Sunshine-exposure variation of human striatal dopamine D2/D3 receptor availability in healthy volunteers

Background

In addition to the serotonergic system, the central dopaminergic system has been reported to be correlated with seasonality. The aim of this study was to explore the difference in striatal dopamine D₂/D₃ receptor availability between healthy volunteers who had a high-sunshine exposure and those who had a low exposure.

Methods

Sixty-eight participants were enrolled, and those in the upper and lower quartiles in terms of sunshine exposure were categorized into high- (n = 17) and low-sunshine-exposure (n = 18) subgroups. Single photon emission computed tomography with [¹²³I] iodo-benzamide was used to measure striatal dopamine D₂/D₃ receptor availability.

Results

Striatal dopamine D₂/D₃ receptor availability was significantly greater in the subjects with high-sunshine exposure than in those with low-sunshine exposure (F = 7.97, p = 0.01) after controlling for age, sex, and smoking status.

Limitations

Different subjects were examined at different time points in our study. In addition, the sex and tobacco use distributions differed between groups.

Conclusion

The central dopaminergic system may play a role in the neurobiological characteristics of sunshine-exposure variation.     

Underuse of evidence-based warfarin dosing methods for atrial fibrillation patients

Introduction

The effectiveness of warfarin for stroke prevention in patients with atrial fibrillation is proportional to the time that the International Normalized Ratio is in the therapeutic range. Evidence-based methods (anticoagulation clinic, computerized decision support system or patient self-management) are available to optimize the time in therapeutic range, but there are no data on how often these methods are actually applied in practice. We assessed to what extent generalist and specialist physicians use evidence-based methods for warfarin maintenance dosing.

Materials and Methods

A survey questionnaire on practice characteristics and warfarin management was sent to 409 primary care physicians and 105 specialists (cardiologists, internists and hematologists) in Hamilton, Ontario.

Results and Conclusions

The survey questionnaire was returned by 233 (57%) of primary care physicians and 57 (54%) of specialists. Compared with specialists, primary care physicians more often managed warfarin solely based on their own experience (33 vs 7%; p < 0.001) or with a manual dosing algorithm (22% vs 4%, p < 0.001) and less often used one or more evidence-based dosing methods (29 vs 61%; p < 0.001). Only 6% of primary care physicians and 2% of specialists (p = 0.561) acknowledged having problems with warfarin dosing.Our survey showed that evidence-based methods for warfarin maintenance dosing are underused by primary care physicians and specialists. Closing this gap between knowledge and practice might improve the quality of warfarin control and patient outcomes.     

Instruments assessing anxiety in adults with intellectual disabilities: a systematic review

Background

In the last decades several instruments measuring anxiety in adults with intellectual disabilities have been developed.

Aim

To give an overview of the characteristics and psychometric properties of self-report and informant-report instruments measuring anxiety in this group.

Method

Systematic review of the literature.

Results

Seventeen studies studying 14 different instruments were found. Methodological quality as measured with the Quality Assessment of Diagnostic Accuracy Studies checklist was insufficient for four studies, sufficient for seven, and good for six. For self-report, the Glasgow Anxiety Scale for people with a learning disability appears most promising, with good internal consistency (a = 0.96), high test-retest reliability (r = 0.95), sensitivity (100%) and specificity (100%). For informant-report, the general anxiety subscale of the Anxiety, Depression and Mood Scale may be promising, with good internal consistency (a = 0.83 and a = 0.84) and excellent test-retest reliability (ICC = 0.78 and ICC = 0.92), but poor interrater reliability (ICC = 0.39).

Conclusions

Two instruments appear promising. However, these instruments have only been studied once or twice, whereas the methodological quality of these studies was varying.     

Warfarin treatment in patients with atrial fibrillation: Observing outcomes associated with varying levels of INR control

Introduction

We aimed to determine the level of INR control associated with reduced stroke and mortality.

Material and methods

The study used a retrospective cohort design using linked inpatient, haematology and mortality data from Cardiff and the Vale of Glamorgan, UK.Anonymised patients admitted with a diagnosis of non-valvular atrial fibrillation (NVAF) were defined as warfarin or non-warfarin treated by number of repeated International Normalised Ratio (INR) tests. Warfarin treated patients (> 5 INR tests) categorised as at moderate or high risk of stroke (CHADS₂ score ≥ 2) with varying levels of INR control were compared to those who did not receive warfarin treatment using Cox proportional hazards models controlling for age, sex and CHADS₂ score. Outcome measures were time to stroke and mortality.

Results

6,108 patients with NVAF were identified. 2,235 (36.6%) of these patients had five or more INR readings and of these 486 (21.7%) had CHADS₂ score ≥ 2. There was significant improvement in time to stroke event in those patients with INR control of greater than 70% of time in therapeutic range (2.0 to 3.0) compared with the non-warfarin treatment group. Overall survival was significantly improved for all warfarin treated groups with INR control of greater than 40% of time in range.

Conclusions

Patients with INR control of above 70% of time in range had a significantly reduced risk of stroke. Patient suitability for warfarin treatment should be continuously assessed based on their ability to maintain a consistently therapeutic INR.     

Decreasing warfarin sensitivity during the first three months after heart valve surgery: Implications for dosing

Introduction

Vitamin K antagonists are prescribed to prevent thromboembolic complications after heart valve surgery. In our experience, patients often show a progressive decrease in sensitivity to warfarin after surgery making it difficult to reach and maintain a therapeutic International Normalized Ratio (INR).We sought to confirm our clinical impression and to gather data for the development of a guide to dosing these patients.

Materials and methods

In a large anticoagulation clinic, we retrospectively reviewed 200 patients who were on warfarin (target range of 2.0-3.0) during the first three months after valve surgery. Data on dosing and INR results were collected and time in therapeutic range (TTR) calculated. Controls were patients started on warfarin for atrial fibrillation.

Results

A steady increase in warfarin requirements was seen over the three months in patients with mechanical valves, bioprosthetic valves or valve repairs. The mean dose of warfarin increased by 26% while the mean INR decreased from 2.5 to 2.1. In contrast, both the mean dose of warfarin and the INR were stable in controls. TTR in patients after valve surgery was 48.5%, with 40.8% of time spent at an INR below 2.0. A dosing algorithm was modeled from the data in this patient group.

Conclusions

Patients steadily become less sensitive to warfarin during the first months after heart valve surgery. This leads to subtherapeutic anticoagulation. A dosing algorithm that takes increasing requirements into account is proposed. This algorithm will need to be validated prospectively.     

KIDCLOT: the importance of validated educational intervention for optimal long term warfarin management in children

Background

Advances in medical and surgical therapy in children have resulted in increased survival in children with primary illnesses. However, thrombosis is a serious complication of this success and results in mortality and morbidity. Prevention or treatment of thrombosis using warfarin is challenging in children due to its narrow therapeutic index and the unique differences in children, including variable nutritional intake and the occurrence of common concomitant viral or bacterial illnesses which alter warfarin metabolism. The variable response to warfarin in children necessitates frequent International Normalized Ratio (INR) monitoring. Education may improve time in therapeutic range (TTR) a measure of warfarin effect, and a surrogate for patient adherence, safety and efficacy.

Methods

The Pediatric Anticoagulation program (Stollery Children's Hospital) developed a novel child-focused educational program KIDCLOT-POC© about warfarin therapy and POC-INR meter use. A total of twenty eight children, and their caregivers, participated in KIDCLOT-POC©. Questionnaire score comparisons and practical demonstrations assessed the learners' theoretical and practical knowledge of warfarin management.

Results

In caregivers, the median pre, post and knowledge retention questionnaire scores were 50 (IQR 27), 93 (IQR 6) (p < 0.0001) and 96 (IQR 6) (p < 0.0001), respectively. In the 18 children who were ≥ 6 years of age, post and knowledge retention questionnaire scores were 90 (IQR 16) and 92 (IQR 23) (p = 0.44), respectively. The TTR for all children was 81.7% (SD 13.1).

Conclusions

Implementation of KIDCLOT-POC© program appears to promote high knowledge development and retention in children and caregivers and high TTR with no adverse events.     

Distal hereditary motor neuropathy

Introduction

Distal hereditary motor neuropathy (dHMN), also known as spinal muscular atrophy, represents a group of clinically and genetically heterogeneous diseases caused by degenerations of spinal motor neurons and leading to distal muscle weakness and wasting. Nerve conduction studies reveal a pure motor axonopathy and needle examination shows chronic denervation.

State of art

dHMN were initially subdivided into seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been characterized. To date, mutations in 11 different genes have been identified for autosomal-dominant, autosomal-recessive, and X-linked recessive dHMN. Most of the genes encode protein involved in housekeeping functions, endosomal trafficking, axonal transport, translation synthesis, RNA processing, oxidative stress response and apoptosis.

Perspectives

The pathophysiological mechanisms underlying dHMN seem to be related to the “length-dependent” death of motor neurons of the anterior horn of the spinal cord, likely because their large axons have higher metabolic requirements for maintenance.

Conclusion

dHMN remain heterogeneous at the clinical and molecular genetic level. The molecular pathomechanisms explaining why mutations in these ubiquitously expressed housekeeping genes result in the selective involvement of spinal motor neurons remain to be unravelled.     

Memory performance related to organic and psychosocial illness attributions in somatoform pain disorder patients

Objective

Somatoform disorders are characterized by patterns of persistent bodily complaints. Organic illness attributions are assumed to represent a central supporting factor in the development and maintenance of somatoform disorders. Using group control design, we aimed to investigate the processing of illness-belief-related word stimuli in somatoform pain disorder patients.

Methods

Organic-related, psychosocial-related, and neutral word stimuli were presented to 14 somatoform pain patients with a predominantly organic illness attribution, 14 somatoform pain patients with a predominantly psychosocial illness attribution, and 14 control participants. Behavioral measures were taken during free recall and recognition tasks.

Results

Our study revealed cognitive impairment in somatoform pain patients with an organic attribution of pain symptoms as compared to somatoform pain patients with a psychosocial attribution and healthy controls in both free recall test and recognition test. However, selective processing of word stimuli was not observed for patient groups.

Conclusion

We conclude that the observed impairment of memory performance in somatoform pain patients with an organic illness attribution may play an important role in the illness behavior of this patient group and ultimately result in the maintenance of symptoms and a more critical clinical outcome.     

Influence of GGCX genotype on warfarin dose requirements in Chinese patients

Introduction

It has been widely accepted that genetic factors were the major sources of the variation in warfarin dose. This study is intended to investigate whether the 3261G>A variation in GGCX gene influences stable warfarin dose in Chinese patient population.

Materials and Methods

A total of 217 patients with stable warfarin dose were enrolled. Genomic DNA was extracted from each subject and the genotype of GGCX 3261G>A was determined by using of denaturing high-performance liquid chromatography (DHPLC). Least significant difference tests (LSDs) were used to compare dose with genotypes. Analysis of variance (ANVOA) was used to calculate the proportion of warfarin dose that could be explained by variation in genotype.

Results

In the total of 217 subjects, 84 patients (38.7%) were GG homozygote, whereas 117 (53.9%) were GA heterozygote and 16 (7.4%) were AA homozygote. Patients with the GGCX 3261AA genotype had a significantly higher average daily maintenance dose (3.39 ± 1.40 mg) than those with the GG genotype (2.69 ± 1.07 mg; P = 0.027), and GGCX 3261G>A explains 2.3% of the univariate warfarin dose variance.

Conclusion

GGCX 3261G>A may affect warfarin dose requirements, and showed a small but significant effect on warfarin dose in a Chinese patient population.     

Single-dose adjustment versus no adjustment of warfarin in stably anticoagulated patients with an occasional international normalized ratio (INR) out of range

Background

Well-controlled patients on warfarin may still have occasional International Normalized Ratios (INRs) outside the therapeutic range. It is unclear whether there is any benefit of a single-dose correction in this situation.

Aim

To evaluate whether patients with very stable INR results should continue with the maintenance dose of warfarin without a single-dose correction, even when the result unexpectedly is moderately below or above the therapeutic range.

Methods

A) We reviewed retrospectively 364 patients with unchanged maintenance dose for at least 6 months and an occasional INR outside the therapeutic range regarding decision on dosing and the effect on the next INR. B) We randomized 160 patients with at least 3 months of unchanged maintenance dose, an occasional INR deviating to a minimum of 1.5 or a maximum of 4.4 and unexplained or temporary, removable cause to a single-dose Change or No change. Follow-up INRs and telephone interviews were obtained after 2 weeks.

Results

A) Retrospectively, the proportion of follow-up INRs outside the therapeutic range was 29.9% after No change, 27.1% after Increased dose and 25.7% after Skipped/reduced dose. However, the decision on No change was mainly taken in case of minimal INR deviations. B) Forty-eight (60%) of the patients randomized to Change were within the therapeutic range at follow-up versus 45 (56%) of those with No change, odds ratio 1.17 (95% confidence interval 0.59-2.30). For baseline INRs deviating down to 1.6 or up to 3.6 (therapeutic range, INR 2.0-3.0) the 2-week INRs did not differ between the groups.

Conclusion

Our results suggest only a small or no difference between the two managements of an occasional INR out of range in terms of the 2-week follow-up INR. In stable patients on warfarin with an occasional INR outside the therapeutic range it seems reasonable to continue with the same dose without a single-dose change and perform a repeat test in about 2 weeks. (ClinicalTrials.gov number, NCT00814177.)     

Peri-procedural bridging with low molecular weight heparin in patients receiving warfarin for venous thromboembolism: A pediatric experience

Introduction

The incidence of venous thromboembolism (VTE) in children appears to be increasing, and warfarin remains one of the few standard anticoagulants used for secondary VTE prevention. When invasive procedures are required in adults with high TE risk who are receiving warfarin, low-molecular weight heparin (LMWH) bridging is recommended, based mainly upon observational evidence; in children, no such studies have been published. We sought to determine the risks of recurrent TE (both VTE and arterial TE [ATE]) and major bleeding with peri-procedural LMWH bridging in children receiving warfarin for VTE.

Methods

Children (age ≤ 21 years of age at the time of bridge) receiving warfarin for VTE and undergoing a standardized clinical care protocol for peri-procedural LMWH bridging were enrolled and followed in an institution-based prospective inception cohort study at Children's Hospital Colorado between March 2006 and February 2012. Outcomes were assessed at 30 days post-procedure, and followed International Society on Thrombosis and Haemostasis guidelines.

Results

Seventeen children comprised the cohort, with a total of 23 bridging episodes. Median age at bridging episode was 17.5 years (range, 12 to 21 years). In 22% of bridging episodes, indication was for major surgery. Median duration of LMWH administration prior to procedure was 6 days (range, 4-10 days); median duration off anticoagulation peri-procedurally was 1.5 days (range: 1-2 days). The risks of major bleeding, recurrent VTE, and ATE at 30 days post-procedure were 4.3% (1/23), 0% and 0%, respectively.

Conclusions

This study provides important preliminary data on safety and efficacy of perioperative LMWH bridging for adolescent VTE patients receiving warfarin. Larger collaborative pediatric studies are warranted to substantiate these findings and to investigate prognostic factors of bleeding and recurrent TE in this setting.     

Dystonie focale fixée de l’épaule à distance d’un traumatisme scapulaire minime : une entité pour quels mécanismes ?

Introduction

Whether post-traumatic focal fixed dystonia has a physiological or psychologically-mediated mechanism is discussed.

Case report

We report the case of an active 22-year-old soldier with shoulder-fixed dystonia, eight months after a fall with minor right-acromioclavicular sprain.

Conclusion

Psychiatric examination and search of complex regional pain syndrome, radicular or accessory nerve damage, and genetic predisposition to dystonia are necessary for selecting a difficult treatment in these patients.     

Periprocedural anticoagulation practices in warfarin-treated patients who require elective angiography with or without percutaneous coronary intervention: A retrospective chart review

Introduction

It may be possible to safely perform some procedures without interrupting warfarin therapy. Coronary angiography with or without percutaneous coronary intervention (PCI) is one such procedure. However, before further high quality research can be performed in this area, information such as current practice and associated event rates is required.

Materials and methods

We performed a retrospective chart review of 100 charts from a tertiary interventional cardiology referral centre. The primary outcome was access site bleeding. The perioperative anticoagulation strategy for each patient was also recorded.

Results and conclusions

All patients were managed with a strategy of warfarin interruption with or without bridging with a heparin. This was associated with an access site event rate of 2%. These results can be used to inform the design of high quality prospective studies, aimed at determining optimal anticoagulation management strategy in warfarin-treated patients who require coronary angiography or PCI.     

Évènements psychotiques inauguraux de sclérose en plaques ?

Introduction

Psychotic symptoms are not readily recognized in multiple sclerosis, especially at the beginning of the disease.

Methods

We report the cases of four patients who developed psychotic symptoms that led to the diagnosis of multiple sclerosis. We describe the psychiatric and neurological features, MRI findings, clinical outcome and treatment.

Results

Two patients developed persecutory delusions, one presented a manic episode and the fourth melancholia with catatonia. Mean age was 39 years (range 20-49 years). Two patients had a personal history, but none a familial history of psychiatric disease. Examination of the cerebrospinal fluid revealed an oligoclonal pattern in all patients. All patients fulfilled Barkhof's MRI criteria. Three have had brain MRI with injection during psychotic symptoms. In these three cases, a frontal lesion appeared. The patient with catatonia also had a new lesion in the cerebellum and in the brainstem. All patients needed a “psychiatric” treatment, including antipsychotics. The psychiatric event lasted three months for two patients and the two others experienced relapse.

Conclusion

Acute psychiatric symptom may reveal multiple sclerosis at the beginning of the disease. Frontal lobe localization is suggested. We propose that a psychotic event may correspond to a multiple sclerosis event.     

Effect of VKORC1 - 1639 G > A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients

Introduction

To establish individualized warfarin therapy, we investigated the contribution of genetic variations of vitamin K epoxide reductase complex subunit 1 gene (VKORC1) - 1639 G > A and Cytochrome P450 2C9 gene (CYP2C9) and clinical factors on warfarin sensitivity in Japanese patients.

Materials and Methods

Genetic analyses of VKORC1 - 1639 G > A and CYP2C9 ?2, ?3, and ?4 were performed in 259 Japanese patients and 341 healthy subjects. We selected 259 patients who have been prescribed warfarin with a 1.5-3.0 range of prothrombin time normalized as an international normalized ratio for at least 3 months and investigated factors that contribute to individual variability in warfarin dose. Furthermore, multivariate analysis was performed to investigate a warfarin dosing algorithm.

Results and Conclusions

There were great inter-individual differences in warfarin maintenance dose in 259 patients, ranging from a minimum dose of 0.75 mg/day to a maximal dose of 8.00 mg/day. VKORC1 - 1639 G > A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variability. The dosing algorithm of warfarin maintenance dose was investigated by multivariate linear regression. The regression equation was able to account for 33.2% (R²_Adj = 0.332) of the overall variability in warfarin dose.     

Comorbidity in posttraumatic stress disorder: a structural equation modelling approach

Objective

Posttraumatic stress disorder (PTSD) is associated with high rates of psychiatric comorbidity. Existing theories consider comorbidity as a consequence of PTSD (model 1), PTSD and comorbidity as a consequence of shared factors of vulnerability (model 2), and comorbidity as a consequence of trauma-type specific mechanisms (model 3).

Method

To compare the explanatory value of these models, we assessed PTSD (model 1), sense of coherence (model 2) and satisfaction with health (model 3) and symptoms of anxiety and depression as indicators of comorbidity 5 days (t1) and 6 months (t2) postaccident in 225 injured accident survivors. Structural equation models representing models 1 to 3 were tested separately and combined.

Results

Combined, models 1 and 3 explained 82% of the variance of comorbid symptoms at t2. Posttraumatic stress disorder and satisfaction with health (t2) exerted strong influences on comorbid symptoms.

Conclusion

Comorbidity besides PTSD is best described by an integration of competing explanatory models.     

Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis

Introduction

Warfarin is a commonly used oral anticoagulant and the dosage is individually adjusted on the basis of the international normalized ratio (INR) monitoring. It is well known that gene polymorphisms of CytochromeP450 (CYP) 2 C9 gene and the vitamin K epoxide reductase complex 1 (VKORC1) were significantly associated with warfarin dose. However, the association between Cytochrome P450 4 F2 (CYP4F2) polymorphism and warfarin dose requirement is still controversial. This study was to investigate the influence of the CYP4F2 polymorphism, V433M (rs2108622) on warfarin dose for patients by meta-analysis.

Methods

Strict inclusion and exclusion criteria were set, and the studies prior to December 19, 2010 were searched in PubMed, EMBASE and CNKI. References were examined and experts of primary studies were consulted for additional information. Revman 5.0.2 software was used to analyze the relationship between warfarin maintenance dose and CYP4F2 polymorphism

Results

Thirteen studies were included in the meta-analysis which consisted of Caucasian, Asian and African populations. Compared to individuals with the homozygous CYP4F2 genotype (CC), carriers of CT, TT genotypes required 10.0% (95% confidence interval(CI) 4.0-15.0) and 21.0% (95% CI 9.0-33.0) higher warfarin doses respectively (P value < 0.05). In addition, T carriers required 11.0% (95% CI 6.0-17.0) higher warfarin dose than CC genotype.

Conclusions

Our study showed that polymorphism of CYP4F2 had a moderate but statistically significant association with the variation of interindividual warfarin dose. However, whether CYP4F2 can improve the prediction of warfarin dose warrants need further investigation when combined with environmental factors.     

Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy

Background

There is uncertainty regarding the efficacy and incidence of thromboembolic events in patients treated with prothrombin complex concentrates (PCC) for the emergency reversal of warfarin effect.

Methods

During 2002 to 2010 we prospectively included 160 patients treated with PCC for emergency reversal of warfarin either for bleeding or because of the need of emergency surgery. A possible relationship to PCC was considered if objectively verified thromboembolism occurred within 7 days of PCC administration. Efficacy was adjudicated as good if the bleeding was controlled promptly or if the surgeon did not report excessive perioperative bleeding.

Results

We included 160 patients; 72% received PCC for bleeding. The median international normalized ratio (INR) before and after treatment with PCC was 3.5 (interquartile range [IQR] 2.6-5.4) and 1.4 (IQR 1.2-1.6). The mean dose of PCC was 1800 IU (IQR 1200-2000). In addition to PCC, 74% of the patients received vitamin K and 34% received plasma. Six patients (3.8%; 95% confidence interval [CI], 1.4-8.0%) developed thromboembolic events (3 strokes, 1 myocardial infarction, 1 deep vein thrombosis, 1 splenic infarction), possibly related to PCC. The clinical efficacy was good in 146 (91%), moderate in 6 (4%), poor in 4 (2.5%) and non-evaluable in 4 patients.

Conclusion

The administration of PCC for the emergency reversal of warfarin may be associated with a low risk of thromboembolism. The contribution of an unmasked thrombotic process by cessation of anticoagulation or of activation of coagulation by the hemorrhagic event should also be considered.     

Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: A meta-analysis

Introduction

The Wells clinical decision rule (CDR) and D-dimer tests can be used to exclude pulmonary embolism (PE). We performed a meta-analysis to determine the negative predictive value (NPV) of an “unlikely” CDR (≤ 4 points) combined with a normal D-dimer test and the safety of withholding anti-coagulants based on these criteria.

Methods

Prospective studies that withheld anti-coagulant treatment from patients with clinically suspected PE and an “unlikely” CDR in combination with a normal D-dimer concentration without performing further tests were searched for in Medline, Cochrane and Embase. Primary endpoints were the recurrence rate of venous thromboembolism (VTE) and PE-related mortality during 3-months follow-up.

Results

Four studies including 1660 consecutive patients were identified. The pooled incidence of VTE after initial exclusion of acute PE based on an “unlikely” CDR and normal D-dimer was 0.34% (95%CI 0.036-0.96%), resulting in a NPV of 99.7% (95%CI: 99.0-99.9%, random effects-model). The risk for PE related mortality was very low: 1/1660 patients had fatal PE (0.06%, 95%CI 0.0017-0.46%).

Conclusion

Acute PE can be safely excluded in patients with clinically suspected acute PE who have an “unlikely” probability and a negative D-dimer test and anticoagulant treatment can be withheld. There is no need for additional radiological tests in these patients to rule out PE.