Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry

Background: Recent evidence supports that most non-lacunar cryptogenic strokes are embolic. Accordingly, these strokes have been designated as embolic strokes of undetermined source (ESUS). Aims: We undertook an international survey to characterize the frequency and clinical features of ESUS patients across global regions. Methods: Consecutive patients hospitalized for ischemic stroke were retrospectively surveyed from 19 stroke research centers in 19 different countries to collect patients meeting criteria for ESUS. Results: Of 2144 patients with recent ischemic stroke, 351 (16%, 95% CI 15% to 18%) met ESUS criteria, similar across global regions (range 16% to 21%), and an additional 308 (14%) patients had incomplete evaluation required for ESUS diagnosis. The mean age of ESUS patients (62 years; SD = 15) was significantly lower than the 1793 non-ESUS ischemic stroke patients (68 years, p ≤ 0.001). Excluding patients with atrial fibrillation (n = 590, mean age = 75 years), the mean age of the remaining 1203 non-ESUS ischemic stroke patients was 64 years (p = 0.02 vs. ESUS patients). Among ESUS patients, hypertension, diabetes, and prior stroke were present in 64%, 25%, and 17%, respectively. Median NIHSS score was 4 (interquartile range 2–8). At discharge, 90% of ESUS patients received antiplatelet therapy and 7% received anticoagulation. Conclusions: This cross-sectional global sample of patients with recent ischemic stroke shows that one-sixth met criteria for ESUS, with additional ESUS patients likely among those with incomplete diagnostic investigation. ESUS patients were relatively young with mild strokes. Antiplatelet therapy was the standard antithrombotic therapy for secondary stroke prevention in all global regions

Fabry-betegség – terápiás útmutató

A Fabry-kór a lizoszomális tárolási betegségek csoportjába tartozó, X-kromoszómához kötötten, recesszív módon öröklődő betegség, amely a globotriaozilceramid felhalmozódásához vezet a szervezet legkülönbözőbb szöveteiben. A betegség első tünetei többnyire gyermekkorban jelentkeznek, a progresszió során a betegek súlyos szervi károsodásokkal és korai halálozással számolhatnak. Elsősorban férfiak érintettek, azonban a betegség tüneteit heterozigóta nők esetében is megfigyelhetjük, de náluk a kórkép súlyossága változó, általában enyhébb lefolyású. Az enzimpótló kezelések megjelenése szükségessé tette, hogy részletes diagnosztikus és terápiás protokollt dolgozzunk ki. A jelen dolgozatban megjelenő ajánlásokat egy, a magyarországi Fabry-kóros betegek kezelésében részt vevő orvosokból, a diagnosztika területén dolgozó biológosukból és egyéb szakemberekből álló multidiszciplináris munkacsoport foglalta össze. A munkacsoport áttekintette a korábbi klinikai tanulmányokat, a publikált vizsgálatokat és a közelmúltban megjelent nemzetközi és nemzeti útmutatókat. | Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive and the first symptoms usually present in childhood. Consequences of the disease are disability and premature death. The disease in females could be as severe as in males although women may be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline has been summarized by a Hungarian multi-disciplinary working group consisting of physicians who are involved in diagnosis and care of Fabry patients. Previous clinical studies, published articles, and recently established international treatment guidelines were reviewed by the group

A case report of isolated distal upper extremity weakness due to cerebral metastasis involving the hand knob area

Unilateral weakness of an upper extremity is most frequently caused by traumatic nerve injury or compression neuropathy. In rare cases, lesion of the central nervous system may result in syndromes suggesting peripheral nerve damage by the initial examination. Pseudoperipheral hand palsy is the best known of these, most frequently caused by a small lesion in the contralateral motor cortex of the brain. The 'hand knob' area refers to a circumscribed region in the precentral gyrus of the posterior frontal lobe, the lesion of which leads to isolated weakness of the upper extremity mimicking peripheral nerve damage. The etiology of this rare syndrome is almost exclusively related to an embolic infarction.We present the case of a 70-year-old male patient with isolated left sided upper extremity weakness and clumsiness without sensory disturbance suggesting a lesion of the radial nerve. Nerve conduction studies had normal results excluding peripheral nerve damage. Neuroimaging (cranial CT and MRI) detected 3 space occupying lesions, one of them in the right precentral gyrus. An irregularly shaped tumor was found by CT in the left lung with multiple associated lymph node conglomerates. The metastasis from this mucinous tubular adenocarcinoma with solid anaplastic parts to the 'hand knob' area was responsible for the first clinical sign related to the pulmonary malignancy.Pseudoperipheral palsy of the upper extremity is not necessarily the consequence of an embolic stroke. If nerve conduction studies have normal results, neuroimaging - preferably MRI - should be performed, as lesion in the hand-knob area of the precentral gyrus can also be caused by a malignancy

UBIQUITIN CYTOCHEMICAL CHANGES DURING AZASERINE-INITIATED PANCREATIC CARCINOGENESIS

The ubiquitin (Ub)- proteasome proteolytic system is highly selective, and the specific proteins involved in cell division, growth, activation, signaling and transcription are degraded at different rate depending on the physio-pathological state of the cell. Ubiquitination serves first of all as a signal for protein degra- dation of short-lived and abnormal proteins under several stressful conditions. The immunocytochemical localization of Ub in some malignant tumours has recently been presented and differences in Ub expres- sion has been observed during malignant transformation. Change in the level of Ub and Ub-conjugated proteins might reflect a higher metabolic-catabolic ratio in neoplastic cells. Most studies have been focused on the malignant stage of tumour progression, and only a few papers have dealt with the change in Ub and Ub-protein conjugates level during the whole progression. To address this problem, we applied an azaserine-induced pancreatic carcinogenesis model, in which premalignant and malignant stages were investigated throughout the progression. The level of Ub immunoreactivity was measured in nucleus and cytoplasm by electron microscopic immunocytochemical and morphometrical methods. We found a sig- nificant increase of Ub level in the nucleus and the cytoplasmic area in premalignant atypical acinar cell nodule (AACN) cells and in malignant adenocarcinoma in situ (CIS) cells at month 20 after initiation

Egyéves követéses vizsgálat stroke után: Megvalósíthatósági előtanulmány a budapesti Józsefvárosban

Stroke is a major public health issue in Hungary with considerable regional differences in mortality. We have limited information to explain such regional differences. To assess these differences, we would need comparative follow-up studies optimally carried out by personal contact with the patient or the carer. According to several epidemiological studies, follow-up can be carried out with significantly lower cost and similar efficiency by telephone contact or regular mail. In this pilot study we intend to assess: 1. the efficacy of telephone follow-up one year after stroke in this geographical region 2. whether the efficacy of follow-up can be further increased with questionnaires sent out by regular mail 3. whether telephone and mail-based assessment is sufficient to perform a larger population based study. We included 135 patients hospitalized consecutively for acute cerebrovascular disease (stroke or TIA) by the Department of Neurology, Semmelweis University in January and February of 2008. Based on residence, patients were divided into three groups: those living in the least wealthy district of Budapest (i.e. District-8); those living in other districts of the city; and those living in suburban areas. One year after the hospital treatment follow-up was possible by telephone in 76%. Further 12 patients could be contacted by questionnaire sent out by regular mail. Efficacy of follow-up was altogether 84%. Even in this small group of patients, we have found a tendency for more severe strokes (p=0.06) and higher acute case fatality (32% vs. 5%, p=0.029) in residents of District-8 of Budapest compared to those residing in more wealthy districts of the city and in suburban areas. Survival rate one year after stroke or TIA was only 39% in those living in District-8, 66% in those living in other districts and 75% in suburban dwellers (p=0.006). Telephone and mail-based questionnaires are insufficient for follow-up in these regions even when applied in combination. These preliminary data raise the possibility that the socio-economical conditions might influence stroke severity and outcome in the population. A larger study to address this issue would require more accurate definition of patient-groups and more efficient follow-up methods

Functional and molecular cross-talk between Dopamine and NMDA receptors in striatum

Molecular and functional interactions between glutamate and dopamine (DA) receptors regulate a large variety of brain functions and, when abnormal, they may contribute to and underlie numerous central nervous system (CNS) diseases. Here we show that modulation of D1 receptor activation at corticostriatal level induces a significant molecular and functional modification of the glutamatergic synapse. In particular, treatment with D1 receptor agonist SKF38393 leads to a significant reduction of NR2A vs NR2B-containing NMDA receptors at synaptic sites. This event is associated with a concomitant increase of GluR1-containing AMPA receptors in the postsynaptic membrane. In addition, morphological analysis of dendritic spines after D1 receptor activation showed a significant increase of dendritic spine head width of medium spiny neurons. Notably, treatment of corticostriatal slices with NR2A antagonist NVP-AAM077 or with TAT2A (a cell-permeable peptide able to reduce NR2A-containing NMDA receptors) was sufficient to induce a similar significant increase of dendritic spine head width. Conversely, NR2B antagonist ifenprodil blocked any morphological effect induced by D1 activation. Overall, we show that, in striatal spiny neurons, dopamine D1 receptor activation leads to a molecular, functional and morphological re-arrangement of the glutamatergic striatal synapse correlated to NR2A/NR2B subunits ratio in the postsynaptic compartment

D1 and NMDA receptor interplay in physiological and pathological conditions : focus on Parkinson's disease

Functional and structural interactions between D1 receptor (D1R) and NMDA receptor (NMDAR) have been shown to play a critical role in many functions of the brain. Interestingly, when these subtle interactions become abnormal, they might contribute to several diseases.Here we show that prolonged activation of D1R by SKF 38393 is able, in vitro as well as in vivo, to significantly reduce the quantity of NR2A subunit at the postsynaptic site. Interestingly, this molecular effect was in agreement with the reduction in the NMDA-AMPA ratio and specifically in NMDA(NR2A)-AMPA ratio as demonstrated by electrophysiological recordings. Considering the effect of this pharmacological approach on the NMDA subunit composition, we used SKF38393 in a model of \u201cearly\u201d Parkinson's Disease (PD), the so called \u201cpartial lesion\u201d model. In this condition, mild motor impairments were observed, compared to the more severe alterations occurring in the full lesion model. In addition, in corticostriatal slices recorded from partial lesioned animals (PL) a lack of Long Term Potentiation (LTP) was found, as well as a strong increase in the NR2A subunit abundance at the postsynaptic site. In the attempt to restore synaptic plasticity in PL, SKF38393 was administered in vivo. Surprisingly, the treatment successfully restored LTP in striatal neurons, by reducing the NR2A subunit levels at the postsynaptic site and it improved the motor performances. Finally, in order to avoid the typical side effects deriving from the dopaminergic treatment in PD, we used an alternative tool able to mimic the effect of the D1 agonist on the NMDAR subunit composition. To this end, we directly targeted NMDAR via a cell permeable peptide, TAT2A, acting towards the interruption of the NR2A subunit delivery to the NMDAR complex. Notably, TAT2A determined a significant improvement in motor behaviour and it rescued LTP thus representing a new therapeutic strategy in P