Human pancreatic carboxypeptidase B. I. Isolation, purification, and characterization of fraction II.

Human carboxypeptidase B fraction II has been purified from pancreatic juice by DEAE-'Sephadex' chromatography, isoelectric focusing, and 'Sephadex' G-100 gel filtration. The enzyme has been characterized by analytical polyacrylamide disc-gel electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, amino acid analysis Km determination, molecular weight determination on 'Sephadex' G-100, zinc analysis, and inhibition by metal chelating agents. Human carboxypeptidase B fraction II appeared homogeneous in analytical polyacrylamide disc-gel electrophoresis, but showed two components of 23,500 and 9,200 daltons in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Zinc analysis revealed 0.96 gram atoms of zinc per mole of enzyme, and a Km of 65 +/- 3 muM was determined for hydrolysis of hippuryl-L-arginine.

Pharmacologic and cognitive-behavioral treatment for bulimia nervosa: a controlled comparison.

OBJECTIVE: This study examined the relative effectiveness of desipramine, cognitive-behavioral therapy, and their combination in the treatment of bulimia nervosa, together with the effects of withdrawing medication after two different lengths of treatment. METHOD: Seventy-one patients meeting DSM-III-R criteria for bulimia nervosa, recruited from an eating disorders clinic or by advertisements, were assigned at random to one of five groups: desipramine (withdrawn at 16 or 24 weeks), combined treatment (medication withdrawn at 16 or 24 weeks), and cognitive-behavioral therapy (15 sessions). All treatments were conducted individually in an outpatient clinic. The primary outcome measures were binge eating and purging rates assessed at pretreatment, 16, 24, and 32 weeks. The results were analyzed as three groups (medication, cognitive-behavioral therapy, and combined treatment) at 16 weeks and as five groups at subsequent assessments. RESULTS: At 16 weeks, both cognitive-behavioral therapy and the combined treatment were superior to medication given for 16 weeks in reducing binge eating and purging. At 32 weeks, however, only the combined 24-week treatment was superior to medication given for 16 weeks. The combined treatment was also more effective in reducing dietary preoccupation and hunger. Continuing cognitive-behavioral therapy appeared to prevent relapse in patients withdrawn from medication at 16 weeks. CONCLUSIONS: Overall, the results favor the use of a combination of medication and cognitive-behavioral therapy in the treatment of bulimia nervosa, with medication continued for at least 24 weeks.

One-year follow-up of psychosocial and pharmacologic treatments for bulimia nervosa.

BACKGROUND: This study examined the outcome 1-year posttreatment of the use of desipramine, cognitive-behavioral therapy (CBT), and their combination in the treatment of bulimia nervosa. METHOD: Sixty-one patients meeting DSM-III-R criteria for bulimia nervosa were randomly assigned to one of five groups--desipramine (withdrawn at 16 or 24 weeks), CBT (18 sessions), or the combined treatment (18 sessions of CBT plus desipramine withdrawn at 16 or 24 weeks)--and were followed to 1-year posttreatment. RESULTS: At 1-year follow-up, both the combined 24-week treatment and CBT alone were significantly superior in reducing binge eating to desipramine given for 16 weeks. The combined treatment was also superior to 16 weeks of desipramine in reducing emotionally driven eating and dietary restraint. Only 18% (2 of 11) of those receiving 16 weeks of desipramine were free of binge eating and purging at follow-up compared with 78% (7 of 9) of those receiving the combined 24-week treatment. The other groups fell between these two extremes. CONCLUSION: With the exception of the group treated for 16 weeks with desipramine alone, maintenance of improvement appeared satisfactory with all the treatments. Since the poorest results were found with 16 weeks of desipramine treatment, this study suggests that desipramine should be continued for at least 24 weeks either alone or combined with CBT. The broadest gain in reducing the psychopathology associated with bulimia nervosa was found with the combined 24-week treatment.

Cognitive-behavioral and response-prevention treatments for bulimia nervosa.

This study was designed to assess the additive effects of major components of cognitive-behavioral treatment for bulimia nervosa. Seventy-seven female patients with bulimia nervosa were allocated at random to one of four conditions: wait-list control, self-monitoring of caloric intake and purging behaviors, cognitive-behavioral treatment, and cognitive-behavioral treatment combined with response prevention of vomiting. In the treatment conditions, participants were seen individually for fourteen 1-hr sessions over a 4-month period. All the treatment groups showed significant improvement, whereas the wait-list control group did not. Cognitive-behavioral treatment was, however, the most successful in reducing purging and in promoting positive psychological changes. Fifty-six percent of participants in this condition ceased binge eating and purging by the end of treatment, and the frequency of purging declined by 77.2% during the same period. Of the three treatment conditions, only cognitive-behavioral treatment was superior to the wait-list control. At the 6-month follow-up, 59% of the cognitive-behavioral group were abstinent, and purging had declined by 80%. Cognitive-behavioral treatment was significantly superior to the other treatment groups at this time. Thus, the addition of response prevention of vomiting did not enhance the efficacy of cognitive-behavioral treatment, and the evidence suggests that it may have had a deleterious effect.

Cognitive-behavioral treatment with and without exposure plus response prevention in the treatment of bulimia nervosa: a reply to Leitenberg and Rosen.

In this reply to Leitenberg and Rosen (1989), we conclude that the evidence that response prevention of vomiting adds significantly to the efficacy of cognitive-behavioral treatment of bulimia nervosa is not strong. In this context and given the finding in our previous study (Agras, Schneider, Arnow, Raeburn, & Telch, 1989) that the addition of response prevention did not increase the efficacy of cognitive-behavioral treatment and may have reduced it, we believe that our cautionary note concerning the addition of response prevention to cognitive-behavioral treatment should stand.

Group cognitive-behavioral therapy and group interpersonal psychotherapy for the nonpurging bulimic individual: a controlled comparison.

This study evaluated the effectiveness of group cognitive-behavioral treatment (CBT) and group interpersonal psychotherapy (IPT) for binge eating. Fifty-six women with nonpurging bulimia were randomly assigned to 1 of 3 groups: CBT, IPT, or a wait-list control (WL). Treatment was administered in small groups that met for 16 weekly sessions. At posttreatment, both group CBT and group IPT treatment conditions showed significant improvement in reducing binge eating, whereas the WL condition did not. Binge eating remained significantly below baseline levels for both treatment conditions at 6-month and 1-year follow-ups. These data support the central role of both eating behavior and interpersonal factors in the understanding and treatment of bulimia.

Comparing the cost effectiveness of psychiatric treatments: bulimia nervosa.

We conducted an exploratory post hoc study that compared the cost effectiveness of five treatments for bulimia nervosa: 15 weeks of cognitive behavioral therapy (CB) followed by three monthly sessions, 16 weeks (Med16) and 24 weeks (Med24) of desipramine (< or = 300 mg/day), and CB combined with desipramine for those durations (Combo16 and Combo24). We illustrate how a treatment's cost effectiveness varies according to when evaluation is done and how effectiveness and cost are defined. At 32 weeks, Med16 appears the most cost-effective treatment, and Combo16 appears the least. At 1 year, Med24 appears the most cost-effective treatment, and Combo16 appears the least. Using this post hoc analysis as an example, we discuss the pitfalls and limitations of cost-effectiveness analysis of psychiatric treatments.

A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23.

BACKGROUND: The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous neurodegenerative disorders in which the cardinal pathologic feature is upper motor neuron degeneration leading to progressive spasticity and weakness of the lower limbs. To date, 14 autosomal recessive HSP loci have been mapped. METHODS: We have identified a large consanguineous Omani family in which an autosomal recessive form of HSP is segregating. The age at onset varied from 6 to 11 years and the course of the disease is progressive with intellectual disability and is associated with seizures in two individuals. To map the chromosomal location of the causative gene we undertook 250K gene chip SNP analyses of all affected individuals assuming that a founder mutation was responsible. RESULTS: All affected individuals shared a 20.4 Mb (3.25 cM) region of homozygosity located on chromosome 16q21-q23.1, defined by SNP markers rs149428 and rs9929635 (peak multipoint lod score of 4.86). Two candidate genes, dynein, cytoplasmic 1, light intermediate chain 2 (DYNC1LI2) and vacuolar protein sorting 4 homolog A (VPS4A), were sequenced but no disease causing mutations were identified. CONCLUSION: We have mapped the chromosomal location of a novel gene responsible for a form of hereditary spastic paraplegia (HSP) (SPG35) and defined its clinical presentation.

Genetics and global health care.

OBJECTIVES: To examine an alternative model for funding genetic health care, on a global basis. METHODS: Internet-based national data on gross domestic product (GDP) per capita, health care funding, and public and private elements of health care costs. RESULTS: Wide variation in GDP per capita and in the proportion available for health care funding. Insufficient funds are available in developing countries. CONCLUSIONS: Health care provision for people with genetic disorders is unlikely to be fully funded unless a different approach to management costs is undertaken. Rare genetic disorders could be funded by an insurance model which may be more equitable and which could be developed to cover the total global health care costs of the genetic disorder.

Mantle redox evolution and the oxidation state of the Archean atmosphere.

Current models predict that the early atmosphere consisted mostly of CO2, N2, and H2O, along with traces of H2 and CO. Such models are based on the assumption that the redox state of the upper mantle has not changed, so that volcanic gas composition has remained approximately constant with time. We argue here that this assumption is probably incorrect: the upper mantle was originally more reduced than today, although not as reduced as the metal arrest level, and has become progressively more oxidized as a consequence of the release of reduced volcanic gases and the subduction of hydrated, oxidized seafloor. Data on the redox state of sulfide and chromite inclusions in diamonds imply that the process of mantle oxidation was slow, so that reduced conditions could have prevailed for as much as half of the earth's history. To be sure, other oxybarometers of ancient rocks give different results, so the question of when the mantle redox state has changed remains unresolved. Mantle redox evolution is intimately linked to the oxidation state of the primitive atmosphere: A reduced Archean atmosphere would have had a high hydrogen escape rate and should correspond to a changing mantle redox state; an oxidized Archean atmosphere should be associated with a constant mantle redox state. The converses of these statements are also true. Finally, our theory of mantle redox evolution may explain why the Archean atmosphere remained oxygen-deficient until approximately 2.0 billion years ago (Ga) despite a probable early origin for photosynthesis.

Cost-effectiveness of hepatic arterial chemoembolization for colorectal liver metastases refractory to systemic chemotherapy.

PURPOSE: To calculate the cost-effectiveness of hepatic arterial chemoembolization (HACE) for the treatment of colorectal liver metastases (CLM) over a range of survival benefits and to determine the survival benefit that HACE must confer to meet three thresholds of cost-effectiveness. MATERIALS AND METHODS: A spreadsheet model was used to estimate the marginal direct cost of HACE compared with palliative care from a payer's perspective. Medicare reimbursement amounts represented costs, while probabilities of reembolization and complications were obtained from records of patients who underwent HACE. Marginal cost-effectiveness was calculated from marginal direct cost by varying the survival benefit of HACE compared with palliative care from 0 to 24 months. Break-even analyses were conducted to determine the survival benefit at which the cost-effectiveness of HACE would decrease below three threshold values derived from a literature review. RESULTS: The marginal cost-effectiveness of HACE compared with palliative care, given survival benefits of 3, 6, and 12 months, was $82,385, $41,193, and $21,045 per life-year (LY) gained, respectively. Cost-effectiveness thresholds of $20,000 (strict), $50,000 (moderate), and $100,000 (generous) per LY gained required survival benefits of 12.63, 4.94, and 2.47 months, respectively, more than the expected baseline. CONCLUSION: The cost-effectiveness of HACE for the treatment of CLM varies considerably according to the anticipated survival benefit. Results of future randomized controlled trials must demonstrate a survival benefit of nearly 5 months for HACE to meet the moderate cost-effectiveness standard of $50,000 per LY gained.