Early phase clinical and biological markers associated with subclinical atherosclerosis measured at 7 years of evolution in an early inflammatory arthritis cohort.

OBJECTIVES: Accelerated atherosclerosis has emerged as a critical issue in rheumatoid arthritis (RA). There is a need to better understand the link between RA and atherosclerosis. Our aim was to identify parameters associated with the development of subclinical atheroma in a very early arthritis (VErA) cohort. METHODS: VErA-cohort patients were prospectively recruited from 1998 to 2002. Arthritis treatment was standardised from onset. The clinical, biological and radiological parameters of all patients were collected from inclusion. Carotid intima-media thickness (cIMT) was measured 7 years after their first symptoms. RESULTS: Among 105 patients included, 82 developed RA (mean age at onset: 51.7±12.8 years). Mean carotid artery IMT at year 7 was 0.67±0.12 mm. Larger thickness defined by values above the median (0.66) was associated with inclusion age (p<10-6), swollen joint count (p=0.01), DAS44 (p=0.048) and hypertension (p=0.006). In contrast, anti-CCP positivity (>50 UA/ml) was associated with thinner cIMT (p=0.03). Baseline as well as cumulated values of markers reflecting systemic inflammation, lymphocyte activation, endothelial dysfunction and oxidative stress were not correlated with carotid subclinical atherosclerosis. Major independent atheroma risk factors retained by multivariate analyses were hypertension (OR 4.33 [1.59-11.73]; p=0.004) and swollen joint count at inclusion (OR 3.87 [1.54-9.72]; p=0.004), while methotrexate use was a protective marker (OR 0.27 [0.11-0.71]; p=0.007). CONCLUSIONS: This study conducted from the VErA vascular cohort of community-cases of RA confirm that cIMT is under the influence of classical CV risk (hypertension), disease marker (SJC) and methotrexate intake.

Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: evidence for tumor necrosis factor α-induced VE-cadherin cleavage.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally attacks synovial joints. However, accelerated atherosclerosis and increased cardiovascular morbidity and mortality are major clinical consequences of endothelial dysfunction in RA patients. Tumor necrosis factor α (TNFα) is the major mediator of inflammation in RA, related to vascular injury by targeting VE-cadherin, an endothelium-specific adhesion molecule of vital importance for endothelium integrity and angiogenesis. We undertook this study to examine the mechanisms regulating VE-cadherin processing by TNFα and their occurrence in RA. METHODS: Human umbilical vein endothelial cells were used in primary culture and treated with recombinant TNFα to study VE-cadherin cleavage. Cell lysates and conditioned media were analyzed by Western blotting for VE-cadherin cytoplasmic domain and extracellular domain (VE-90) generation, respectively. VE-90 was analyzed at baseline and at the 1-year followup in sera from 63 RA patients (from the Very Early Rheumatoid Arthritis cohort) with disease duration of <6 months. RESULTS: TNFα induced a time-dependent shedding of VE-90 in cell media. This effect was prevented by tyrosine kinase inhibitors (genistein and PP2) or by knocking down Src kinase. In contrast, tyrosine phosphatase blockade enhanced VE-cadherin cleavage, confirming the requirement of tyrosine phosphorylation processes. In addition, using the matrix metalloproteinase (MMP) activator APMA and the MMP inhibitor GM6001, we demonstrated that MMPs are involved in TNFα-induced VE-cadherin cleavage. Of major importance, VE-90 was detected in sera from the 63 RA patients and was positively correlated with the Disease Activity Score at baseline and after 1-year followup. CONCLUSION: These findings provide the first evidence of VE-cadherin proteolysis upon TNFα stimulation and suggest potential clinical relevance of soluble VE-cadherin in management of RA.

Identified circuit in rat postrhinal cortex encodes essential information for performing specific visual shape discriminations.

Learning theories hypothesize specific circuits encode essential information for performance. For simple tasks in invertebrates and mammals, the essential circuits are known, but for cognitive functions, the essential circuits remain unidentified. Here, we show that some essential information for performing a choice task is encoded in a specific circuit in a neocortical area. Rat postrhinal (POR) cortex is required for visual shape discriminations, protein kinase C (PKC) pathways mediate changes in neuronal physiology that support learning, and specific PKC genes are required for multiple learning tasks. We used direct gene transfer of a constitutively active PKC to prime a specific POR cortex circuit for learning visual shape discriminations. In the experiment, rats learned a discrimination, received gene transfer, learned new discriminations, received a small lesion that ablated approximately 21% of POR cortex surrounding the gene transfer site, and were tested for performance for discriminations learned either before or after gene transfer. Lesions of the genetically targeted circuit selectively interfered with performance for discriminations learned after gene transfer. Activity-dependent gene imaging confirmed increased activity in the genetically targeted circuit during learning and showed the essential information was sparse-coded in approximately 500 neurons in the lesioned area. Wild-type rats contained circuits with similar increases in activity during learning, but these circuits were located at unpredictable, different positions in POR cortex. These results establish that some essential information for performing specific visual discriminations can be encoded in a small, identified, neocortical circuit and provide a foundation for characterizing the circuit and essential information.

Characteristic and intermingled neocortical circuits encode different visual object discriminations.

Synaptic plasticity and neural network theories hypothesize that the essential information for advanced cognitive tasks is encoded in specific circuits and neurons within distributed neocortical networks. However, these circuits are incompletely characterized, and we do not know if a specific discrimination is encoded in characteristic circuits among multiple animals. Here, we determined the spatial distribution of active neurons for a circuit that encodes some of the essential information for a cognitive task. We genetically activated protein kinase C pathways in several hundred spatially-grouped glutamatergic and GABAergic neurons in rat postrhinal cortex, a multimodal associative area that is part of a distributed circuit that encodes visual object discriminations. We previously established that this intervention enhances accuracy for specific discriminations. Moreover, the genetically-modified, local circuit in POR cortex encodes some of the essential information, and this local circuit is preferentially activated during performance, as shown by activity-dependent gene imaging. Here, we mapped the positions of the active neurons, which revealed that two image sets are encoded in characteristic and different circuits. While characteristic circuits are known to process sensory information, in sensory areas, this is the first demonstration that characteristic circuits encode specific discriminations, in a multimodal associative area. Further, the circuits encoding the two image sets are intermingled, and likely overlapping, enabling efficient encoding. Consistent with reconsolidation theories, intermingled and overlapping encoding could facilitate formation of associations between related discriminations, including visually similar discriminations or discriminations learned at the same time or place.

Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein.

BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses. OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD. METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria. RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (<0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p < 0.0001). CONCLUSION: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.

Prevalence of depression and other psychiatric disorders among incarcerated youths.

OBJECTIVE: To determine the prevalence of selected psychiatric disorders among incarcerated youths, compare prevalence rates by sex and ethnicity, assess comorbidity, and determine previous diagnosis. METHOD: From July-December 2000, a total of 1,024 incarcerated adolescents completed self-administered questionnaires that included the Beck Depression Inventory (BDI) and the Patient Health Questionnaire (PHQ), linked to DSM-IV, that assesses depression, drug and alcohol abuse, and somatoform, panic, and anxiety disorders. RESULTS: From the BDI, 261/1,024 (25%) had moderate and 223/1,024 (22%) severe depression. From the PHQ, 100/1,024 (9.77%) had major depressive disorder, 420 (41%) drug abuse, 275 (27%) alcohol abuse, and 297 (29%) one of the other disorders. In comparisons by sex and ethnic group, noteworthy findings included no differences between the sexes for moderate and severe depression from the BDI or for major depressive disorder from the PHQ; less drug and alcohol abuse in African-American males and females; and more anxiety disorder in white males and in females. Sixty percent had one or more psychiatric disorder: comorbidity was particularly common between both depression and anxiety and drug and alcohol abuse. Of depressed youths, 20% had been previously diagnosed and treated, as had approximately 10% with other disorders. CONCLUSIONS: Incarcerated youths had a high prevalence of psychiatric disorders, usually undiagnosed, and comorbidity was common.