Neurophysiological correlates of cognitive disturbances in multiple sclerosis

Cognitive impairment is common in multiple sclerosis, mostly attributed to involvement of cortico-cortical and cortico-subcortical connections. The latter may be explored using the analysis of bioelectrical activity such as power and coherence of the electroencephalogram at rest and its reactivity to stimulus processing and cognitive activities, such as event-related desynchronization and event-related potentials. Although these methods are very useful for assessing information processing during cognitive tasks and other activities, their value in detecting cognitive impairment concerning sensitivity and specificity needs to be validated and they have been mostly used for understanding the physiopathology of cognitive impairment in different forms and stages of the diseases. Nevertheless, newer applications such as longitudinal monitoring and effects of treatment, although explored only in pilot studies, seem quite promising allowing objective measures potentially useful as secondary endpoints in clinical trials aimed at preserving or improving cognition in MS patients.     

Functional Anatomy of Motor Recovery After Early Brain Damage

Functional magnetic resonance imaging and transcranial magnetic stimulation were used to examine a 34 year-old right-handed patient, who, at the age of 6 years, had experienced sudden right hemiplegia, seizures, and stupor during a bout of measles encephalitis, followed by incomplete distal right motor recovery. Morphological MRI showed massive unilateral enlargement of the left ventricle, associated with extreme thinning of the white and gray matter, with partial preservation of the pyramidal tract. Functional MRI and transcranial magnetic stimulation revealed reorganization of the motor cortices, and integrity of the corticospinal pathway, respectively. Our findings indicate that complete hand motor recovery may require functional connections between the motor cortical areas and cortical-subcortical structures, in addition to the retained integrity of the primary sensorimotor area and pyramidal tract.     

Inner ear abnormalities in four patients with dRTA and SNHL: clinical and genetic heterogeneity

A significant number of patients affected by autosomal recessive primary distal renal tubular acidosis (dRTA) manifest sensorineural hearing loss (SNHL). Mutations in ATP6V1B1 are associated with early onset SNHL, whereas ATP6V0A4 mutations have been described in dRTA and late-onset SNHL. Enlarged vestibular aqueduct (EVA) was described in patients with recessive dRTA and SNHL, and recently, this abnormality has been associated with mutations in the ATP6V1B1 gene. In our study, we evaluated the presence of inner-ear abnormalities in four patients affected by dRTA and SNHL, characterized by molecular analysis. Two patients affected by severe dRTA with early onset SNHL showed the same mutation in the ATP6V1B1 gene and bilateral EVA with a different degree of severity. The other two presented similar clinical manifestations of dRTA and different mutations in the ATP6V0A4 gene: one patient, showing EVA, developed an early SNHL, whereas in the other one, the SNHL appeared in the second decade of life and the vestibular aqueduct was normal. Our study confirms the association of EVA and mutations in the ATP6V1B1 gene and demonstrates that mutations in the ATP6V0A4 gene can also be associated with EVA probably only when the SNHL has an early onset. The pathophysiology of SNHL and EVA are still to be defined.     

Induction and add-on therapy with Mitoxantrone and Interferon beta in multiple sclerosis

We retrospectively analyzed data from 70 multiple sclerosis (MS) patients treated with mitoxantrone (MX) before Interferon-β (IFN-β) because of clinically and MRI very active isolated syndrome (CIS) or relapsing-remitting MS (induction therapy) or due to breakthrough/ persistently active disease in spite of IFN-β (add-on/combination therapy), or for increased disability suggesting a secondary progression (rescue therapy). After almost 2-year follow-up, relapse rate and disability decreased very significantly in the two former groups while MX was essentially ineffective as rescue therapy. Induction therapy is a valid option for very aggressive/active CIS and MS at onset.     

Risk factors for venous thromboembolism in the elderly: results of the master registry

Approximately 50-75% of patients with venous thromboembolism have a readily identifiable risk factor, either transient or permanent, whereas the remaining episodes are classified as unprovoked. The incidence of first-time venous thromboembolism rises exponentially with age. Whether the prevalence and the relative weight of major risk factors differ between elderly and younger patients is unclear. We performed a multicenter, prospective, observational study on consecutive patients with objectively confirmed acute venous thromboembolism admitted to 25 Italian hospitals. Baseline characteristics and information on temporary and permanent risk factors at the time of the index event were secured by an electronic data network. We enrolled 2119 patients (49.8% men), of whom 440 (20%) were more than 75 years of age and 1679 (79.2%) 75 years of age or less. Elderly patients were more likely to have pulmonary embolism at presentation (33.6 and 25.6%, respectively, P < 0.001). After binary logistic regression analysis, we found that the risk of venous thromboembolism in the elderly, compared with the younger age group, was significantly associated with immobilization (odds ratio: 2.46, 95% confidence interval: 1.85-3.27) and with severe medical disorders (odds ratio: 1.99, 95% confidence interval: 1.41-2.80), whereas male sex (odds ratio: 0.53, 95% confidence interval: 0.42-0.66), surgery (odds ratio: 0.61, 95% confidence interval: 0.43-0.85), and trauma (odds ratio: 0.49, 95% confidence interval: 0.31-0.77) were less common risk factors in the elderly than in younger patients. Use of thromboprophylaxis prior to the index event was not different between the two age groups. Severe medical disorders and immobilization are strongly associated with the occurrence of venous thromboembolism in the elderly. Our findings stress the need for adequate thromboprophylaxis in this setting.     

Pre-stimulus alpha rhythms are correlated with post-stimulus sensorimotor performance in athletes and non-athletes: a high-resolution EEG study.

OBJECTIVE: In this study, we tested the hypothesis that a pre-stimulus brief (1 min) 10-Hz audio-visual flickering stimulation modulates alpha EEG rhythms and cognitive-motor performance in elite athletes and in non-athletes during visuo-spatial demands. METHODS: Electroencephalographic (EEG) data were recorded (56 channels; EB-Neuro) in 14 elite fencing athletes and in 14 non-athletes during visuo-spatial-motor demands (i.e. subjects had to react to pictures of fencing and karate attacks). The task was performed after pre-stimulus 15- (placebo) or 10-Hz (experimental) flickering audio-visual stimulation lasting 1 min and after no stimulation (baseline). RESULTS: With reference to the baseline condition, only the 10-Hz stimulation induced a negative correlation between pre-stimulus alpha power and reaction time in the fencing athletes and non-athletes as a single group. The higher the enhancement of alpha power before the pictures, the stronger the improvement of the reaction time. The maximum effects were observed in right posterior parietal area (P4 electrode) overlying sensorimotor integrative cortex. Similar results were obtained in a control experiment in which eight elite karate subjects had to react to pictures of karate and basket attacks. CONCLUSIONS: The present results suggest that a preliminary 10-Hz sensory stimulation can modulate EEG alpha rhythms and sensorimotor performance in both elite athletes and non-athletes engaged in visuo-spatial-motor demands. SIGNIFICANCE: Identification of the EEG state of sporting experts prior to their performance provides a plausible rationale for the modulation of alpha rhythms to enhance sporting performance in athletes and sensorimotor performance in patients to be rehabilitated.     

Quantification of prostate-specific antigen immunoreactivity in human breast cyst fluids

Summary The frequency of gross cystic breast disease in premenopausal women and its possible association with in-creased breast cancer risk emphasises the importance of investigations relating to breast cyst fluid composition. In order to contribute to a better analysis of this medium, we have measured the presence of prostate-specific antigen immuno-reactivity in sixty-four human breast cyst fluids. Data analyses show that 35% of samples presented a level of this antigen < 0.05 µg/L, whereas 42 out of 64 cysts show a significant increase in the mean value of metabolically active apocrine cysts when compared to flattened cysts (p < 0.01). We report the first evidence that breast epithelium of gross cysts produces, secretes, and accumulates large amounts of prostate-specific antigen, a glycoprotein produced by prostatic tissue but recently detected in breast tumours, normal tissues, and during pregnancy. The production and intracystic accumulation of this serine protease in biosynthetically active apocrine type cyst can play a feasible role in the natural history of gross cystic breast disease as well as in the mechanism of cyst formation, enlargement, and transformation.     

hMSH6 deficiency and inactivation of the αE-catenin invasion-suppressor gene in HCT-8 colon cancer cells

Transition from an epithelioid (E) to a round (R) morphotype, in the human colon cancer cell line HCT-8, is associated with loss or truncation of αE-catenin and acquisition of invasiveness in organ culture. In E clones, like in parental HCT-8 cells, one allele of the αE-catenin gene (CTNNA1) is mutated. HCT-8 cells have also a “Microsatelite Instability-High” (MSI-H) phenotype presumably due to a mutated hMSH6 gene. Fusion of E type cells doubles the wild type CTNNA1 alleles and prevents the loss of αE-catenin. Introduction of an extra chromosome 2, carrying a wild type hMSH6 gene, restores post-replicative mismatch repair and also prevents the frequent inactivation of the remaining wild type CTNNA1 allele. This revised version was published online in July 2006 with corrections to the Cover Date.     

Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study.

None of the available osteoporosis therapies have been shown to completely abolish the risk of fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that observed in randomized clinical trials, and it was significantly related to poor compliance and lack of supplementation with calcium and vitamin D. INTRODUCTION: Osteoporotic fracture is one of the most important public health concerns among the elderly. Currently available therapies have been shown to significantly decrease the risk of fracture, although none of them completely abolishes this risk. In clinical practice, poor treatment response may also result from a number of other factors. MATERIALS AND METHODS: The Incidence and ChAracterization of inadequate clinical Responders in Osteoporosis (ICARO) is a multicenter, observational study carried out in Italy. It aimed to analyze, in postmenopausal women with established osteoporosis, the risk factors for an "inadequate clinical response" to drug therapy, defined as the occurrence of new vertebral or nonvertebral fragility fractures in patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with a compliance >50%. RESULTS: In 880 patients treated with antiresorptive agents for a median of 2.0 years (95% CI: 1.0-4.5) years, the "inadequate clinical responder (ICR)" subjects over the observation period were 220 (25%), with an annual incidence of 8.9%. ICRs, compared with "adequate clinical responders (ACRs)," had more pretreatment fractures and were treated longer (2.8 versus 1.8 years; p < 0.001). After multiple adjustment for these confounding factors, significant determinants of inadequate clinical response were a poorer treatment compliance and a less frequent co-administration of calcium and vitamin D supplements. CONCLUSIONS: The incidence of fractures during treatment with antiresorptive agents in a clinical setting is considerably higher than that observed in randomized clinical trials. Inadequate compliance to treatment and lack of supplementation of calcium and vitamin D are major determinants of this poor response.