Predicting clinical progression and cognitive decline in patients with relapsing-remitting multiple sclerosis: a 6-year follow-up study.

INTRODUCTION: Cognitive impairment occurs from the earliest stages of multiple sclerosis (MS) and progresses over time. The introduction of disease modifying therapies (DMTs) has changed the prognosis for MS patients, offering a potential opportunity for improvement in the cognitive arena as well. MATERIAL AND METHODS: 41 patients with relapsing-remitting multiple sclerosis (MS) were recruited to the study. Thirty patients were available for final follow-up and were included in the analysis. Baseline (BL) brain MRI including volumetry and neuropsychological tests were performed. Blood samples were collected at BL and follow-up (FU) and were tested for: vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM1), soluble platelet-endothelial CAM-1 (sPECAM1), and soluble intercellular CAM-1 (sICAM-1). Patients were invited for a final neuropsychological follow-up after a median of 6 years. Disease activity (relapses, EDSS increase, new/active brain lesions on MRI) was analysed between BL and FU. RESULTS: The study group deteriorated in the Rey-Osterrieth Complex Figure (ROCF) test (p = 0.001), but improved significantly in three other tests, i.e. semantic fluency test (p = 0.013), California Verbal Learning Test (CVLT, p = 0.016), and Word Comprehension Test (WCT, p < 0.001). EDSS increase correlated negatively with semantic fluency and WCT scores (r = -0.579, p = 0.001 and r = -0.391, p = 0.033, respectively). Improvements in semantic fluency test and WCT correlated positively with baseline deep grey matter, grey matter, and cortical volumes (p < 0.05, r > 0). Higher EDSS on FU correlated significantly negatively with baseline left and right pallidum, right caudate, right putamen, right accumbens, and cortical volume (p < 0.05, r < 0). No significant relationship was found between the number of relapses and EDSS on FU or neuropsychological deteriorations. Improvements in WCT and CVLT correlated positively with baseline sPECAM1 and sVCAM1 results, respectively (r > 0, p < 0.05). Deterioration in ROCF test correlated significantly with higher levels of baseline VEGF and sVCAM1 (p < 0.05). CONCLUSIONS: Brain volume is an important predictor of future EDSS and cognitive functions outcome. MS patients have a potential for improving in neuropsychological tests over time. It remains to be established whether this is related to successful disease modification with immunotherapy. Baseline volumetric measures are stronger predictors of cognitive performance than relapse activity, which yet again highlights the importance of atrophy in MS prognosis.

Neural and Onconeural Autoantibodies and Blood-Brain Barrier Disruption Markers in Patients Undergoing Radiotherapy for High-Grade Primary Brain Tumour.

Radiotherapy (RT) plays a key role in brain tumours but can negatively impact functional outcomes and quality of life. The aim of this study was to analyse anti-neural and onconeural autoantibodies and markers of blood-brain barrier (BBB) disruption in patients with primary brain cancer undergoing RT. MATERIALS AND METHODS: A prospective study was conducted on 45 patients with a brain tumour scheduled for intensity-modulated radiotherapy. Assessments were performed at baseline, post-RT, and at three months. We measured serum levels of BBB disruption biomarkers and anti-neural, onconeural, and organ-specific antibodies. RESULTS: Antibodies against nucleosome antigens and neuronal surface antigens were detected in 85% and 3% of cases, respectively; anti-neural and onconeural antibodies were observed in 47% and 5.8%. In 44% patients, ≥2 antibody types were detected. No significant changes in BBB biomarkers were observed. CONCLUSION: The findings of this study show that a humoral immune response is common in patients undergoing RT for brain cancer. This response appears to be non-organ specific but rather directed against nucleosome antigens, but onconeural antibodies were uncommon, suggesting a low risk of a neurological paraneoplastic syndrome. Our data suggested that radiotherapy may not affect BBB integrity, but larger studies are needed to better characterise the pathophysiological effects of RT.

Bruns syndrome in a patient with intraventricular subependymoma: a case report.

Purpose: Subependymoma is a slow-growing benign brain neoplasm, classified by the World Health Organization (WHO) as a grade I tumor, which typically presents in middle-aged male adults. Case description: A case of Bruns syndrome and an intraventricular subependymoma in a 49-year-old patient who presented with intractable headache and vertigo is discussed in this paper. Imaging revealed a well-delimited cystic and solid mass near the lateral ventricle. Comment: Complete surgical excision of the tumor resulted in the restoration of normal cerebrospinal fluid pathway and resolution of clinical symptoms with no signs of tumor recurrence in the 4-year follow-up period.

Blood-Brain Barrier Disintegration in Growth-Restricted Fetuses with Brain Sparing Effect.

The endothelial cells of the blood-brain barrier adhere closely, which is provided by tight junctions (TJs). The aim of the study was to assess the damage to the endothelial TJs in pregnancy, complicated by fetal growth restriction (FGR) and circulatory centralization (brain-sparing effect, BS). The serum concentrations of NR1 subunit of the N-methyl-D-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), and zonula occludens protein - 1 (zo-1), and the placental expressions of OCLN, claudin-4 (CLN4), CLN5, and zo-1 were assessed with ELISA. The significantly higher serum NME1 concentrations and the serum CLN5/zo-1 index were observed in FGR pregnancy with BS, as compared to the FGR group without BS. The FGR newborns with BS were about 20 times more likely to develop an intraventricular hemorrhage (IVH) than the FGR infants without BS. The cerebroplacental ratio (CPR) allowed to predict the IVH in growth-restricted fetuses. The significantly lower placental CLN4 expression was observed in the FGR group with BS and who postnatally developed an IVH, as compared to the growth-restricted infants with BS without IVH signs. Pregnancy complicated by FGR and BS is associated with the destabilization of the fetal blood-brain barrier. The IVH in newborns is reflected in the inhibition of the placental CLN4 expression, which may be a useful marker in the prediction of an IVH among growth-restricted fetuses.

The Clinical Spectrum of Autoimmune-Mediated Neurological Diseases in Paediatric Population.

Neurological autoimmune diseases have various origins and pathogeneses. Specific antibodies are associated with paraneoplastic syndromes, other infectious agents, or inherited disorders. We aim to evaluate the relation between the autoantibodies, the chosen symptoms, demographic characteristics, and infection history. We retrospectively analysed 508 children during neurological diagnostics. We investigated serum antineuronal, IgG, IgM anti-ganglioside, and anti-aquaporin-4 in both the serum and cerebrospinal fluid (CSF) anti-cell surface and anti-synaptic protein antibodies in 463, 99, 44, 343, and 119 patients, respectively. The CSF polymerase chain reaction detection of Herpesviridae, enterovirus, B19 parvovirus, adenovirus, and parechovirus involved 261 patients. We included available clinical information and electroencephalographic, radiologic, and microbiological results. The IgM anti-ganglioside antibodies increased the risk of tics and positive symptoms (p = 0.0345, p = 0.0263, respectively), the anti-glutamic acid decarboxylase particle of paresis (p = 0.0074), and anti-neuroendothelium of mutism (p = 0.0361). Anti-neuroendothelium, IgM anti-ganglioside, and CSF anti-N-methyl-D-aspartate antibodies were more often associated with consciousness loss (p = 0.0496, p = 0.0044, p = 0.0463, respectively). Anti-myelin antibodies co-occured with Herpes simplex virus (HSV)-2 IgG (p = 0.0415), anti-CV2 with HSV-1 IgM (p = 0.0394), whereas anti-glial fibrillary acidic protein was linked with past Epstein-Barr virus infection. The anti-ganglioside IgM and anti-myelin particles were bilaterally correlated (p = 0.0472). The clinical pictures may overlap, requiring specialistic diagnostics. We noticed the links between the infection aetiology and the specific autoantibody's positivity.

Relationship between blood-brain permeability and antibodies against aquaporins in neuromyelitis optica spectrum disorders and multiple sclerosis patients.

AIM OF THE STUDY: To evaluate serum anti-aquaporin antibodies profile, to measure serum levels of cell-cell adhesion molecules as potential markers of blood-brain barrier (BBB) permeability, and to assess their relationship in neuromyelitis optica spectrum disorders (NMOsd) and multiple sclerosis (MS). CLINICAL RATIONALE FOR THE STUDY: Serum levels of cell-cell adhesion molecules could provide information about BBB disruption in demyelinating diseases of the central nervous system. Improved knowledge about differences in their profile in NMOsd and MS patients, as well as about their relationship with antibody serostatus, would facilitate early and accurate diagnosis. MATERIAL AND METHODS: Sera from 20 NMOsd and 59 MS patients were collected and assessed for anti-aquaporin 4 antibodies (AQP4-IgG) and antibodies against myelin oligodendrocyte glycoprotein (MOG-Ab) using an indirect immunofluorescence test (IIFT). Anti-aquaporin 1 antibodies (AQP1-Ab), vascular endothelial growth factor (VEGF), and vascular endothelial cadherin (VE-Cadherin) levels were assessed using commercial enzyme-linked immunosorbent assay (ELISA) kits. For occludin (OCLN) and claudin-5 (CLDN5) serum levels, we employed home-made ELISAs elaborated in the Department of Neurochemistry and Neuropathology, Poznan University of Medical Sciences, Poland. RESULTS: AQP4-IgG appeared only in 6/20 NMOsd patients who were all originally AQP4-IgG seropositive. All MS and NMOsd patients were seronegative for MOG-Ab. Patients with MS had higher AQP1-Ab levels than those with NMOsd (median 782.32 vs. 203.16 pg/mL; p < 0.001). CLND5 levels were significantly higher in MS than in NMOsd patients (median 1.65 vs. 1.00 ng/mL; p = 0.004). No statistically significant differences between MS and NMOsd were found for OCLN, VEGF and VE-Cadherin serum levels. In MS, AQ1-Ab levels were significantly lower in MS patients treated with immunomodulatory drugs vs. the treatment-naive (median 712.46 pg/mL vs. 942.73 pg/mL, respectively). There was a positive correlation between CLDN5 and OCLN in both the MS and the NMOsd groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: There is a different BBB disruption profile in MS and NMOsd, reflected by significantly higher CLDN5 and AQP1-Ab levels in MS samples. AQP1-Ab can be considered as a promising indicator of BBB disruption possibly associated with astrocytopathy.

The involvement of small heat shock protein in chemoresistance in ovarian cancer - in vitro study.

Ovarian cancer is the most deadly gynecologic malignancy worldwide. Although the primary response to chemotherapy is high, the majority of patients will develop resistance against applied treatment. In this study, we focused on resistance to cisplatin, a first-line drug used for the treatment of ovarian cancer. The mechanism of the resistance development process is widely described, but there is a lack of information about the involvement of members of small heat shock proteins (HSPs) and their transport via exosomes. In this study, we used two cell lines: A2780 and SKOV3, and their cisplatin-resistance variants: A2780 CDDP and SKOV3 CDDP. We have shown that the expression of three small HSPs (HSPB5, HSPB6, and HSPB8) in cisplatin-resistant cell lines differs from their sensitive counterparts. Further, we isolated exosomes and determined the small HSPs in their cargo. In A2780 WT we observed a low amount of HSPB5 and HSPB6. We did not observe the expression of small HSPs in the SKOV3 cell line in both sensitive and resistant variants. Our data suggest the involvement of small HSPs in drug resistance of ovarian cancer and their presence is not related to exosomal transport. Analysis of the biological consequences of the imbalance of small HSPs expression in cisplatin resistance needs further investigation.

Granzyme B in peripheral blood mononuclear cells as a measure of cell-mediated immune response in paraneoplastic neurological syndromes and malignancy.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) may coexist with ovarian or lung cancers. Some tumors coexisting with PNS are smaller and have a better prognosis than tumors without PNS. PNS may constitute an opportunity to observe a natural immune antitumor response. We aimed to investigate a cytotoxic immune response by measuring granzyme B (GrB) in peripheral blood mononuclear cells (PBMC) in patients affected with ovarian or lung malignancy, with and without accompanying PNS. METHODS: We enrolled patients with: nonmalignant lesions (n = 21), ovarian cancer (n = 19), lung cancer (n = 57), and PNS (n = 30). PBMC were isolated by density gradient centrifugation with Ficoll-Paque. We evaluated the expression of GrB in PBMC lysates by ELISA and normalized to protein content as measured by the Lowry method. RESULTS: GrB levels in PBMC in the group with malignant tumors-median 1650 pg/mg protein (interquartile range 663-3260 pg/mg) and in patients with PNS-median 1890 pg/mg protein (range 1290-2640 pg/mg) was lower than in control group with nonmalignant lesions-median 5240 pg/mg protein (range 2160-7440 pg/mg), p = 0.0003 and p = 0.0038, respectively. The differences in GrB levels in PBMC between these groups were independent of epidemiological factors-age, sex, body mass index (BMI), and the number of immune cells, as confirmed by multiple regression analysis. Within the group of patients with malignancy and PNS, GrB levels in PBMC were elevated if onconeural antibodies were detected (2610; 2390-3700 pg/mg protein) as compared to patients without antibodies (1680; 970-1880 pg/mg protein, p = 0.035). GrB in PBMC was higher if the malignancy was diagnosed at the low (3060; 2120-5220 pg/mg protein) as compared to the high stage (1330; 348-2140, p = 0.00048). In patients with lung cancer, the expression of GrB in PBMC was lower (1430; 635-2660 pg/mg protein) than in the group with ovarian cancer (2580; 1730-3730, p = 0.02). CONCLUSION: The cytotoxic response measured in peripheral blood by GrB in PBMC is impaired both in the course of malignancy and PNS. Levels of GrB in PBMC were higher if onconeural antibodies were detected. Tracking reactive immune responses, such as GrB in PBMC may have diagnostic and monitoring value in malignancy and PNS.

Expression of small heat shock proteins in exosomes from patients with gynecologic cancers.

Small Heat shock proteins (sHsp) are a group of chaperone proteins. Under conditions of stress, the expression of sHsp is increased. Therefore, they are implicated in the pathogenesis of various autoimmune-mediated disorders and cancer. The purpose of this study was to analyze sHsp expression in exosomes from patients with gynecologic cancers and correlate these results with markers of cytotoxic immune response. The study group included patients with ovarian cancer, endometrial cancer, and patients with endometriosis. The levels of sHsps and cytotoxic markers were analyzed in serum, peritoneal fluid and exosomes using ELISA method. We found the highest levels of sHsp in exosomes from patients with ovarian cancer, but they were also elevated in patients with endometrial cancer and endometriosis. Moreover, we identified the presence of small Hsps in serum and peritoneal fluid in all study groups, but again the highest level was in patients with ovarian cancer. Small Hsps expression levels were positively correlated with markers of cytotoxic immune response.

Autoimmune response in lung cancer patients with neurological paraneoplastic syndromes.

AIM OF THE STUDY: The aim of this study was to evaluate granzyme B, perforin and FasL expression in peripheral blood mononuclear cells (PBMCs) in lung cancer patients and in paraneoplastic neurological syndromes (PNS). CLINICAL RATIONALE FOR THE STUDY: Cellular immune response is activated as part of anti-tumour reaction of the malignancy-bearing host. Paraneoplastic neurological syndromes (PNS) are defined as indirect effects of cancer on the nervous system and are considered immune-mediated. Such stimulation of the immune system may limit the aggressiveness of cancer and the development of metastasis, and thereby improve survival. Granzyme B and perforin pathway, and Fas ligand (FasL) - Fas receptor interaction play an important role in cytotoxic response. MATERIALS AND METHODS: Fifty-two patients were included in the study: 28 subjects with PNS and 24 subjects with lung cancer. PNS cases were diagnosed according to the Graus criteria. The presence of onconeural antibodies (anti-Hu/anti-Ri/anti-Yo/anti-Ma/Ta/anti-CV2/anti-amphiphysin/anti-myelin/anti-neuroendothelium/anti-MAG/anti-GAD) was detected with indirect immunofluorescence and confirmed with Line Blotting. The expression of granzyme B, perforin and FasL was detected in PBMCs with ELISA. RESULTS: PPBMC-FasL expression was increased in lung cancer compared to other patient groups. The granzyme to FasL ratio was significantly higher in lung cancer patients with peripheral than with central PNS involvement. In a multiple regression model, sex was an independent factor influencing PBMC expression of granzyme and perforin. CONCLUSIONS: FasL expression in PBMCs is up-regulated in lung cancer patients. The interplay between granzyme B and FasL may be involved in the development of PNS at the level of the peripheral and the central nervous systems in different manners. Gender is associated with PBMC expression of granzyme B and perforin in lung cancer patients. CLINICAL IMPLICATIONS: The novel findings that we report broaden the current knowledge on PNS pathomechanism, with aspects that have not been previously explored. Our findings provide a rationale for further exploration of the granzyme B/FasL pathway with regards to its potential diagnostic value. However, our study is preliminary and needs further research, especially in the context of the prognostic value of the proposed markers.

The expression of Platelet-derived Growth factor receptors (PDGFRs) and their correlation with overall survival of patients with ovarian cancer.

OBJECTIVES: The main aim of the study was to investigate the expression of Platelet-Derived Growth Factor Receptors alpha (PDGFR-alpha) and beta (PDGFR-beta) in malignant and benign ovarian tumors. We performed an analysis of the correlation of PDGFRs expression and stage of the disease, tumor grade and histopathological type of epithelial ovarian cancer (EOC). Additionally, we evaluated patient prognosis according to PDGFR expression. MATERIAL AND METHODS: Our study group was composed of 52 samples of EOCs, 35 samples of benign ovarian tumors (BOTs), and 21 samples of unchanged ovaries (UOs). The samples were collected from patients who had been operated on in the Division of Gynecological Surgery of the Poznan University of Medical Sciences. RESULTS: PDGFR-alpha was found to be expressed more frequently in cancer cells of EOCs, when compared with tumor cells of BOTs and epithelium of UOs. On the other hand, PDGFR-alpha receptors were present less frequently in the stroma of EOCs, when compared with the stroma of BOTs and UOs. Comparing the studied groups, there were no statistically significant differences in the expression of PDGFR-beta. The expression of both PDGFRs was not related to the FIGO stage, grade or histopathological type of EOCs. The expression of the PDGFR-beta receptor in cancer cells was associated with an improved overall survival among patients with EOCs. Patient prognosis was not affected by either PDGFR-alpha expres- sion or by PDGFR-beta tumor stroma expression. CONCLUSIONS: The expression of PDGFR-alpha is significantly different when comparing EOCs, BOTs and UOs. However, the prognosis of EOC only seems to be affected by PDGFR-beta expression in cancer cells.

Airway Obstruction in Sleep Apnea Patients.

Obstructive sleep apnea (OSA) is a condition of breathing pathology occurring during sleep, characterized by repeated episodes of upper airway obstruction. The aim of the study was to determine the occurrence of airway obstruction in smoking males with OSA in whom lung function tests had not been performed before. One hundred and four current smokers selected from 1241 patients were enrolled for the research. The subjects included in the study smoked minimum 20 cigarettes a day for at least 10 years. The diagnosis of OSA was confirmed by polysomnography (PSG) in the Sleep Laboratory and subjects were assigned to one of three groups, depending on the severity of OSA. The control group consisted of 30 age-matched male smokers in whom OSA was not confirmed in PSG. Patients from the study and control group scored ≥ 11points in the Epworth Sleepiness Scale. Spirometry, impulse oscillometry, and body plethysmography were used to assess pulmonary function. Airflow limitation in subjects of the control group and OSA patients was confirmed. There were no significant differences in the incidence of bronchial obstruction between the control and study groups, and among the patients of various OSA severity. We conclude that the severity of OSA in smokers does not associate with the presence of airway obstruction. However, the increased peripheral respiratory resistance found in oscillometry did relate to a longer smoking time in OSA patients.

The associations between serum vascular endothelial growth factor, tumor necrosis factor and interleukin 4 with the markers of blood-brain barrier breakdown in patients with paraneoplastic neurological syndromes.

The blood-brain barrier (BBB) disruption is a critical step in paraneoplastic neurological syndrome (PNS) development. Several cytokines have been implicated in BBB breakdown. However, the exact step-by-step mechanism in which PNS develops is unknown, and the relationship between a systemic neoplasm and BBB is multilevel. The aim of the present study was to examine serum markers of BBB breakdown (S100B protein, neuron-specific enolase, NSE) and concentrations of proinflammatory (TNF-alpha, VEGF) and anti-inflammatory/immunosuppressive cytokines (IL-4), and to establish their interrelationship in patients with PNS. We analyzed 84 patients seropositive for onconeural antibodies that originated from a cohort of 250 cases with suspected PNS. Onconeural antibodies were estimated with indirect immunofluorescence and confirmed with Western blotting. Serum S-100B was estimated using electrochemiluminescence immunoassay. NSE, VEGF, TNF-alpha and IL-4 were analyzed with ELISA. We found that S-100B protein and NSE serum concentrations were elevated in PNS patients without diagnosed malignancy, and S-100B additionally in patients with peripheral nervous system manifestation of PNS. Serum VEGF levels showed several abnormalities, including a decrease in anti-Hu positive patients and increase in PNS patients with typical manifestation and/or central nervous system involvement. Increase in TNF-alpha was observed in patients with undetermined antibodies. To conclude, the presence of paraneoplastic neurological syndrome in seropositive patients does not affect serum markers of BBB breakdown, with the exception of the group without clinically demonstrated malignancy and patients with peripheral manifestation of PNS. S-100B and NSE might increase during early phase of PNS. VEGF may be involved in typical PNS pathophysiology.

Paraneoplastic movement disorders.

Paraneoplastic movement disorders are rare, autoimmune-mediated, nonmetastatic complications of malignant neoplasms. Common paraneoplastic movement disorders include paraneoplastic chorea, dystonia, cerebellar degeneration, different types of encephalitis, opsoclonus-myoclonus syndrome, stiff person syndrome, and neuromyotonia. Syndromes usually develop before tumor diagnosis, have subacute onset, and are associated with serum or cerebrospinal fluid antibodies. Two types of antibodies can be distinguished: antibodies against nuclear and cytoplasmic neuronal antigens (anti-Hu, anti-Ri, anti-Yo, anti-Ma, anti-CV2/CRMP5, anti-Gephrin, and anti-GABATRAP) and antibodies recently identified against cell surface and synaptic proteins (anti-NMDAR, anti-LGI1, and anti-Caspr2). These two types differ from each other in a few important aspects. Antibodies against cell surface and synaptic protein disrupt cell-surface antigens. Clinical symptoms are related to the disruption of antigens and potentially can be reversed by immunotherapy. The association between these antibodies and malignancy is much less consistent. On the other hand, antibodies against nuclear and cytoplasmic neuronal antigens seem to be not pathogenic; however, they most likely indicate a T-cell-mediated immune response against neurons. Due to T-cell-mediated neuronal loss, response to immunotherapy is generally disappointing. Early recognition of all these diseases is crucial because it may lead to the disclosure of occult cancer. This review is focused on paraneoplastic movement disorders with emphasis on clinical presentations, investigational findings, and therapeutic results.

Free thyroxine and TSH interact with secreted protein acidic and rich in cysteine-like 1 in ischemic stroke.

The role of the thyroid gland in ischemic stroke pathology is not well understood. As thyroid hormones modulate the extracellular matrix, we explored the possible link between them and secreted protein acidic and rich in cysteine like 1 (SC1) - one of the extracellular matrix molecules. In the 81 patients with acute ischemic stroke, serum SC1 levels were much higher compared with 30 control subjects: 4.47 vs 2.43ng/mL (p<0.001). Serum levels of free thyroxine (fT4) were higher in stroke subjects compared to those of controls (p=0.03). In stroke patients, TSH concentration was lower than in the control group (p=0.03). SC1 levels positively correlated with fT4 levels (p=0.02) and negatively with TSH (p=0.03) in stroke patients. Our results confirmed the association between thyroid hormones and SC1 - extracellular matrix protein.

The Association between Serum Matricellular Protein: Secreted Protein Acidic and Rich in Cysteine-Like 1 Levels and Ischemic Stroke Severity.

BACKGROUND: The role of matricellular proteins like secreted protein acidic and rich in cysteine-like 1 (SC1) has been shown in important functions in the central nervous system, including the regulation of synaptic stability with upregulation throughout axonal regeneration. The aim of this study was to determine whether SC1 is related to ischemic stroke severity. METHODS: A total of 132 consecutively recruited patients admitted for acute ischemic stroke were included in this observational prospective study. Stroke severity was evaluated in the National Institutes of Health (NIHSS) scale on hospital admission. RESULTS: There was a positive correlation between SC1 levels and NIHSS score (r = .22, P = .009). Compared with patients with NIHSS scores lower than 5 at admission, patients with moderate and severe stroke (NIHSS ≥ 6) had significantly higher SC1 levels: 4.84 (2.53-11.58) ng/mL versus 3.31 (1.67-8.95) ng/mL (P = .01). SC1 was an independent predictor of stroke severity at admission (adjusted odds ratio =1.25; 95% confidence interval, 1.03-1.97; P = .04). CONCLUSION: SC1 levels were independently associated with ischemic stroke severity evaluated by the NIHSS.

The Levels of Circulating Proangiogenic Factors in Migraineurs.

Migraine has been reported as a risk factor for ischemic stroke or cardiovascular events, and dysfunction of endothelial cells has been evidenced in migraine patients. Proangiogenic factors are potential endothelial stimulators, and their disturbances can link abnormalities of endothelium with increased risk of vascular disorders. The aim of this study was to evaluate the levels of circulating proangiogenic factors in sera of migraineurs during interictal period. Fifty-two patients aged 37.9 ± 9.6 years, fulfilling International Headache Society criteria for migraine, were included in this observational case-control study. The control group included 39 healthy volunteers, matched according to age and gender. All subjects underwent full neurological examination and clinimetric evaluation with the use of: MIDAS, MIGSEV, QVM, VAS and VRS scales. Serum concentrations of vascular endothelial growth factor (VEGF), angiogenin, angiopoietin-2, thrombopoietin and Tie-2 were estimated in migraineurs and in the control group with the use of ELISA. In migraineurs during interictal period, we have found decreased serum VEGF and angiogenin concentrations compared with controls. Age of migraine onset correlated with VEGF, angiopoietin-2 and thrombopoietin concentrations. Furthermore, angiopoietin-2 level correlated with QVM score and Tie-2 with pain intensity evaluated using MIGSEV scale. In migraine patients during interictal period, depletion of VEGF and angiogenin, two cooperating proangiogenic factors, can be responsible for endothelial dysfunction and increased risk for vascular disorders.

Increased Serum CD14 Level Is Associated with Depletion of TNF-α in Monocytes in Migraine Patients during Interictal Period.

The aim of the present study was to investigate the levels of circulating CD14 in relation to the expression of tumor necrosis factor alpha (TNF-α) in monocytes, and serum levels of TNF-α and macrophage inflammatory protein-1 (MIP-1) in migraine patients. Numerous studies revealed controversial changes in the components of the immune system during attacks and the interictal period in migraine patients. Our study included 40 migraineurs and 39 controls. The levels of TNF-α, MIP-1 and CD14 were measured in peripheral monocytes and in sera with the Enzyme-Linked Immunosorbent Assay (ELISA) method, and the monocyte expression of TNF-α was also analysed by immunostaining. Serum CD14 concentrations were higher and the expression of TNF-α in monocytes was decreased in migraineurs. The serum MIP-1 level correlated with Verbal Rating Scale (VRS); the MIP-1:CD14 ratio in monocytes correlated with Visual Analogue Scale (VAS); the MIP-1:CD14 ratio correlated with Migraine Severity (MIGSEV)-Pain scores; and serum CD14 concentration correlated with migraine duration in years. Increased serum CD14 and depletion of TNF-α in monocytes can orchestrate other components of the immune system during the interictal period.

Profile of autonomic dysfunctions in patients with primary brain tumor and possible autoimmunity.

OBJECTIVE: Cerebral lesion due to different neurological conditions could be complicated by autonomic dysfunction, reported in the literature as a sympathetic hyperactivity. The mechanisms of dysautonomia still remains partial. The aim of the study was to assess the profile of autonomic dysfunction in patient with primary brain tumors, with attempt to estimate the additional factors in pathogenesis of dysautonomia. MATERIAL AND METHODS: Neurological examinations, the Low's autonomic disorder questionnaire, electrophysiological autonomic tests (Heart Rate Variability test at rest and during deep breathing, spectral analysis of R-R intervals, sympathetic skin response test), studies of peripheral nerves, blood sampling collection for antibodies were done in 33 patients with recognized primary brain tumors. RESULTS: The averaged Low's Questionnaire score in the patients group was significantly higher than in the controls, systolic blood pressure was increased, heart rate tended to be higher without significance, but heart rate variability was severe low, LF/HF ratio also tended to be higher in the patients group. In SSR test the amplitude of responses from hand and foot was significantly lower without changes in their latencies. We found changes in the electrophysiological tests of peripheral nerves, and positive anti-neural antibodies in 5 patients. CONCLUSIONS: The results of the study indicated to the sympathetic nervous system hyperactivity in patients with primary brain tumors. Local brain lesion with high intracranial pressure, additional peripheral nerve damage probably in the course of autoimmunity, and direct influence of autoimmunity to the central part of autonomic nervous system are possible in the pathogenesis of dysautonomia.

The associations between serum VEGF, bFGF and endoglin levels with microvessel density and expression of proangiogenic factors in malignant and benign ovarian tumors.

AIM OF THE STUDY: To investigate whether serum levels of VEGF, bFGF and endoglin correlate with tumor VEGF and bFGF expression or microvessel density (MVD) in ovarian cancer. PATIENTS AND METHODS: Forty five patients with epithelial ovarian cancers (EOCs) and 38 patients with benign ovarian tumors (BOTs) were included into the study. Serum levels of VEGF, bFGF and endoglin were assessed using ELISA. The expression of VEGF and bFGF in tumor samples were evaluated using ELISA of supernatants obtained from tumor homogenization. MVD was analyzed using immunohistochemistry with antibodies against CD31, CD34 and CD105. RESULTS: Serum VEGF levels were significantly higher in EOCs than in BOTs (436.6pg/ml [19.67-2860] vs 295.5pg/ml [123-539], P=0.025). Serum endoglin levels were lowered in the group EOCs when compared to BOTs (33,720g/ml [12,220-73,940] vs 42,390pg/ml [19,380-56,910], P=0.015). There were no differences in bFGF levels between studied groups. EOCs have significantly higher CD105 MVD (25 vessels/mm2 [0-57] vs 6 vessels/mm2 [0-70], P<0.001) and tumor VEGF (405.9pg/mg protein [0-3000] vs 2.225 [0-634.7], P<0.001) expression than BOTs, while, bFGF expression was higher in BOTs than in EOCs (2076pg/mg protein [668.1-8718] vs 847.3pg/mg protein [188.9-8333], P=0.003). In patients with EOCs we have observed negative correlation between serum VEGF concentration and its tissue expression (r Spearman=-0.571, P=0.0261), and serum VEGF concentration correlated positively with CD34-MVD (r Spearman=0.545, P=0.0289). In a multiple regression analysis we have observed only the negative correlation between serum VEGF and CD105-MVD (r=-0.5288, P=0.0427). CONCLUSIONS: Serum VEGF is a useful marker for prediction of ovarian cancer MVD and tumor VEGF expression.