). Correlations were found between several measures of motor improvement and thalamic and sensorimotor networks (0.87 ≤ r ≤ 0.93, 0.001 ≤ P ≤ 0.03). No changes in cerebral volumes and diffusion tensor imaging derived measures were detected. CONCLUSIONS: Progressive multiple sclerosis patients with mild UL dysfunction benefit from task-oriented UL rehabilitation, which seems to be more efficient than simple passive mobilization. Despite a high burden of disability and brain damage, functional adaptive capacities seem to be preserved, thus providing a rationale for the use of rehabilitative treatments in late PMS.

Imaging of activated complement using ultrasmall superparamagnetic iron oxide particles (USPIO)--conjugated vectors: an in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development.

In the current study, we have developed a magnetic resonance imaging-based method for non-invasive detection of complement activation in placenta and foetal brain in vivo in utero. Using this method, we found that anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles bind within the inflamed placenta and foetal brain cortical tissue, causing a shortening of the T2* relaxation time. We used two mouse models of pregnancy complications: a mouse model of obstetrics antiphospholipid syndrome (APS) and a mouse model of preterm birth (PTB). We found that detection of C3 deposition in the placenta in the APS model was associated with placental insufficiency characterised by increased oxidative stress, decreased vascular endothelial growth factor and placental growth factor levels and intrauterine growth restriction. We also found that foetal brain C3 deposition was associated with cortical axonal cytoarchitecture disruption and increased neurodegeneration in the mouse model of APS and in the PTB model. In the APS model, foetuses that showed increased C3 in their brains additionally expressed anxiety-related behaviour after birth. Importantly, USPIO did not affect pregnancy outcomes and liver function in the mother and the offspring, suggesting that this method may be useful for detecting complement activation in vivo in utero and predicting placental insufficiency and abnormal foetal neurodevelopment that leads to neuropsychiatric disorders.

Multimodal MRI Longitudinal Assessment of White and Gray Matter in Different SPG Types of Hereditary Spastic Paraparesis.

Hereditary spastic paraplegias (HSP) are a group of genetically and clinically heterogeneous neurologic disorders. Hereby we describe a relatively large group of patients (pts) affected by HSP studied at baseline (31 pts) and at follow-up (mean period 28.9 ± 8.4 months; 23 pts) with multimodal advanced MRI: high-resolution T1 images for voxel-based morphometry (VBM) analysis, magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI). An age-matched healthy control (HC) group underwent the same neuroimaging protocol in a time schedule matched with the HSP patients. At baseline, VBM showed gray matter (GM) reduction in HSP in the right pre-frontal cortex and bilaterally in the thalami. MRS at baseline depicted in HSP patients compared to the HC group reduction of NAA/Cr ratio in the right pre-frontal region, increase of Cho/Cr ratio in the right pre-central regions, and increase of mI/Cr ratio on the left pre-central area. At cross-sectional follow-up analysis and longitudinal evaluation, no VBM and MRS statistically significant results were obtained. Tract-based spatial statistics (TBSS) analysis showed widespread DTI brain white matter (WM) alterations in patients compared to HC at baseline, which are characterized by reduction of fractional anisotropy (FA) and increase of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity, as confirmed on cross-analysis of the follow-up dataset. A longitudinal analysis with TBSS in HSP patients did not show significant variations, while upon applying region-based analysis we found increased FA and decreased MD and AD in specific brain WM fiber complex during follow-up. The changes were not correlated with the clinical presentation (pure vs complicated HSP), motor function, and motility indexes or history of specific treatments (botulinum toxin). In conclusion, the cross-sectional analysis of the multiparametric MRI data in our HSP patients confirmed the non-prominent involvement of the cortex in the primary motor regions but rather of other more associative areas. On the contrary, DTI demonstrated a widespread involvement of the brain WM, including the primary motor regions, which was confirmed at follow-up. The longitudinal analysis revealed an apparent inversion of tendency when considering the expected evolution of a neurodegenerative process: we detected an increase of FA and a decrease of MD and AD. These time-related modifications may suggest a repair attempt by the residual central WM fibers, which requires confirmation with a larger group of patients and with a longer time interval.

Simultaneous detection of macroevolutionary patterns in phenotypic means and rate of change with and within phylogenetic trees including extinct species.

Recognizing evolutionary trends in phenotypic means and rates requires the application of phylogenetic comparative methods (PCMs). Most PCMs are unsuited to make full use of fossil information, which is a drawback, given the inclusion of such data improves, and in some cases even corrects, the proper understanding of trait evolution. Here we present a new computer application, written in R, that allows the simultaneous computation of temporal trends in phenotypic mean and evolutionary rate along a phylogeny, and to contrast such patterns among different clades within the tree. By using simulation experiments, we show the new implementation, names search.trend is as powerful as existing PCM tools in discerning macroevolutionary patterns in phenotypic means and rates, but differently from any other PCM allows comparing individual clades to each other, and provides rich information about trait evolution for all lineages in the tree.

Mercuric chloride effects on rat renal redox enzymes activities: SOD protection.

This study was done to determine the effect of mercuric chloride treatment on the redox cycle enzymes in rat kidney ex-vivo. Glutathione peroxidase (GSH-Px) and catalase (Cat) activities were measured in kidney homogenates from rats with different nonprotein sulfhydrils levels and different mercury content. The results indicated that GSH-Px activity was enhanced in mercury-treated rats in direct relationship with kidney mercury content, whereas Cat activity was increased in the presence of the highest mercury kidney content obtained. Superoxide dismutase (SOD) was administered to rats prior to mercury chloride injection and renal function, development of lipid peroxidation and renal glutathione level were measured 1 h later. Renal function, renal glutathione, and renal lipid peroxidation production were maintained similar to control values. Moreover, SOD pretreatment also protected kidney from mercuric chloride histological alterations observed 24 h post mercury treatment. Thus, an inhibition of renal redox cycle enzymes "in vivo," did not appear to be an important determinant of the increased lipid peroxidation observed during mercuric chloride nephrotoxicity.

Osteitis caused by bacille Calmette-Guérin vaccination: an emergent problem in Chile?

SETTING: Osteitis caused by bacille Calmette-Guérin (BCGOST) vaccination has not been described in Latin American countries. OBJECTIVE: To evaluate the incidence, clinical features and prognosis of patients with BCGOST in one of the most populated areas of Santiago, Chile. DESIGN: A retrospective analysis of medical records kept over twenty years (1976-1995). RESULTS: In ten children (four in the last five years), diagnostic criteria of BCGOST were fulfilled. Six were boys, the mean age was 11 months (range 6.5-21), symptoms were present with a mean of 31 days (range 15-60) before diagnosis and the sites of predilection of osteitis were the lower extremity (8/10 cases). Culture was positive in one case, and nine patients had typical histopathological lesions (two with acid-fast bacilli). All had normal chest X-ray. Mantoux testing was performed in four cases (mean 21.5 mm, range 16-28). None of the ten patients had a history of underlying immunodeficiency. In this area BCG coverage was 90.2 +/- 9.7% of all newborn infants, and the annual risk of tuberculosis infection was 24.6/100,000 population per year. CONCLUSION: Our study demonstrated an estimated incidence for BCGOST in this area of 3.2/100,000 vaccinated newborns. Based on the epidemiological situation of tuberculosis in Chile (29.5/100,000), universal BCG vaccination in newborns should be encouraged.

Effectiveness of N-acetylcysteine in protecting against mercuric chloride-induced nephrotoxicity.

Mercuric chloride (HgCl2)-induced nephrotoxicity, as measured by functional and biochemical parameters was evaluated in rats at different kidney non-protein sulfhydryls (NPS) levels. Diethylmaleate (DEM) induced a 75% of NPS diminution 1 h after the administration. Renal function (clearance) and biochemical measurements (gamma-glutamyltranspeptidase activity in urine, and lipoperoxides in kidney tissue) were impaired when the animals were HgCl2-treated. Values were highly impaired when the kidneys were NPS-depleted and were improved when NPS pools were previously increased although they were not similar to control values. DEM treatment promoted a higher accumulation of HgCl2 in both kidney and liver while NAC-treatment reduced significantly the metal content in these organs. These data are in favour of a positive relationship among mercury content and organ injury. On the other hand, mercury content increased while NPS levels diminished. NPS might play a role in the HgCl2 detoxification and thus avoids mercury accumulation and mercury effects.

Effect of different renal glutathione levels on renal mercury disposition and excretion in the rat.

Mercury renal disposition has been studied following HgCl2 injection (5.0 mg/kg body wt., s.c.) in controls, diethylmaleate and N-acetylcysteine-treated rats. The different treatments were used to generate statistically different degrees of non-protein sulfhydryls concentration in kidneys. Diethylmaleate (4 mmol/kg body wt., i.p.) diminished kidney glutathione levels to 25% and N-acetylcysteine (2 mmol/kg body wt., i.p.) increased kidney non-protein sulfhydryls levels up to 75% compared with new controls. The amount of mercury in the kidneys, the mercury excretion rate in urine and the mercury plasma disappearance curves were calculated during 3 h post HgCl2 injection. BUN was measured in plasma at the same time period to determine the onset of kidney damage. The results indicate a higher HgCl2 renal clearance in N-acetylcysteine-treated rats compared to controls and less renal mercury accumulation. The data agree with diminished renal toxicity. On the other hand, renal mercury accumulation was higher and mercury renal clearance lower in diethylmaleate-treated animals, associated with higher renal toxicity. The results suggest that non-protein sulfhydryl levels (principally glutathione) might determine renal accumulation of mercury as well as its elimination rate and hence might enhance or mitigate the nephrotoxicity induced by the metal.

Bronchodilator effect of fenoterol and ipratropium bromide in infants with acute wheezing: use of MDI with a spacer device.

Twenty-eight infants admitted to Exequiel González Cortes Children's Hospital because of acute wheezing (AW) were randomly assigned to three study groups. Fenoterol (FNT), ipratropium bromide (IB), and placebo were administered respectively to children in the different groups by means of metered dose inhalers (MDI) with spacers, using doses of 3 puffs every hour, for 4 hours. The degree of bronchial obstruction was assessed clinically and scored with the single-blind method every hour prior to each treatment. The criterion of a bronchodilator effect was a significant decrease in the degree of bronchial obstruction at subsequent scorings. The scores of the three groups were compared using the Student's t test for matched samples. The same test was also applied to the independent samples for determining the superiority of one treatment, FNT or IB, over the other. The results indicated a significant decrease in the scores of the groups receiving FNT and IB (P less than 0.05); this did not occur in the group in which placebo was used. FNT produced a more rapid and sustained effect than IB (P less than 0.05). Significant bronchodilator effect was obtained in infants with AW when repeated doses of FNT or IB were administered with MDI and spacers. This effect was significantly greater in the group treated with FNT.

Randomized trial of salbutamol via metered-dose inhaler with spacer versus nebulizer for acute wheezing in children less than 2 years of age.

The aim of this study was to compare the efficacy of salbutamol delivered via a metered-dose inhaler with a spacer and facial mask (MDI-S) vs. a nebulizer (NEB) for the treatment of acute exacerbations of wheezing in children. In a single-blind, prospective, randomized clinical trial, 123 outpatients (1-24 months of age), presenting with "moderate to severe" wheezing, were seen in the emergency department. Children were randomly assigned to one of two salbutamol treatment groups. In the first hour, the MDI-S group received 2 puffs (100 microg/puff) every 10 min for 5 doses, and the NEB group received 0.25 mg/kg every 13 min for 3 doses. If the clinical score was >5 at the end of the first hour, the patients received another hour of the same treatment and also betamethasone (0.5 mg/kg intramuscular). On enrollment and after the first and the second hour of treatment each child had a validated clinical score assigned by a blinded investigator. There were no differences at the time of admission to the emergency department between groups in clinical score or demographic data. Success (clinical score 0.05). We conclude that in this study population, children less than 2 years of age with moderate-severe exacerbations of wheezing responded faster to salbutamol delivered by MDI with a spacer and facial mask than to salbutamol delivered by nebulizer.

Relation between pulse oximetry and clinical score in children with acute wheezing less than 24 months of age.

The aim of this study was to determine the relation between transcutaneous hemoglobin oxygen saturation, measured by pulse oximetry (SpO2), and clinical score values in 138 infants (mean+/-SD, 6.6+/-5.5 months of age) with acute wheezing episodes presenting in a primary care outpatient setting. A single investigator evaluated the severity of the acute wheezing episodes by assigning a clinical score and was unaware of the SpO2 values. Another investigator measured SpO2 values on all subjects. The mean (+/-SD) SpO2 value was 98.2+/-1.1% for children with clinical scores of 2-5 (n = 32); 95.4+/-1.5% for those with scores of 6-7 (n = 82), and 92.9+/-2% for children with scores of 8-10 (n = 24), (P < 0.001 by Bonferroni's multiple comparison, when all two-way comparisons were done for each pair of results). The clinical score showed a good correlation with SpO2 (r = -0.76; 95% CI, -0.83 to -0.68). We conclude that if pulse oximetry is not available, it is advisable to include oxygen in the therapy of wheezy infants with clinical scores values >8.

Effects of nebulized fenoterol, associated with ipratropium or steroids, on the heart rate of infants under one year of age with acute wheezing.

The main objective of this study was to evaluate the effect of fenoterol alone or associated with ipratropium bromide or steroid on the heart rate in young children. Ninety-four infants less than 1 year of age were randomly allocated to receive nebulized fenoterol alone, fenoterol plus ipratropium bromide, fenoterol plus corticosteroids, or normal saline solution. An increase in heart rate was observed in all four groups. The increases were statistically significant (P less than 0.001) in all three treatment groups, and no difference between them was observed (F = 0.65, NS). However, the heart rate remained within clinically acceptance limits. We conclude that nebulized fenoterol alone or combined with ipratropium or steroids can be safely used in the treatment of wheezy infants.

Use of nebulized bronchodilators in infants under 1 year of age: analysis of four forms of therapy.

The main purpose of this study was to evaluate four different forms of treatment in young infants admitted for acute wheezing (AW). Seventy-nine infants less than one year of age were randomly assigned to one of five groups. Group 1 received nebulized fenoterol plus ipratropium bromide, group 2 fenoterol, group 3 fenoterol plus steroids, and group 4 aminophylline, IV, plus steroids and oral fenoterol; the control group, or group 5, received nebulized normal saline solution. Clinical evaluation was done by means of a scoring system. The effectiveness of treatments was estimated by a score decrease in the first 24 hours, by the percentage of patients whose scores did not decrease during the same period, and by the number of days in the hospital. All infants had significantly decreased scores, except those in the control group; the aminophylline group included a greater percentage of patients who did not abate their scores, and they stayed in the hospital for more days than those in the other groups. The fenoterol group had the shortest hospital stay. All four treatments produced objective clinical improvement in bronchial obstruction. However, the nebulized bronchodilator treatments were more effective than aminophylline IV in decreasing scores on the first day, and they resulted in shorter hospitalization.

Effects of clenbuterol as a repartitioning agent on beta-adrenoceptor concentrations in heart, bronchi and brain of veal calves.

The effects induced by dietary clenbuterol (20 micrograms kg-1 body weight day-1 for 40 days) on beta-adrenergic receptor (beta-AR) subtypes in the heart, bronchial smooth muscles and the CNS of veal calves were investigated using a binding method. Clenbuterol exposure caused a significant (P < 0.05, P < 0.01, P < 0.001) decrease in beta 1-AR and beta 2-AR in both cardiac atria and ventricles of treated animals (excluding the beta 2-AR of the right atrium). Similarly, a significant (P < 0.01, P < 0.001) down-regulation of beta-AR subtypes in bronchial smooth muscles of treated calves was observed. In the CNS (cerebral cortex, hippocampus, hypothalamus and cerebellum) the down-regulation was limited to beta 2-AR, with the exception of the hippocampus in which both beta 1-AR and beta 2-AR concentrations were significantly (P < 0.05; P < 0.01) reduced. Scatchard analysis of the binding of the beta-AR antagonist, (-) [3H]CGP 12177, revealed that the down-regulation of beta-AR was not associated with any modification in binding affinity, as Kd values were unaffected by clenbuterol treatment. Data obtained indicated that prolonged clenbuterol exposure induced a remarkable beta-AR down-regulation in the heart, bronchi and brain of veal calves.

[Free autogenous muscle grafts in nine children with total and incontinence (author's transl)]. / Autotrapianto muscolare libero in nove bambini con incontinenza anale totale.

Nine children with total anal incontinence after surgery for anorectal agenesis were successfully operated on by free autogenous muscle transplantation. Skeletal muscles were first denervated and 3 weeks later transplanted to the anal region as a U--sling around the rectum, imitating the normal position and function of the puborectalis muscle. The grafts were placed in contact with the normal muscles of the region to make reinnervation possible. Eight children were completely evaluated after operation. Two years after surgical procedure six children were "continent" and only two were still incontinent, but improved. In these cases the indication for muscle transplantation was not quite correct. The return of the function of the muscle grafts completely changed the lives of these children. The results of this new surgical procedure are encouraging and invite further trials.

Role of tissue factor in feto-maternal development: a xiphos.

In this review, the dual role of tissue factor (TF) in pregnancy is described. On the one hand, TF is required for embryonic and placental development in a successful pregnancy, and on the other hand, pathologic expression of TF can lead to serious pregnancy complications in humans and mice. Human studies show increased TF levels in plasma, amniotic fluid and and/or placentas of abnormal pregnancies affected by miscarriages, preterm birth, or pre-eclampsia. Interestingly, using two mouse models, we found that blood-borne TF plays a crucial role in the pathogenesis of pregnancy complications. TF on neutrophils and monocytes is a critical mediator in trophoblast injury and embryo damage in pregnancy loss induced by antiphospholipid antibodies and in the antibody-independent CBA/J × DBA/2 model of miscarriages. Blockade of TF or genetic diminution prevented pregnancy complications, suggesting that TF may be a good target for therapy in patients with recurrent miscarriages, pregnancy loss, and pre-eclampsia. In addition, statins, which downregulate TF, may constitute a good therapeutic option for women with pregnancy complications. Clinical trials should be conducted to confirm these observations in women.