Neurodevelopmental outcome of neonates treated with nitric oxide for persistent pulmonary hypertension

Persistent pulmonary hypertension of the newborn (PPHN) is a life threatening condition associated with an increased risk of neurodevelopmental impairment. The recommended treatment for this condition is inhaled nitric oxide (iNO) and has been used in our Neonatal Intensive Care Unit since 1998. We prospectively offered neurodevelopmental follow-up to children treated with iNO for PPHN, including extensive neurological evaluation, developmental/cognitive evaluation at 18 months and 3.5-5 years old, and evaluated the rate of severe and moderate handicap and normal neurodevelopmental outcome, compared to a control group and the literature. Population consisted of 29 patients treated only with iNO, born between 01.01.1999 and 31.12.2005 (study group), and 32 healthy term infants born in 1998 in our maternity (control group). During those seven years, 65 infants were admitted in our Unit with PPHN, of whom 40 were treated with iNO alone. 34 children survived (85%) and were offered neurodevelopmental follow-up, 7 children were lost to follow-up due to various reasons. 22 children were examined at the age of 18 months (76%) with a rate of moderate handicap of 22% (2 with expressive language delay, 2 with difficult behavior, and 1 child with moderate hearing loss), and a rate of major handicap of 4.5% (1 child with cerebral palsy due to perinatal stroke, and moderate hearing loss). At preschool age, 17 (50%) were examined, the rate of moderate handicap was 22% (4 borderline intelligence, 1 hearing loss), and the rate of major handicap was 4.5% (one child with cerebral palsy and hearing loss), compared to 26.9% and 0% in the control group. Mean developmental quotient at 18 months was 100.3 ± 8.7 (control group 118.3), and at preschool age mean cognitive indices were within normal limits for the 2 tests performed at 3.5 or 5 years (108 ± 21, 94.4 ± 17). Most of the children with a less favorable neurodevelopmental outcome suffered from birth asphyxia (ruptured uterus, placental abruption, maternal hypotension, diabetic cardiomyopathy), and notably, the 2 children with sensorineural hearing loss both suffered from severe hypoxic-ischemic enkelopathy. Treatment with iNO was not the direct cause of the neurodevelopmental impairments observed in children treated for PPHN.

Randomized double-blind controlled Phase I/IIa trial to assess the efficacy of malaria vaccine PfCS102 to protect against challenge with P. falciparum.

The aim of this Phase I/IIa double-blind controlled trial was to test the efficacy of the sporozoite-based malaria vaccine PfCS 282-383 (PfCS102) to protect against Plasmodium falciparum parasitaemia. 16 volunteers were randomized to receive twice 30 μg of PfCS102 formulated in Montanide ISA 720 or ISA 720 alone (control). Two weeks after 2nd immunization, volunteers were challenged using 5 infected mosquitoes. All vaccinees developed antibodies against PfCS102 versus none control. 8/8 vaccinees and 6/6 controls challenged developed malaria parasitaemia. The duration from infection to onset of patent parasitaemia was similar in both groups (214 h in vaccinees and 216 in controls). PfCS102 is safe and immunogenic but provides no protection against artificial challenge in its current formulation.

Plasmid electrotransfer of eye ciliary muscle: principles and therapeutic efficacy using hTNF-alpha soluble receptor in uveitis.

Due to its small size and particular isolating barriers, the eye is an ideal target for local therapy. Recombinant protein ocular delivery requires invasive and painful repeated injections. Alternatively, a transfected tissue might be used as a local producer of transgene-encoded therapeutic protein. We have developed a nondamaging electrically mediated plasmid delivery technique (electrotransfer) targeted to the ciliary muscle, which is used as a reservoir tissue for the long-lasting expression and secretion of therapeutic proteins. High and long-lasting reporter gene expression was observed, which was restricted to the ciliary muscle. Chimeric TNF-alpha soluble receptor (hTNFR-Is) electrotransfer led to elevated protein secretion in aqueous humor and to drastic inhibition of clinical and histological inflammation scores in rats with endotoxin-induced uveitis. No hTNFR-Is was detected in the serum, demonstrating the local delivery of proteins using this method. Plasmid electrotransfer to the ciliary muscle, as performed in this study, did not induce any ocular pathology or structural damage. Local and sustained therapeutic protein production through ciliary muscle electrotransfer is a promising alternative to repeated intraocular protein administration for a large number of inflammatory, degenerative, or angiogenic diseases.

The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn's disease after failure of two other anti-TNF antibodies.

BACKGROUND: Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn's disease (CD) patients previously treated with infliximab (IFX). AIM: To assess the efficacy and tolerability of a third anti-TNF in CD after failure of and/or intolerance to two different anti-TNF antibodies. METHODS: Crohn's disease patients who received ADA or CZP after loss of response and/or intolerance to two anti-TNF agent were included in this retrospective study. Data were collected using a standardized questionnaire. Clinical response, duration, safety and reasons for discontinuation were assessed. RESULTS: Sixty-seven patients treated with CZP (n = 40) or ADA (n = 27) were included. A clinical response was observed in 41 (61%) at week 6 and 34 patients (51%) at week 20. The probability of remaining under treatment at 3 months, 6 months and 9 months was 68%, 60% and 45%, respectively. At the end of follow-up, the third anti-TNF had been stopped in 36 patients for intolerance (n = 13), or failure (n = 23). Two deaths were observed. CONCLUSIONS: The treatment with a third anti-TNF (CZP or ADA) agent of CD patients, who have experienced loss of response and/or intolerance to two anti-TNF antibodies, has favourable short-term and long-term efficacy. It is an option to be considered in patients with no other therapeutic options.

Résumés actualisés de l'évaluation systématique de l'efficacité d'interventions médicales. [Up-to-date résumés of the systematic evaluation of efficacy of medical interventions]

La Cochrane Library (www.thecochranelibrary.com) est une bibliothèque en ligne répertoriant à ce jour plus de 3000 revues systématiques. Ces revues systématiques sont issues de l'activité continue de plus de 50 groupes de revues de la Collaboration Cochrane (www.cochrane.org ), une organisation à laquelle participent plus de 20 000 personnes dans le monde entier et dont le financement est indépendant de sources pouvant créer un conflit d'intérêt. Le public cible est constitué par les professionnels de la santé, les décideurs en matière sanitaire et le public (patients, consommateurs). En sus de la production et de la diffusion de revues systématiques, la Collaboration Cochrane propose également des activités de formation aux méthodes de la médecine factuelle et des revues systématiques. En Francophonie, de telles formations sont proposées par des partenaires du Réseau francophone Cochrane (www.res_franco.cochrane.org ), dont la coordination est assurée depuis Lausanne par une petite équipe basée à l'Institut universitaire de médecine sociale et préventive (IUMSP). [Extrait]

Efficacy and Safety of Certolizumab Pegol in an Unselected Crohn's Disease Population: 26 Week Data of the FACTS II Survey.

BACKGROUND: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients. METHODS: Evaluation questionnaires at baseline, week 6 and 26 were completed by gastroenterologists in hospitals and private practices. RESULTS: Sixty patients (38F/22M) were included, 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of Harvey Bradshaw Index (HBI) was observed under CZP therapy (12.24.9 at week 0 vs 6.34.7 at week 6 and 6.75.3 at week 26, both P <0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36% respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. CONCLUSIONS: In a population of CD patients with predominantly complicated disease behaviour, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice.

L'efficacité c'est bien, l'impact c'est top [Efficacy is good, impact is great].

This article summarizes the different stages of research for the development of medical interventions and their specific characteristics in terms of design, population, resources, importance of results and scientific interest. The emphasis is focused on the two final stages of development, the effectiveness and the impact. An example from our own experience is given to illustrate the reduction of the effect of an intervention against malaria in young children at different stages of the development of the intervention, and the parallel decrease of the recognition by the scientific community of the importance of these results.

Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled trial.

BACKGROUND: A few recent studies have found indications of the effectiveness of inpatient psychotherapy for depression, usually of an extended duration. However, there is a lack of controlled studies in this area and to date no study of adequate quality on brief psychodynamic psychotherapy for depression during short inpatient stay exists. The present article describes the protocol of a study that will examine the relative efficacy, the cost-effectiveness and the cost-utility of adding an Inpatient Brief Psychodynamic Psychotherapy to pharmacotherapy and treatment-as-usual for inpatients with unipolar depression. METHODS/DESIGN: The study is a one-month randomized controlled trial with a two parallel group design and a 12-month naturalistic follow-up. A sample of 130 consecutive adult inpatients with unipolar depression and Montgomery-Asberg Depression Rating Scale score over 18 will be recruited. The study is carried out in the university hospital section for mood disorders in Lausanne, Switzerland. Patients are assessed upon admission, and at 1-, 3- and 12- month follow-ups. Inpatient therapy is a manualized brief intervention, combining the virtues of inpatient setting and of time-limited dynamic therapies (focal orientation, fixed duration, resource-oriented interventions). Treatment-as-usual represents the best level of practice for a minimal treatment condition usually proposed to inpatients. Final analyses will follow an intention-to-treat strategy. Depressive symptomatology is the primary outcome and secondary outcome includes measures of psychiatric symptomatology, psychosocial role functioning, and psychodynamic-emotional functioning. The mediating role of the therapeutic alliance is also examined. Allocation to treatment groups uses a stratified block randomization method with permuted block. To guarantee allocation concealment, randomization is done by an independent researcher. DISCUSSION: Despite the large number of studies on treatment of depression, there is a clear lack of controlled research in inpatient psychotherapy during the acute phase of a major depressive episode. Research on brief therapy is important to take into account current short lengths of stay in psychiatry. The current study has the potential to scientifically inform appropriate inpatient treatment. This study is the first to address the issue of the economic evaluation of inpatient psychotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12612000909820).

Superior oblique myokymia: efficacy of medical treatment.

PURPOSE: Superior oblique myokymia (SOM) is an uncommon disorder characterized by episodic monocular oscillopsia. Several medications have been reported to be of benefit for some patients with this condition, but the efficacy of medical treatment has not been well established and little long-term follow-up data are available. The purpose of this study was to better clarify the role of medical therapy in the management of SOM. METHODS: A retrospective review of patients with this disorder seen in an outpatient neuro-ophthalmology clinic. The diagnosis of SOM was based on a history of episodic unilateral oscillopsia with or without torsional diplopia. Twenty-seven patients with SOM were identified. Twenty of these were treated medically and these formed the basis of the study. Follow-up interval ranged from 1 to 12.5 years (mean, 6.5 years). The main outcome measure was relief of oscillopsia. RESULTS: Fifteen of the 18 patients treated with carbamazepine (83%) reported some benefit, 6 of whom continue to do well on medication 9 months to 5 years later. In four patients improvement was only transient and in five others treatment was subsequently discontinued for various reasons. In addition, one patient had sustained benefit from phenytoin, one from propranolol, and one from propranolol plus valproic acid. We found no treatment success with baclofen. Overall, nine patients (45%) enjoy sustained benefit unassociated with adverse side effects. CONCLUSIONS: In contrast to previous reports emphasizing the efficacy of surgery for SOM, our data demonstrate the potential benefits of medical treatment for patients with this disorder.

Hormonothérapie dans le cancer du sein: efficacité et effets adverses [Endocrine therapy in breast cancer: efficacy and adverse events].

Endocrine therapy remains a mainstay in the treatment of endocrine-sensitive breast cancer. In the adjuvant setting, 5 years of endocrine therapy significantly reduces recurrence rate and mortality. Tamoxifen is the molecule of choice for premenopausal women, whereas for postmenopausal women aromatase inhibitors are currently part of the standard treatment. Endocrine therapy can induce side effects, which can affect patient's quality of life and lead to premature treatment interruption. Identification and adequately addressing these side effects is fundamental to maintain good treatment compliance and therefore improve breast cancer specific outcome.

Benefit of anti-HER2-coated paclitaxel-loaded immuno-nanoparticles in the treatment of disseminated ovarian cancer: Therapeutic efficacy and biodistribution in mice.

The benefit of polymeric immuno-nanoparticles (NPs-Tx-HER), consisting of paclitaxel (Tx)-loaded nanoparticles coated with anti-HER2 monoclonal antibodies (Herceptin, trastuzumab), in cancer treatment was assessed in a disseminated xenograft ovarian cancer model induced by intraperitoneal inoculation of SKOV-3 cells overexpressing HER2 antigens. The study was focused on the evaluation of therapeutic efficacy and biodistribution of NPs-Tx-HER compared to other Tx formulations. The therapeutic efficacy was determined by two methods: bioluminescence imaging and survival rate. The treatment regimen consisted in an initial dose of 20mg/kg Tx administered as 10mg/kg intravenously (IV) and 10mg/kg intraperitonealy (IP), followed by five alternative IP and IV injections of 10mg/kg Tx every 3 days. The bioluminescence study has clearly shown the superior anti-tumor activity of NPs-Tx-HER compared to free Tx. As a confirmation of these results, a significantly longer survival of mice was observed for NPs-Tx-HER treatment compared to free Tx, Tx-loaded nanoparticles coated with an irrelevant mAb (Mabthera, rituximab) or Herceptin alone, indicating the potential of immuno-nanoparticles in cancer treatment. The biodistribution pattern of Tx was assessed on healthy and tumor bearing mice after IV or IP administration. An equivalent biodistribution profile was observed in healthy mice for Tx encapsulated either in uncoated nanoparticles (NPs-Tx) or in NPs-Tx-HER. No significant difference in Tx biodistribution was observed after IV or IP injection, except for a lower accumulation in the lungs when NPs were administered by IP. Encapsulated Tx accumulated in the organs of the reticulo-endothelial system (RES) such as the liver and spleen, whereas free Tx had a non-specific distribution in all tested organs. Compared to free Tx, the single dose injection (IV or IP) of encapsulated Tx in mice bearing tumors induced a higher tumor accumulation. However, no difference in overall tumor accumulation between NPs-Tx-HER and NPs-Tx was observed. In conclusion, the encapsulation of Tx into NPs-Tx-HER immuno-nanoparticles resulted in an improved efficacy of drug in the treatment of disseminated ovarian cancer overexpressing HER2 receptors.