Models of community care for severe mental illness: a review of research on case management

We describe different models of community care for persons with severe mental illness and review the research literature on case management, including the results of 75 studies. Most research has been conducted on the assertive community treatment (ACT) or intensive case management (ICM) models. Controlled research on ACT and ICM indicates that these models reduce time in the hospital and improve housing stability, especially among patients who are high service users. ACT and ICM appear to have moderate effects on improving symptomatology and quality of life. Most studies suggest little effect of ACT and ICM on social functioning, arrests and time spent in jail, or vocational functioning. Studies on reducing or withdrawing ACT or ICM services suggest some deterioration in gains. Research on other models of community care is inconclusive. We discuss the implications of the findings in terms of the need for specialization of ACT or ICM teams to address social and vocational functioning and substance abuse. We suggest directions for future research on models of community care, including evaluating implementation fidelity, exploring patient predictors of improvement, and evaluating the role of the helping alliance in mediating outcome.     

A phase I clinical and pharmacokinetic study of the angiogenesis inhibitor, tecogalan sodium

BACKGROUND: Tecogalan sodium is an angiogenesis inhibitor isolated from a sulfated polysaccharide produced by the bacterium Arthrobacter. The antiangiogenic effect of tecogalan sodium is thought to be mediated by the inhibition of binding of basic fibroblast growth factor to cellular receptors. PATIENTS AND METHODS: A phase I study was conducted in thirty-three patients with refractory malignancies, including AIDS-associated Kaposi's sarcoma. Patients received a single i.v. infusion every three weeks with the infusion duration ranging from one to twenty-four hours. Seven different dosage levels were studied (125, 185, 240, 300, 390, 445, and 500 mg/m2). RESULTS: The primary dose-limiting toxicity was prolongation of the activated partial thromboplastin time with peak times being between 1.0-4.0 times the upper limit of normal. This toxicity was ameliorated at a given dose level by prolonging the infusion time. Other common toxicities included fever (40%) and rigors (31%) which were well controlled with acetominophen and meperidine. The serum half-life of tecogalan sodium was between 1-1.5 hours and < 25% of unchanged drug was excreted in the urine. CONCLUSIONS: The recommended phase II dose of tecogalan sodium on this schedule is 390 mg/m2 over 24 hours. Other schedules including continuous administration should be investigated to maximize the efficacy of this novel angiogenesis inhibitor.     

Cloning and analysis of the genes for a novel electron-transferring flavoprotein from Megasphaera elsdenii. Expression and characterization of the recombinant protein

The genes that encode the two different subunits of the novel electron-transferring flavoprotein (ETF) from Megasphaera elsdenii were identified by screening a partial genomic DNA library with a probe that was generated by amplification of genomic sequences using the polymerase chain reaction. The cloned genes are arranged in tandem with the coding sequence for the beta-subunit in the position 5' to the alpha-subunit coding sequence. Amino acid sequence analysis of the two subunits revealed that there are two possible dinucleotide-binding sites on the alpha-subunit and one on the beta-subunit. Comparison of M. elsdenii ETF amino acid sequence to other ETFs and ETF-like proteins indicates that while homology occurs with the mitochondrial ETF and bacterial ETFs, the greatest similarity is with the putative ETFs from clostridia and with fixAB gene products from nitrogen-fixing bacteria. The recombinant ETF was isolated from extracts of Escherichia coli. It is a heterodimer with subunits identical in size to the native protein. The isolated enzyme contains approximately 1 mol of FAD, but like the native protein it binds additional flavin to give a total of about 2 mol of FAD/dimer. It serves as an electron donor to butyryl-CoA dehydrogenase, and it also has NADH dehydrogenase activity.     

Phosphoinositide 3-kinase regulates phospholipase Cgamma-mediated calcium signaling

It has been demonstrated that the lipid products of the phosphoinositide 3-kinase (PI3K) can associate with the Src homology 2 (SH2) domains of specific signaling molecules and modify their actions. In the current experiments, phosphatidylinositol 3,4, 5-trisphosphate (PtdIns-3,4,5-P3) was found to bind to the C-terminal SH2 domain of phospholipase Cgamma (PLCgamma) with an apparent Kd of 2.4 microM and to displace the C-terminal SH2 domain from the activated platelet-derived growth factor receptor (PDGFR). To investigate the in vivo relevance of this observation, intracellular inositol trisphosphate (IP3) generation and calcium release were examined in HepG2 cells expressing a series of PDGFR mutants that activate PLCgamma with or without receptor association with PI3K. Coactivation of PLCgamma and PI3K resulted in an approximately 40% increase in both intracellular IP3 generation and intracellular calcium release as compared with selective activation of PLCgamma. Similarly, the addition of wortmannin or LY294002 to cells expressing the wild-type PDGFR inhibited the release of intracellular calcium. Thus, generation of PtdIns-3,4,5-P3 by receptor-associated PI3K causes an increase in IP3 production and intracellular calcium release, potentially via enhanced PtdIns-4, 5-P2 substrate availability due to PtdIns-3,4,5-P3-mediated recruitment of PLCgamma to the lipid bilayer.     

Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1. Possible role in causing human autosomal dominant cone degeneration

Photoreceptor membrane guanylate cyclases (RetGC) are regulated by calcium-binding proteins, GCAP-1 and GCAP-2. At Ca2+ concentrations below 100 nM, characteristic of light-adapted photoreceptors, guanylate cyclase-activating protein (GCAPs) activate RetGC, and at free Ca2+ concentrations above 500 nM, characteristic of dark-adapted photoreceptors, GCAPs inhibit RetGC. A mutation, Y99C, in human GCAP-1 was recently found to be linked to autosomal dominant cone dystrophy in a British family (Payne, A. M., Downes, S. M., Bessant, D. A. R., Taylor, R., Holder, G. E., Warren, M. J., Bird, A. C., and Bhattachraya, S. S. (1998) Hum. Mol. Genet. 7, 273-277). We produced recombinant Y99C GCAP-1 mutant and tested its ability to activate RetGC in vitro at various free Ca2+ concentrations. The Y99C mutation does not decrease the ability of GCAP-1 to activate RetGC. However, RetGC stimulated by the Y99C GCAP-1 remains active even at Ca2+ concentration above 1 microM. Hence, the cyclase becomes constitutively active within the whole physiologically relevant range of free Ca2+ concentrations. We have also found that the Y99C GCAP-1 can activate RetGC even in the presence of Ca2+-loaded nonmutant GCAPs. This is consistent with the fact that cone degeneration was dominant in human patients who carried such mutation (Payne, A. M., Downes, S. M., Bessant, D. A. R. , Taylor, R., Holder, G. E., Warren, M. J., Bird, A. C., and Bhattachraya, S. S. (1998) Hum. Mol. Genet. 7, 273-277). A similar mutation, Y104C, in GCAP-2 results in a different phenotype. This mutation apparently does not affect Ca2+ sensitivity of GCAP-2. Instead, the Y104C GCAP-2 stimulates RetGC less efficiently than the wild-type GCAP-2. Our data indicate that cone degeneration associated with the Y99C mutation in GCAP-1 can be a result of constitutive activation of cGMP synthesis.     

A novel MADS-box gene of potato (Solanum tuberosum L.) expressed during the early stages of tuberization

Cyclic ADP-ribose (cADPR) is a Ca(2+)-mobilizing cyclic nucleotide derived from NAD+. Accumulating evidence indicates that it is an endogenous modulator of the Ca(2+)-induced Ca2+ release mechanism in cells. In this study, we show that ADP-ribosyl cyclase catalyzes the cyclization of not only NAD+ but also several of its analogs with various purine bases (guanine, hypoxanthine, or xanthine) substituting for adenine. Unlike cADPR, the resulting cyclic products are fluorescent. Comparisons with various model compounds indicate that only 7-methyl substituted purine nucleosides and nucleotides are fluorescent, and the pH-dependence of their UV spectra is most similar to that of the fluorescent cADPR analogs, indicating that the site of cyclization of these analogs is at the N7-position of the purine ring. This finding is novel since the site of cyclization is at the N1-position for cADPR as determined by X-ray crystallography. That a single enzyme can cyclize a variety of substrates at two different sites has important implications mechanistically, and a model is proposed to account for these novel catalytic properties. Among the analogs synthesized, cyclic GDP-ribose is highly resistant to hydrolysis, while cyclic IDP-ribose can be readily hydrolyzed by CD38, a bifunctional enzyme involved in the metabolism of cADPR. These unique properties of the analogs can be used to develop fluorimetric assays for monitoring separately the cyclization and hydrolytic reactions catalyzed by the metabolic enzymes of cADPR. The convenience of the method in measuring kinetic parameters, pH-dependence, and modulator activity of the metabolic enzymes of cADPR is illustrated.     

Persistent gastroesophageal reflux disease after antireflux surgery in children: I. immediate postoperative evaluation using extended esophageal pH monitoring

PURPOSE: There is a paucity of quantitative and reproducible follow-up data on childhood operations for gastroesophageal reflux disease (GERD). With the development of minimally invasive techniques for antireflux operations in children, there is a need to quantitatively determine immediate outcomes for such operations performed by laparotomy for comparison. METHODS: A retrospective review of 385 children (age range, 1 week to 15 years) who had a primary antireflux operation in a Children's or University Hospital performed by laparotomy between 1983 and 1997, and who also had an extended esophageal pH study performed within the first 12 postoperative weeks, was conducted. The operations performed included Nissen fundoplication (n = 135), Thal fundoplication (n = 195), and Boerema gastropexy (n = 55). An immediate postoperative failure of the operation to control GERD was defined as an abnormal esophageal pH score persisting up to the twelfth postoperative week. RESULTS: Eleven patients (2.9%) were classified as having an immediate postoperative failure of their operation to control GERD. An additional three patients had an abnormal esophageal pH score 2 weeks postoperatively, which subsequently reverted to a normal esophageal pH score by 12 weeks. The immediate postoperative failure rate was 1.5% (2 of 135) for the Nissen fundoplication, 1.5% (3 of 195) for the Thal fundoplication, and 10.9% (6 of 55) for the Boerema gastropexy. A higher failure rate (five patients, 36%) was seen for the first 14 patients who underwent a Boerema gastropexy during the learning curve period for this operation before 1985, and by excluding these patients the failure rate was 2.4% (1 of 41) after 1985. There was no significantly increased probability of immediate postoperative failure in patients with central nervous system disorders, prematurity, repaired esophageal atresia, or gastric emptying abnormalities. Only 5 (36%) of the 14 children with persisting symptoms suggestive of GERD had immediate postoperative failure of their operation. CONCLUSIONS: Extended esophageal pH monitoring during the first 12 postoperative weeks is a helpful tool to assess the immediate outcome of antireflux operations in children because clinical symptoms alone may be unreliable. The immediate failure rate for an antireflux operation performed in children by laparotomy is very low and seems to be unaffected by comorbid factors.