Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke.

BACKGROUND: Several lines of evidence support the involvement of the lectin pathway of complement (LP) in the pathogenesis of acute ischemic stroke. The aim of this multicenter observational study was to assess the prognostic value of different circulating LP initiators in acute stroke. METHODS: Plasma levels of the LP initiators ficolin-1, -2, and -3 and mannose-binding lectin (MBL) were measured in 80 stroke patients at 6 h only and in 85 patients at 48 h and later. Sixty-one age- and sex-matched healthy individuals served as controls. Stroke severity was measured on admission using the National Institutes of Health Stroke Scale (NIHSS). The outcome was measured at 90 days by the modified Rankin Scale (mRS). RESULTS: Ficolin-1 was decreased in patients compared with controls measured at 6 h (median 0.13 vs 0.33 µg/ml, respectively, p < 0.0001). At 48 h, ficolin-1 was significantly higher (0.45 µg/ml, p < 0.0001) compared to the 6 h samples and to controls. Likewise, ficolin-2 was decreased at 6 h (2.70 vs 4.40 µg/ml, p < 0.0001) but not at 48 h. Ficolin-3 was decreased both at 6 and 48 h (17.3 and 18.23 vs 21.5 µg/ml, p < 0.001 and <0.05, respectively). For MBL no difference was detected between patients and controls or within patients at the different time points. In multivariate analysis, early ficolin-1 was independently associated with unfavorable mRS outcome (adjusted odds ratio (OR): 2.21, confidence interval (CI) 95 % 1.11-4.39, p = 0.023). Early ficolin-1 improved the discriminating ability of an outcome model including NIHSS and age (area under the curve (AUC) 0.95, CI 95 % 0.90-0.99, p = 0.0001). CONCLUSIONS: The ficolins are consumed within 6 h after stroke implicating activation of the LP. Early ficolin-1 is selectively related to 3-month unfavorable outcome.

Genetics of cerebral hemorrhage and microbleeds.

Intracerebral haemorrhage (ICH) is the least treatable and often fatal form of stroke. Literature data suggest a strong familial contribution to ICH. The identification of genetic factors with a role in ICH could enhance the understanding of the pathogenesis of hemorrhagic brain injury leading to new treatment and prevention approaches with the final goal of identifying high risk individuals in which genetic pattern may influence clinical and therapeutical decisions. Herein, we provide an updated review on genetic factors associated with occurrence and outcome of ICH. Except for monogenic disease which account for a minor proportion of hemorrhages, most of hemorrhagic stroke heritability is believed to be polygenic. However, the results of candidate gene studies did not show significant results except for the association between apoE genotype and ICH, which has been replicated in large population studies. These data may support the hypothesis that the risk that can be attributed to each of these polymorphisms taken individually is still moderate and some relatively common variants could contribute in determining the disease acting in synergy with other genetic factors.

The genetics of small-vessel disease.

Cerebral small-vessel disease (SVD) is a well-known cause of stroke, dementia and death, but its pathogenesis is not yet completely understood. The spectrum of neuroradiological manifestations associated with SVD is wide and may result from chronic and diffuse or acute and focal ischemia (leukoaraiosis and lacunar infarction) as well as from small-vessel rupture (cerebral microbleeds and intracerebral hemorrhage). Several lines of evidence from family and twin studies support the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge of SVD pathogenesis and help to identify new therapeutic targets to reduce the burden of SVD-related cognitive decline and stroke disability. A number of monogenic conditions presenting with clinical features of SVD have been described. Although monogenic disorders account for only a small proportion of SVD, study of these diseases may provide further insight into the pathogenesis of SVD. In most cases, however, SVD is thought to be a multifactorial disorder. Several genetic association studies, conducted using the candidate gene and, more recently, the genome-wide approach, have so far failed to demonstrate a convincing association between SVD and genetic variants. Methodological issues, particularly related to inaccurate or heterogeneous phenotyping and insufficient sample sizes, have been invoked as possible reasons for this. Large collaborative efforts and robust replication, as well as implementation of new genetic approaches, are necessary to identify genetic susceptibility factors for complex SVD.

Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy.

Fabry disease is a multisystem, X-linked, lysosomal storage disorder caused by a mutation in the GLA gene on chromosome Xq22 resulting in alpha-galactosidase A enzyme (α-Gal A) deficiency. Neurological manifestations other than cerebrovascular accidents include small fibre neuropathy and dysautonomic disorders, which may be the presenting clinical features in a proportion of patients. An atypical disease onset may be misdiagnosed until the emergence of a more typical clinical picture, characterized by chronic renal and cardiac failure. Thus, neurologists should consider Fabry disease in differential diagnosis and provide an appropriate diagnostic work up. This review focuses on central and peripheral nervous system involving available diagnostic tools and diagnostic work up in Fabry disease. It also covers the most recent evidence regarding enzyme replacement therapy.

Anti-MuSK-Positive Myasthenia Gravis in a Patient with Parkinsonism and Cognitive Impairment.

Muscle-specific tyrosine kinase- (MuSK-) antibodies-positive Myasthenia Gravis accounts for about one third of Seronegative Myasthenia Gravis and is clinically characterized by early onset of prominent bulbar, neck, shoulder girdle, and respiratory weakness. The response to medical therapy is generally poor. Here we report a case of late-onset MuSK-antibodies-positive Myasthenia Gravis presenting with signs of cognitive impairment and parkinsonism in addition to bulbar involvement and external ophthalmoplegia. The pattern of involvement of both peripheral and central nervous system dysfunction might suggest a common pathogenic mechanism, involving impaired cholinergic transmission.

Determination of the nateglinide polymorphic purity through DSC.

It is well known that the control of the crystallization of drugs to ensure that only the approved and desired polymorph is present in the formulation is a crucial point of a preformulation study. In this regard, the aim of the present work is to devise a method for the quantification of the polymorphic purity of nateglinide in mixtures formed by polymorphs H and B. In order to achieve this goal, binary systems of known composition have been prepared and the melting peaks of both polymorphs have been recorded by differential scanning calorimetry. Experiments have determined that the method of preparation of the mixtures has to be carefully evaluated. Indeed it has been shown that grinding the samples induces transition from B to H form. Furthermore, it could be observed that the enrichment of the binary mixture with H form is caused by heating. Therefore, after having prepared the mixture without grinding stage, we propose a method to evaluate the content of H polymorph in mixture with the B one from the melting peak of B.

Growth factors in ischemic stroke.

Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1α and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects.

Stenting for the treatment of high-grade intracranial stenoses.

To date, evidence to recommend endovascular treatment in patients with intracranial stenoses is lacking. Recently, the introduction of self-expanding stents (Wingspan Stent System) aroused considerable expectations in their employ for stroke prevention. We report a single-center experience of percutaneous transluminal angioplasty and stenting in a series of consecutive patients with intracranial stenoses and compare the safety and performance of balloon-mounted stents versus self-expanding stent systems (Wingspan). Thirty-four patients with 39 severe (>70%) intracranial stenoses were treated during a 6-year period. An independent stroke neurologist collected data about intra and periprocedural complications and short-term outcome. We considered as endpoint measures (1) any 30-day stroke or death (2) any major 30-day complication and (3) procedure technical success. Technical success was achieved in all patients. No vessel dissection or ruptures were observed. The 30-day stroke/death rate was 17.9%. Five ischemic strokes in the territory of treated vessels and two intracranial hemorrhages occurred respectively within 24 h and 5 days after endovascular treatment. Three (17.6%) patients of Wingspan treated group and four (18.2%) of the patients treated with different stent systems had unfavorable outcome. Our study confirms that endovascular treatment can be performed with a high technical success rate, even though the safety of these devices has still to be demonstrated.

New solid modifications of nateglinide.

New modifications of the antidiabetic drug nateglinide were found and characterized by means of thermal analysis, vibrational spectroscopy and X-ray powder diffractometry. In particular it has been verified that the product obtained during the final steps of the nateglinide synthesis is the hemihydrate form which melts at about 86 degrees C provided that the adopted experimental conditions hinder the removal of the crystallization water. Otherwise, if the crystallization water is removed, the hemihydrate transforms to a new anhydrous polymorph that melts at 102.8 degrees C. The anhydrous polymorph, if stored at room temperature and humidity, gradually changes to H polymorph while, if stored in water vapour saturated atmosphere, it gets back water and reverts to the hemihydrate form. On the contrary, both an isothermal treatment at 80 degrees C and melt cooling bring to the B polymorph.

Thermodynamic relationships between nateglinide polymorphs.

The physico-chemical characterization of the polymorphs of nateglinide (named B, H and S), an antidiabetic agent, has been performed by means of thermal, diffractometric, spectroscopic and electron microscopic measurements. It has been established that S polymorph can crystallize from the melt obtained from both B and H samples or also following an isothermal treatment of both forms at temperatures lower than the relevant melting points. By X-ray diffraction it could be shown that the three polymorphs have different crystal structure. On the other hand the indication has been drawn from IR spectra that the molecular structure of B is sensibly different from those of H and S forms that have a very similar molecular structure. Finally, the microstructure features of the three polymorphs have been examined by scanning electron microscopy. Our analyses have allowed to evaluate the relative stability of the three polymorphs through the construction of the energy vs. temperature diagram. In particular, S polymorph, the highest-melting form, has resulted to be the only stable form, while the B and H forms are metastable.

Transthyretin Asn90 variant: amyloidogenic or non-amyloidogenic role.

A number of mutations were described in the TTR gene. They were generally related to a variety of inherited syndromes named 'familial TTR-related amyloidoses'. Although TTR mutations were mostly associated with familial amyloid polyneuropathy (FAP), these molecular variants were also found in patients with recurrent stroke, subarachnoidal bleeding and radiological findings of cerebral, cerebellar, cortical-subcortical infarctions and hemosiderosis. We describe a 46 y.o. man with recurrent cerebral haemorrhages carrying Asn90His variant of TTR gene. This mutation has been reported both in FAP and asymptomatic subjects raising the doubt on the possible amyloidogenetic role of this variant. The absence of mutation in the patient's father, who had a history of unexplained cerebral haemorrhage and the lack of symptoms and sign of cerebral bleeding in the two patient's sisters, carrying the same mutation, seem to support the hypothesis that His90Asn TTR mutation do not have an impact in amyloid formation. It has still to be established whether other gene variants in our patient could act synergistically with His90Asn TTR mutation in increasing the risk of CNS haemorrhages.

Safety of carotid stenting for stroke prevention: need of an independent outcome assessor.

Safety and efficacy of carotid artery stenting have still to be fully established. We propose a standardized registry of carotid artery stenting in use at our hospital to evaluate whether the presence of an independent neurologist performing basal, procedural and post-procedural observation increases the accuracy of outcome assessment. We collected a cohort of patients receiving carotid stenting. An external neurologist supervised the endovascular intervention and monitored the patient's clinical conditions during procedure and follow-up time (12 months). The procedure was carried out successfully in all cases. We registered two intra-procedural strokes and two strokes within 24 h. The risk of major complications in our study was 9.1% at 30 days. Our complication rate is higher than in previous studies. These findings could be partly explained by the unemployment of distal protection devices, but also by the presence of an independent observer that might have increased the accuracy of neurological evaluation.

Stem cell therapy in stroke.

Recent work has focused on cell transplantation as a therapeutic option following ischemic stroke, based on animal studies showing that cells transplanted to the brain not only survive, but also lead to functional improvement. Neural degeneration after ischemia is not selective but involves different neuronal populations, as well as glial and endothelial cell types. In models of stroke, the principal mechanism by which any improvement has been observed, has been attributed to the release of trophic factors, possibly promoting endogenous repair mechanisms, reducing cell death and stimulating neurogenesis and angiogenesis. Initial human studies indicate that stem cell therapy may be technically feasible in stroke patients, however, issues still need to be addressed for use in human subjects.

Statins and stroke.

Pharmacological studies highlighted pleiotropic effects of statins, that seem to influence atherogenesis not only by increasing atherosclerotic plaque stability but also by modulating endothelial function and inflammation and acting on platelet aggregation and thrombosis. Despite a strong association between increased levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of coronary heart disease (CHD) has been well proven, it not yet established whether serum LDL-C levels are related to stroke incidence. The major aim of this paper is to perform a comprehensive up-to-date review of research papers, meta-analyses and randomized controlled clinical trials reporting the effects of statins in primary and secondary stroke prevention strategies. In addition, our work provides an overview on statin chemical structure, mechanism of action and pharmacological properties, investigating also most common adverse effects and relationship between statin therapy and haemorrhagic stroke risk, in order to assess drugs safety. Although studies are heterogeneous, our analysis shows that statins reduce the risk of stroke occurrence in high risk patients and seem also to reduce stroke recurrence. Moreover, the low incidence and reversibility of adverse effects, and the unclear association with hemorrhagic events, support the safe use of these drugs.