MYST opportunities for growth control: yeast genes illuminate human cancer gene functions.

The MYST family of histone acetyltransferases (HATs) was initially defined by human genes with disease connections and by yeast genes identified for their role in epigenetic transcriptional silencing. Since then, many new MYST genes have been discovered through genetic and genomic approaches. Characterization of the complexes through which MYST proteins act, regions of the genome to which they are targeted and biological consequences when they are disrupted, all deepen the connections of MYST proteins to development, growth control and human cancers. Many of the insights into MYST family function have come from studies in model organisms. Herein, we review functions of two of the founding MYST genes, yeast SAS2 and SAS3, and the essential yeast MYST ESA1. Analysis of these genes in yeast has defined roles for MYST proteins in transcriptional activation and silencing, and chromatin-mediated boundary formation. They have further roles in DNA damage repair and nuclear integrity. The observation that MYST protein complexes share subunits with other HATs, histone deacetylases and other key nuclear proteins, many with connections to human cancers, strengthens the idea that coordinating distinct chromatin modifications is critical for regulation.

Esa1p is an essential histone acetyltransferase required for cell cycle progression.

Histones are dynamically modified during chromatin assembly, as specific transcriptional patterns are established, and during mitosis and development. Modifications include acetylation, phosphorylation, ubiquitination, methylation, and ADP-ribosylation, but the biological significance of each of these is not well understood. For example, distinct acetylation patterns correlate with nucleosome formation and with transcriptionally activated or silenced chromatin, yet mutations in genes encoding several yeast histone acetyltransferase (HAT) activities result in either no cellular phenotype or only modest growth defects. Here we report characterization of ESA1, an essential gene that is a member of the MYST family that includes two yeast silencing genes, human genes associated with leukemia and with the human immunodeficiency virus type 1 Tat protein, and Drosophila mof, a gene essential for male dosage compensation. Esa1p acetylates histones in a pattern distinct from those of other yeast enzymes, and temperature-sensitive mutant alleles abolish enzymatic activity in vitro and result in partial loss of an acetylated isoform of histone H4 in vivo. Strains carrying these mutations are also blocked in the cell cycle such that at restrictive temperatures, esa1 mutants succeed in replicating their DNA but fail to proceed normally through mitosis and cytokinesis. Recent studies show that Esa1p enhances transcription in vitro and thus may modulate expression of genes important for cell cycle control. These observations therefore link an essential HAT activity to cell cycle progression, potentially through discrete transcriptional regulatory events.

Randomised trial of oral morphine for painful episodes of sickle-cell disease in children.

BACKGROUND: Oral controlled-release morphine can provide effective analgesia through a non-invasive route and may facilitate outpatient management of severe episodes of sickle-cell pain. We compared the clinical efficacy and safety of oral morphine with continuous intravenous morphine in children with severe episodes of sickle-cell pain, by a double-blind, randomised, parallel-group design. METHODS: 56 children aged 5-17 years received loading doses of intravenous morphine of up to 0.15 mg/kg, followed by randomly assigned oral morphine 1.9 mg/kg every 12 h plus intravenous placebo (saline), or intravenous morphine 0.04 mg kg-1 h-1, plus placebo tablet. Breakthrough pain was treated with oral, immediate-release morphine 0.4 mg/kg every 2-3 h as required. Pain was assessed daily at 0900 h, 1300 h, 1700 h, and 2100 h with a picture face scale, a pictorial scale (Oucher), a behavioural-observational scale (CHEOPS), and by an investigator. FINDINGS: 50 children completed the study (28 boys, 22 girls; mean age 11.2 years [SD 3.5]; mean oral morphine dose 2.99 mg/kg daily [0.75]; mean intravenous morphine dose, 0.81 mg/kg daily [0.30]). Mean overall pain scores were similar for oral and intravenous morphine (CHEOPS, 6.3 [1.5] vs 6.4 [1.4], p = 0.8; Oucher, 31.5 [25.4] vs 39.2 [21.7], p = 0.3; Faces, 2.2 [1.4] vs 2.4 [1.3], p = 0.6; clinical rating, 1.7 [0.7] vs 1.9 [0.5], p = 0.3). Opioid analgesia was required for a mean of 4.2 days (1.7) and 5.4 days (2.6), respectively (p = 0.0591). Pain scores from all scales correlated significantly (r = 0.5865-0.8980, p = 0.0001). Frequency of rescue analgesia did not differ significantly between the oral and intravenous morphine groups (0.7 [0.8] vs 0.9 [0.7] doses daily, p = 0.2). Frequency and severity of adverse events did not differ significantly. INTERPRETATION: Oral, controlled-release morphine is a reliable, non-invasive alternative to continuous intravenous morphine for the management of painful episodes of sickle-cell disease in children.

A randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children.

OBJECTIVE: To compare the effectiveness of intravenous penicillin vs clindamycin for the treatment of aspiration pneumonia. DESIGN: A double-blind, randomized controlled trial. SETTING: A tertiary care pediatric hospital. PATIENTS: We enrolled 42 children, aged 6 months to 18 years, who were admitted to the hospital for the treatment of aspiration pneumonia. All of the children had underlying conditions that predispose to aspiration. INTERVENTION: The patients were randomly assigned to receive intravenous penicillin G sodium, 250,000 U/kg every 24 hours, or intravenous clindamycin phosphate, 30 mg/kg every 24 hours. MAIN OUTCOME MEASURE: The primary outcome measure was "time to ready for discharge" from the hospital. RESULTS: In an effectiveness (intention to treat) analysis, the median time (interquartile range) to ready for discharge from the hospital was 4.9 days (range, 2.8-6.5 days) in the penicillin-treated group and 3.4 days (range, 2.3-6.8 days) in the clindamycin-treated group (P = .66). Results were not markedly altered when adjusted for the age difference of the groups or in the efficacy analysis (after the exclusion of 9 patients who withdrew from the trial). Rates for readmission to the hospital were similar in the 2 groups. CONCLUSION: Penicillin and clindamycin seem to be equally effective for the treatment of aspiration pneumonia in children hospitalized for this illness.

Social phobia in disabled workers with chronic musculoskeletal pain.

The present study assessed the prevalence and impact of social phobia and other anxiety disorders in disabled workers with chronic musculoskeletal pain. Potential participants were 200 disabled workers consecutively referred to an interdisciplinary tertiary care centre. A two stage screening process was used in which: (a) a self-report battery was given during a pre-admission visit, and (b) pre-planned selection criteria were applied to the self-report instruments to select patients for a structured diagnostic interview. Fifty-four of the 146 patients who provided complete responses on the self-report battery met criteria for interview. Twenty-six patients (17.8%) met DSM-IV criteria for a current anxiety disorder and, of these, 16 (11.0%) were diagnosed with social phobia. Subjects with social phobia rated themselves as having less social support than subjects with no psychiatric disorder, but the groups did not differ in pain-related life interference, personal control, or health care utilization. The results suggest that social phobia is over-represented in disabled workers with chronic musculoskeletal pain and should be noted as a comorbid condition that may compound both suffering and disability.

Social, blood/injury, and agoraphobic fears in patients with physically unexplained chronic pain: are they clinically significant?

Recently, there has been increased interest in the extent to which chronic pain patients fear and avoid activities that are thought to be related to the experience of pain. To date, however, few studies have evaluated the nature and extent of nonpain fears in these patients. The purpose of the present study was to address this paucity. The Fear Questionnaire was administered to 130 patients with physically unexplained chronic pain and 93 patients with a chronic condition unrelated to pain. Results indicated that the chronic pain patients were more fearful and avoidant of social interactions/situations and blood/injury than were the patient controls. Agoraphobia was minimal and did not differ significantly between groups. As well, the proportions of chronic pain patients indicating definite avoidance of particular situations related to blood/injury phobia (i.e., injection/minor surgery, hospitals, sight of blood, and thoughts of injury/illness) and social phobia (i.e., being watched/stared at, and speaking/acting to an audience) were significantly greater when compared to the patient controls. These results indicate that nonpain fear and avoidance are common in patients with chronic pain. Implications regarding the significance of these fears and avoidance behaviours on the experience and maintenance of pain symptoms and related disability are discussed.

The efficacy and safety of granisetron in pediatric cancer patients who had failed standard antiemetic therapy during anticancer chemotherapy.

PURPOSE: This study was undertaken to evaluate the safety and efficacy of granisetron (a 5-hydroxytryptamine. antagonist) in children with malignant disease who had previously experienced unacceptable nausea and vomiting and/or adverse effects associated with standard antiemetic therapy. PATIENTS AND METHODS: Thirty children 3-18 years of age who were receiving anticancer chemotherapy were enrolled in the study. Patients received a prophylactic dose of granisetron before chemotherapy and two subsequent doses as needed. If further antiemetics were required, standard therapy was given and those patients were classified as treatment failures. Patients received granisetron during one to three cycles of chemotherapy; a total of 66 courses were given. RESULTS: Eighty-seven percent of patients had good control of nausea and vomiting with granisetron alone; 90% of patients elected to receive granisetron with subsequent chemotherapy. No loss of efficacy was noted with repeated cycles in 21 patients. No serious adverse events occurred. CONCLUSIONS: Intravenous granisetron (20 micrograms/kg/dose) appears to be a safe and effective drug for pediatric patients receiving emetogenic chemotherapy.

Biochemical and genetic evidence for a pseudoknot structure at the 3' terminus of the poliovirus RNA genome and its role in viral RNA amplification.

The sequences in the plus-stranded poliovirus RNA genome that dictate the specific amplification of viral RNA in infected cells remain unknown. We have analyzed the structure of the 3' noncoding region of the viral genome by thermodynamic-based structure calculation and by chemical and enzymatic probing of in vitro-synthesized RNAs and provide evidence for the existence of an RNA pseudoknot structure in this region. To explore the functional significance of this structure, revertants of a mutant bearing a lesion in the proposed pseudoknot and exhibiting a temperature-sensitive defect in viral RNA synthesis were isolated and mapped. The results of this genetic analysis established a correlation between the structure of the 3' terminus of the viral RNA and its function in vivo in RNA amplification. Furthermore, phylogenetic analysis indicated that a similar structure could be formed in coxsackievirus B1, a related enterovirus, which further supports a role for the pseudoknot structure in viral RNA amplification in infected cells.

Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester.

Lithium carbonate is an effective drug for prophylaxis and treatment of major affective disorders. In-utero exposure to lithium during the first trimester of pregnancy might be associated with an increased risk of cardiac malformations, especially the rare Ebstein's anomaly. We prospectively recruited and followed 148 women (mean age 30 years, SD 5 range 15-40) using lithium during the first trimester of pregnancy, who consulted four teratogen information centres in the USA and Canada. Pregnancy outcome was compared with that of controls matched for maternal age. We had complete follow-up of pregnancy outcome in 138 of 148 patients recruited. In the other 10, fetal echocardiograms were available but postnatal follow-up was not done. Mean daily dose of lithium was 927 mg (SD 340). Rates of major congenital malformations did not differ between the lithium (2.8%) and control (2.4%) groups. 1 patient in the lithium group chose to terminate pregnancy after Ebstein's anomaly was detected by a prenatal echocardiogram. There was 1 ventricular septal defect in the controls. Birthweight was significantly higher in the lithium-exposed infants than in the controls despite identical gestational ages (3475 [660] g vs 3383 [566] g, p = 0.02). The true difference in birthweight might have been even larger, since significantly more women using lithium than controls were cigarette smokers (31.8% vs 15.5%, p = 0.002). These results indicate that lithium is not an important human teratogen. Women with major affective disorders who wish to have children may continue lithium therapy, provided that adequate screening tests, including level II ultrasound and fetal echocardiography, are done.