H3 histamine receptor-mediated activation of protein kinase calpha inhibits the growth of cholangiocarcinoma in vitro and in vivo

Histamine regulates functions via four receptors (HRH1, HRH2, HRH3, and HRH4). The D-myo-inositol 1,4,5-trisphosphate (IP(3))/Ca(2+)/protein kinase C (PKC)/mitogen-activated protein kinase pathway regulates cholangiocarcinoma growth. We evaluated the role of HRH3 in the regulation of cholangiocarcinoma growth. Expression of HRH3 in intrahepatic and extrahepatic cell lines, normal cholangiocytes, and human tissue arrays was measured. In Mz-ChA-1 cells stimulated with (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH), we measured (a) cell growth, (b) IP(3) and cyclic AMP levels, and (c) phosphorylation of PKC and mitogen-activated protein kinase isoforms. Localization of PKC alpha was visualized by immunofluorescence in cell smears and immunoblotting for PKC alpha in cytosol and membrane fractions. Following knockdown of PKC alpha, Mz-ChA-1 cells were stimulated with RAMH before evaluating cell growth and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation. In vivo experiments were done in BALB/c nude mice. Mice were treated with saline or RAMH for 44 days and tumor volume was measured. Tumors were excised and evaluated for proliferation, apoptosis, and expression of PKC alpha, vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF receptor 2, and VEGF receptor 3. HRH3 expression was found in all cells. RAMH inhibited the growth of cholangiocarcinoma cells. RAMH increased IP(3) levels and PKC alpha phosphorylation and decreased ERK1/2 phosphorylation. RAMH induced a shift in the localization of PKC alpha expression from the cytosolic domain into the membrane region of Mz-ChA-1 cells. Silencing of PKC alpha prevented RAMH inhibition of Mz-ChA-1 cell growth and ablated RAMH effects on ERK1/2 phosphorylation. In vivo, RAMH decreased tumor growth and expression of VEGF and its receptors; PKC alpha expression was increased. RAMH inhibits cholangiocarcinoma growth by PKC alpha-dependent ERK1/2 dephosphorylation. Modulation of PKC alpha by histamine receptors may be important in regulating cholangiocarcinoma growth. (Mol Cancer Res 2009;7(10):1704-13

Bilateral sudden sensorineural hearing loss and chronic venous cerebrospinal insufficiency : a case report

OBJECTIVES: We report a case of bilateral sudden sensorineural hearing loss (SSHL) in a patient suffering from chronic venous cerebrospinal insufficiency (CCSVI). METHODS: Audiometric testing confirmed bilateral sensorineural hearing loss with hypoexcitability to caloric stimulation on the left side and echo-colour Doppler examination showed abnormal cerebral venous deficiency. RESULTS: The patient's condition improved after 15 days following medical treatment. CONCLUSIONS: CCSVI may explain the anatomical background which provides a predisposing factor for SSHL although further studies are needed to verify whether this observation is casual or coincidental

Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment

The aim of the present study was to investigate the effect of long-term infliximab treatment on various autoantibodies in patients with rheumatoid arthritis. Serum samples from 30 consecutive patients, who were prospectively followed during infliximab and methotrexate therapy for refractory rheumatoid arthritis, were tested at baseline and after 30, 54 and 78 weeks. At these points, median values of the Disease Activity Score were 6.38 (interquartile range 5.30-6.75), 3.69 (2.67-4.62), 2.9 (2.39-4.65) and 3.71 (2.62-5.06), respectively. Various autoantibodies were assessed by standard indirect immunofluorescence and/or ELISA. Initially, 50% of patients were positive for antinuclear antibodies, and this figure increased to 80% after 78 weeks (P=0.029). A less marked, similar increase was found for IgG and IgM anticardiolipin antibody titre, whereas the frequency of anti-double-stranded DNA antibodies (by ELISA) exhibited a transient rise (up to 16.7%) at 54 weeks and dropped to 0% at 78 weeks. Antibodies to proteinase-3 and myeloperoxidase were not detected. The proportion of patients who were positive for rheumatoid factor (RF) was similar at baseline and at 78 weeks (87% and 80%, respectively). However, the median RF titre exhibited a progressive reduction from 128 IU/ml (interquartile range 47-290 IU/ml) to 53 IU/ml (18-106 IU/ml). Anti-cyclic citrullinated peptide (CCP) antibodies were found in 83% of patients before therapy; anti-CCP antibody titre significantly decreased at 30 weeks but returned to baseline thereafter. In conclusion, the presence of anti-double-stranded DNA antibodies is a transient phenomenon, despite a stable increase in antinuclear and anticardiolipin antibodies. Also, the evolution of RF titres and that of anti-CCP antibody titres differed during long-term infliximab therapy

Characteristics of multiple sclerosis patient stance control disorders, measured by means of posturography and related to brainstem lesions

Balance disorders are commonly observed during the course of multiple sclerosis (MS). The aim of this study is to report characteristics of MS patient stance control disorders, measured by means of posturography and related to the brainstem lesions. Thirty-eight patients affected by MS, mildly to moderately disable according to Kurtzke\u2019s Expanded Disability Status Scale, underwent a complete clinical neurological and vestibular evaluation and brain MRI scanning. All patients were then tested on a static posturography platform (Tetrax, Israel) in four conditions: eyes open and eyes closed standing on a firm surface and on a foam pad. Clinical and/or magnetic resonance imaging evidence of brainstem involvement was observed in 55.3% of patients. When brainstem lesion was detected, Fourier analysis showed a typical pattern characterized by inversion of the 0- 0.1 Hz and 0.1-0.25 Hz frequency bands. In conclusion, MS leads to pervasive postural disturbances in the majority of subjects, including the visuo-vestibular loops and proprioception involving vestibulospinal pathways in at least 55.3% of patients. Our results may also suggest the presence of Fourier inversion in patients with brainstem lesions

Chronic cerebro-spinal insufficiency in multiple sclerosis and meniere disease: same background, different patterns?

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by demyelinating lesions with acute phases and progressive loss of sensori-motor functions. M\ue8ni\ue9re disease (MD) is a disorder of the inner ear characterized by acute spells of vertigo and hearing loss and progressive loss of cochleo-vestibular function. Both the diseases have a multifactorial pathogenesis and quite the same chronic cerebro-spinal insufficiency (CCSVI) frequency. However, as far as Author\u2019s knowledge concerns, no patients affected with both diseases are described so far. The aim of this paper is to investigate whether MS and MD present different CCSVI patterns. Three groups of patients were enrolled: 60 definite MS - 27 definite unilateral MD (MEN) - 41 with other no-M\ue8ni\ue9re, audio-vestibular disorders (OVD). All subjects underwent magnetic resonance venography (MRV) and venous Duplex (ECD) and only patients that satisfied both MRV and ECD CCSVI diagnostic criteria were considered. J1 was normal in 57% of MS, 88% of MEN and 95% of OVD. Stenosis (ST) were detected, respectively, in 30% of MS and 2% in MEN and OVD. J2 was normal in 78% of MS, 64% of MEN and 95% of OVD. At this level alterations of the trunk (AT) were detected in 17% in MS and 26% in MEN; J3 was normal in 74% of MS, 64% of MEN and 86% of OVD. AT were found in 15% of MS, 26% of MEN and 8% of OVD. Hyperplasia of the Vertebral Veins was observed in 35% of MS, 40% of MEN and in 15% of OVD. Other compensatory collaterals were detected in 25% in MS and only in 5% in MEN and OVD. Our results indicate that the MS pattern is characterized by J1 stenosis, J2 trunk alterations, a prevalence of J1-J2 medial-distal alterations, compensatory collaterals besides vertebral venous system. MD pattern is characterized by trunk alteration in J3, a prevalence of J3-J2 medial-proximal alterations and vertebral veins hyperplasia without other detectable collaterals. Although the group of patients with venous alterations is very small, OVD patients show a CCSVI pattern that is more similar to MD than MS pattern. The difference between MS and MD patterns indicates that CCSVI is not a unique entity and it could be an explanation of the fact that subjects affected with both the diseases are not reported

Early, incomplete, or preclinical autoimmune systemic rheumatic diseases and pregnancy outcome

OBJECTIVE: To evaluate the impact of preclinical systemic autoimmune rheumatic disorders on pregnancy outcome. METHODS: In this longitudinal cohort study, patients were enrolled during the first trimester of pregnancy if they reported having had connective tissue disorder symptoms, were found to be positive for circulating autoantibodies, and on clinical evaluation were judged to have a preclinical or incomplete rheumatic disorder. The incidence of fetal growth restriction (FGR), preeclampsia, and adverse pregnancy outcomes in patients with preclinical rheumatic disorders was compared with that in selected controls, after adjustment for confounders by penalized logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Of 5,232 women screened, 150 (2.9%) were initially diagnosed as having a suspected rheumatic disorder. After a mean\u2009\ub1\u2009SD postpartum follow-up of 16.7\u2009\ub1\u20095.5 months, 64 of these women (42.7%) had no clinically apparent rheumatic disease and 86 (57.3%) had persistent symptoms and positive autoantibody results, including 10 (6.7%) who developed a definitive rheumatic disease. The incidences of preeclampsia/FGR and of small for gestational age (SGA) infants were 5.1% (23 of 450) and 9.3% (42 of 450), respectively, among controls, 12.5% (8 of 640) (OR 2.7 [95% CI 1.1-6.4]) and 18.8% (12 of 64) (OR 2.2 [95% CI 1.1-4.5]), respectively, among women with no clinically apparent disease, and 16.3% (14 of 86) (OR 3.8 [95% CI 1.9-7.7]) and 18.6% (16 of 86) (OR 2.3 [95% CI 1.2-4.3]), respectively, among those with persisting symptoms at follow-up. Mean\u2009\ub1\u2009SD umbilical artery Doppler pulsatility indices were higher among women with no clinically apparent disease (0.95\u2009\ub1\u20090.2) and those with persisting symptoms (0.96\u2009\ub1\u20090.21) than in controls (0.89\u2009\ub1\u20090.12) (P\u2009=\u20090.01 and P\u2009<\u20090.001, respectively). CONCLUSION: In our study population, preclinical rheumatic disorders were associated with an increased risk of FGR/preeclampsia and SGA. The impact of these findings and their utility in screening for FGR/preeclampsia need to be confirmed in population studies

Inferior vestibular neuritis: 3 cases with clinical features of acute vestibular neuritis, normal calorics but indications of saccular failure

BACKGROUND: Vestibular neuritis (VN) is commonly diagnosed by demonstration of unilateral vestibular failure, as unilateral loss of caloric response. As this test reflects the function of the superior part of the vestibular nerve only, cases of pure inferior nerve neuritis will be lost. CASE PRESENTATIONS: We describe three patients with symptoms suggestive of VN, but normal calorics. All 3 had unilateral loss of vestibular evoked myogenic potential. A slight, asymptomatic position dependent nystagmus, with the pathological ear down, was observed. CONCLUSION: We believe that these patients suffer from pure inferior nerve vestibular neuritis

Bridging the gap between chronic cerebrospinal venous insufficiency and Ménière disease

M\ue9ni\ue8re disease (MD) is a chronic illness of the inner ear that affects a substantial number of patients every year worldwide. Because of a dearth of well-controlled studies, the medical and surgical management of MD remains quite empirical. The main reason is that it is very difficult to investigate patients affected with \u201cCertain MD\u201d due to the post-mortem criterion necessary for this diagnostic grade. The aim of this paper is an attempt to approach MD into the context of the more recent findings about the global brain waste clearance system, to which inner ear is anatomically and functionally connected, in order to build a reasonable model of MD pathogenesis. it seems nowadays reasonable to state that CCSVI may be the anatomical background to develop endolymphatic hydrops in MD, the worldwide accepted pathogenetic mechanism of the disease. The mechanism leading from CCSVI to MD is still debated. Since MD has been correlated mostly to a wide and different diseases and treatments, CCSVI may be considered more than a cause of MD per se, rather the anatomical predisposition to develop the disease. CCSVI may lead to endolymphatic hydrops through a pure \u201chydraulic\u201d mechanism but in the model proposed in this paper CCSVI interplays with the Glymphatic (GS) and Brain Lymphatic System (LS) and MD development is due to a failure of the congenital venous abnormalities: MD develops when vascular and/or glymphatic and/or lymphatic compensation fails

Functional role of the secretin/secretin receptor signaling during cholestatic liver injury

Liver diseases are a major health concern and affect a large proportion of people worldwide. There are over 100 types of liver disorders, including cirrhosis, cholangiocarcinoma (CCA), hepatocellular carcinoma, and hepatitis. Despite the relevant number of people who are affected by liver diseases, and the increased awareness with regard to these disorders, the number of deaths corresponding to liver injury is expected to increase in the foreseeable future. One of the possible reasons for this is that a complete comprehension of the mechanisms of hepatic damage involving specific liver anatomical districts is lacking, and, as a consequence, current treatments available are suboptimal

Serum prealbumin is an independent predictor of mortality in systemic sclerosis outpatients

OBJECTIVE: Serum prealbumin is a recognized marker of malnutrition, but its role in the prognosis of patients with SSc has not yet been investigated. The aim of the present multicentre prospective study was to investigate the association between prealbumin and mortality, independent of clinical features, in a cohort of SSc outpatients. METHODS: Patients were followed up according to standard clinical guidelines with visits at least every 6 months. Data collected included records of skin and internal organ involvement, survival and causes of death. RESULTS: During a median follow-up of 48 months [interquartile range (IQR) 25-58], 34/299 patients (11%) died. In univariable survival analysis, age; male sex; lung, gastrointestinal or multiple visceral organ involvement (two or more); co-morbidities (two or more) and low serum prealbumin were significant predictors of mortality. In bivariable Cox models, alternatively adjusted for significant predictors, prealbumin was independently and significantly associated with the outcome. Mortality rates were particularly influenced by low prealbumin in patients without significant co-morbidities or multiple organ involvement. CONCLUSION: In SSc patients, low serum prealbumin is an independent predictor of mortality, particularly in those without significant internal organ involvement. Further research on this nutritional marker is warranted