Mixture Analysis of Age at Onset in Migraine Without Aura: Evidence for Three Subgroups

(Headache 2010;50:1313‐1319) Objective. — To verify the presence of different age at onset (AAO) subgroups of patients in a sample of patients with migraine without aura (MWA) and compare clinical correlates among them. Background.— MWA is a long‐lasting disease whose prognosis has not yet been fully investigated. Patients may present complete remission, partial clinical remission, persistence and progression (migraine attack frequency and disability may increase over time leading to chronic migraine). Limited evidence exists regarding the identification of risk factors or predictors which might influence migraine prognosis. AAO has been proven a useful tool in the investigation of the clinical, biological, and genetic characteristics able to influence the prognosis of a number of neuropsychiatric disorders. AAO distribution was studied using mixture analysis, a statistical approach that breaks down the empirical AAO distribution observed into a mixture of normal components. Methods.— A sample of 334 outpatients affected by MWA, recruited in a clinical genetic study at our Headache Center from 2004 to 2008, was enrolled for this study. Diagnosis was made according to International Headache Society criteria 2004. AAO distribution in patients was studied using mixture analysis. Chi‐square test was used to compare clinical correlates among identified subgroups. Logistic regression was performed in order to correct for effect of possible confounders. Results.— Mixture analysis broke up the observed distribution of AAO into 3 normal theoretical distributions. Informational criteria clearly showed a better 3‐component model rather than the 2‐component one. An early‐onset (≤7 years of age), an intermediate‐onset (≥8 and ≤22), and a late‐onset group (≥23) were identified. Comparison of clinical correlates among subgroups by means of chi‐square test showed a statistically significant result for migraine frequency (χ² = 7.41, P = .02). Considering the frequency of migraine attacks as a main outcome, the regression model showed a higher AAO is associated with low frequency (odds ratio = 0.95; P = .02). Conclusions.— The significant association between AAO and attack frequency found in our study supports the hypothesis that AAO could act as a predictor factor able to influence prognosis. AAO could represent a phenotype suitable for identifying MWA susceptibility genes.     

Adherence to Long-Acting Bronchodilators After Discharge for COPD: How Much of the Geographic Variation is Attributable to the Hospital of Discharge and How Much to the Primary Care Providers?

In moderate–severe chronic obstructive pulmonary disease (COPD), long-acting bronchodilators (LBs) are recommended to improve the quality of life. The aims of this study were to measure adherence to LBs after discharge for COPD, identify determinants of adherence, and compare amounts of variation attributable to hospitals of discharge and primary care providers, i.e. local health districts (LHDs) and general practitioners (GPs). This cohort study was based on the Lazio region population, Italy. Patients discharged in 2007–2011 for COPD were followed up for 2 years. Adherence was defined as a medication possession ratio >80%. Cross-classified models were performed to analyse variation. Variances were expressed as median odds ratios (MORs). An MOR of 1.00 stands for no variation, a large MOR indicates considerable variation. We enrolled 13,178 patients. About 29% of patients were adherent to LBs. Adherence was higher for patients discharged from pneumology wards and for patients with GPs working in group practice. A relevant variation between LHDs (MOR = 1.21, p = 0.001) and GPs (MOR = 1.28, p = 0.035) was detected. When introducing the hospital of discharge in the model, the MOR related to LHDs decreased to 1.05 (p = 0.345), MOR related to GPs dropped to 1.22 (p = 0.086), whereas MOR associated with hospitals of discharge was 1.38 (p < 0.001). Treatments with proven benefit for COPD were underused. Moreover, a relevant geographic variation was observed. This heterogeneity raises equity concerns in access to optimal care. The reduction of variability among LHDs and GPs after entering the hospital level proved that differences we observe in primary care partially ‘reflect’ the clinical approach of hospitals of discharge.     

The cardiac pacemaker current

In mammals cardiac rate is determined by the duration of the diastolic depolarization of sinoatrial node (SAN) cells which is mainly determined by the pacemaker I_f current. f-channels are encoded by four members of the hyperpolarization-activated cyclic nucleotide-gated gene (HCN1-4) family. HCN4 is the most abundant isoform in the SAN, and its relevance to pacemaking has been further supported by the discovery of four loss-of-function mutations in patients with mild or severe forms of cardiac rate disturbances. Due to its selective contribution to pacemaking, the I_f current is also the pharmacological target of a selective heart rate-reducing agent (ivabradine) currently used in the clinical practice. Albeit to a minor extent, the I_f current is also present in other spontaneously active myocytes of the cardiac conduction system (atrioventricular node and Purkinje fibres). In working atrial and ventricular myocytes f-channels are expressed at a very low level and do not play any physiological role; however in certain pathological conditions over-expression of HCN proteins may represent an arrhythmogenic mechanism. In this review some of the most recent findings on f/HCN channels contribution to pacemaking are described.     

Vitamin D status, dependence on age, and seasonal variations in the concentration of vitamin D in Croatian postmenopausal women initially screened for osteoporosis

Vitamin D deficiency is associated with secondary hyperparathyroidism, increased bone turnover, and bone loss, leading to increased risk for osteoporotic fractures. The objective of this study was to investigate the prevalence of inadequate (insufficient or deficient) serum vitamin D levels in Croatian postmenopausal women initially screened for osteoporosis. Assessment of 25-hydroxyvitamin D (25(OH)D) was performed in 120 Croatian postmenopausal women aged ≥50 years. Three cut-off levels of vitamin D inadequacy were investigated: <75, <50, and <30 nmol/L. Among the included patients, only 14.2% of women complied with diagnostic criteria for osteoporosis. A total of nine (7.5%) had vitamin D levels greater than 75 nmol/L, suggesting that 92.5% of postmenopausal women had inadequate vitamin D status. The prevalence of two different cut-off point groups was 63.3% (<50 nmol/L) and 14.2% (<30 nmol/L). Mean (±SD) serum level of 25(OH)D was 46.94 (16.77) nmol/L. Vitamin D was exhibiting declining values with increasing age (r = −0.28; P = 0.002). The prevalence of vitamin D levels below 30 nmol/L was high in patient aged ≥65 years (23.8%). The highest mean level of vitamin D was detected in summer, with significant differences from spring and winter (P = 0.015 and P = 0.022, respectively). The results of this study indicate a high prevalence of vitamin D inadequacy in Croatian postmenopausal women initially screened for osteoporosis. High prevalence coupled with the rising recognition of potential clinical significance of the vitamin D inadequacy makes this highly interesting intervention target, suggesting that the attempts to increase the awareness on this issue are needed.     

Membrane binding and anticoagulant properties of protein S natural variants

Introduction

Protein S (PS) is a vitamin K-dependent plasma glycoprotein with a key role in the control of coagulation pathway on phospholipid membranes. We compared anticoagulant and membrane binding properties of PS altered by natural mutations (N217S, DelI203D204) affecting the epidermal growth factor like-domain 4 (EGF4) and causing PS deficiency.

Materials and methods

Binding of recombinant, immunopurified PS (rPS) to several conformation-specific antibodies, to C4BP and to phospholipid liposomes was investigated by ELISA. PS binding to cells was analysed by flow cytometry. PS inhibitory activities were studied in plasma and purified systems.

Results and conclusions

Conformational changes produced by mutations were revealed by mapping with calcium-dependent antibodies. The immunopurified recombinant mutants (rPS) showed at 200-800nM concentration reduced inhibition of coagulation (rPS217S, 10.2-17.3%; rPSDelI203D204, 5.8-8.9% of rPSwt) in FXa 1-stage clotting assay with APC. In thrombin generation assays the inhibition of ETP was reduced to 51.6% (rPS217S) and 24.1% (rPSDelI203D204) of rPSwt. A slightly shortened lag time (minutes) was also observed (rPS217S, 2.58; rPSDelI203D204, 2.33; rPSwt, 3.17; PS deficient plasma, 2.17).In flow cytometry analysis both mutants efficiently bound apoptotic cells in adhesion or in suspension. The affinity for phosphatidylserine-rich vesicles (apparent Kd: rPSwt 27.7 ± 1.6 nM, rPS217S 146.0 ± 16.1 nM and rPSDelI203D204 234.1 ± 28.1 nM) was substantially increased by membrane oxidation (10.9 ± 0.6, 38.2 ± 3.5 and 81.4 ± 6.0 nM), which resulted in a virtually normal binding capacity of mutants at physiological PS concentration.These properties help to define the molecular bases of PS deficiency, and provide further elements for PS-mediated bridging of coagulation and inflammation.     

Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel

We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel. Pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cyclic AMP (cAMP)-dependent autonomic modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site; functional analysis found that mutant channels respond normally to cAMP but are activated at more negative voltages than are wild-type channels. These changes, which mimic those of mild vagal stimulation, slow the heart rate by decreasing the inward diastolic current. Thus, diminished function of pacemaker channels is linked to familial bradycardia.     

Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men

CONTEXT: In animals, repeated exposure to stimulant drugs leads to an enhanced drug-induced psychomotor response and increased dopamine release. This phenomenon, known as sensitization, may confer vulnerability to drug addiction or drug-induced psychosis in humans. A similar phenomenon, referred to as endogenous sensitization, is also believed to play a role in the emergence of positive symptoms in patients with schizophrenia. OBJECTIVE: To determine whether behavioral and neurochemical sensitization occur in healthy individuals after limited exposure to amphetamine in the laboratory. DESIGN: Open-label, 1-year follow-up of repeated amphetamine administration in healthy volunteers. SETTING: Department of Psychiatry, McGill University, and McConnell Brain Imaging Center, Montreal Neurological Institute. PARTICIPANTS: Ten healthy men (mean +/- SD age, 25.8 +/- 1.8 years). INTERVENTION: Three single doses of amphetamine (dextroamphetamine sulfate, 0.3 mg/kg by mouth) were administered on days 1, 3, and 5. MAIN OUTCOME MEASURES: Using positron emission tomography and [11C]raclopride, we measured dopamine release in response to amphetamine on the first exposure (day 1) and 14 days and 1 year after the third exposure. RESULTS: The initial dose of amphetamine caused dopamine release in the ventral striatum (a reduction in [11C]raclopride binding). Consistent with a sensitization-like phenomenon, 14 and 365 days after the third dose of amphetamine there was a greater psychomotor response and increased dopamine release (a greater reduction in [11C]raclopride binding), relative to the initial dose, in the ventral striatum, progressively extending to the dorsal caudate and putamen. A high novelty-seeking personality trait and self-rating assessments indicating impulsivity predicted proneness to sensitization. CONCLUSIONS: Sensitization to stimulants can be achieved in healthy men in the laboratory. This phenomenon is associated with increased dopamine release and persists for at least 1 year.