Bi-hemispheric transcranial direct current stimulation for upper-limb hemiparesis in acute stroke: a randomized, double-blind, sham-controlled trial.

BACKGROUND AND PURPOSE: Neuromodulation is a promising approach to increasing motor recovery in stroke; however, to date, there is a scarcity of evidence documenting the clinical potential of transcranial direct current stimulation (tDCS) administered in the acute phase of stroke. The present study aims to examine the clinical effects of a treatment involving the application of tDCS in the acute stage post-stroke. METHODS: This was a randomized, double-blind, sham-controlled trial. A cohort of 32 stroke patients with severe motor impairment underwent 5 days of treatment with real or sham bi-hemispheric tDCS over the motor cortex. During the treatment, tDCS was applied twice per day (two daily applications each of 15 min), starting 48 to 72 h after stroke onset. RESULTS: We found statistically significant improvements after both real and sham tDCS treatments in primary (hand grip strength, Motricity Index) and secondary (National Institutes of Health Stroke Scale score, Barthel Index) outcomes. Patients receiving real tDCS showed a larger improvement of upper-limb muscle strength at the end of treatment phase; this advantage was no longer present after 6 months. CONCLUSIONS: Transcranial direct current stimulation may be used to accelerate the rate of upper-limb motor recovery during the spontaneous recovery period.

Insomnia and menopause: a narrative review on mechanisms and treatments.

The menopausal transition is associated with an increased frequency of sleep disturbances. Insomnia represents one of the most reported symptoms by menopausal women. According to its pathogenetic model (3-P Model), different predisposing factors (i.e. a persistent condition of past insomnia and aging per se) increase the risk of insomnia during menopause. Moreover, multiple precipitating and perpetuating factors should favor its occurrence across menopause, including hormonal changes, menopausal transition stage symptoms (i.e. hot flashes, night sweats), mood disorders, poor health and pain, other sleep disorders and circadian modifications. Thus, insomnia management implies a careful evaluation of the psychological and somatic symptoms of the individual menopausal woman by a multidisciplinary team. Therapeutic strategies encompass different drugs but also behavioral interventions. Indeed, cognitive behavioral therapy represents the first-line treatment of insomnia in the general population, regardless of the presence of mood disorders and/or vasomotor symptoms (VMS). Different antidepressants seem to improve sleep disturbances. However, when VMS are present, menopausal hormone therapy should be considered in the treatment of related insomnia taking into account the risk-benefit profile. Finally, given its good tolerability, safety, and efficacy on multiple sleep and daytime parameters, prolonged-released melatonin should represent a first-line drug in women aged ≥ 55 years.

Prehospital stroke scales and large vessel occlusion: A systematic review.

BACKGROUND AND PURPOSE: Time sensitivity for pharmacological and mechanical arterial recanalization in acute ischemic stroke influences the choice of the reference hospital. The accurate selection and identification of patients with high probability of a large vessel occlusion (LVO) in the prehospital setting improve the rationalization of the transport in the more suitable centers. Aim of this analysis was to determine the diagnostic accuracy of prehospital stroke scales detecting LVO. MATERIAL AND METHODS: Studies were searched into MEDLINE, EMBASE, and CINHAL databases between January 1990 and September 2017. Principal measurements of the meta-analysis were the overall accuracy level, sensitivity, and specificity of prehospital stroke scales. RESULTS: Nineteen scoring systems were included in the analysis coming from 13 studies. A total of 9824 patients were considered. Although a higher heterogeneity was observed in the analysis, three scores showed better results in predicting a LVO (the stroke Vision, Aphasia, Neglect assessment, the National Institute of Health Stroke scale and the Los Angeles Motor Scale). We observed significant differences of overall accuracy only for scores including hemineglect as cortical neurological sign (P < .05). CONCLUSIONS: This meta-analysis suggests that some prehospital scoring systems including cortical signs showed better accuracy to predict stroke due to LVO. However, the assessment of these signs could be difficult to investigate by paramedics and personnel of Emergency Medical Services, and for this reason, further prospective evaluations are needed.

The organisation of the acute ischemic stroke management: key notes of the Italian Neurological Society and of the Italian Stroke Organization.

The main aim of acute ischemic stroke treatment is the as much possible prompt, safe and effective arterial recanalisation, in order to restore reperfusion into the ischemic brain area. The procedures obtaining this result are rapidly evolving and in the last years, we observed new evidences that affirmed the therapeutical benefit of the concomitant treatment using endovenous thrombolysis and mechanical thrombectomy in selected patients with ischemic stroke. However, all treatments are time-sensitive and the main limitation for their application is represented by the time. For this reason, the optimisation of the acute stroke management that includes a pre-hospital and an in-hospital phase is essential to reduce the avoidable delay, increasing the number of patients potentially treatable. The purpose of this document is to define the main elements and to suggest the principal key points constituting the optimal pathway of stroke management in Italian care settings, in line with the recommendations coming from the current national and international guidelines.

Headache in subarachnoid hemorrhage and headache attributed to intracranial endovascular procedures.

Headache is a critical problem in the emergency setting. In this paper we briefly review the epidemiological data regarding headache in Subarachnoid Hemorrhage (SAH), considering the role of headache as a warning symptom and the other clinical manifestation of SAH. We have also introduced a recent clinical entity, represented by headache associated to intracranial endovascular procedures (IEPs).

Improving thrombolysis for acute ischemic stroke in Lombardia stroke centers.

The purpose of this study is to identify which factors are able to limit or hamper the access to systemic thrombolysis (evTPA) in Lombardia to define corrective interventions. We analyzed 1,015 patients with ischemic stroke admitted to emergency departments (ED) participating to the Lombardia Stroke Unit Registry and eligible for evTPA; 303 (29.9%) patients were treated with evTPA (evTPA+ group) and 712 (70.1%) were not (evTPA- group). We collected case-mix and stroke care process variables.The evTPA+ group was characterized by a shorter ED arrival time, a greater neurological impairment, a more chance to be admitted to ED linked to comprehensive stroke center (CSC) and a shorter waiting time to access to diagnostic procedures. The chance to be treated with evTPA was greater if neurological evaluation anticipated neuroimaging (p = 0.0003). The multivariate analysis confirmed that the admission to ED linked to CSC (OR: 2.50, 95% CI: 1.39-4.48, p < 0.0001) and neurological evaluation performed before neuroimaging (OR: 2.34, 95% CI: 1.35-4.04, p = 0.002) increased the probability to receive rtPA. The evTPA treatment is strictly dependent on pre-hospital and ED care process phases and strongly influenced by the degree of stroke severity. Door-to-needle time is shorter in patients with a greater stroke severity and a shorter ED arrival time. A 24-h/week availability of the neurologist in ED can increase the percentage of thrombolysis optimizing the selection of patients and the timing of the diagnostic procedures.

Migraine and small vessel diseases.

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies affecting small cerebral vessels, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy and hereditary infantile hemiparesis, retinal arteriolar tortuosity and leucoencephalopathy. Moreover, several studies have reported an association between migraine and white matter lesions or clinically silent infarct-like abnormalities in the posterior circulation. In this review, we focus on genetic vasculopathies associated with migraine and speculate about the pathophysiological mechanism that can explain this comorbidity.

Thunderclap headache and benign angiopathy of the central nervous system: a common pathogenetic basis.

Thunderclap headache (TCH) is a head pain that begins suddenly and is severe at onset; TCH might be the first sign of different neurological illnesses, and primary TCH is diagnosed when no underlying cause is discovered. Patients with TCH who have evidence of reversible, segmental, cerebral vasoconstriction of circle of Willis arteries and normal or near-normal results on cerebrospinal fluid assessment are thought to have reversible cerebral vasoconstriction syndrome (RCVS). Herein, we discuss the differential diagnosis of TCH and offer pathophysiological considerations for TCH and RCVS.

Medical and endovascular treatments of symptomatic intracranial stenosis. A Bayesian network meta-analysis.

Intracranial stenosis is a well-established stroke risk factor with an increase of stroke recurrence or TIA up to 12.6% at 1 year. Treatments are different: medical and endovascular. We performed a multiple treatment comparison analysis to detect the best treatment in reducing the risk of stroke recurrence. We searched in Medline, Embase, Cochrane Central Register of Controlled Trials databases between 1979 and October 2017. Inclusion criteria were prospective randomized trials that evaluated patients with TIA or stroke due to intracranial stenosis and treated with different medical therapies and/or endovascular procedures. Primary endpoint was the recurrence of TIA or stroke in the territory of intracranial stenosis, while secondary endpoint was represented by any stroke or vascular death. Multiple treatment comparison meta-analysis based on a Bayesian fixed and random effects Poisson model was performed. Seven trials were included with a total of 1337 patients. At multiple treatment comparison, no significant differences between treatments were observed for both primary (median fixed effect standard OR: 0.40; 95%CI: 0.02-1.07) and secondary endpoints (median random effect standard OR: 1.17; 95%CI: 0.32-1.92). Treatment with aspirin alone ranked with high values both for primary and secondary endpoints (surface under the cumulative ranking curve of 70% and 82%, respectively). In patients with symptomatic intracranial stenosis, no differences between treatments were observed. However, aspirin alone was more effective than stenting in the reduction of TIA or stroke recurrences, with a better safety profile than oral anticoagulants.

Rho-dependent regulation of cell spreading by the tetraspan membrane protein Gas3/PMP22.

Gas3/PMP22 plays a crucial role in regulating myelin formation and maintenance, and different genetic alterations in gas3/PMP22 are responsible for a set of human peripheral neuropathies. We have previously demonstrated that Gas3/PMP22 could regulate susceptibility to apoptosis in NIH3T3 cells but not in REF 52 cells. In this report we demonstrate that when the apoptotic response triggered by gas3/PMP22 was counteracted by Bcl-2 coexpression, morphological changes were observed. Time-lapse analysis confirmed that Gas3/PMP22 can modulate cell spreading, and this effect was strengthened after inhibition of phosphoinositide 3-kinase. Using the active form of the small GTPase RhoA, we have been able to dissect the different Gas3/PMP22 biological activities. RhoA counteracted the Gas3/PMP22-dependent morphological response but was unable to neutralize the apoptotic response. Treatment of NIH3T3 cells with cytotoxic necrotizing factor 1, which activates endogenous Rho, also counteracted Gas3/PMP22-mediated cell shape and spreading changes. Treatment of REF 52 cells, which are unresponsive to Gas3/PMP22 overexpression, with the C3 exoenzyme, inhibiting Rho activity, renders REF 52 cells responsive to Gas3/PMP22 overexpression for cell shape and spreading changes. Finally, assembly of stress fibers and focal adhesions complexes, in response to lysophosphatidic acid-induced endogenous Rho activation, was impaired in Gas3/PMP22-overexpressing cells. We hypothesize that cell shape and spreading regulated by Gas3/PMP22 through the Rho GTPase might have an important role during Schwann cells differentiation and myelinization.

HLA-DRB1*15 association with multiple sclerosis is confirmed in a multigenerational Italian family.

Environmental and genetic factors seem to play a pathogenetic role in multiple sclerosis (MS). The genetic component is partly suggested by familial aggregation of cases; however, MS families with affected subjects over different generations have rarely been described. The aim of this study was to report clinical and genetic features of a multigenerational MS family and to perform a review of the literature on this topic. We describe a multigenerational Italian family with six individuals affected by MS, showing different clinical and neuroradiological findings. HLA-DRB1* typing revealed the presence of the DRB1*15:01 allele in all the MS cases and in 4/5 non-affected subjects. Reports on six multigenerational MS families have previously been published, giving similar results. The HLA-DRB1*15:01 allele was confirmed to be linked to MS disease in this family; moreover, its presence in non-affected subjects suggests the involvement of other susceptibility factors in the development and expression of the disease, in accordance with the complex disease model now attributed to MS.

Identification and characterization of a new member of the gas3/PMP22 gene family in C. elegans.

The Gas3/PMP22 protein family is characterized by tetraspan transmembrane proteins. The gas3/PMP22 gene is highly expressed in Schwann cells of the peripheral nervous system, and different alterations of this gene are associated with hereditary demyelinating neuropathies, such as the Charcot-Marie-Tooth type 1A, the Dejerine-Sottas syndrome and the Hereditary Liability to Pressure Palsies (HNPP).Here, we report on the identification of at least one member of the Gas3/PMP22 family in the nematode C. elegans (C01C10.1b). C01C10.1b shares 36% of identical amino acids with the human Gas3/PMP22 and is characterized by four hydrophobic putative transmembrane domains. It lacks the typical N-linked glycosylation consensus in the first extracellular loop. C01C10.1b is transcribed as an operon downstream to the gene C01C10.1a, which encodes for a putative tetraspan protein with less conserved homology with the Gas3/PMP22 family. Interestingly, C01C10.1a contains three N-glycosylation sites at the C-terminus. Both genes are expressed in different nematode developmental stages and in the adults. The characterization of one member of the gas3/PMP22 family in C. elegans gives the opportunity to use this model organism to investigate the role of gas3/PMP22 in the regulation of cell proliferation and differentiation and its relation to the hereditary neurodegenerative diseases in humans.

Macromolecule transfer through mesothelium and connective tissue.

Diffusional permeability (P) to inulin (P(in)), albumin (P(alb)), and dextrans [70 (P(dx 70)), 150 (P(dx 150)), 550 (P(dx 550)), and 2, 000 (P(dx 2,000))] was determined in specimens of parietal pericardium of rabbits, which may be obtained with less damage than pleura. P(in), P(alb), P(dx 70), P(dx 150), P(dx 550), and P(dx 2, 000) were 0.51 +/- 0.06 (SE), 0.18 +/- 0.03, 0.097 +/- 0.021, 0. 047 +/- 0.011, 0.025 +/- 0.004, and 0.021 +/- 0.005 x 10(-5) cm/s, respectively. P(in), P(alb), and P(dx 70) of connective tissue, obtained after removal of mesothelium from specimens, were 10.3 +/- 1.42, 2.97 +/- 0.38, and 2.31 +/- 0.16 x 10(-5) cm/s, respectively. Hence, P(in), P(alb), and P(dx 70) of mesothelium were 0.54, 0.20, and 0.10 x 10(-5) cm/s, respectively. Inulin (like small solutes) fitted the relationship P-solute radius for restricted diffusion with a 6-nm "pore" radius, whereas macromolecules were much above it. Hence, macromolecule transfer mainly occurs through "large pores" and/or transcytosis. In line with this, the addition of phospholipids on the luminal side (which decreases pore radius to approximately 1.5 nm) halved P(in) but did not change P(alb) and P(dx 70). P(in) is roughly similar in mesothelium and capillary endothelium, whereas P to macromolecules is greater in mesothelium. The albumin diffusion coefficient through connective tissue was 17% of that in water. Mesothelium provides 92% of resistance to albumin diffusion through the pericardium.

Pleural liquid pressure.

The knowledge of pleural liquid pressure (Pliq) is essential for understanding the mechanical coupling between lung and chest wall and the liquid exchanges of the pleural space. In the last decade, research in this field contributed new ideas and stimulating controversies but also caused some confusion. These aspects, along with the older contributions, are considered in this review, which is divided into three sections. The topics of the first section are 1) measurements of Pliq with different techniques in various mammals and various regions of the pleural space, 2) comparison of Pliq with the pressure exerted by the lung recoil (Ppl), and 3) vertical gradient of Pliq and downward flow of pleural liquid. In the second section the mechanisms absorbing liquid from the pleural space are analyzed: 1) Starling forces of the visceral pleura, 2) lymphatic drainage through the stomata of the parietal pleura, and 3) active transport of solutes. The third section deals with 1) measurements of pleural liquid thickness with two approaches in the costal region of various mammals and 2) mechanisms preventing a complete removal of pleural liquid and, thus, ensuring the lubrication.

Equivalent radius of paracellular "pores" of the mesothelium.

Diffusional permeability (P) to water (P(w)), Cl(-) (P(Cl(-))), and mannitol (P(man)) was determined in specimens of rabbit parietal pericardium without and with phospholipids added on the luminal side, as previously done with sucrose and Na(+). P to the above-mentioned molecules and to Na(+) (P(Na(+))) was also determined after mesothelium was scraped away from specimens. P(w), P(Cl(-)), P(Na(+)), and P(man) of connective tissue were the following (x10(-5) cm/s): 73.1 +/- 7.3 (SE), 59.5 +/- 4.5, 41.7 +/- 3.4, and 23.4 +/- 2.4, respectively. From these and corresponding data on integer pericardium, P(w), P(Cl(-)), P(Na(+)), and P(man) of mesothelium were computed. They were the following: 206, 17.9, 9.52, and 3.93, and 90.2, 14.4, 4.34, and 1.75 x 10(-5) cm/s without and with phospholipids, respectively. As previously found for P to sucrose, P to solutes is smaller in mesothelium than in connective tissue, although the latter is approximately 35-fold thicker; instead, P(w) is higher in mesothelium, suggesting marked water diffusion through cell membrane. Equivalent radius of paracellular "pores" of mesothelium was computed with two approaches, disregarding P(w). The former, a graphical analysis on a P-molecular radius diagram, yielded 6.0 and 1.7 nm without and with phospholipids, respectively. The latter, on the basis of P(man), P to sucrose, and function for restricted diffusion, yielded 7.8 and 1. 1 nm, respectively.

Pleural pressure between diaphragm and rib cage during inspiratory muscle activity.

We measured the changes in pleural surface pressure (delta Ppl) in the area of apposition of the rib cage to the diaphragm (Aap) in anesthetized dogs during spontaneous breathing, inspiratory efforts after airway occlusion at functional residual capacity, and phrenic stimulation. Intact dogs were in supine or lateral posture; partially eviscerated dogs were in lateral posture. delta Ppl,ap often differed significantly from changes in abdominal pressure (delta Pab); sometimes they differed in sign (except during phrenic stimulation). Changes in transdiaphragmatic pressure in Aap (delta Pdi,ap) could be positive or negative and were less in eviscerated than in intact dogs. delta Pdi,ap could differ in sign among respiratory maneuvers and over different parts of Aap. Hence average delta Pdi,ap should be closer to zero than delta Pdi,ap at a given site. Since delta Ppl,ap = delta Prc,ap, where Prc,ap represents rib cage pressure in Aap, delta Pdi,ap = delta Pab - delta Prc,ap. Hence, considering that delta Pab and delta Prc depend on different factors, delta Pdi,ap may differ from zero. This pressure difference seems related to the interaction between two semisolid structures (contracted diaphragm and rib cage in Aap) constrained to the same shape and position.

Transdiaphragmatic pressure and rib motion in area of apposition during paralysis.

Changes in pleural surface pressure in area of apposition of diaphragm to rib cage (delta Ppl,ap), changes in abdominal pressure (delta Pab), and redial displacement of the 11th rib have been recorded in anesthetized, paralyzed dogs during lung inflation or deflation. Above functional residual capacity (FRC) changes in transdiaphragmatic pressure in area of apposition (delta Pdi,ap) were essentially nil in intact (INT) dogs either in lateral or supine posture, and in partially eviscerated (EVS) dogs in lateral posture, either in the 10th or 11th intercostal space. Below FRC delta Pdi,ap could be positive (INT lateral and EVS), nil (EVS), or negative (INT supine and EVS); it could be different in the 10th and 11th intercostal spaces. Hence, with stretched (like with contracted) diaphragm, delta Ppl,ap measured at one site often differs from delta Pab and is not representative of average pressure acting on area of apposition. With volume increase above FRC, the 11th rib moved slightly in and then out in EVS and linearly out in INT. With volume decrease below FRC it moved out progressively in EVS, and it moved in and eventually reversed in INT. In paralyzed dogs in lateral posture the factor having the greatest influence on displacement of the abdominal rib cage is Pab. Mechanical linkage with pulmonary rib cage becomes relevant at large volume, whereas insertional traction of diaphragm becomes relevant at low volume.

Diffusional permeability of rabbit mesothelium.

Diffusional permeability (P) to sucrose (Psuc) and Na+ (PNa+) was determined in specimens of rabbit sternal parietal pericardium, which may be obtained without stripping. Specimens were mounted in an Ussing apparatus with 3H-labeled sucrose and 22Na+ in a luminal (L) or interstitial (I) chamber. Psuc was 2.16 +/- 0.44 for L-->I and 2.63 +/- 0.45 (SE) x 10(-5) cm/s for I-->L, i.e., approximately 10 times smaller than that previously obtained in stripped specimens of pleura despite the similarity of intercellular junctions in pericardium and pleural mesothelium of various species. These findings suggest that previous Psuc was overestimated because stripping damages the mesothelium. PNa+ (x10(-5) cm/s) was 7.07 +/- 0.71 for L-->I and 7.37 +/- 0.69 x 10(-5) cm/s for I-->L. Measurements were also done with phospholipids, which are adsorbed on the luminal side of mesothelium in vivo. With phospholipids in L, Psuc was 0.75 +/- 0.10 and 0.65 +/- 0.08 and PNa+ was 3.80 +/- 0.32 and 3.76 +/- 0.15 x 10(-5) cm/s for L-->I and I-->L, respectively, i. e., smaller than without phospholipids. With phospholipids in I (where they are not adsorbed), Psuc (2.33 +/- 0.42 x 10(-5) cm/s) and PNa+ (7.01 +/- 0.45 x 10(-5) cm/s) were similar to those values without phospholipids. Hence, adsorbed phospholipids decrease P of mesothelium. If the mesothelium were scraped away from the specimen, Psuc of the connective tissue would be 13.2 +/- 0.76 x 10(-5) cm/s. Psuc of the mesothelium, computed from Psuc of the unscraped and scraped specimens, corrected for the effect of unstirred layers (2. 54 and 19.4 x 10(-5) cm/s, respectively), was 2.92 and 0.74 x 10(-5) cm/s without and with phospholipids, respectively. Hence, most of the resistance to diffusion of the pericardium is provided by the mesothelium.

Mechanical coupling and liquid exchanges in the pleural space.

The pleural space provides the mechanical coupling between lung and chest wall: two views about this coupling are reported and discussed. Information on volume, composition, thickness, and pressure of the pleural liquid under physiologic conditions in a few species is provided. The Starling pressures of the parietal pleura filtering liquid into pleural space, and those of the visceral pleura absorbing liquid from the space are considered along with the permeability of the mesothelium. Information on the lymphatic drainage through the parietal pleura and on the solute-coupled liquid absorption from the pleural space under physiologic conditions and with various kinds of hydrothorax are provided.