Effect of gelatinase inhibition on adipogenesis and adipose tissue development.

1. The potential of the matrix metalloproteinase (MMP) inhibitor ABT-518 to affect pre-adipocyte differentiation in vitro and adipose tissue development in vivo was investigated using mouse models of adipogenesis and obesity. 2. Differentiation of 3T3-F442A pre-adipocytes into mature adipocytes was enhanced in a dose-dependent manner by the addition of ABT-518 (0-100 µmol/L). This was associated with increased expression of the adipogenic markers adipocyte fatty acid-binding protein 2 (AP2), peroxisome proliferator-activated receptor γ and adiponectin. 3. Feeding 5-week-old male wild-type mice with a high-fat diet, with or without ABT-518 (to achieve a dose of 100 mg/kg per day), for 16 weeks resulted in a significant reduction in bodyweight throughout the experimental period. Magnetic resonance spectroscopy revealed that the lipid : water ratio was significantly lower in ABT-518-treated mice. The total weight of isolated subcutaneous or gonadal fat depots did not differ significantly following ABT-518 treatment, but adipocyte and blood vessel size were significantly reduced in the gonadal fat. 4. Administration of ABT-518-2 (100 mg/kg per day for 10 weeks) to 5-week-old male wild-type mice with established obesity maintained on a high-fat diet had no effect on total bodyweight at the end of the experiment, but was associated with reduced blood vessel size in the fat depots. 5. Thus, the MMP inhibitor ABT-518 stimulates differentiation of 3T3-F442A pre-adipocytes in vitro. It mildly reduces bodyweight gain in a murine model of diet-induced obesity, but does not affect established obesity.

Group and multifamily behavioral treatment for obsessive compulsive disorder: a pilot study.

Recent trends toward managed care in mental health settings require investigation of the efficacy and cost-effectiveness of treatments conducted over shorter time frames or with less therapist involvement. Findings are presented in an uncontrolled trial of two types of group behavioral treatments of OCD: group (GBT) and multifamily (MFBT). Seventeen patients (10 women and 7 men) diagnosed with OCD received a partially manualized GBT delivered by co-therapy teams in three groups of ten 2-hr sessions. Mean interview-based YBOCS scores reduced significantly at posttest and at 1-year follow-up, as did measures of overall functioning on the Sheehan Disability Scale at posttest and follow-up. A second cohort of 19 patients (14 women and 5 men) was treated with MFBT that included spouses/partners and parents in three co-therapy groups. Two groups received ten 2-hr sessions and one received twelve 2-hr sessions. YBOCS scores reduced significantly at posttest and at 1-year follow-up, with corresponding gains in disability scores. Both group treatments showed large effects comparable to those reported for a more intensive individual behavioral treatment. Comparisons of treatments indicated that similar proportions of subjects were reliably changed at posttest and follow-up respectively, but more MFBT than GBT participants were clinically significantly improved. These promising cost effective group treatments remain to be tested in a controlled trial.

Autolytic degradation of ocriplasmin: a complex mechanism unraveled by mutational analysis.

Ocriplasmin, a truncated form of plasmin, is commercialized in the USA and in Europe under the trade name Jetrea(®), and indicated for the treatment of symptomatic vitreomacular adhesion and vitreomacular traction including when associated with macular hole ≤400 µm, respectively. We have shown in a previous study that ocriplasmin undergoes autolytic degradation when injected in eye vitreous, which leads to its rapid inactivation. In order to investigate this process further, we have introduced in ocriplasmin a variety of amino acid substitutions within or in the immediate vicinity of the three major autolytic cleavage sites. We demonstrate here that autolytic inactivation of ocriplasmin is a sequential process where initial cleavage occurs primarily between residues 156 and 157. Reduction or even blocking of autolysis can be achieved by mutating a limited number of key residues. In this study, we also report the identification of a series of ocriplasmin variants with improved resistance to autolysis and unimpaired catalytic activity. Such variants represent useful tools for the exploration of therapeutic approaches aiming at non-surgical resolution of vitreomacular adhesion.

Obsessive-compulsive disorder: a concealed diagnosis.

Epidemiologic data suggest that obsessive-compulsive disorder is the fourth most common mental disorder, after phobias, substance abuse and depression, and is nearly as common as asthma and diabetes mellitus. The understanding of obsessive-compulsive disorder and its treatment have significantly improved over the past decade. Positron emission tomographic scanning has demonstrated characteristic changes in the cerebral metabolism of patients with obsessive-compulsive disorder. Selective serotonin reuptake inhibitors have been shown to alleviate the symptoms of this disorder. Treatment of obsessive-compulsive disorder includes drug therapy, behavior therapy and family therapy. The family physician can play a key role in recognizing the clinical markers of obsessive-compulsive disorder and negotiating a treatment plan that significantly lessens the psychosocial morbidity associated with it.

A time-limited behavioral group for treatment of obsessive-compulsive disorder.

In vivo exposure with response prevention is an effective treatment for obsessive-compulsive disorder (OCD) either alone or combined with pharmacotherapy. Widespread application of this technique has been limited by lack of trained therapists and the expense of intensive individual behavioral therapy. This report describes a time-limited 10-session behavioral therapy group for OCD whose key elements are exposure, response prevention, therapist and participant modeling, and cognitive restructuring. In a naturalistic open trial of 90 patients meeting DSM-III-R criteria for OCD who completed the 10-session group, self-administered Yale-Brown Obsessive-Compulsive Scale scores (mean +/- SD) were 21.8 +/- 5.6 at baseline and 16.6 +/- 6.4 after the 10-week treatment, a significant decrease. A descriptive analysis of the therapeutic elements of the group and its advantages over individual behavioral treatment are presented.

Family accommodation of obsessive-compulsive symptoms: instrument development and assessment of family behavior.

Relatives frequently accommodate patients' obsessive-compulsive symptoms and clinicians hypothesize that such accommodations adversely affect patient outcome. This study's purpose was to develop a valid and reliable measure, the Family Accommodation Scale for Obsessive-Compulsive Disorder (FAS), and to investigate the family accommodation construct. We administered the FAS and additional family and patient measures to 36 adult obsessive-compulsive patients and their primary caregivers. The FAS demonstrated excellent interrater reliability and good internal consistency and performed well on assessment of its convergent and discriminant validity. Family accommodation was significantly associated with patient symptom severity and functioning, and with relatives' own obsessive-compulsive symptoms. Although most relatives accommodated patient symptoms, many did not believe that such accommodations improved the patient's clinical status. The FAS will provide researchers and clinicians with a useful tool for assessing family accommodation and for identifying families who may benefit from interventions aimed at developing more adaptive coping strategies.