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M McLeod

Publications and source records attributed to M McLeod.

At least 19 recordsLinked to original sources
PubMed2000

Cpc2, a fission yeast homologue of mammalian RACK1 protein, interacts with Ran1 (Pat1) kinase To regulate cell cycle progression and meiotic development.

The Schizosaccharomyces pombe ran1/pat1 gene regulates the transition between mitosis and meiosis. Inactivation of Ran1 (Pat1) kinase is necessary and sufficient for cells to exit the cell cycle and undergo meiosis. The yeast two-hybrid interaction trap was used to identify protein partners for Ran1/Pat1. Here we report the identification of one of these, Cpc2. Cpc2 encodes a homologue of RACK1, a WD protein with homology to the beta subunit of heterotrimeric G proteins. RACK1 is a highly conserved protein, although its function remains undefined. In mammalian cells, RACK1 physically associates with some signal transduction proteins, including Src and protein kinase C. Fission yeast cells containing a cpc2 null allele are viable but cell cycle delayed. cpc2Delta cells fail to accumulate in G(1) when starved of nitrogen. This leads to defects in conjugation and meiosis. Copurification studies show that although Cpc2 and Ran1 (Pat1) physically associate, Cpc2 does not alter Ran1 (Pat1) kinase activity in vitro. Using a Ran1 (Pat1) fusion to green fluorescent protein, we show that localization of the kinase is impaired in cpc2Delta cells. Thus, in parallel with the proposed role of RACK1 in mammalian cells, fission yeast cpc2 may function as an anchoring protein for Ran1 (Pat1) kinase. All defects associated with loss of cpc2 are reversed in cells expressing mammalian RACK1, demonstrating that the fission yeast and mammalian gene products are indeed functional homologues.

Amino Acid Sequence↗
PubMed1999

Prolonged xenograft survival of islets infected with small doses of adenovirus expressing CTLA4Ig.

BACKGROUND: Systemic administration of the inhibitor of costimulation, CTLA4Ig, has been shown to prolong islet graft survival. The purpose of this study was to compare local and systemic expression of murine CTLA4Ig in transplants of rat islets into mice. METHODS: Murine CTLA4Ig was made by joining two polymerase chain reaction products, the extracellular portion of CTLA4 and the Fc portion of IgG2a. Recombinant adenovirus expressing CTLA4Ig (AdCTLA4Ig) was generated using the strategy of Cre-lox recombination. Isolated rat islets infected with AdCTLA4Ig at multiplicities of infection (MOIs) ranging from 0.1 to 10 were transplanted into streptozocin diabetic male B6AF1 mice. Control islets were mock infected or infected with AdLacZ or AdsIg, a recombinant adenovirus expressing only the Fc portion of IgG2a. Also, AdCTLA4Ig and control viruses were injected intramuscularly into mouse transplant recipients at the time of islet transplantation to provide CTLA4Ig systemically. RESULTS: Control islets transplanted into diabetic mice were rejected in 13-17 days. Islets infected with AdCTLA4Ig had dose-dependent prolongation of graft survival. Prolonged survival was even found with very low MOIs of 0.1 and 0.5, with survivals of 24+/-4.2 and 25+/-2.2 days, respectively. Survival with an MOI of 10 was 39+/-8.7 days. With intramuscular injection, no prolongation was found at the lowest relative MOIs of 0.2 and 1, but there was dose-dependent prolongation of graft survival with larger doses. At the highest relative MOI of 400, survival was prolonged to 58+/-10 days. CONCLUSIONS: Rat islets infected with AdCTLA4Ig transplanted into mice had prolonged graft survival. Prolonged survival with MOIs as low as 0.1 and 0.5 indicates that only a minority of islet cells need to express CTLA4Ig to exert an effect. Moreover, the results suggest that the improved islet graft survival is due to a local influence of CTLA4Ig.

Abatacept↗
PubMed1999

Establishing a method of vector contamination identification in database sequences.

MOTIVATION: The nucleotide sequence databases are invaluable tools both for the private and the academic research communities, from the retrieval of sequences to homology searching. Several issues related to data quality, such as the existence of sequencing artifacts and errors, are facing the databases. We investigated a major source of these errors, i.e. the presence of vector-contaminated sequences. RESULTS: Using a panel of 180 vector polylinker sequences, we found 0.36% or 3029 vector-matching sequences in GenBank Release 95-96, with an average vector-matching length of 72 nucleotides. The number of vector-contaminated sequences has been growing with the database; however, the percent contamination has remained approximately constant at an average of 0.28% from 1982 to 1996. AVAILABILITY: Access to the database of vector polylinker sequences via sequence similarity searching is available at http://seqsim.ncgr.org/vector/ CONTACT: gas@molinfo.com

Animals↗
PubMed1998

E-cadherin germline mutations in familial gastric cancer.

The identification of genes predisposing to familial cancer is an essential step towards understanding the molecular events underlying tumorigenesis and is critical for the clinical management of affected families. Despite a declining incidence, gastric cancer remains a major cause of cancer death worldwide, and about 10% of cases show familial clustering. The relative contributions of inherited susceptibility and environmental effects to familial gastric cancer are poorly understood because little is known of the genetic events that predispose to gastric cancer. Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer in a large kindred from New Zealand (Aotearoa). Genetic linkage analysis demonstrated significant linkage to markers flanking the gene for the calcium-dependent cell-adhesion protein E-cadherin. Sequencing of the E-cadherin gene revealed a G --> T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product. Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas. Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells. The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families. In one family, a frameshift mutation was identified in exon 15, and in a second family a premature stop codon interrupted exon 13. These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.

Adolescent↗
PubMed1998

The Genome Sequence DataBase (GSDB): improving data quality and data access.

In 1997 the primary focus of the Genome Sequence DataBase (GSDB; www. ncgr.org/gsdb ) located at the National Center for Genome Resources was to improve data quality and accessibility. Efforts to increase the quality of data within the database included two major projects; one to identify and remove all vector contamination from sequences in the database and one to create premier sequence sets (including both alignments and discontiguous sequences). Data accessibility was improved during the course of the last year in several ways. First, a graphical database sequence viewer was made available to researchers. Second, an update process was implemented for the web-based query tool, Maestro. Third, a web-based tool, Excerpt, was developed to retrieve selected regions of any sequence in the database. And lastly, a GSDB flatfile that contains annotation unique to GSDB (e.g., sequence analysis and alignment data) was developed. Additionally, the GSDB web site provides a tool for the detection of matrix attachment regions (MARs), which can be used to identify regions of high coding potential. The ultimate goal of this work is to make GSDB a more useful resource for genomic comparison studies and gene level studies by improving data quality and by providing data access capabilities that are consistent with the needs of both types of studies.

Base Sequence↗
PubMed1998

Characterization of functional regions in the Schizosaccharomyces pombe mei3 developmental activator.

The Schizosaccharomyces pombe mei3(+) gene is expressed only in diploid cells undergoing meiosis. Ectopic expression of mei3(+) in haploid cells causes meiotic catastrophe. Mei3 is an inhibitor of Ran1/Pat1 kinase and contains a nine-amino-acid motif, Mei3-RKDIII, that resembles two regions in the Ste11 substrate for Ran1/Pat1. Substitution of serine for Arg-81 within Mei3-RKDIII transforms the inhibitor into a substrate for Ran1/Pat1. Thus, it is likely that Mei3-RKDIII defines a pseudosubstrate sequence. In this study, we constructed a series of mei3 deletion mutations and assayed each for activity. This analysis indicates that the carboxy-terminal domain of Mei3 is sufficient for function in vivo. Alanine-scanning mutagenesis identifies critical residues within the inhibitory domain. Two mutations, SM1 and SM8, fail to cause meiotic catastrophe. The SM1 mutation contains alterations of amino acid residues in Mei3-RKDIII. Recombinant SM1 protein exhibits reduced ability to inhibit Ran1/Pat1 kinase in vitro and interacts inefficiently with the kinase in a two-hybrid assay. The SM8 protein binds to Ran1/Pat1 in a two-hybrid assay but fails to inhibit Ran1/Pat1 substrate phosphorylation in vitro. These findings provide evidence that Mei3-RKDIII defines a Ran1/Pat1-binding site that is necessary but not sufficient for inhibition of the kinase. Using fusions to green fluorescent protein, the cellular localization of Ran1 and Mei3 was examined in living cells. Ran1 is concentrated in the nucleus. Mei3 is also enriched in the nucleus and, consistent with the genetic and biochemical results, the inhibitory domain of Mei3 is sufficient for nuclear localization.

Amino Acid Sequence↗
PubMed1998

A low-viscosity soluble-fiber fruit juice supplement fails to lower cholesterol in hypercholesterolemic men and women.

This study was designed to determine whether a soluble dietary fiber supplement containing gum arabic and pectin in apple juice would lower serum lipids in 110 hypercholesterolemic men and women. Subjects were stabilized on an American Heart Association Phase I Diet for 8 wk. Those with elevated low density lipoprotein cholesterol levels, despite dietary modification, continued to follow the diet and were randomly assigned to receive 720 mL/d of apple juice containing 0 (control), 5, 9 or 15 g of gum arabic and pectin (4:1 ratio) for 12 wk, followed by a 6-wk apple juice-only washout phase. Serum lipid profiles, body weight and 3-day diet records were collected at 3-wk intervals. No significant differences among groups were observed in serum lipid responses during treatment or washout. During the treatment phase, mean serum total cholesterol and triglyceride concentrations increased by 3.5 and 28.5%, respectively (all groups combined, P < 0.0001). The high density lipoprotein cholesterol level did not change significantly from baseline in any group. During washout, mean total cholesterol concentration rose by an additional 2.4% (P < 0.05) compared with the value at the end of the treatment period, suggesting that the apple juice used to deliver the fiber supplement may have contributed to the adverse changes observed in the serum lipid profile. These findings do not support the hypothesized hypocholesterolemic effect of the gum arabic/pectin (4:1) mixture studied, but do underline the importance of selecting appropriate vehicles for delivery of dietary fiber mixtures.

Adult↗
PubMed1997

The Genome Sequence DataBase version 1.0 (GSDB): from low pass sequences to complete genomes.

The Genome Sequence DataBase (GSDB) has completed its conversion to an improved relational database. The new database, GSDB 1.0, is fully operational and publicly available. Data contributions, including both original sequence submissions and community annotation, are being accomplished through the use of a graphical client-server interface tool, the GSDB Annotator, and via GIO (GSDB Input/Output) files. Data retrieval services are being provided through a new Web Query Tool and direct SQL. All methods of data contribution and data retrieval fully support the new data types that have been incorporated into GSDB, including discontiguous sequences, multiple sequence alignments, and community annotation.

Animals↗
PubMed1997

Duration of postlaparoscopic pneumoperitoneum.

BACKGROUND: Patients who present with abdominal pain after recent laparoscopic surgery present a diagnostic dilemma when pneumoperitoneum is present. Previous studies do not define the duration of postlaparoscopic pneumoperitoneum. In this study, we attempted to define the duration of laparoscopic pneumoperitoneum and to identify factors which affect resolution time. METHODS: We followed 57 patients who underwent laparoscopic cholecystectomy (34), inguinal herniorraphy (20), or appendectomy (three). Serial abdominal films were taken until all residual gas was resolved. RESULTS: Thirty patients resolved their pneumoperitoneum within 24 h; 16 patients resolved between 24 h and 3 days; nine patients resolved between 3 and 7 days; two patients resolved between 7 and 9 days. Mean resolution time for all patients was 2.6 +/- 2.1 days. There was no apparent difference in resolution time between the three types of procedures; however, the sample size may be insufficient. Duration of the pneumoperitoneum did not correlate with gender, age, weight, initial volume of CO2 used, length of time for the procedure, or postoperative complications. Sixteen patients had bile spillage during cholecystectomy which significantly reduced the duration of postoperative pneumoperitoneum (p < 0.008), resulting in a mean resolution time of 1.3 +/- 0.9 days. While 14 patients reported postoperative shoulder pain, no correlation was found between the presence or duration of shoulder pain and the extent or duration of pneumoperitoneum. CONCLUSIONS: We conclude that the residual pneumoperitoneum following laparoscopic surgery resolves within 3 days in 81% of patients and within 7 days in 96% of patients. The resolution time was significantly less in patients sustaining intraoperative bile spillage during cholecystectomy. There was no correlation found between postoperative shoulder pain and the presence or duration of the pneumoperitoneum.

Adolescent↗
PubMed1997

Longitudinal study of nutrient and food intakes of infants aged 2 to 24 months.

OBJECTIVE: To determine the nutrient and food intakes of healthy, white infants from families of middle and upper socioeconomic status and to compare intakes to current recommendations. DESIGN: Using an incomplete random block design, we interviewed 98 mother-infant pairs longitudinally when infants were 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 months old. Data obtained included 24-hour dietary recalls, usual food intake, and food likes and dislikes. SETTING: Interviews were conducted in the mother's home by registered dietitians. Subjects resided in two urban areas of Tennessee. SUBJECTS: Of the original 98 subjects, 94 completed the 2-year study. RESULTS: Mean energy and nutrient intakes generally met or exceeded the Recommended Dietary Allowance (RDA). Exceptions were zinc and vitamin D, which were each below 100% of the RDA at 9 of the 10 data points, and vitamin E, which was below the RDA in the infants' second year. Fat intake decreased from more than 40% of energy in the first 6 months to 30% to 32% from 10 to 24 months. One third of the infants drank reduced-fat milks at 12 months and more than half drank them at 24 months. Although infants ate a variety of foods, vegetables often were the least favorite foods. A variety of dairy products provided calcium for the infant but lacked vitamin D. CONCLUSIONS: Several nutritional issues about infant feeding before 2 years of age arose. Low intakes of zinc, vitamin D, and vitamin E were observed. In the second year, low fat intake, use of reduced-fat milks, and dislike of vegetables were areas of concern.

Age Factors↗
PubMed1997

Transitions in infant feeding during the first year of life.

OBJECTIVE: To document ages at which transitions in infant feeding occur, to compare these transitions to literature reports from the 1970s and 80s, and to identify maternal characteristics related to the age of the infant when solid food was first introduced. METHODS: Ninety-eight mother/infant pairs (middle and upper socioeconomic status) participated in the longitudinal study. Using a randomized, incomplete block design, in-home interviews were conducted by trained personnel when infants were 2, 3, 4, 6, 8, 10, and 12 months of age; each mother/infant pair was seen four or five times. Information on food intake, including breast milk/formula, was collected at each interview. Means +/- SD and frequencies were calculated, and least squares analysis of variance was used to develop a predictive model related to the introduction of cereal. RESULTS: Most mothers decided on the initial feeding mode (breastfeeding or formula) prior to pregnancy; 83% breastfed initially although most (76%) totally discontinued breastfeeding by 6 months. Infants' ages varied greatly when each of the seven categories of food was introduced, cereal was added to the infants' diets at a mean age of 3.8 +/- 1.4 (SD) months, juice 4.7 +/- 2.2, fruit 4.9 +/- 1.6, vegetables 5.2 +/- 1.3, mixed foods 7.8 +/- 2.1, table foods 8.2 +/- 2.1, and meat 8.2 +/- 2.1. The multivariate model explained 59% of the variability in ages of infants when cereal (generally the first solid food) was added. Significant variables (p < or = 0.05) were feeding mode, recommendation by the physician, and the interaction between feeding mode and education of the mother. Mother's employment and sibling rank of the infant contributed to the model (p = 0.06 and p = 0.09, respectively). Infants' age when cereal was added was not related to the variables of gender or birth weight. CONCLUSIONS: The finding that the mothers' decision whether or not to breastfeed was made prior to conception supports the importance of population-based education aimed at women in the child-bearing years as well as patient instruction early in the pregnancy. However, the duration of breastfeeding was shorter than was reported in the 1980s. Infants varied greatly in ages when the seven categories of complementary foods were added to their diets. Although recommendations for delaying introduction of solid foods until the infant is 4 to 6 months of age have been in place for more than a decade, about half the mothers in this study did so earlier. Characteristics of mothers who introduced cereal earliest (i.e., mean age of infants < 4 months) were more likely to be formula feeding when cereal was added, to feed cereal via the bottle, to be primiparous, to be employed outside the home, and/or not to cite the physician as a source for guiding the infant's transition to supplemental food.

Adult↗
PubMed1996

Molecular mimicry in development: identification of ste11+ as a substrate and mei3+ as a pseudosubstrate inhibitor of ran1+ kinase.

ran1+ (pat1+) kinase inhibits exit from the mitotic cell cycle and entry into meiosis. Inactivation of ran1+ by mei3+ is sufficient to precipitate the entire meiotic developmental program. Here, we show that the ste11+ transcription factor is a substrate for ran1+ in vitro and that this reaction is directly inhibited by mei3+. Sequence comparison reveals that ste11+ contains two domains homologous to each other and to a domain of mei3+. Mutagenesis studies reveal that the regions of homology contain substrate specificity determinants. These results identify sequences critical for phosphorylation of ste11+ by ran1+ and suggest that mei3+ employs a pseudosubstrate mechanism for its inhibitory function.

Alanine↗
PubMed1996

The Genome Sequence DataBase (GSDB): meeting the challenge of genomic sequencing.

The genome sequence database (GSDB) is a complete, publicly available relational database of DNA sequences and annotation maintained by the National Center for Genome Resources (NCGR) under a Cooperative Agreement with the US Department of Energy (DOE). GSDB provides direct, client- server access to the database for data contributions, community annotation and SQL queries. The GSDB Annotator, a multi-platform graphic user interface, is freely available. Automatically updated relational replicates of GSDB are also freely available.

Amino Acid Sequence↗
PubMed1995

Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors.

Previous studies from this laboratory have shown that progesterone (PROG) treatment in ovariectomized rats produces an anti-anxiety response similar to that observed after the administration of prototypical anxiolytic benzodiazepine (BDZ) compounds. The PROG-induced anxiolytic response was highly correlated with an increased level of 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in the blood and brain, and was also associated with a facilitation of GABA-stimulated chloride ion (Cl-) influx in cortical synaptoneurosomes. This correlative evidence suggested that the anxiolytic effect of PROG was a result of its in vivo reduction to the neuroactive steroid, allopregnanolone. In this report, a series of studies was conducted to determine the mechanism(s) by which PROG alters behavior in animal models of anxiety. In the first experiment, ovariectomized rats were injected with PROG (1 mg/0.2 ml, SC) 4 h prior to a test in the elevated plus-maze. Some animals also received an injection of picrotoxin (0.75 mg/kg, IP), a GABAA receptor-gated Cl- channel antagonist, whereas other animals were pretreated with RU 38486 (5 mg/0.2 ml, SC), a progestin receptor antagonist. PROG elicited anxiolytic behavior in the plus-maze, an effect that was blocked by picrotoxin administration. Pretreatment with RU 38486 was not effective in altering PROG-induced anxiolytic behavior in the plus-maze. In a second experiment, the effect of PROG on behavior in the plus-maze was determined in the presence of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; 10 mg/0.2 ml, SC), a 5 alpha-reductase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

The sak1+ gene of Schizosaccharomyces pombe encodes an RFX family DNA-binding protein that positively regulates cyclic AMP-dependent protein kinase-mediated exit from the mitotic cell cycle.

In Schizosaccharomyces pombe, meiosis is initiated by conditions of nutrient deprivation. Mutations in genes encoding elements of the cyclic AMP-dependent protein kinase (cAPK) pathway interfere with meiosis. Loss-of-function alleles of genes that stimulate the activity of cAPK allow cells to bypass the normal requirement of starvation for conjugation and meiosis. Alternatively, loss-of-function alleles of genes that inhibit cAPK lead to the inability to undergo sexual differentiation. The cgs1+ gene encodes the regulatory subunit of cAPK, and the cgs2+ gene encodes a cyclic AMP phosphodiesterase. Thus, both genes encode proteins which negatively regulate the activity of cAPK. Loss of either cgs1 or cgs2 prevents haploid cells from conjugating and diploid cells from undergoing meiosis. In addition to these defects, cells are unable to enter stationary phase. We describe a novel gene, sak1+, which when present on a plasmid overcomes the aberrant phenotypes associated with unregulated cAPK activity. Genetic analysis of sak1+ (suppressor of A-kinase) reveals that it functions downstream of cyclic AMP-dependent protein kinase to allow cells to exist the mitotic cycle and enter either stationary phase or the pathway leading to sexual differentiation. The sak1+ gene is essential for cell viability, and a null allele causes multiple defects in cell morphology and nuclear division. Thus, sak1+ is an important regulatory element in the life cycle of S. pombe. Sequence analysis shows that the predicted product of the sak1+ gene is an 87-kDa protein which shares homology to the RFX family of DNA-binding proteins identified in humans and mice. One member of this family, RFX1, is a transcription factor for a variety of viral and cellular genes.

Alleles↗
PubMed1991

Interaction between ran1+ protein kinase and cAMP dependent protein kinase as negative regulators of fission yeast meiosis.

In fission yeast, meiosis is initiated by transcriptional activation of the mei3+ gene under the combined influence of the four mating type genes. The mei3+ gene product acts as a meiotic inducer by binding to and inhibiting the ran1+ protein kinase. Inactivation of ran1+ kinase is both necessary and sufficient to allow meiotic differentiation. We describe a class of mutants which are unable to undergo both normal meiosis and meiosis induced by inactivation of ran1+. In addition to these defects, the cells are sterile and unable to enter stationary phase. We have determined that the mutants define two complementation groups, designated cgs1+ and cgs2+ (continues to grow in stationary). The wild type allele of each gene has been isolated and sequence analysis of cgs1+ shows that it encodes a protein homologous to the regulatory subunit of cyclic AMP dependent protein kinase (cAPK). Biochemical studies demonstrate that in cgs1-1 containing cells, cAPK activity is unregulated by cyclic AMP (cAMP). Sequence analysis of cgs2+ shows that the predicted protein it encodes shares homology with a phosphodiesterase from Dictyostelium discoideum and biochemical studies demonstrate that cells containing a mutant allele of cgs2+ have elevated levels of cAMP. Thus, both genes encode proteins that regulate the activity of cAPK. We have previously shown that cells overproducing ran1+ kinase are meiotically defective. Here, we provide direct evidence that the meiotic defect caused by either unregulated cAPK activity or unregulated ran1+ kinase activity is due to inability to induce transcription of the mei2+ gene, which is required for meiotic initiation. We propose that the switch from vegetative growth to meiosis in fission yeast requires inactivation of ran1+ kinase and is prevented by unregulated levels of cAPK.

Amino Acid Sequence↗
PubMed1991

Controlled trial of a home and ambulatory program for asthmatic children.

Care of asthmatic children is often episodic and more therapeutic than preventive. A 2-year randomized, controlled trial involving 95 children measured the impact of a comprehensive home and ambulatory program for pediatric asthma management using objective outcome measures. Interventions for the study group during the first year included 3-month clinic visits, education, and home visits by a specially trained research nurse. Control subjects continued to receive regular care from a family physician or pediatrician. Eight-nine subjects (93%) completed the study. Study subjects had less school absenteeism than control subjects (10.7 vs. 16.0 days, P = .04) and showed significantly better small airway function after 1 year. Asthma severity improved in 13 study subjects and worsened in 5. The reverse was true for control subjects. Study subjects exhibited better metered aerosol technique than control subjects (P = .0005). Fewer days were spent in hospital by the study subjects admitted compared with control subjects (3.67 vs 11.2 days, P = .02). After 1 year, more study than control families (72.1% vs 33.1%, P = .006) reported that their asthmatic child took responsibility for the asthma management. The intervention failed to reduce exposure to secondhand smoke or to household pets. There were no significant differences in medical visits, theophylline levels, or records of asthma symptoms. One year after discontinuing the intervention, a marked "washout" effect was observed. Comprehensive ambulatory programs of childhood asthma management can improve objective measures of illness severity but must be sustained.

Adolescent↗