Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis.

OBJECTIVES: Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). We examined whether single nucleotide polymorphisms (SNPs) in enzymes of the folic acid pathway (folylpoly-gamma-glutamate synthetase [FPGS], gamma-glutamyl hydrolase [GGH], and methylenetetrahydrofolate reductase [MTHFR]) associate with significant adverse events (SigAE). METHODS: Patients (n=319) enrolled in the Veterans Affairs RA (VARA) registry taking MTX were genotyped for HLA-DRB1-SE and the following SNPs: FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, rs719235, rs11988534), MTHFR (rs1801131, rs1801133). AE were abstracted from the medical record using a structured instrument. SigAE were defined as an AE leading to MTX discontinuation. Covariates included: age, gender, race, RA antibody status, tobacco, RA disease duration between diagnosis and MTX course, Charlson-Deyo comorbidity index, glucocorticoids, use of prior RA medications, and mean 4-variable disease activity score. Cox regression was performed to determine factors associated with time-to-SigAE. A p-value ≤ 0.005 established significance in the final model. RESULTS: The presence of ≥ 1 copy of the minor allele in MTHFR rs1801131 was associated with an increased hazard ratio (HR) of SigAE (HR 3.05, 95% CI 1.48-6.29, p-value 0.003 and HR 3.88, 95% CI 1.62-9.28, p-value 0.002 for heterozygotes and homozygotes for the minor allele, respectively). An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001. CONCLUSIONS: RA subjects taking MTX may have decreased time-to-SigAE with ≥ 1 copy of the minor allele in MTHFR rs1801131. Further investigation is warranted, as these SNPs may indicate susceptibility to MTX toxicity.

CARD9 in the pathogenesis of axial spondyloarthritis.

Axial spondyloarthritis (axSpA) has been long classified as an autoimmune disease caused by a breakdown in the ability of the immune system to delineate self from foreign, resulting in self-reactive T cells. The strong genetic association of HLA-B27 supports this role for T cells. More recently, genetic and clinical studies indicate a prominent role of the environment in triggering axSpA, including an important role for microbes and the innate immune response. As an example, mutations in genes associated with innate immunity, including the anti-fungal signaling molecule Caspase recruitment domain-containing protein 9 (CARD9), have been linked to axSpA susceptibility. Thus, current thought classifies axSpA as a "mixed pattern condition" caused by both autoimmune and autoinflammatory mechanisms. The goal of this review is to convey.

The ASCOD phenotyping of ischemic stroke (Updated ASCO Phenotyping).

ASCO phenotyping (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes) assigns a degree of likelihood of causal relationship to every potential disease (1 for potentially causal, 2 for causality is uncertain, 3 for unlikely causal but the disease is present, 0 for absence of disease, and 9 for insufficient workup to rule out the disease) commonly encountered in ischemic stroke describing all underlying diseases in every patient. In this new evolution of ASCO called ASCOD, we have added a 'D' for dissection, recognizing that dissection is a very frequent disease in young stroke patients. We have also simplified the system by leaving out the 'levels of diagnostic evidence', which has been integrated into grades 9 and 0. Moreover, we have also changed the cutoff for significant carotid or intracranial stenosis from 70% to more commonly used 50% luminal stenosis, and added a cardiogenic stroke pattern using neuroimaging. ASCOD captures and weights the overlap between all underlying diseases present in ischemic stroke patients.

Factors affecting the prevalence of chronic diseases in Palestinian people: an analysis of data from the Palestinian Central Bureau of Statistics.

This study determined whether there are significant differences in the prevalence of diabetes, hypertension, cardiovascular disease (CVD) and cancer among Palestinians with respect to different demographic variables using secondary data from the Palestinian Central Bureau of Statistics. Living in the Gaza Strip was a protective factor, with this group being 21% less likely to have diabetes, 35% less likely to have hypertension, and 48% less likely to have CVD than those living in the West Bank. No significant difference was found for cancer. Being a refugee was a significant risk factor for diabetes and CVD while being married/engaged or divorced/ separated/widowed was a risk factor for diabetes and hypertension. Gender was a risk factor for hypertension with females being 60% more likely to have hypertension than males. Living in a rural setting was protective against hypertension. As expected, age was a risk factor for diabetes, hypertension and CVD; the magnitude of this increased risk was alarming, 36 to 434 times greater in those aged 40-65 years compared with those aged 0-19 years.

An observational study of glucocorticoid-induced osteoporosis prophylaxis in a national cohort of male veterans with rheumatoid arthritis.

UNLABELLED: We applied regression techniques to a large cohort of patients to understand why certain patients are prescribed medications to prevent glucocorticoid-induced osteoporosis (GIO). Rates of prescriptions to prevent osteoporosis were low. The presence of drugs and disorders associated with osteoporosis and gastrointestinal conditions actually are associated with a decreased likelihood of receiving osteoporosis-preventing medications. INTRODUCTION: To understand why some patients are prescribed medications to prevent GIO while other patients are not, we examined whether there is an association among osteoporosis-inducing medical conditions or medications and prescriptions for osteoporosis prophylaxis in a large cohort of rheumatoid arthritis patients on chronic glucocorticoids. METHODS: Department of Veterans' Affairs national administrative databases were used to construct a cohort (n = 9,605) and provide the data for this study. Multivariate logistic regression was performed to determine medical conditions and medications associated with dispensing of GIO-preventive medications, controlling for sociodemographic variables, comorbidities, glucocorticoid dosage, prior fractures, and rheumatoid arthritis severity. A subanalysis examined predictors of early GIO prevention. RESULTS: Subjects were more likely to receive GIO prophylaxis if they were older, African American, treated with multiple antirheumatic disease-modifying drugs, or received greater glucocorticoid exposure. The prescription of certain drug classes (loop diuretics and anticonvulsants) and conditions (malignancy, renal insufficiency, alcohol abuse, and hepatic disease) were associated with lower likelihood of GIO prophylaxis, despite putative links between these agents/conditions and osteoporosis. The presence of gastrointestinal disorders dramatically decreased likelihood of GIO prophylaxis. Few characteristics predicted the dispensing of GIO-preventing medications within 7 days of the initial glucocorticoid start date. CONCLUSIONS: Rates of prescriptions to prevent osteoporosis in a cohort of older men with rheumatoid arthritis on chronic glucocorticoids were low. Gastrointestinal disorders and drugs and disorders potentially linked to osteoporosis are associated with diminished odds of being prescribed GIO-preventing medications.

Classification of stroke subtypes.

This article reviews published stroke subtype classification systems and offers rules and a basis for a new way to subtype stroke patients. Stroke subtyping can have different purposes, e.g. describing patients' characteristics in a clinical trial, grouping patients in an epidemiological study, careful phenotyping of patients in a genetic study, and classifying patients for therapeutic decision-making in daily practice. The classification should distinguish between ischemic and hemorrhagic stroke, subarachnoid hemorrhage, cerebral venous thrombosis, and spinal cord stroke. Regarding the 4 main categories of etiologies of ischemic stroke (i.e. atherothrombotic, small vessel disease, cardioembolic, and other causes), the classification should reflect the most likely etiology without neglecting the vascular conditions that are also found (e.g. evidence of small vessel disease in the presence of severe large vessel obstructions). Phenotypes of large cohorts can also be characterized by surrogate markers or intermediate phenotypes (e.g. presence of internal carotid artery plaque, intima-media thickness of the common carotid artery, leukoaraiosis, microbleeds, or multiple lacunae). Parallel classifications (i.e. surrogate markers) may serve as within-study abnormalities to support research findings.

New approach to stroke subtyping: the A-S-C-O (phenotypic) classification of stroke.

We now propose a new approach to stroke subtyping. The concept is to introduce a complete 'stroke phenotyping' classification (i.e. stroke etiology and the presence of all underlying diseases, divided by grade of severity) as distinguished from past classifications that subtype strokes by characterizing only the most likely cause(s) of stroke. In this phenotype-based classification, every patient is characterized by A-S-C-O: A for atherosclerosis, S for small vessel disease, C for cardiac source, O for other cause. Each of the 4 phenotypes is graded 1, 2, or 3. One for 'definitely a potential cause of the index stroke', 2 for 'causality uncertain', 3 for 'unlikely a direct cause of the index stroke (but disease is present)'. When the disease is completely absent, the grade is 0; when grading is not possible due to insufficient work-up, the grade is 9. For example, a patient with a 70% ipsilateral symptomatic stenosis, leukoaraiosis, atrial fibrillation, and platelet count of 700,000/mm(3) would be classified as A1-S3-C1-O3. The same patient with a 70% ipsilateral stenosis, no brain imaging, normal ECG, and normal cardiac imaging would be identified as A1-S9-C0-O3. By introducing the 'level of diagnostic evidence', this classification recognizes the completeness, the quality, and the timing of the evaluation to grade the underlying diseases. Diagnostic evidence is graded in levels A, B, or C: A for direct demonstration by gold-standard diagnostic tests or criteria, B for indirect evidence or less sensitive or specific tests or criteria, and C for weak evidence in the absence of specific tests or criteria. With this new way of classifying patients, no information is neglected when the diagnosis is made, treatment can be adapted to the observed phenotypes and the most likely etiology (e.g. grade 1 in 1 of the 4 A-S-C-O phenotypes), and analyses in clinical research can be based on 1 of the 4 phenotypes (e.g. for genetic analysis purpose), while clinical trials can focus on 1 or several of these 4 phenotypes (e.g. focus on patients A1-A2-A3).

Poor to modest agreement between rheumatoid arthritis response measures in clinical practice.

OBJECTIVE: To evaluate the agreement among several rheumatoid arthritis (RA) response measures in a clinical setting. METHODS: 529 patients with RA were seen at 2 regular visits where the following response measures were determined: ACR-20, EULAR good or moderate (EULAR-GM), Simplified Disease Activity Index moderate (SDAI-M), Clinical DAI moderate (CDAI-M), and Patient Reported Outcomes Index-M 20 (PRO-IM-20). Each measure was modified to include a "worse" response, i.e. the inverse of the respective guidelines for a positive improvement response.Introduced for comparison was the Real-time Assessment of Disease Activity in Rheumatoid Arthritis (RADARA), a response measure that registers improvement if the patient's tender and swollen joint counts and HAQ score all improve and worsening if all three increase. Contingency tables comparing the three responses (worse, no change, and improvement) along with Cohen's kappa were calculated. RESULTS: The mean (SD) baseline characteristics of the patients included: age 66.5 (10.7) years, RA duration 12.9 (11.0) years, 91.3% male, 84.1% rheumatoid factor positive, and a Disease Activity Score-28 of 3.5 (1.3). The percentage of patients who improved/worsened were as follows: ACR-20 4.7/9.1, EULAR-GM 23.4/26.3, SDAI-M 16.1/20.6, CDAI-M 16.3/20.0, PRO-IM-20 22.5/34.4, and RADARA 7.0/11.5. Agreement (kappa) was poor to slight (

Post-traumatic stress disorder and serum cytokine and chemokine concentrations in patients with rheumatoid arthritis✰.

OBJECTIVE: Although post-traumatic stress disorder (PTSD) is identified as a risk factor in the development of rheumatoid arthritis (RA), associations of PTSD with disease progression are less clear. To explore whether PTSD might influence disease-related measures of systemic inflammation in RA, we compared serum cytokine/chemokine (cytokine) concentrations in RA patients with and without PTSD. METHODS: Participants were U.S. Veterans with RA and were categorized as having PTSD, other forms of depression/anxiety, or neither based on administrative diagnostic codes. Multiplex cytokines were measured using banked serum. Associations of PTSD with cytokine parameters (including a weighted cytokine score) were assessed using multivariable regression, stratified by anti-CCP status and adjusted for age, sex, race, and smoking status. RESULTS: Among 1,460 RA subjects with mean (SD) age of 64 (11) years and disease duration of 11 (11) years, 91% were male, 77% anti-CCP positive, and 80% ever smokers. Of these, 11.6% had PTSD, 23.7% other depression/anxiety, and 64.7% had neither. PTSD, but not depression/anxiety, was associated with a higher cytokine score and number of high-concentration analytes in adjusted models, though this was limited to anti-CCP positive subjects. PTSD was associated with heightened expression of several individual cytokines including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-17, IFN-γ, GM-CSF, MCP-1, and TNF-α. CONCLUSION: Anti-CCP positive RA patients with PTSD have higher serum cytokine concentrations than those without PTSD, demonstrating that systemic inflammation characteristic of RA is heightened in the context of this relatively common psychiatric comorbidity.

Diabetes and brain ischemia.

Diabetes influences brain ischemia in a number of different ways. Diabetes causes and exacerbates macroangiopathies, increases the severity of ischemia, and increases stroke mortality. Unfortunately, few studies have examined in sufficient depth the influence of diabetes on the various vascular lesions that cause brain ischemia. These can be divided into: 1) cardiac-origin brain embolism; 2) atherosclerosis of the aorta and the large extracranial arteries--the internal carotid arteries (ICAs) and the vertebral arteries (VAs); 3) atherosclerosis of the large intracranial arteries--ICAs, anterior, middle, and posterior cerebral arteries, the VAs, and the basilar artery; 4) intracranial atheromatous branch disease of macroscopically visible branches of the intracranial arteries enumerated in 3; and 5) degenerative abnormalities such as lipohyalinosis and fibrinoid changes within penetrating artery branches visible only microscopically. The last three types of disorders all can cause deep subcortical brain infarcts, the predominant type of brain infarction found in Japan.

The Oklahoma complex. A common form of conversion hysteria.

Hysteria is not a homogeneous illness. Some patients with symptoms of apparent neurological dysfunction develop a disability because they cannot cope with life's demands. This article calls attention to several hysterical patients who share similar histories. Treatment by a nonpsychiatric physician in these three cases consisted of simple emotional support and easing of responsibilities, ie, saying no for the patient. Recognition of the psychological state of some patients with hysterical symptoms, and administration of treatment that eases environmental stresses, can be effective.

Differences in stroke subtypes among natives and caucasians in Boston and Buenos Aires.

BACKGROUND AND PURPOSE: Several issues regarding ethnic-cultural factors, sex-related variation, and risk factors for stroke have been described in the literature. However, there have been no prospective studies comparing ethnic differences and stroke subtypes between populations from South America and North America. It has been suggested that natives from Buenos Aires, Argentina, may have higher frequency of hemorrhagic strokes and penetrating artery disease than North American subjects. The aim of this study was to validate this hypothesis. METHODS: We studied the database of all consecutive acute stroke patients admitted to the Ramos Mejia Hospital (RMH) in Buenos Aires and to the Beth Israel Deaconess Medical Center (BIMC) in Boston, Massachusetts, from July 1997 to March 1999. Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. All information on patients (demographic, clinical, and radiographic) was recorded prospective to the assessment of the stroke subtype. RESULTS: Three hundred sixty-one and 479 stroke patients were included at RMH and BIMC stroke data banks, respectively. Coronary artery disease was significantly more frequent in BIMC (P:<0.001), whereas tobacco and alcohol intake were significantly more frequent in RMH (P:<0.001). Intracerebral hemorrhage (P:<0.001) and penetrating artery disease (P:<0.001) were significantly more frequent in the RMH registry, whereas large-artery disease (P:<0.02) and cardioembolism (P:<0.001) were more common in the BIMC data bank. CONCLUSIONS: Penetrating artery disease and intracerebral hemorrhage were the most frequent stroke subtypes in natives from Buenos Aires. Lacunar strokes and intracerebral hemorrhage were more frequent among Caucasians from Buenos Aires than Caucasians from Boston. Poor risk factor control and dietary habits could explain these differences.

New therapies for stroke.

The treatment of patients with stroke and cerebrovascular disease has entered a new era. During the 1990s there has been a revolution in technology able to define quickly, safely, and accurately stroke pathophysiological characteristics and the cardiovascular lesions that cause stroke in individual patients. Advanced brain imaging with computed tomography, magnetic resonance imaging, and newer magnetic resonance modalities, including fluid attenuating inversion recovery imaging, diffusion, perfusion, functional magnetic resonance imaging, and magnetic resonance spectroscopy, show clinicians the localization, severity, and potential reversibility of ischemia. Vascular lesions can be defined using spiral computed tomographic angiography, magnetic resonance angiography, and extracranial and transcranial ultrasonography. Cardiac and aortic sources of stroke are now better studied using transesophageal echocardiography. More sophisticated hematologic testing gives new insights into the role of altered coagulability in causing or contributing to thromboembolism. Clinicians can now recognize the key data elements needed to logically treat brain ischemia, including the following: The nature, location, and severity of cardiac and cerebrovascular lesions. The mechanism by which these lesions cause ischemia--hypoperfusion? embolism? functional changes such as vasoconstriction? The cellular and serologic components of the blood that relate to coagulability, viscosity, and blood flow. The state of the brain--normal, reversibly ichemic ("stunned"), or infarcted. With these diagnostic advances have come new treatments, new ideas about treatment, and more and new information about conventional treatments.

Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke.

OBJECTIVE: To explore the relationship between hypoperfusion, embolism, and brain infarction. DESIGN: We studied 4 situations in which brain infarction is related to hypoperfusion: extracranial and intracranial occlusive vascular disease, reduced functional vascular reserve in patients with carotid artery occlusive disease, reduced collateral blood flow in patients given thrombolytic treatment, and cardiac surgery. We reviewed results of emboli monitoring using transcranial Doppler ultrasonography. RESULTS: Hypoperfusion is strongly linked to brain ischemia and infarction. The evidence includes close correlation of (1) the severity of arterial stenosis with brain infarction; (2) impaired functional blood flow reserve in patients with carotid artery disease and subsequent brain infarction; (3) reduced collateral blood flow with poor prognosis after thrombolysis; and (4) stroke-related neurologic deficits after cardiac surgery to hypoperfusion during surgery. Microembolization is common in patients with severe symptomatic carotid artery stenosis and during and after cardiac surgery. CONCLUSIONS: Hypoperfusion and embolism often coexist and their pathophysiological features are interactive. Arterial lumenal narrowing and endothelial abnormalities stimulate clot formation and subsequent embolization. Reduced perfusion limits the ability of the bloodstream to clear or wash out emboli and microemboli and reduces available blood flow to regions rendered ischemic by emboli that block supply arteries. The brain border zones are a favored destination for microemboli that are not cleared. We posit that impaired washout is an important but neglected concept that intertwines hypoperfusion, embolization, and brain infarction.

Convulsive-like movements in brainstem stroke.

BACKGROUND: Involuntary convulsive-like movements sometimes occur in patients with brainstem strokes. These movements vary in nature, frequency, and trigger, including fasciculation-like, shivering, jerky, tonic-clonic, and intermittent shaking movements. Some are interpreted as decerebrate postures or seizures. It is important to recognize this type of motor phenomenon since it may be a diagnostic clue for early diagnosis and treatment of brainstem strokes. DESIGN: Case report and review of the literature OBSERVATION: A 72-year-old-man presented with impaired consciousness and jerks of the upper limbs mimicking seizures. These episodes consisted of brief clonic contractions of the proximal and distal upper extremities. They were observed in paroxysms lasting for 3 to 5 seconds. Magnetic resonance imaging showed large midpontine infarction. Magnetic resonance angiography revealed the absence of basilar artery blood flow. No seizure discharges were observed in the electroencephalogram. Anticoagulation with intravenous heparin was started. Two days after admission, the patient had a cardiac arrest and died. We review the frequency and nature of convulsive-like movements in brainstem stroke in the literature. CONCLUSIONS: Movements associated with brainstem lesions are not easily differentiated from convulsions. Unexpected onset and inexperience of the observers limit the characterization of this phenomenon. Convulsive-like movements in brainstem stroke may occur more frequently than reported. Early detection of this motor phenomenon may have practical implications.

Speech arrest in a dextral with a right mesial frontal astrocytoma.

A right-handed man had clustered groups of seizures characterized by speech arrest over a period of eight years. Later, speech arrest was accompanied by head-turning to the left and altered tone of the left limbs. An astrocytoma, centered in the right supplementary motor region, was identified. This case confirms the experimental data of speech arrest emanating from the right paramedian cortex of a right handed man.

Anterior choroidal artery-territory infarction. Report of cases and review.

Occlusion of the anterior choroidal artery (AChA) can cause infarction in the posterior limb of the internal capsule. Infarction is less frequent in the thalamus, midbrain, temporal lobe, and lateral geniculate body territories of the AChA. The most common clinical sign is hemiparesis. Hemisensory loss is usually transient but may be severe at onset. Homonymous upper-quadrant anopia, hemianopia, or upper- and lower-quadrant sector anopsia can be present. A homonymous defect in the upper and lower visual fields sparing the horizontal meridian is probably diagnostic of a lesion in the lateral geniculate body in the territory of the AChA. The most common stroke mechanism is small-vessel occlusive disease, predominantly found in hypertensive and diabetic patients, but cardiac-origin embolism also can affect the AChA territory. Two of our patients had infarction after temporal lobe resection for epilepsy. Occasionally patients have associated disabilities of higher cortical function that are usually transient. The lesion should be recognizable by computed tomography.

Intracerebral hemorrhage and oral amphetamine.

Four patients suffered intracerebral hemorrhages following the oral or nasal use of amphetamine or related compounds. Two of these patients had abnormal-appearing cerebral blood vessels on angiography. Review of previously reported cases showed that intracerebral hemorrhage may occur in patients using the drug for the first time and for nonrecreational purposes.

Posterior cerebral artery territory infarcts in the New England Medical Center Posterior Circulation Registry.

BACKGROUND: Infarcts in the territory of the posterior cerebral arteries (PCAs) are common. Although associated clinical symptoms and signs are known, the mechanisms of stroke and the anatomical distribution of PCA territory lesions caused by the various stroke mechanisms are less well defined. Published reports have selected only special subgroups of patients. PATIENTS AND METHODS: We studied stroke mechanisms, infarct distribution, and clinical findings among 79 patients in the New England Medical Center Posterior Circulation Registry in whom brain imaging scans showed infarcts that involved 1 or more cortical territories of the PCA. RESULTS: Forty-eight patients (61%) had infarcts limited to the PCA territory (pure PCA), while 31 (39%) also had infarcts in other territories (PCA+). Infarcts were in the cortical territory of the PCA in 47 patients (59%) and were cortical and deep in 32 (41%). Infarcts that were cortical and deep were more common in PCA+ lesions. Stroke mechanisms were embolism of cardiac origin (32 [41%]), proximal arterial disease (25[32%]), cryptogenic embolism (8[10%]), intrinsic PCA disease (7[9%]), vasoconstriction (4[5%]), and coagulopathy (3[4%]). Patients with cardiogenic embolism and intrinsic PCA disease often had pure PCA territory infarcts, while patients with proximal arterial disease more often had PCA+ infarcts. Visual abnormalities were present in 66 patients (84%). Motor weakness, cognitive and behavioral abnormalities, and ataxia were found in 20 patients (25%); only 12 (15%) had sensory signs. CONCLUSIONS: The great majority of pure PCA and PCA+ territory infarcts are caused by cardiac or intra-arterial embolism. Intrinsic PCA disease, vasoconstriction, and coagulopathy are less common causes of infarction.

Isopropyl alcohol intoxication.

Three patients had neurologic signs due to isopropyl alcohol (IPA) intoxication. Over a several-week period, a known alcoholic developed apathy, confusion, ataxia, and hyperreflexia. During this period, there was no ethanol available to him, and he denied use of other intoxicants. He was found stuporous in the hospital after drinking IPA and admitted to IPA abuse during the preceding weeks. Two other men were admitted in a stupor after large ingestions of IPA. Intoxication with IPA has two different presentations: stupor in a known alcoholic and encephalopathy of unknown cause in individuals who hide their addiction. Ethanol, methanol, IPA, and ethylene glycol intoxications are associated with different clinical and laboratory findings.