[Supervised off-label prescribing of methylphenidate in adult ADHD]. / Prescriptions hors AMM supervisées de méthylphénidate dans le TDAH de l'adulte.

OBJECTIVE: Off-label prescription is a common practice in psychiatry, raising health and economic concerns. Collegial consultation could allow a framed prescription of treatments that are not authorized in specific indications. Attention Deficit Hyperactivity in adult populations (ADHD) is a striking example of a pathology where off-label prescription is frequent. First considered to be a childhood disorder, the awareness of this condition in adults is increasing, leading to the development of new clinical practices and treatments. However, the adult ADHD diagnosis and its management are still emerging in France despite a high prevalence. Treatment of adult ADHD relies on methylphenidate prescription, but the initiation of this drug is not authorized in adult populations. Methylphenidate is a central nervous system stimulant that is structurally close to amphetamine and acts as a norepinephrine and dopamine reuptake inhibitor. Due to these pharmacological properties, neuropsychiatric and cardiovascular side-effects could occur. Furthermore, its addictive potential has led France to classify it as a psychoactive drug, dispensed via secured prescription. The first prescription and the one-year follow-up are restricted to neurologists, paediatrics, psychiatrists and sleep disorders specialists at hospital. The objective of this article is to propose a multidisciplinary framework for the off-label prescription of methylphenidate in adult ADHD. METHODS: The Multidisciplinary Advice Consultation for Exceptional Addiction Treatments (Consultation d'Avis Multidisciplinaire de Traitements d'Exception en Addictologie CAMTEA) was first set up in Lille for the prescription of baclofen in alcohol dependence and was then extended to topiramate in binge eating disorder. This procedure has been adapted to the particularities of ADHD in adult populations, the differential diagnosis (bipolar disorder, depressive disorder, anxious disorder, personality disorder, substance use disorder) and the co-morbidities requiring a full psychiatric and neuropsychological assessment. Moreover, a particular attention has been paid to the monitoring of neuropsychiatric, cardiovascular and misuse risk because of the potential side-effects of methylphenidate. RESULTS: The proposed prescription framework is structured into several specialized consultations. A first psychiatric evaluation aims to diagnose adult ADHD, using the French version of the Diagnostisch Interview Voor ADHD 2.0 questionnaire (DIVA 2.0), and to assess the quality of life impact with the Weiss Functional Inventory Rating Scale (WIFRS). It also searches for the presence of differential diagnosis or co-morbidities. The second appointment consists of a pharmacological evaluation that aims to search for contraindications and potential drug interaction. A neuropsychological evaluation based on standardized tests (Weschler Adulte Intelligence Scale [WAIS IV], Conner's Continuous Performance Test 3 [CPT] and the Minnesota Multiphasic Personnality Inventory [MMPI]) is also required to evaluate neurocognitive disabilities and personality features. Once the parameters of the different assessments have been collected, the synthesis is presented during a multidisciplinary meeting in order to assess the risk-benefit ratio for each patient. Several specialties are involved in this multidisciplinary meeting: psychiatry, addictology, general medicine, addictovigilance, pharmacovigilance and neuropsychology. One strategy among three possibilities can be decided: (1) contraindication to treatment with methylphenidate, (2) attention deficit disorder that does not require medication management, and (3) indication of treatment with methylphenidate with the choice of the pharmacological form (immediate or prolonged release). A biological check-up and an electrocardiogram are carried out systematically before any treatment. If the decision is made to initiate treatment, it is started at the lowest dosage and followed by a titration phase. A weekly follow-up is carried out during the titration phase in order to assess treatment efficacy and safety. After treatment stabilization, the general practitioner can carry out the renewal, and the patient will be reassessed within the framework of the multidisciplinary consultation every 3 months. CONCLUSION: When an off-label prescription is being considered, it must comply with the basic rules of good clinical practice, and the benefit/risk ratio should be constantly reassessed. The proposed multidisciplinary framework, adapted to the characteristics of adult ADHD and the pharmacological properties of methylphenidate, appears to be an interesting strategy to meet the requirements of the good clinical practice. The complementary assessments carried out and the collegial framework allow enhancing the patient's follow-up and minimize the drug risk, particularly in the psychiatric, addictive and cardiovascular adverse events. Finally, this framework could also help the monitoring of other off-label treatments for ADHD, such as atomoxetine or guanfacine.

Post-operative use of heparin increases morbidity of pacemaker implantation.

AIMS: The objective of this study is to characterize the incidence of peri-operative severe adverse events (AEs) related to the post-operative use of heparin in patients undergoing pacemaker surgery. METHODS AND RESULTS: We retrospectively compared the outcome of 38 patients with mechanical valves (MVs) and 76 patients with atrial fibrillation (AF) with control cases matched for gender, age, and surgical details. Heparin was systematically used post-operatively in MV patients, but left to clinical judgment in AF patients. The relative risk for severe haemorrhagic AEs was 11 (CI 1.5-81.1, P < 0.01) in the MV group when compared with matched controls and 8 (CI 1.0-62.5, P < 0.05) in the AF group. Overall, the relative risk of heparin use in the post-operative period was 14 (CI 1.88-104, P = 0.0006) and the post-operative stay was prolonged from 7 days in this group when compared with control cases (P < 0.0001).The variables associated with haemorrhage were the delay to restart heparin after surgery and the presence of an MV. CONCLUSION: Post-operative use of heparin increases morbidity of pacemaker implantation. A different approach to management of these patients is possible.

Cardiac resynchronisation therapy reduces functional mitral regurgitation during dynamic exercise in patients with chronic heart failure: an acute echocardiographic study.

OBJECTIVES: To assess non-invasively the acute effects of cardiac resynchronisation therapy (CRT) on functional mitral regurgitation (MR) at rest and during dynamic exercise. METHODS: 21 patients with left ventricular (LV) systolic dysfunction and functional MR at rest, treated with CRT, were studied. Each patient performed a symptom-limited maximal exercise with continuous two dimensional Doppler echocardiography twice. The first exercise was performed with CRT; the second exercise was performed without CRT. Mitral regurgitant flow volume (RV), effective regurgitant orifice area (ERO) and LV dP/dt were measured at rest and at peak exercise. RESULTS: CRT mildly reduced resting mitral ERO (mean 8 (SEM 2) v 11 (2) mm(2) without CRT, p = 0.02) and RV (13 (3) v 18 (3) ml without CRT, p = 0.03). CRT attenuated the spontaneous increase in mitral ERO and RV during exercise (1 (1) v 9 (2) mm(2), p = 0.004 and 1 (1) v 8 (2) ml, p = 0.004, respectively). CRT also significantly increased exercise-induced changes in LV dP/dt (140 (46) v 479 (112) mm Hg/s, p < 0.001). CONCLUSION: Attenuation of functional MR, induced by an increase in LV contractility during dynamic exercise, may contribute to the beneficial clinical outcome of CRT in patients with chronic heart failure and LV asynchrony.

Local symptoms at the site of pacemaker implantation indicate latent systemic infection.

BACKGROUND: To determine whether local complications at the site of pacemaker implantation indicate infection of the intravascular part of the lead as well as of the pacemaker pocket. METHODS: 105 patients admitted for local inflammatory findings, impending pacemaker or lead exteriorisation, frank pacemaker or lead exteriorisation, or overt infection were studied prospectively. After systematic lead extraction, the initial clinical presentation was related to the results of lead cultures. RESULTS: Regardless of the initial presentation, the intravascular parts of the leads gave positive cultures in 79.3% of patients. Additionally, 91.6% of the cultures of the extravascular lead segments were positive, in contrast to 38.1% positivity for wound swab cultures. No clinical observations or laboratory investigations permitted identification of patients with negative lead cultures. In a subgroup of 50 patients with manifestations strictly limited to the pacemaker implantation site, cultures of intravascular lead segments were positive in 72%. Infection recurred in 4/8 patients without complete lead body extraction (50%) v 1/97 patients (1.0%) whose leads were totally extracted (p < 0.001). CONCLUSIONS: Local complications at the site of pacemaker implantation are usually associated with infection of the intravascular part of the leads, with a risk of progressing to systemic infection. Such local symptoms should prompt the extraction of leads even in the absence of other infectious manifestations.

[Complications of permanent cardiac pacing]. / Complications de la stimulation cardiaque définitive.

The implantation of a pacemaker is an everyday medical procedure. New indications are under evaluation. However, it should be recalled that this is a surgical intervention with implantation of a prosthesis with possible complications. This should, therefore, be a considered decision. There are early complications which occur in the first 6 weeks after implantation. Their incidence is underestimated (up to 7%) as is their seriousness. There are late complications. Some are responsible for pacemaker dysfunction, the risk of which is proportional to the dependence of the patient on permanent cardiac pacing. The migration of a pacing catheter or the fracture of an Accufix catheter expose the patient to much greater risk. Venous complications are overlooked as they are usually asymptomatic. The superior vena cava syndrome is, however, a serious complication of cardiac pacing. Two recent studies (MOST and DAVID) underline the deleterious haemodynamic effects of unnecessary right ventricular pacing. This right ventricular pacing may have a pro-arrhythmic effect on the ventricles and be responsible for sudden death. It may also cause atrial arrhythmia even if atrio-ventricular synchronisation is preserved. Infectious complications are also under-reported, partially because of the difficulty of diagnosis. They may be life-threatening and require extraction of the implanted material. In conclusion, it is wrong to think that even if a patient does not benefit from his implanted device this cannot have deleterious consequences. Pacemakers should be adjusted especially to avoid inappropriate right ventricular stimulation.

[Contribution of the implantable ECG monitor in the etiologic diagnosis of syncope and unexplained recurrent syncopal attacks. Initial experience with 32 patients]. / Apport du moniteur ECG implantable pour le diagnostic étiologique des syncopes et lipothymies récidivantes inexpliquées. Expérience initiale à propos de 32 patients.

UNLABELLED: Following an exhaustive aetiological investigation, 10 to 26% of syncopal attacks remain unexplained. In these cases the correlation between symptoms and rhythm is a deciding step for the aetiological diagnosis. We report our initial experience using an implantable electrocardiographic monitor, a new diagnostic tool in patients suffering from syncope and recurrent unexplained syncopal attacks. RESULTS: The study included 32 patients (average age 55 +/- 22 years; 23 males) suffering from syncope and/or recurrent syncopal attacks remaining unexplained following an exhaustive aetiological investigation. The average follow up was 10.2 +/- 2.5 months. No case of sudden death was registered, and the device was removed in only one patient due to poor tolerance. During follow up, 21 recordings were memorized and analysed in 15 patients (45%), giving an average of 1.4 recordings per patient. The average interval for recurrence of symptoms after implantation was from 84 +/- 104 days, 75% of the episodes coming in the first 2 months following implantation. An arrhythmia was detected on 10 occasions: a malignant ventricular arrhythmia in 2 patients, a non-sustained ventricular tachycardia in 1 patient, a junctional tachycardia in 1 patient, entry into paroxysmal atrial fibrillation in 4 patients, a sinus bradycardia in 1 patient, and a sinus pause for 19 seconds in 1 patient. In one patient ST segment depression was documented following anterior chest pain. The tracing was normal with sinus rhythm recorded on 10 occasions, representing the only documented information in 4 patients. In total, an aetiology was found in 11 of the 32 patients evaluated (34%). Once the aetiological diagnosis was established and a specific treatment initiated, all the patients became asymptomatic. CONCLUSIONS: Our preliminary results underline the significance of the implantable ECG monitor in the diagnostic approach to recurrent unexplained syncopal attacks. The exact place of this tool in the decisional algorithm for syncope remains to be defined with further studies.

Chemical reactions in cottonseed protein cross-linking by formaldehyde, glutaraldehyde, and glyoxal for the formation of protein films with enhanced mechanical properties.

Amino acids involved in cottonseed protein cross-linking by formaldehyde, glutaraldehyde, and glyoxal during protein film formation were identified by an original technique. The entire HPLC amino acid profile (after acid hydrolysis) was studied, along with variations in reactive lysine contents, in films cross-linked or not with increasing quantities of formaldehyde, glutaraldehyde, and glyoxal. This strategy highlighted the formation of acid-resistant lysine derivatives that a simple reactive lysine determination would not have detected. The results-which agree with previously published data-enhance the overall understanding of cross-linking activities that occur in aqueous alkaline solutions during the formation of protein films made with cottonseed flour. Lysine was found to have a key role in protein cross-linking by dialdehydes, with the involvement of tyrosine in the presence of formaldehyde and of arginine in the presence of glyoxal. These results could provide valuable chemical tools for adjusting the mechanical properties of cottonseed protein films.

Prospective evaluation of a simplified approach for common atrial flutter radio frequency ablation with only two catheters.

UNLABELLED: Intra-atrial conduction block within the inferior vena cava-tricuspid annulus isthmus (IVCT) has been shown to predict successful common atrial flutter ablation. However, its demonstration requires the use of several electrode catheters and mapping of the line of block. The aim of this study was prospectively to test the feasibility of a simplified ablation procedure using only two catheters. METHODS: Radio frequency (RF) ablation of common atrial flutter was performed in 30 patients with the sole use of a catheter for atrial pacing and a RF catheter. RF ablation lesions were created in the IVCT. Surface ECG criteria were used to monitor the conduction within the IVCT. The end point during low lateral atrial pacing was an increment in the interval between the pacing artefact and the peak of the R wave in surface lead II >50 ms and clockwise rotation of the P wave axis beyond -30 degrees and inferiorly. Then, the line of lesions was mapped during atrial pacing with the RF catheter. Additional RF lesions were applied if mapping disclosed a zone of residual conduction. Otherwise the procedure was stopped if mapping showed parallel double potentials all along the line. Finally, the block was reassessed with a 'Halo' catheter. RESULTS: Surface ECG criteria were met in 26 patients. Mapping the line of lesions showed a complete corridor of parallel double potentials in these 26 cases and in 3 of the 4 patients in whom ECG criteria were not met. Conduction evaluated with the Halo catheter showed bi-directional complete block in these 29 patients. After a follow-up of 16 +/- 4 months there was no recurrence of atrial flutter. CONCLUSION: Surface ECG criteria combined with mapping of the line of block demonstrate evidence of bi-directional IVCT block. This simplified RF ablation of common atrial flutter is feasible with a low recurrence rate.

Processability of cottonseed proteins into biodegradable materials.

The manufacture of biodegradable materials from agricultural sources is a real challenge, because of environmental concerns and the need to make full use of resources. Cottonseed is an important protein source that could be used in nonfood applications, as a substitute for synthetic polymers. For the first time, the viscoelastic behavior of cottonseed protein isolate (CPI), plasticized with glycerol, was characterized in order to determine the temperature range within which cottonseed protein-based materials can be formed by extrusion or thermomolding. Research involved three main techniques: dynamic mechanical analysis to study the alpha protein relaxation associated with glass transition, as a function of plasticization by glycerol; DSC analysis to determine the effect of glycerol content on the protein denaturation and degradation temperatures; and ATG-TG/FTIR to characterize the protein degradation. The results indicated that cottonseed proteins are thermoplastics with a T(g) ranging from 80 to 200 degrees C when the glycerol content varies from 0% to 40% (w/w, dry basis). The proteins' thermal denaturation temperature increased from 141 (without glycerol) to 195 degrees C in the presence of 40% (w/w) glycerol. Protein degradation occurred at 230 degrees C irrespective of glycerol content, with the release of a variety of compounds. Glycerol acts as a plasticizer and thermal stabilizer of the proteins and increases the range of temperatures (80-175 degrees C) at which the material can be processed.

[Infections secondary to the implantation of a pacemaker: update]. / Infections secondaires à l'implantation d'un stimulateur cardiaque: mise au point.

Pacemaker lead infection is a major complication of endovascular permanent pacing. The incidence is less than 1% but it is a frequent disease due to the high number of pacemaker implanted. The diagnosis is difficult due to the insidious symptoms. Pacemaker infection must be systematically considered in patients with a pacemaker and symptoms of infection. Several investigations are useful for the diagnosis particularly the transesophageal echocardiography, but all investigations have a low negative predictive value. All of the implanted material must be completely removed.