Acute revascularization treatments for ischemic stroke in the Stroke Units of Triveneto, northeast Italy: time to treatment and functional outcomes.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0-1 and 0-2 at 3 months. The unfavorable outcome measures were mRS score 3-5 and death at 3 months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3 months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60 min (OR 4.005, 95% CI 1.232-13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983-0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975-0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988-1.000) were associated with mRS 0-1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984-0.998), door-to-groin time ≤ 90 min (OR 12.146, 95% CI 2.193-67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972-0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987-0.999) were associated with mRS 0-2. Longer door-to-groin time (OR 1.007, 95% CI 1.001-1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005-1.034) were associated with mRS 3-5, while door-to-groin time ≤ 90 min (OR 0.229, 95% CI 0.065-0.808) was inversely associated with mRS 3-5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002-1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.

Posterior reversible encephalopathy syndrome associated with Guillain-Barré syndrome: Case report and clinical management considerations.

Around half of the patients with Guillain-Barré syndrome (GBS) present autonomic dysfunction requiring admission to intensive care unit in up to a quarter of patients. Treatment of GBS consists of plasma exchange (PE) and intravenous immunoglobulins (IVIG). Posterior reversible encephalopathy syndrome (PRES) consists in a reversible subcortical vasogenic brain edema caused by endothelial damage triggered by abrupt blood pressure changes. We report on a woman who presented with PRES in the course of GBS treated first with IVIG, and then with PE. The present report underlines the challenge that the clinicians face when these two rare syndromes concur. The literature is not helpful considering that both blood pressure fluctuations and IVIG are reported to be involved in the pathogenesis of PRES. In the present letter, both pathogenic mechanisms and clinical management considerations are discussed.

Intravenous thrombolysis for ischemic stroke in the Veneto region: the gap between eligibility and reality.

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.

Clinical and Imaging Study of Isolated and Mixed Rest and Action Tremor-Essential Tremor versus Parkinson's Disease.

BACKGROUND: Some patients present an unusual association of both action tremor (AT) and rest tremor (RT) making the differential diagnosis between essential tremor (ET) and Parkinson's disease (PD) difficult. AIM: To investigate this particular clinical picture trying to focus on possible peculiar clinical inferences. PATIENTS AND METHODS: Twenty-three patients with atypical tremor syndrome were selected for the study. They underwent neurological examination, neuroimaging study, and brain DaTSCAN single-photon emission computed tomography. RESULTS: Twenty-three patients were evaluated; 17 presented mixed-tremor syndrome, while six patients showed only isolated AT or RT. DaTSCAN was pathological in 19 patients and normal in 3 patients. The emerging statistical data highlighted a positive correlation between disease duration and DaTSCAN abnormalities; Fisher's exact test showed a marked difference in evolution toward a dysfunction of dopaminergic pathways in patients with both AT and RT phenotype. CONCLUSION: The possible correlation between PD and ET has often been discussed without any clear findings. Are these patients suffering from ET prone to develop PD? Or are they the expression of a specific clinical phenotype? Our clinical survey has not led to absolute considerations; however, it seeks to highlight the clinical markers that might arouse the suspicion of extrapyramidal disease in patients with atypical tremor syndrome.

Mild Encephalitis with a Reversible Splenial Lesion: A Clinical Benign Condition, often Underrecognized - Clinical Case and Literature Review.

Mild encephalitis with reversible lesion in the splenium is a clinicoradiological syndrome characterized by a variegated symptomatology with a solitary mass in the central portion of the splenium of the corpus callosum. Complete spontaneous resolution is the hallmark of this syndrome, though its pathogenesis is still unknown. We describe the clinical picture of a 51-year-old woman who developed a partial sensitive seizure, with MRI evidence of a lesion localized in the posterior portion of the corpus callosum. The patient made a full recovery thanks to the administration of antiepileptic drugs. Acquiring knowledge of this syndrome, in the wide diagnostic panel which includes vertebrobasilar diseases besides the broad range of metabolic and electrolyte disorders, is crucial to a prompt clinical diagnosis and in establishing a reliable prognosis at an early stage.

Abnormal nociceptive processing occurs centrally and not peripherally in pain-free Parkinson disease patients: A study with laser-evoked potentials.

BACKGROUND: Several studies documented abnormal nociceptive processing in PD patients. Pain central pathways are accessible by laser-evoked potentials (LEPs). LEPs recording show a N2/P2 complex mostly generated by the anterior cingulate cortex, preceded by an earlier negative component (N1), originating from the opercular cortex. Previous work demonstrated N2/P2 amplitude reduction in PD patients and suggested a centrally-acting pathomechanism for the genesis of pain. However, since a peripheral deafferentation has been recently demonstrated in PD, it is not clear if such LEP abnormalities reflect a mechanism acting centrally or not. OBJECTIVE: To assess whether abnormalities of nociceptive inputs occur at central and/or peripheral level in pain-free PD patients with hemiparkinson using Nd:YAP LEPs. METHODS: We recorded scalp Nd:YAP-LEPs to hand stimulation in 13 pain-free patients with unilateral PD and in 13 healthy subjects. Additionally, we collected laser pain-rating in both groups. RESULTS: PD patients and normal subjects showed comparable N1, N2 and P2 latencies. The N2/P2 amplitude was significantly lower in PD patients than in controls, regardless of the clinically affected side, whereas the N1/P1 amplitude was not different. PD patients had higher pain-rating, indicative of hyperalgesia. CONCLUSIONS: These findings demonstrate that in the PD patients the abnormal processing of pain stimuli occurs at central rather than peripheral level. The co-existence of hyperalgesia and reduced amplitude of the N2/P2 complex, in spite of a normal N1/P1 component, suggests an imbalance between the medial and lateral pain systems. Such a dissociation might explain the genesis of central pain in PD.

Obesity decreases B cell responses in young and elderly individuals.

OBJECTIVE: To evaluate the effects of obesity-associated inflammation on influenza vaccine responses. METHODS: In young and elderly individuals, both lean and with obesity, antibody responses to influenza vaccination were measured. RESULTS: A decrease in in vivo vaccine responses, circulating switched memory, and transitional B cells and an increase in pro-inflammatory late/exhausted memory B cells were found. In vitro B cell function was measured by activation-induced cytidine deaminase and E47, markers of optimal antibody responses. Moreover, IL-6 production was increased, whereas IL-10 production was decreased in cultures of B cells from individuals with obesity. Markers of immune activation (TNF-α, TLR4, micro-RNAs) in unstimulated B cells were also found increased and were negatively correlated with B cell function. In order to reveal potential mechanisms, we stimulated B cells from lean individuals in vitro with leptin, the adipokine increased in obesity. Leptin increased phospho-STAT3, crucial for TNF-α production, and decreased phospho-AMPK, the energy sensing enzyme upstream of phospho-p38 MAPK and E47. Leptin-induced phospho-STAT3 and phospho-AMPK levels were similar to those in B cells from individuals with obesity. CONCLUSIONS: These results demonstrate that leptin can be responsible for decreased B cell function in obesity.

MicroRNAs miR-155 and miR-16 Decrease AID and E47 in B Cells from Elderly Individuals.

Our research in the past few years has identified B cell-specific biomarkers able to predict optimal Ab responses in both young and elderly individuals. These biomarkers are activation-induced cytidine deaminase (AID), the enzyme of class switch recombination and somatic hypermutation; the transcription factor E47, crucial for AID expression; and the ability to generate optimal memory B cells. Moreover, we have found that the increased proinflammatory status of the elderly, both in sera and intrinsic to B cells, negatively impacts B cell function. We have now investigated whether particular inflammatory microRNAs (miRs) contribute to decreased E47 and AID in aged B cells. Our data indicate that E47 and AID mRNA stability is lower in stimulated B cells from elderly individuals. We measured the expression of two miRs crucial for class switch recombination, miR-155 and miR-16, in human unstimulated B cells from young and elderly individuals with the rationale that increases in these before stimulation would decrease E47/AID upon cell activation. We found these miRs and B cell-intrinsic inflammation upregulated in aged unstimulated B cells and negatively associated with AID in the same B cells after stimulation with CpG. We propose that the downregulation of AID in aged human B cells may occur through binding of miR-155 to the 3'-untranslated regions of AID mRNA and/or binding of miR-16 to the 3'-untranslated regions of E47 mRNA, as well as at the transcriptional level of less E47 for AID. Our results indicate novel molecular pathways leading to reduced B cell function with aging.

Keratinocytes produce IL-6 in response to desmoglein 1 cleavage by Staphylococcus aureus exfoliative toxin A.

Many skin infections are caused by Staphylococcus aureus, a bacterial pathogen that produces virulence factors associated with these conditions such as exfoliative toxins A and B (ETA, ETB) and the leukotoxin Panton-Valentine leukocidin (PVL). Herein, we examine the potential of skin-infecting S. aureus to produce virulence factors and their impact on the local immune response. Toxin gene profiles were generated from 188 S. aureus isolated as single infecting organisms from skin lesions and demonstrated a higher potential to express ETA, ETB, and PVL than community isolates (p < 0.001). Within the study isolate group, the prevalence of genes encoding PVL was higher among methicillin-resistant S. aureus (MRSA; n = 49), while genes encoding ETs were more prevalent in methicillin-susceptible S. aureus (MSSA; n = 139). When lesion-associated white blood cell (WBC) counts were dichotomized into high- or low-WBC-count-associated bacteria, the gene for ETA was found to be associated with a low WBC count among MSSA (p = 0.001). The ETA-induced mouse model of staphylococcal scalded skin syndrome was used to investigate the link between ETA and cytokine production. Elevated IL-6 levels in the serum and increased expression of IL-6 mRNA in the skin were detected in response to ETA exposure. These findings were recapitulated in vitro using primary human keratinocytes. Thus, S. aureus may influence the local immune response via ETA cleavage of desmoglein 1 and the induction of cutaneous IL-6 expression.

Isolated polio-like syndrome after tick-borne encephalitis presenting with acute hyperckemia.

Tick borne encephalitis virus infection usually shows a biphasic course. In the first stage of illness symptoms are similar to a flu-like syndrome, then after a defervescence period, fever may represent with neurological manifestations ranging from mild meningitis to severe encephalomyelitis. We report the clinical case of an adult man presented with an acute proximal hyposthenia, severe hyperckemia, clinical and laboratoristic evidence of acute tick borne virus infection. This virus has a favourite tropism for the anterior horn cells of the cervical spine segment. Polio-like syndrome, usually affecting the upper limbs, is the clinical phenotype of an infection of the cervical motoneurons. Usually myelitis is associated to severe encephalitis and a complete diagnosis may be difficult in comatose patients. Rarely, an isolated polio-like syndrome may be the sole neurological complication of tick-borne encephalitis.

Peroneal nerve orthodromic sensory conduction technique: normative data.

In some definite patients, a standard neurophysiological tool may not solve a complete differential diagnosis in common nerve peroneal neuropathy. In this study we have assessed a new simple procedure to study the orthodromic sensory conduction of both the superficial peroneal nerves (SPN) and deep peroneal nerves (DPN) in a heterogeneous group of 55 normal subjects. The mean sensory orthodromic conduction velocity of the SPN was 58.35 m/s. The mean sensory orthodromic conduction velocity of the mixed nerve action potential (MNAP) of the DPN was 55.27 m/s. The sensory conduction velocity, the amplitude of sensory-evoked potentials of SPN and DPN across the fibular head and the normative values are discussed. Our results confirm that these recording methods are easy to repeat and reliable in identifying peroneal neuropathy.

Novel autoantigens recognized by CSF IgG from Hashimoto's encephalitis revealed by a proteomic approach.

To identify the target of IgG autoimmune response in Hashimoto's encephalopathy (HE), we studied the binding of IgG present in serum and cerebro-spinal fluid (CSF) from six patients with HE and 15 controls to human central nervous system (CNS) white matter antigens by 2D-PAGE and immunoblotting and by immunohistochemistry. We found that CSF IgG from HE patients specifically recognized 3 spots, which were identified as dimethylargininase-I (DDAHI) and aldehyde reductase-I (AKRIAI). DDAHI was present in two isoforms recognized respectively by five and four HE patients; immunohistochemistry with anti-DDAHI antiserum depicted endothelial cells in normal human CNS. AKRIAI was recognized by three HE CSF and this enzyme was widely distributed on neurons and endothelia by immunohistochemistry. IgG from HE CSF immunostained both neuronal and endothelial cells in mouse CNS. The presence of these autoantibodies selectively in the CSF of HE patients may have important diagnostic and pathogenetic implications, since the autoimmune response to these enzymes may lead to vascular and/or neuronal damage, two major mechanisms involved in the pathogenesis of HE.

Membrane localization and topology of the Yersinia pestis YscJ lipoprotein.

The localization and membrane topology of the Yersinia pestis YscJ lipoprotein, an essential component of the type III secretion apparatus, was investigated. YscJ was demonstrated to be an inner membrane (IM) lipoprotein that is anchored to the periplasmic face of the IM via an N-terminal lipid moiety and via a C-terminal transmembrane (TM) domain. Localization of the N-terminal lipid moiety to the IM occurred regardless of the amino-acid residues found in the +2 or +3 positions. IM localization was dependent upon an intact N-terminal domain (amino acids +1 to +61), suggesting that this region plays a role in YscJ localization. In contrast, the YscJ C-terminal domain and TM domain were not required for IM localization. N-terminal sequence analysis demonstrated that a significant proportion of membrane-localized YscJ lacks N-acylation, the final modification required for Lol-dependent transport of a lipoprotein to the OM. Interestingly, attachment of the N-terminus to the IM was required for YscJ function; however, the YscJ secretion signal and lipo-box could be functionally replaced by the first TM domain of the YscV protein, suggesting that the mechanism of attachment to the IM was not critical.

Measurement of effector protein injection by type III and type IV secretion systems by using a 13-residue phosphorylatable glycogen synthase kinase tag.

Numerous bacterial pathogens use type III secretion systems (T3SSs) or T4SSs to inject or translocate virulence proteins into eukaryotic cells. Several different reporter systems have been developed to measure the translocation of these proteins. In this study, a peptide tag-based reporter system was developed and used to monitor the injection of T3S and T4S substrates. The glycogen synthase kinase (GSK) tag is a 13-residue phosphorylatable peptide tag derived from the human GSK-3beta kinase. Translocation of a GSK-tagged protein into a eukaryotic cell results in host cell protein kinase-dependent phosphorylation of the tag, which can be detected with phosphospecific GSK-3beta antibodies. A series of expression plasmids encoding Yop-GSK fusion proteins were constructed to evaluate the ability of the GSK tag to measure the injection of Yops by the Yersinia pestis T3SS. GSK-tagged YopE, YopH, LcrQ, YopK, YopN, and YopJ were efficiently phosphorylated when translocated into HeLa cells. Similarly, the injection of GSK-CagA by the Helicobacter pylori T4SS into different cell types was measured via phosphorylation of the GSK tag. The GSK tag provides a simple method to monitor the translocation of T3S and T4S substrates.

The neurological disorder associated with thyroid autoimmunity.

The neurological disorder associated with thyroid autoimmunity is an elusive disease that neurologists have learned to recognize in the last few years. The diagnosis is made, after excluding more common diseases, when neuropsychiatric symptoms develop in a patient with high serum concentrations of anti-thyroid antibodies. The clinical presentations of the disease and the many controversial issues surrounding the diagnosis, the pathogenesis, the role of thyroid autoantibodies, and the choice of therapy are reviewed and discussed in the light of the medical literature in English.

Selection and characterization of Yersinia pestis YopN mutants that constitutively block Yop secretion.

Secretion of Yop effector proteins by the Yersinia pestis plasmid pCD1-encoded type III secretion system (T3SS) is regulated in response to specific environmental signals. Yop secretion is activated by contact with a eukaryotic cell or by growth at 37 degrees C in the absence of calcium. The secreted YopN protein, the SycN/YscB chaperone and TyeA form a cytosolic YopN/SycN/YscB/TyeA complex that is required to prevent Yop secretion in the presence of calcium and prior to contact with a eukaryotic cell. The mechanism by which these proteins prevent secretion and the subcellular location where the block in secretion occurs are not known. To further investigate both the mechanism and location of the YopN-dependent block, we isolated and characterized several YopN mutants that constitutively block Yop secretion. All the identified amino-acid substitutions that resulted in a constitutive block in Yop secretion mapped to a central domain of YopN that is not directly involved in the interaction with the SycN/YscB chaperone or TyeA. The YopN mutants required an intact TyeA-binding domain and TyeA to block secretion, but did not require an N-terminal secretion signal, an intact chaperone-binding domain or the SycN/YscB chaperone. These results suggest that a C-terminal domain of YopN complexed with TyeA blocks Yop secretion from a cytosolic, not an extracellular, location. A hypothetical model for how the YopN/SycN/YscB/TyeA complex regulates Yop secretion is presented.

Expression of a functional secreted YopN-TyeA hybrid protein in Yersinia pestis is the result of a +1 translational frameshift event.

YopN is a secreted protein that prior to secretion directly interacts with the cytosolic SycN/YscB chaperone complex and TyeA. This study identifies a secreted YopN-TyeA hybrid protein that is expressed by Yersinia pestis, but not by Yersinia enterocolitica. DNA sequence analysis and site-directed mutagenesis studies demonstrate that the hybrid protein is the result of a +1 translational frameshift event.

Hashimoto's encephalopathy: epidemiologic data and pathogenetic considerations.

BACKGROUND: Hashimoto's encephalopathy (HE) is a condition believed to complicate Hashimoto's thyroiditis (HT). The diagnosis is suspected in the presence of high levels of serum anti-thyroid antibodies. We have recently demonstrated that in patients with HE there is an intrathecal synthesis of anti-thyroid antibodies, and concluded that the diagnosis of HE should be based on this cerebrospinal fluid (CSF) finding. OBJECTIVE: getting an estimate of the prevalence of the disease, verifying the association with HT and investigating the pathogenetic role of anti-thyroid antibodies. METHODS: 34-months prospective study in a hospital setting serving a community of 150,000 people. Patients with unexplained symptoms of acute or subacute encephalopathy or myelopathy or with a history of thyroid disorders were selected for the measurement of anti-thyroid antibodies. In the presence of high serum levels of autoantibodies, the same tests were performed in the CSF. RESULTS: Twelve patients had increased concentrations of serum autoantibodies but HE was diagnosed only in nine patients. The estimated prevalence of HE is 2.1/100,000. Only six HE patients had also HT. Four patients received corticosteroids, five patients were not treated. Five patients improved, four patients spontaneously, one patient after corticosteroids. Repeated CSF examinations showed that the titer of CSF autoantibodies did not correlate with the clinical stage of the disease nor was influenced by corticosteroids. In addition, the course of symptoms was independent of therapy. CONCLUSIONS: The association of encephalopathy and high titers of anti-thyroid antibodies is not sufficient to make a diagnosis of HE. Independent of the clinical status of the thyroid gland, the intrathecal synthesis of autoantibodies is a distinctive marker of this elusive condition.