CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study

Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Among our group of CCM Italian patients, we selected a cohort of sporadic cases negative for mutations in CCM genes. In this cohort, five variants in CCM2 gene were detected, which proved to be the known polymorphisms in intronic regions (IVS2-36A>G and IVS8 +119 C>T) and in coding sequence (c.157 G>A in exon 2, c.358 G>A in exon 4 and c.915 G>A in exon 8). Therefore, we undertook a case-control study to investigate the possible association of these polymorphisms with sporadic CCMs. The five polymorphisms were identified in 91 CCM sporadic patients and in 100 healthy controls by direct sequencing methods using lymphocyte DNA. Polymorphisms IVS2-36A>G and c.915 G>A showed statistically significant differences in frequencies between patients and controls [(χ2, 6.583; P<0.037); (χ2, 14.205; P<0.001)]. The prevalence of the wild-type genotype was significantly lower in the CCM group than in the control sample. Patients with the A/G and G/G genotypes (IVS2-36A>G) had a significant increase for CCM risk (OR, 3.08; 95% CI, 1.5-5.9 and OR, 4.3; 95% CI, 1.4-22.6) and the same was observed for the polymorphism c.915 G> A (genotype G/A OR, 6.1; 95% CI, 3.0-12.6 and genotype A/A OR, 2.79). In addition, the polymorphisms c.358 G>A in exon 4 (χ2, 15.977; P<0.04) and c.915 G>A in exon 8 (χ2, 18.109; P<0.02) were significantly associated with different types of symptoms. Haplotype analysis, performed only on polymorphisms c.358 G>A (p.Val120Ile), c.915 G>A (p.Thr305 Thr) and IVS2-36A>G, shows that haplotype GAG (+--) significantly increased among CCM sporadic patients compared to the control group. Significant differences between patients and controls were observed only for IVS2-36A>G and c.915 G>A polymorphisms indicating their possible association with sporadic CCMs and an increased risk of CCM. On the other hand, polymorphisms c.358 G>A and c.915 G>A were associated with a more benign course of the disease. These data were confirmed by the haplotype GAG (+--) frequencies.     

Salvage chemotherapy with CCNU and methotrexate for small cell lung cancer resistant to CAV/PE alternating chemotherapy.

CCNU and methotrexate were employed as salvage treatment in 34 small cell lung cancer patients resistant to CAV/PE alternating induction chemotherapy. In the 33 evaluable patients we observed an objective response rate of 21.2% and 3% complete response; median survival was 4 months with 2 patients alive 18 months from starting salvages chemotherapy. The treatment was well tolerated. CCNU and methotrexate has shown to be a moderately active and tolerable salvage treatment for small cell lung cancer after CAV/PE alternating first-line chemotherapy.     

Lipoprotein patterns in follicular fluid

Samples of follicular fluid have been obtained from 23 women in order to evaluate the concentration of the different classes of lipoproteins. In the Authors' preliminary experience the determination of these biochemical parameters could help the diagnosis of LUF syndrome.     

Role of natural killer cells in the pathogenesis and progression of multiple sclerosis.

Natural killer (NK) cells are a subset of lymphocytes which have long been alleged to play an immunoregulatory role in the prevention of autoimmune diseases. Here, we briefly review NK cell features and the major findings from studies on NK cells in human and animals susceptible to multiple sclerosis (MS). Although most studies in human seem to suggest an association between disease and deficiencies in NK cells, it is also clear that NK cells can be both protective and pathogenic in MS models. These contrasting observations could result from differences in experimental procedures as well as from differences in NK cell subset targeted. Whatever the case, the functional features of these cells and their potential role in regulation of autoimmunity suggest that NK cell-based therapies might be an interesting approach for the treatment of multiple sclerosis.     

N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone reduces severity of experimental spinal cord injury

The aim of this study was to investigate the effects of N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketones (z-VAD-fmk) on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with z-VAD-fmk, a potent broad specific caspase inhibitor, significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nitrotyrosine formation, and (4) apoptosis (TUNEL staining and Bax and Bcl-2 expression). In a separate set of experiments, z-VAD-fmk significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with z-VAD-fmk reduces the development of inflammation and tissue injury associated with spinal cord trauma.     

Cognitive training for patients with dementia living in a sicilian nursing home: a novel web-based approach

Dementia is an increasing challenge for health care and social system in developed countries. Interventions with a cognitive focus, also using assistive technology, are leading to promising results in improving cognitive and behavior symptoms in individuals with dementia. Aim of our study was to evaluate the combined effects of the standard cognitive training in addition to web-based rehabilitation in dementia people living in a nursing home. We have studied twenty dementia people (10 females and 10 males) with a mild to moderate cognitive decline (MMSE 25 ± 3.4) associated to moderate behavioral alterations, and mainly due to vascular causes. These patients were randomly assigned to one of two groups (experimental or standard treatment—namely the control group). All participants in the experimental group completed the specific training, consisting of 24 sessions of web-based cognitive training, for 8 weeks, in addition to standard rehabilitation. Each participant was evaluated by a skilled neuropsychologist before and after each treatment. The experimental group had a statistically significant change of the Geriatric Depression Scale (p = 0.03), Constructive Apraxia (p < 0.001), Matrices Attentive (p = 0.01), and Mini Mental State Examination (p = 0.04). Web-based cognitive rehabilitation can be useful in improving cognitive performance, besides psychological well-being, in demented individuals living in home care.     

Coenzyme Q10‐responsive ataxia: 2‐year‐treatment follow‐up

We assessed the clinical outcome after coenzyme Q₁₀ (CoQ₁₀) therapy in 14 patients presenting ataxia classified into two groups according to CoQ₁₀ values in muscle (deficient or not). We performed an open‐label prospective study: patients were evaluated clinically (international cooperative ataxia rating scale [ICARS] scale, MRI, and videotape registration) at baseline and every 6 months during a period of 2 years after CoQ₁₀ treatment (30 mg/kg/day). Patients with CoQ₁₀ deficiency showed a statistically significant reduction of ICARS scores (Wilcoxon test: P = 0.018) after 2 years of CoQ₁₀ treatment when compared with baseline conditions. In patients without CoQ₁₀ deficiency, no statistically significant differences were observed in total ICARS scores after therapy, although 1 patient from this group showed a remarkable clinical amelioration. Biochemical diagnosis of CoQ₁₀ deficiency was a useful tool for the selection of patients who are good candidates for treatment as all of them responded to therapy. However, the remarkable clinical response in 1 case without CoQ₁₀ deficiency highlights the importance of treatment trials for identification of patients with CoQ₁₀‐responsive ataxia. © 2010 Movement Disorder Society     

Characterization of the immune response of human cord-blood derived gamma/delta T cells to stimulation with aminobisphosphonate compounds

Vγ9Vδ2 T lymphocytes have been shown to respond to a variety of non-peptide antigens including alkylamines and phosphoantigens. Recently, aminobisphosphonates have also been shown to stimulate this subset of γδ+ T cells. In this study we analyzed the proliferative responses of freshly isolated γδ T lymphocytes obtained from human cord blood when challenged with pyrophosphomonoesters or aminobisphosphonates. Nitrogen-containing aminobisphopsphonates, in contrast to phoshoantigens, readily stimulated expansion of Vδ2Vγ9 cells in human cord blood. Expanded cells displayed an activated mature phenotype, and were capable of producing TNFalpha and IFNgamma but not perforin following secondary stimulation, consistent with the development of a regulatory, as opposed to cytotoxic, phenotype. This approach may provide a useful strategy for a new approach to the treatment of neonatal pathologies.