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Biomedical subjects

Joab Chapman

Publications and source records attributed to Joab Chapman.

At least 19 recordsLinked to original sources
PubMed2006

Reduced anticardiolipin antibodies in first episode and chronic schizophrenia.

The objective of this study was to measure anticardiolipin antibodies (aCL) in major psychiatric diseases. In Experiment 1, 96 subjects were evaluated: 20 first episode schizophrenia patients, [SCZ1] 20 chronic schizophrenia patients in acute exacerbation [SCZ2], l9 bipolar patients, 20 schizoeffective patients and 17 healthy age matched controls. In Experiment 2, 97 subjects were studied: 20 first episode schizophrenia patients [SCZ1], 60 chronic schizophrenia patients in acute exacerbation [SCZ2] and 17 healthy matched controls. Diagnosis was performed according to DSM-IV. Serum samples were tested for aCL in parallel by enzyme-linked immunosorbent assay in the presence of bovine serum. Five positive control samples with high levels of aCL were run in parallel. Background binding to wells uncoated with cardiolipin (CL) was also measured. In Experiment 1, aCL levels were similar in the control, bipolar and schizoeffective groups. In contrast, aCL levels in the SCZ1 and SCZ2 groups were significantly lower than in controls. In Experiment 2, Significantly lower levels of aCL antibodies were found in all schizophrenic patients versus controls. Interestingly, background levels in both experiments were higher in the schizophrenic groups than in controls. Serum aCL levels are lower in schizophrenic patients, and especially in first episode cases, than in controls. One possible explanation for the lower levels of aCL in schizophrenic patients is the consumption of these antibodies in the acute phase and exacerbation of the disease. The higher background levels in schizophrenic patients may indicate a high level of antibodies to some serum component in schizophrenic patients that is still unclear and needs further elucidation.

Acute Disease↗
PubMed2006

Thrombin in inflammatory brain diseases.

Inflammatory brain diseases such as multiple sclerosis (MS) include hyperactivation of the coagulation pathway which includes thrombin. In the experimental autoimmune encephalomyelitis (EAE) model we have found significantly higher levels of thrombin inhibitors which include the very early elevation of protease nexin 1. The physiological importance of excess thrombin in neural tissue is demonstrated by recent experiments which link thrombin with conduction block in the sciatic nerve.

Amyloid beta-Protein Precursor↗
PubMed2006

Genetic and immunological factors interact in a mouse model of CNS antiphospholipid syndrome.

The antiphospholipid syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and beta(2)-glycoprotein I (beta(2)-GPI). We have recently reported the induction of APS associated with behavioral and cognitive deficits in BALB/c female mice that developed 4-5 months after immunization with beta(2)-GPI. In the present study, we examined the influence of genetic factors on the ability to induce experimental APS with CNS involvement by testing several mouse strains immunized with beta(2)-GPI. Female mice from five strains were immunized once with beta(2)-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). Autoantibody levels were examined at 1 and 5 months after immunization. Neurological assessment in a staircase test was performed 4-5 months following the immunization. Induction of APS resulted in elevated levels of antibodies against negatively charged phospholipids and beta(2)-GPI in all five mouse strains. Autoantibody levels were significantly higher in Balb/c, ICR, and C57BL/6 mouse strains compared to AKR and C3H. aPL levels dropped significantly more in the C57BL/6 compared to Balb/c mice over a period of 4 months. Hyperactivity reflected by higher number of stairs climbed in 3 min, was induced by APS in the Balb/c and ICR, mouse strains. Exploratory behavior reflected by more frequent rears, was seen in the APS-Balb/c and AKR mice. Hypoactivity and less exploration were seen in the APS-C57BL/6 and C3H mice. The study supports a link between high levels of aPL and behavioral changes in a mouse APS model. Qualitative differences in behavioral patterns may be due to nervous system as well as immune genetic factors. The minimal effect of APS in C57BL/6 mice may provide a suitable background for the study of transgenes in these mice.

Analysis of Variance↗
PubMed2005

Antiphospholipid antibodies, thrombin and LPS activate brain endothelial cells and Ras-dependent pathways through distinct mechanisms.

BACKGROUND: The antiphospholipid syndrome (APS) commonly affects the central nervous system through mechanisms that may include small vessel pathology and activation of thrombin. Antiphospholipid antibodies (aPL) activate endothelial cells but the specific activation of brain vascular endothelial cells (BVEC) and the receptors and signaling pathways involved have not been fully characterized. OBJECTIVE: To examine whether aPL, the inflammatory stimulant lipopolysacharide (LPS) and thrombin activate BVECs through a Ras-dependent pathway. METHODS: Rat BVEC (G8) were grown to confluence on 24-well plates. IgG was purified from 8 APS patients on a protein G column. Phosphorylation of ERK in the BVEC was measured by immunoblot utilizing a specific antibody. RESULTS: Significant phosphorylation of ERK was measured following exposure of the cells to LPS and thrombin and this was blocked by the Ras inhibitor farnesylthiosalicylate (FTS). aPL IgG (1:100 relative to serum) from 7/8 patients also induced phosphorylation of ERK. CONCLUSIONS: Activation of the Ras-ERK pathway is an effect of both APS IgG and thrombin. This pathway is potentially amenable to drugs such as FTS and may serve as a therapeutic target in APS.

Animals↗
PubMed2005

Focal seizures after treatment with fluvastatin in a patient with a history of catastrophic antiphospholipid syndrome.

We report a 36-year-old woman with the occurrence of painful focal seizures of her left hand and the left leg. She also had focal motor seizures at the left corner of her mouth. The duration and frequency of the episodes increased over four days from a few seconds once a day to frequent intervals lasting more than four hours at a time. The symptoms appeared one day after start of the treatment with fluvastatin (40 mg) administered in order to diminish the endothelial activation induced by antiphospholipid antibodies (aPL). The patient suffered from severe manifestations of the antiphospholipid syndrome (APS) including Catastrophic Antiphospholipid Syndrome (CAPS, Asherson's syndrome). In this case a single 40 mg dose of oral fluvastatin was linked to seizures. After discontinuation of this treatment, the seizures immediately disappeared and the patient fully recovered without evidence of permanent neurological damage. This data links statins to seizures in patients with compromised blood brain barrier such as APS.

Adult↗
PubMed2005

Increased thrombin inhibition in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS). Activated coagulation factors are associated with inflammation and are elevated in the plasma of animals with EAE. Thrombin is a key coagulation factor and its major endogenous inhibitors are antithrombin III (ATIII) in the plasma and protease nexin 1 (PN-1) in the brain. We measured the capacity of brain homogenates to inhibit exogenous thrombin and the CNS levels of ATIII and PN-1 during the course of EAE. Acute EAE was induced in SJL/J mice by immunization with mouse spinal cord homogenates. On Days 8, 13, and 22 post-immunization, inhibition of exogenous thrombin activity was measured by a recently developed fluorimetric assay. PN-1 and ATIII were assayed both by immunohistochemistry and by immunoblots in the brain and spinal cord. Total brain thrombin inhibitory activity increased (32%) in EAE mice at the peak of clinical disease (Day 13, P=0.04 compared to controls). Brain ATIII also increased at the peak of disease (2.5-fold higher than controls, P=0.0001), and correlated significantly with clinical scores at all stages of disease (r=0.72, P=0.0068). In contrast, PN-1 elevations were more pronounced at the preclinical stage on Day 8 (3-fold higher than controls, P=0.01) than on Day 13 (1.4-fold higher, P=0.005). Increased brain thrombin inhibition at the clinical peak of EAE probably reflects increased influx of plasma thrombin inhibitors. Early PN-1 changes represent a potential target for thrombin modulating drugs in EAE and MS.

Amyloid beta-Protein Precursor↗
PubMed2005

Hidden function of neuronal nicotinic acetylcholine receptor beta2 subunits in ganglionic transmission: comparison to alpha5 and beta4 subunits.

Neuronal nicotinic acetylcholine receptors (nAChR), which modulate fast excitatory postsynaptic potentials (f-EPSP), are located on both pre- and postganglionic sites in the autonomic nervous system (ANS). The receptor subunits alpha3, alpha5, alpha7, beta2 and beta4 are present in autonomic ganglia in various combinations and modulate acetylcholine (ACh) transmission. In the present study, autonomic functions were systemically examined in mice lacking beta2 subunits (beta2-/-) to further understand the functional role of beta2 subunits in modulating ganglionic transmission. The results show normal autonomic functions, both under physiological conditions and in perturbed conditions, on thermoregulation, pupillary size, heart rate responses and ileal contractile reactions. This suggests that the function of beta2-containing receptors in ganglionic transmission is hidden by the predominant beta4 containing receptors and confirms previous studies which suggest that alpha3alpha5beta4 nAChRs are sufficient for autonomic transmission. On the other hand, beta2-containing receptors have only a minor function on postsynaptic responses to ACh, but may modulate ACh release presynaptically, although there is no evidence for this.

Acetylcholine↗
PubMed2005

Inhibition of Ras attenuates the course of experimental autoimmune neuritis.

EAN induced in Lewis rats by immunization with peripheral bovine myelin was treated by the Ras inhibitor farnesylthiosalicylate (FTS). Treatment from day 0 with FTS (5 mg/kg intraperitoneally twice daily) attenuated peak clinical scores (mean+/-S.E., 2.5+/-0.5 compared to 4.1+/-0.5 in saline treated controls, p=0.018, t-test) but not recovery. Treatment from day 10 with FTS attenuated peak disability (2.5+/-0.6, p=0.032 compared to saline treated controls) and improved recovery (0.84+/-0.42, untreated controls 2.4+/-0.6, p=0.028 by repeated measures ANOVA). Effects were confirmed by rotarod and nerve conduction studies. An inactive analogue, geranylthiosalicylate, had no clinical effect. Inhibition of Ras is of potential use in the treatment of inflammatory neuropathies.

Analysis of Variance↗
PubMed2005

White matter changes in multiple sclerosis: correlation of q-space diffusion MRI and 1H MRS.

OBJECTIVE: To explore the diagnostic usefulness of high b-value diffusion magnetic resonance brain imaging ("q-space" imaging) in multiple sclerosis (MS). More specifically, we aimed at evaluating the ability of this methodology to identify tissue damage in the so-called normal-appearing white matter (NAWM). DESIGN: In this study we examined the correlation between q-space diffusion imaging and magnetic resonance spectroscopy (MRS)-based two-dimensional 1H chemical shift imaging. Eight MS patients with different degree of disease severity and seven healthy subjects were scanned in a 1.5-T magnetic resonance imaging (MRI) scanner. The MRI protocol included diffusion tensor imaging (DTI) (with bmax of 1000 s/mm2), high b-value diffusion-weighted imaging (with bmax of 14,000 s/mm2) and 2D chemical shift imaging. The high b-value data set was analyzed using the q-space methodology to produce apparent displacement and probability maps. RESULTS: We found that the q-space diffusion displacement and probability image intensities correlated well with N-acetylaspartate levels (r=.61 and .54, respectively). Furthermore, NAWM that was abnormal on MRS was also found to be abnormal using q-space diffusion imaging. In these areas, the q-space displacement values increased from 3.8+/-0.2 to 4.6+/-0.6 microm (P<.02), the q-space probability values decreased from 7.4+/-0.3 to 6.8+/-0.3 (P<.002), while DTI revealed only a small, but still significant, reduction in fractional anisotropy values from 0.40+/-0.02 to 0.37+/-0.02 (P<.05). CONCLUSION: High b-value diffusion imaging can detect tissue damage in the NAWM of MS patients. Despite the theoretical limitation of this method, in practice it provides additional information which is clinically relevant for detection of tissue damage not seen in conventional imaging techniques.

Adult↗
PubMed2005

Effectiveness of establishing a dedicated acute stroke unit in routine clinical practice in Israel.

BACKGROUND: Clinical trials have demonstrated the superiority of managing acute stroke in a dedicated stroke unit over conventional treatment in general medical wards. Based on these findings, nationwide stroke unit care programs have been implemented in several countries. OBJECTIVE: To assess the effect of establishing a new dedicated acute stroke unit within a department of neurology on indicators of process of care and outcome of acute stroke in a routine clinical setting in Israel. METHODS: Stroke patients admitted to the Sheba Medical Center during the period March 2001 to June 2002 were included in a prospective study according to selection criteria. Data on demographics, risk factors, co-morbidities and stroke severity were collected. Indicators of process of care and outcome were assessed at hospital discharge and 30 days follow-up. Comparison between outcome variables by hospitalization ward was done using logistic regression analysis adjusting for confounders. RESULTS: Of 616 acute stroke patients (mean age 70 years, 61% men, 84% ischemic stroke), 353 (57%) were admitted to general wards and 263 (43%) to the stroke unit. Diagnostic procedures were performed more often and the infection rate was lower in the setting of the stroke unit. Poor outcome (modified Rankin scale > or = 3 or death) was present less often in patients managed in the stroke unit both at hospital discharge (adjusted odds ratio 0.5, 95% confidence interval 0.3-0.8) and at 30 day follow-up (adjusted OR 0.6, 95%CI 0.3-0.9). A Functional Independence Measure score < or = 90 or death at 30 day follow-up was less frequent among patients managed in the stroke unit than in general wards (adjusted OR 0.5, 95%CI 0.2-0.8). CONCLUSIONS: Improved outcomes and higher adherence to guidelines were observed in patients treated in a stroke unit within a department of neurology. The results suggest that patients with acute stroke should have access to treatment in a dedicated stroke unit.

Acute Disease↗
PubMed2004

Nicotinic acetylcholine receptor alpha5 subunits modulate oxotremorine-induced salivation and tremor.

Neuronal nicotinic acetylcholine receptors (nAChRs) are composed of 12 subunits (alpha2-alpha10 and beta2-beta4). alpha5 Subunits, expressed throughout the central nervous system (CNS) and the autonomic nervous system (ANS), possess unique pharmacological properties. The effects of oxotremorine (OXO) on autonomic functions and tremor were examined in mice lacking alpha5 nAChR subunits (alpha5-/-) and compared with those in wild-type (WT) control mice. The alpha5-/- mice showed significantly increased salivation and tremor responses to OXO. The hypothermia, bradycardia and defecation induced by OXO were of similar magnitudes in the two mouse strains. The enhanced OXO effects in alpha5-/- mice indicate inhibitory effects of alpha5 subunits in autonomic ganglia, and support the participation of these subunits in cholinergic transmission in autonomic ganglia.

Acetylcholine↗
PubMed2004

The interface of multiple sclerosis and antiphospholipid antibodies.

The interface between multiple sclerosis (MS) and the antiphospholipid syndrome (APS) is of great clinical relevance and may also shed some light on their pathogenesis. Although formal diagnostic criteria of these two immune syndromes are ostensibly mutually exclusive, many patients with subcortical white matter brain lesions share features of both MS and APS. The main diagnostic feature of APS, the antiphospholipid antibodies (aPLAb), is relatively common in multiple sclerosis and increased fibrin deposition is a feature of both APS lesions and MS plaques. A closer examination of the clinical and laboratory data reveals, however, fundamental differences between the syndromes: MS is a diffuse disease of white matter compared to a much more patchy disease in APS as demonstrated by recent studies in imaging and electrophysiology. Furthermore, a closer examination of the specific aPLAb profile reveals significant differences: we have found that although aPLAb were common in MS patients (32%), these antibodies did not depend on the presence of serum factors for binding to phospholipids and none of the MS patients had antibodies to beta2-glycoprotein-I (beta2-GPI), the major autoantigen in APS. Animal models of the two syndromes are induced by very different antigens and may serve to assess overlapping pathogenic mechanisms. The most common treatment used in MS are beta-interferons which theoretically may exacerbate APS, while anticoagulation, the mainstay of APS treatment, is of unknown value in MS. The relationship of MS to APS remains to be clarified by focused large collaborative studies.

Antibodies, Antiphospholipid↗
PubMed2004

Neurological dysfunction associated with antiphospholipid syndrome: histopathological brain findings of thrombotic changes in a mouse model.

The aim of this work was to study the pathological processes underlying neurological dysfunctions displayed by BALB/C mice induced with experimental antiphospholipid syndrome (APS), as we have previously reported. Experimental APS was induced in female BALB/C mice by immunization with a pathogenic monoclonal anticardiolipin (aCL) antibody, H-3 (n = 10), or an irrelevant immunoglobulin in controls (n = 10). Mice immunized with H-3 developed clinical and neurological manifestations of APS, including: embryo resorption, thrombocytopenia neurological defects and behavioral disturbances. In mouse sera, the titer of various autoantibodies were elevated, including: anti-phospholipids (aPLs), anti-beta2 glycoprotein-I (beta2GPI), anti-endothelial cell antibodies (AECA) and low titer of anti-dsDNA antibodies. Five months after APS induction, mice were sacrificed and brain tissue specimens were processed for hematoxylin and eosin (H&E), immunofluorescence staining and transmission electron microscopy (TEM). H&E staining of cortical tissue derived from all APS mice revealed mild inflammation, localized mainly in the meninges. Prominent IgG deposits in the large vessel walls and perivascular IgG leakage were observed by immunofluorescence. No large thrombi were observed in large vessels. However, EM evaluation of cerebral tissue revealed pathological changes in the microvessels. Thrombotic occlusion of capillaries in combination with mild inflammation was the main finding and may underlie the neurological defects displayed by mice with APS.

Animals↗
PubMed2004

Intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke: initial Israeli experience.

BACKGROUND: Intravenous recombinant tissue plasminogen activator therapy within 3 hours of stroke onset is a proven effective treatment for acute ischemic stroke. OBJECTIVE: To assess the feasibility and safety of rt-PA therapy for reperfusion in routine clinical practice in Israel, in the setting of a dedicated stroke unit. METHODS: Consecutive patients presenting within less than 3 hours of stroke onset were evaluated by an emergency physician and the neurology stroke team. After brain computerized tomography, eligible patients were treated with intravenous rt-PA (0.9 mg/kg, maximum dose 90 mg) according to an in-hospital protocol corresponding to recommended criteria. Patients were admitted to the acute stroke unit. Safety and clinical outcome were routinely assessed. Recanalization was assessed by serial transcranial Doppler. RESULTS: The study group comprised 16 patients, mean age 61 years (range 47-80 years), male to female ratio 10:6, whose median baseline National Institutes of Health stroke scale was 13 (range 6-24). They were treated within a mean door-to-CT time of 39 minutes (range 17-62 min), door-to-drug time 101 minutes (range 72-150), and stroke onset-to-drug time 151 minutes (range 90-180). There was an early improvement within 24 hours (of > or = 4 points in the NIHSS score) in 7 patients (44%) and no early deteriorations. There were no protocol deviations, no symptomatic intracranial hemorrhages, and no major systemic hemorrhage within 36 hours of rt-PA treatment. Three asymptomatic hemorrhagic transformations of the infarct were noted on routine follow-up brain CT associated with neurologic improvement. Outcome data were comparable to the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study. CONCLUSION: Intravenous rt-PA treatment within 3 hours of stroke onset in routine clinical practice in Israel is feasible and appears safe in the setting of a neurology stroke unit and team. Careful implementation of rt-PA therapy for selected patients in Israel is encouraged.

Aged↗
PubMed2004

Features associated with epilepsy in the antiphospholipid syndrome.

OBJECTIVE: To assess the frequency of epilepsy in primary and secondary antiphospholipid syndrome (APS); to analyze the clinical and laboratory features characterizing those with epilepsy in a cohort of 538 patients with APS; and to find associated features that would suggest risk factors for epilepsy in APS. METHODS: We analyzed the clinical features of patients with APS who had epilepsy and compared them to the clinical features of non-epileptic APS patients. RESULTS: Of 538 APS patients, 46 (8.6%) had epilepsy. Epilepsy was more prevalent among APS secondary to systemic lupus erythematosus (SLE) compared to primary APS (13.7% vs 6%; p < 0.05). The patients with epilepsy had a higher prevalence of central nervous system (CNS) manifestations including focal ischemic events (strokes or transient ischemic events, 54.3% vs 24.6%; p < 0.0001) and amaurosis fugax (15.2% vs 4.9%; p < 0.05). APS patients with epilepsy had a higher frequency of valvular pathology (30.4% vs 14.6%; p < 0.01), thrombocytopenia (43.5% vs 25%; p < 0.05), and livedo reticularis (26.1% vs 11.5%; p < 0.01). The multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio (OR) of 4.05 (95% confidence interval, CI: 2.05-8), followed by SLE (OR 1.4, 95% CI 1.2-4.7), and valvular vegetations (OR 2.87, 95% CI 1-8.27). CONCLUSION: Epilepsy is common in APS and most of the risk seems to be linked to vascular disease as manifested by extensive CNS involvement, valvulopathy, and livedo reticularis and to the presence of SLE. These factors, however, explain only part of the increased occurrence of epilepsy in APS and other causes such as direct immune interaction in the brain should be investigated.

Adult↗
PubMed2003

Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice.

The allele E4 of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease (AD) and the chronic brain inflammation which is associated with AD is more pronounced in subjects who carry this allele. In the present study, we employed mice transgenic for the human apoE isoforms apoE3 or apoE4 on a null mouse apoE background and intracerebroventricular injection of LPS to investigate the possibility that the regulation of brain inflammation is affected by the apoE genotype. LPS treatment of control mice resulted in activation of brain astrocytes and microglia whose extent decreased with age. LPS treatment of 6-month-old apoE transgenic and control mice resulted in marked activation of brain astrocytes in the control and apoE3 transgenic mice but had no effect on astrogliosis of age-matched apoE-deficient and apoE4 transgenic mice. In contrast, there were no significant differences between the levels of activated microglia of the apoE3 and apoE4 transgenic mice following LPS treatment. Immunoblot assays revealed that the apoE4 and apoE3 transgenic mice had the same levels of brain apoE, which were similarly increased following LPS treatment. These results show that LPS-induced astrogliosis in apoE transgenic mice is regulated isoform-specifically by apoE3 and not by apoE4 and suggest that similar mechanisms may mediate the phenotypic expression of the apoE4 genotype in AD and in other neurodegenerative diseases.

Age Factors↗
PubMed2003

Inhibition of ras by farnesylthiosalicylate significantly reduces the levels of autoantibodies in two animal models of the antiphospholipid syndrome.

BACKGROUND: Stimulation and proliferation of lymphocytes require activation of Ras. S-farnesylthiosalicylic acid (FTS) is a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. Antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies detected in patients with antiphospholipid syndrome (APS), which is associated with thrombosis, pregnancy losses, and thrombocytopenia. OBJECTIVE: To examine the effect of FTS treatment on aPL levels in a genetic autoimmune model (the MRL/lpr mice) and in an induced model of APS. METHODS: Female Balb/C mice immunized once with beta2-glycoprotein I (beta2-GPI) in complete Freund's adjuvant (CFA) and female MRL/lpr mice were treated intraperitoneally with either FTS (5 mg/Kg/day) or saline 3-5 times a week. aPL and anti-beta2-GPI antibodies were measured by ELISA. RESULTS: FTS treatment 3 times a week resulted in significant decreases of aPL and anti-beta2-GPI antibodies in both animal models. In contrast, more frequent treatment (5 times a week) had no significant effect on autantibody levels in both animal models. We further compared 2 protocols in the induced APS model, one for alternate day treatment and the other for daily treatment on the first 3 days each week, and found a decrease in autoantibody levels only in the alternate day protocol. CONCLUSIONS: Inhibition of Ras activation by FTS is effective in decreasing autoantibody levels in models of APS. The differential modulation of immune function by alternate day compared to daily treatment may provide better understanding of the role of Ras activation in this system.

Animals↗