A missense mutation in the coiled-coil domain of the KIF5A gene and late-onset hereditary spastic paraplegia

BACKGROUND: To our knowledge, up to now, only 2 mutations in the KIF5A gene, a member of the kinesin superfamily, have been identified as the molecular cause of early-onset autosomal dominant hereditary spastic paraparesis (ADHSP). OBJECTIVE: To assess the genetic defect in a family with late-onset ADHSP. PATIENTS AND METHODS: Only the proband agreed to undergo complete neurological testing and mutational analysis. The proband was screened for mutations in the spastin, atlastin, NIPA1, and KIF5A genes, either by denaturing high-performance liquid chromatography or sequence analysis. RESULTS: The history of the family was consistent with ADHSP characterized by late onset of the disease. Mutational analysis results were negative for the spastin, atlastin, and NIPA1 genes but identified a missense mutation (c.1082C>T) in the coiled-coil coding region of the KIF5A gene. CONCLUSIONS: This finding enlarges the phenotypic spectrum of ADHSP linked to KIF5A and enhances the role of that gene in the epidemiology of this disease. We propose that the KIF5A gene should be routinely analyzed in patients with hereditary spastic paraplegia negative for spastin and atlastin mutations.     

Obsessive-compulsive disorder: a 3-year prospective follow-up study of patients treated with serotonin reuptake inhibitors OCD follow-up study

This study aimed to evaluate the long-term course of obsessive-compulsive disorder (OCD) in patients treated with serotonin reuptake inhibitors (SRIs) and to identify predictors of clinical outcome. Seventy-nine patients fulfilling DSM-IV criteria for OCD were followed prospectively for 3 years. Baseline information was collected on demographic and clinical characteristics, using standardized instruments. During the follow-up period, the clinical status of each patient was evaluated monthly in the first year and bimonthly thereafter by means of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Hamilton Rating Scale for Depression (HDRS). The cumulative probability of achieving at least partial remission from obsessive-compulsive (OC) symptoms during the 3-year period was 65%. The probability of full remission was 38%. For subjects who achieved at least partial remission, the probability of subsequent relapse was 60%. Significant predictors of poor outcome included a longer duration of illness, a greater severity of OC symptoms at intake, and the presence of comorbid schizotypal personality disorder. The findings confirm that the course of illness in OCD is usually continuous with fluctuations in the intensity of OC symptoms. Despite adequate SRI therapy, relatively few patients achieve a completely asymptomatic state, and of those who achieve at least a partial remission, a substantial proportion subsequently relapse. One third of OCD patients is treatment-resistant. Further studies with large samples are required to adequately identify predictors of long-term outcome of OCD in order to optimize the choice among the existing treatment modalities. The development of alternative strategies is needed to improve the treatment approaches for treatment-resistant OCD patients.     

CSF markers in Alzheimer disease patients are not related to the different degree of cognitive impairment

Standard markers in cerebrospinal fluid (CSF), as soluble amyloid beta 1-42 (Abeta1-42) and total tau protein (t-tau), may contribute to dementia subtypes diagnostic accuracy. Yet, their sensitivity to assess the different degree of cognitive deficit is not fully clarified. Our study analyses Abeta1-42 and t-tau CSF levels in different cohorts of Alzheimer's disease (AD) patients, distinguished as early AD (mild cognitively impaired subjects recently converted to AD), mild AD (MMSE<23; > or =18), and moderately advanced AD (MMSE<18). The control group was represented by age-matched patients affected by depressive pseudo-dementia. Reduced Abeta1-42 and increased t-tau CSF levels were confirmed as hallmarks of AD at any disease stage. In early AD patients, Abeta1-42 levels were already significantly low, if compared to the control group (336 vs 867 ng/L; p<0.0001). On the contrary, Abeta1-42 levels did not differ between AD subgroups, and in particular between mild to moderate AD. A significant progressive increase of t-tau concentration was found when comparing early AD (269 ng/L) to more advanced AD stages (468 ng/L and 495 ng/L for mild and moderate AD, respectively). Our findings confirm that the impairment of amyloidogenic cascade is an early, even pre-clinical process, but suggest that soluble Abeta1-42 concentration has a negligible correlation with the clinical progression. Conversely, t-tau concentration correlates with the transition towards marked cognitive impairment.     

Hypohidrosis during topiramate treatment: a rare and reversible side effect

Topiramate is an antiepileptic drug with a beneficial clinical effect on various seizure types. Topiramate does not seem to be associated with serious adverse effects and is also well tolerated in pediatric patients. Only few cases of hypohidrosis have been described. This report presents one young patient with complex partial seizures who was medicated with topiramate when she developed fatigue, headache, intermittent hyperthermia, inability to produce sweat secretion, and dryness of the skin. Reduced sweat response was determined using the Wescor Macroduct collection procedure. Topiramate was discontinued, and within 3 weeks a repeat sweat test was completely normal. At that time, clinical signs had also disappeared. Hypohidrosis is an uncommon and reversible side effect reported in association with topiramate therapy. It is rare in patients on monotherapy. Although a definite causal relationship still needs to be established, this side effect might be attributed to an autonomic dysfunction by inhibition of isoenzymes of carbonic anhydrase localized in human eccrine sweat glands.     

Long-term incubation with β-amyloid peptides impairs endothelium-dependent vasodilatation in isolated rat basilar artery

Alzheimer's disease is associated to a cerebral amyloid angiopathy with dysregulation of cerebral blood flow (CBF). In vitro studies have shown that short-term application of β-amyloid (Aβ) peptides to isolated vessels affects vascular tone within 1 h, but no studies have examined the effect of long-term incubation with Aβ. Here we evaluate the effect of Aβ_(1–40) and Aβ_(25–35) in rat basilar artery for up to 24 h. Basilar artery segments were incubated with 25 μM Aβ_(1–40) or Aβ_(25–35), for 6 or 24 h. After treatment, arteries were mounted in a wire myograph, in physiological salt solution gassed with O₂/CO₂, in the absence of Aβ, and challenged with vasoconstrictors and vasodilators. Vasomotor responses were not significantly changed by 6 h treatment with Aβ peptides whereas 24 h treatment with either Aβ_(25–35) or Aβ_(1–40) increased vasoconstriction to 5-hydroxytryptamine (5-HT) and reduced endothelium-dependent vasodilatation to acetylcholine (ACh). Analysis of endothelial cells did not show apoptotic changes associated to endothelial dysfunction, as assessed by TUNEL immunostaining and examination of nuclear morphology, but basal phosphorylation of endothelial nitric oxide synthase (at serine 1177) appeared reduced.These data suggest that long incubation with Aβ peptides induces an alteration of endothelial function in isolated basilar artery, involving eNOS activity without changing cell morphology. This endothelial dysfunction may play a role in the pathogenesis of CBF dysregulation occurring in cerebral amyloid angiopathy and Alzheimer's disease.     

Optimizing the Dose Distribution in Stereotactic Body Radiotherapy with Standard Multileaf Collimator(MLC): A Planning Study

Purpose: To evaluate in stereotactic body radiotherapy (SBRT) setting the impact of the spatial relationship between the target volume and main organ at risk (mOAR) using different target-multi-leaf collimator (MLC) block margins with or without fluence intensity modulation (IMRT technique).Methods/Patients: Dosimetric evaluation of 3 scenarios was performed.In the first one, the target and the main organ at risk (mOAR) had a partial overlap.In the second, the target was completely surrounded by the mOAR and in the third the target was near without touching the mOAR.Results and Conclusions: Maximal mOAR sparing was obtained with 6 mm (patients 1 and 3) and 4mm (patient 2) block margins.Concerning irradiation technique, IMRT plans showed a significant mOAR sparing in patients 1 and 3.In conclusion, a 5mm standard block margin can be proposed as optimal.Moreover, the use of IMRT in the SBRT setting may carry out a potential benefit, except when the mOAR surrounds the target.     

Immune Response after the Fourth Dose of SARS-CoV-2 mRNA Vaccine Compared to Natural Infection in Three Doses’ Vaccinated Solid Organ Transplant Recipients

Solid organ transplant recipients (SOTRs) show higher rates of COVID-19 breakthrough infection than the general population, and nowadays, vaccination is the key preventative strategy. Nonetheless, SOTRs show lower vaccine efficacy for the prevention of severe COVID-19. Moreover, the emergence of new SARS-CoV-2 variants of concern has highlighted the need to improve vaccine-induced immune responses by the administration of repeated booster doses. In this study, we analyzed the humoral and cellular responses in a cohort of 25 SOTRs, including 15 never-infected SOTRs who received the fourth dose of the mRNA vaccine and 10 SOTRs who contracted SARS-CoV-2 infection after the third dose. We analyzed the serum IgG and IgA levels through CLIA or ELISA, respectively, and the Spike-specific T cells by ELISpot assay. We report a significant increase in anti-Spike IgG and no differences in IgA secretion in both groups of patients before and after the booster dose or the natural infection. Still, we show higher IgA levels in recovered SOTRs compared to the fourth dose recipients. Conversely, we show the maintenance of a positive Spike-specific T-cell response in SOTRs who received the fourth dose, which, instead, was significantly increased in SOTRs who contracted the infection. Our results suggest that the booster, either through the fourth dose or natural infection, in vulnerable poor responder SOTRs, improves both humoral and cellular-specific immune responses against SARS-CoV-2.