Biomedical subjects
M Shannon
Publications and source records attributed to M Shannon.
Methylenedioxymethamphetamine (MDMA, "Ecstasy").
Ecstasy (MDMA) is an amphetamine derivative of growing popularity. The drug produces a range of toxicities when taken either in standard doses or overdose. In overdose it has major toxicity, producing several different life-threatening manifestations. Hepatotoxicity and hyponatremia are common but poorly understood consequences of MDMA overdose. The drug can produce long-term, if not permanent, neurologic sequelae by destruction of serotonergic neurons. Chronic Ecstasy use can result in psychosis, depression, and suicidal ideation. In the ED setting, it is essential for physicians to recognize and treat appropriately those who present with intoxication from this drug.
Gamma-hydroxybutyrate, gamma-butyrolactone, and 1,4-butanediol: a case report and review of the literature.
GHB, GBL, and 1,4-BD are prevalent drugs of abuse in the United States. Unfortunately, attempts to regulate GHB have been circumvented by clandestine trafficking through the Internet and marketing of "natural" chemical precursors . Despite repeated FDA warnings to the public about their dangers as well as recent federal scheduling of GHB and GBL, they remain accessible as "club drugs" on Internet websites, as natural dietary supplements in health food stores, and as illicit products manufactured at home or in clandestine laboratories. EDs and poison control centers nationwide will undoubtedly continue to manage GHB, GBL, and 1,4-BD toxicities.
Immune function in female elite rowers and non-athletes.
OBJECTIVE: To compare immune function in female rowers and controls in the resting state, and then correlate the results with a two month history of upper respiratory tract infection (URTI). METHODS: Subjects included 20 elite female rowers located at the ARCO Olympic Training Centre in Chula Vista, California, and 19 non-athletic female controls. These two groups were compared cross sectionally for immune function and infection rates. RESULTS: Granulocyte/monocyte phagocytosis, oxidative burst activity, and plasma cytokine concentrations (interleukin-6, tumour necrosis factor-alpha, and interleukin-1 receptor antagonist) did not differ significantly between groups. Phytohaemagglutinin induced lymphocyte proliferative response (adjusted whole blood method) was significantly higher (31% and 36% for optimal and suboptimal concentrations respectively) in rowers than in controls. Natural killer cell activity was substantially higher (1.6-fold for total lytic units) in the female rowers than in controls. Two month health logs disclosed 5.2 (1.2) and 3.3 (1.1) days with URTI symptoms for the rowers and controls respectively (p = 0.268). For all 39 subjects combined, and for the 20 rowers separately, none of the immune parameters correlated significantly with number of days with URTI symptoms. CONCLUSIONS: In this cross sectional comparison of elite female rowers and non-athletes, a group difference was found for natural killer cell activity and phytohaemagglutinin induced proliferative response (whole blood technique), but not other measures of immune function. The number of days with URTI symptoms during the spring season did not differ between groups, and variations in blood measures of immunity were unrelated to URTI.
Characterization of the mouse Xpf DNA repair gene and differential expression during spermatogenesis.
The human XPF protein, an endonuclease subunit essential for DNA excision repair, may also function in homologous recombination. To investigate a possible link between mammalian XPF and recombination that occurs during meiosis, we isolated, characterized, and determined an expression profile for the mouse Xpf gene. The predicted mouse XPF protein, encoded by a 3.4-kb cDNA, contains 917 amino acids and is 86% identical to human XPF. Appreciable similarity also exists between mouse XPF and homologous proteins in budding yeast (Rad1), fission yeast (Rad16), and fruit fly (Mei-9), all of which have dual functions in excision repair and recombination. Sequence analysis of the 38.3-kb Xpf gene, localized to a region in proximal mouse chromosome 16, revealed greater than 72% identity to human XPF in 16 regions. Of these conserved elements, 11 were exons and 5 were noncoding sequence within introns. Xpf transcript and protein levels were specifically elevated in adult mouse testis. Moreover, increased levels of Xpf and Ercc1 mRNAs correlated with meiotic and early postmeiotic spermatogenic cells. These results support a distinct role for the XPF/ERCC1 junction-specific endonuclease during meiosis, most likely in the resolution of heteroduplex intermediates that arise during recombination.
Differential gene expression of mammalian SPO11/TOP6A homologs during meiosis.
As the initiator of DNA double-strand breaks during meiosis in Saccharomyces cerevisiae, the SPO11 protein is essential for recombination. Similarity between SPO11 and archaebacterial TOP6A proteins points to evolutionary specialization of a DNA cleavage function for meiotic recombination. To determine whether this extends to mammals, we isolated and characterized mouse and human SPO11 cDNAs. Mammalian SPO11 genes were found to be expressed at high levels only in testis, wherein mouse Spo11 transcript is restricted primarily to meiotic germ cells and is maximally expressed at midpachynema. Mouse Spo11 is located near the distal end of chromosome 2, while human SPO11 is found in the homologous position of chromosome 20q13.2-13.3, a region that is amplified in some breast cancers. Sequence homology and differential expression together support a highly conserved role for SPO11 in the enzymatic cleavage of DNA that accompanies meiotic recombination.
Expression specificity of the mouse exonuclease 1 (mExo1) gene.
Genetic recombination involves either the homo-logous exchange of nearly identical chromosome regions or the direct alignment, annealing and ligation of processed DNA ends. These mechanisms are involved in repairing potentially lethal or mutagenic DNA damage and generating genetic diversity within the meiotic cell population and antibody repertoire. We report here the identification of a mouse gene, termed mExo1 for mouse exonuclease 1, which encodes a approximately 92 kDa protein that shares homology to proteins of the RAD2 nuclease family, most notably human 5' to 3' exonuclease Hex1/hExo1, yeast exonuclease 1 (Exo1) proteins and Drosophila melanogaster Tosca. The mExo1 gene maps to distal chromosome 1, consistent with the recent mapping of the orthologous HEX1 / hEXO1 gene to chromosome 1q42-q43. mExo1 is expressed prominently in testis, an area of active homologous recombination, and spleen, a prominent lymphoid tissue. An increased level of mExo1 mRNA was observed during a stage of testis development where cells that are actively involved in meiotic recombination arise first and represent a significant proportion of the germ cell population. Comparative evaluation of the expression patterns of the human and mouse genes, combined with previous biochemical and yeast genetic studies, indicate that the Exo1-like proteins are important contributors to chromosome processing during mammalian DNA repair and recombination.
Lead poisoning in adolescents who are competitive marksmen.
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Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice.
Antibodies to single-stranded (ss)DNA are expressed in patients with systemic lupus erythematosus and in lupus-prone mouse models such as the MRL/Mp-lpr/lpr (MRL/lpr) strain. In nonautoimmune mice, B cells bearing immunoglobulin site-directed transgenes (sd-tgs) that code for anti-ssDNA are functionally silenced. In MRL/lpr autoimmune mice, the same sd-tgs are expressed in peripheral B cells and these autoantibodies gain the ability to bind other autoantigens such as double-stranded DNA and cell nuclei. These new specificities arise by somatic mutation of the anti-ssDNA sd-tgs and by secondary light chain rearrangement. Thus, B cells that in normal mice are anergic can be activated in MRL/lpr mice, which can lead to the generation of pathologic autoantibodies. In this paper, we provide the first direct evidence for peripheral rearrangement in vivo.
Models for antigen receptor gene rearrangement. I. Biased receptor editing in B cells: implications for allelic exclusion.
Recent evidence suggests that lymphocyte Ag receptor gene rearrangement does not always stop after the expression of the first productively rearranged receptor. Light chain gene rearrangement in B cells, and alpha-chain rearrangement in T cells can continue, which raises the question: how is allelic exclusion maintained, if at all, in the face of continued rearrangement? In this and the accompanying paper, we present comprehensive models of Ag receptor gene rearrangement and the interaction of this process with clonal selection. Our B cell model enables us to reconcile observations on the kappa:lambda ratio and on kappa allele usage, showing that B cell receptor gene rearrangement must be a highly ordered, rather than a random, process. We show that order is exhibited on three levels: a preference for rearranging kappa rather than lambda light chain genes; a preference to make secondary rearrangements on the allele that has already been rearranged, rather than choosing the location of the next rearrangement at random; and a sequentiality of J segment choice within each kappa allele. This order, combined with the stringency of negative selection, is shown to lead to effective allelic exclusion.
Life-threatening events after theophylline overdose: a 10-year prospective analysis.
BACKGROUND: Despite the declining use of theophylline, episodes of intoxication continue to occur, producing seizures, arrhythmias, and death. OBJECTIVES: To further characterize major toxic effects and to examine the efficacy of existing interventions. METHODS: We conducted a longitudinal cohort study of patients with theophylline overdose. For a 125-month period, all patients referred to the Massachusetts Poison Control System in Boston with a serum theophylline concentration of 167 micromol/L (> or =30 microg/mL) or more were followed up prospectively. Recommended management by the poison center was uniform and protocol based. RESULTS: Three hundred fifty-six patients were enrolled. Mean age was 34.5 years (range, 3 days to 98 years). Mean peak serum theophylline concentration was 336 micromol/L (60 microg/mL) (range, 167-1360 micromol/L [30-245 microg/mL]). One hundred sixty-two patients (45.5%) had acute, 144 (40.4%) had chronic, and 50 (14.0%) had acute-on-therapeutic poisoning. Seventy-four patients (20.8%) developed cardiac arrhythmias, and 29 (8.2%) developed seizures. Fifteen patients (4.2%) died, 11 (73%) of whom had chronic overmedication. Arrhythmias were significantly more common after chronic overmedication than after acute intoxication (35% vs. 10%; odds ratio, 4.97; 95% confidence interval, 2.68-9.23; P<.001). Eight percent of patients with chronic overmedication died compared with 2.5% of those with acute intoxication (odds ratio, 3.20; 95% confidence interval, 1.01-10.39; P = .04). There was no significant difference in the rate of major toxic effects (25.9% vs. 30.0%) or death (4.6% vs. 3.7%) among patients referred from 1986 to 1991 and from 1992 to 1996. CONCLUSIONS: Theophylline intoxication results in substantial morbidity and mortality, particularly in those with chronic overmedication. Treatment strategies fail to improve clinical outcome. With safer alternative options available, the current indications for theophylline should be rigorously evaluated with a goal toward minimal use of this agent.
Reconciling repertoire shift with affinity maturation: the role of deleterious mutations.
The shift in Ab repertoire, from Abs dominating certain primary B cell responses to genetically unrelated Abs dominating subsequent "memory" responses, challenges the accepted paradigm of affinity maturation. We used mathematical modeling and computer simulations of the dynamics of B cell responses, hypermutation, selection, and memory cell formation to test hypotheses attempting to explain repertoire shift. We show that repertoire shift can be explained within the framework of the affinity maturation paradigm, only when we recognize the destructive nature of hypermutation: B cells with a high initial affinity for the Ag are less likely to improve through random mutations.
Prevalence of alcohol problems among pediatric residents.
OBJECTIVE: To measure the prevalence of alcohol-related problems among pediatric trainees. METHODS: An alcoholism screening test was administered anonymously to participants at a mandatory substance abuse education and prevention program. SETTING: A large urban pediatric residency training program. SUBJECTS: One hundred fifteen pediatric residents attended the program during 3 consecutive years (1996-1998). Eighty-five (74%) screening tests were returned and 81 (70%) were analyzed MAIN OUTCOME MEASURE: The 25-item Michigan Alcoholism Screening Test (MAST). Differential MAST cutpoints have been established to "suggest" or "indicate" a lifetime diagnosis of alcoholism. RESULTS: Twelve residents (15%) had scores suggestive and 6 (7%) indicative of alcoholism. Twenty-eight (35%) admitted to having alcohol-associated amnesia (blackouts), 13 (16%) to "feeling bad" about their drinking, 9 (11%) to drinking before noon, 6 (7%) to getting into fights when drunk, and 2 (2%) to alcohol-related marital problems. However, only 1 (1%) had gone to anyone for help and none admitted to alcohol-related problems at work. CONCLUSIONS: These screening data suggest that alcohol abuse and related problems exist among pediatric trainees at troubling rates. While more than one third of the trainees had experienced a serious consequence from heavy drinking, only 1 had gone for help and problems were not apparent at work. Greater emphasis should be placed on alcohol prevention and early intervention programs as a routine part of pediatric training.
Molecular characterization of Zfp54, a zinc-finger-containing gene that is deleted in the embryonic lethal mutation tw18.
Mapping studies have indicated that hundreds of Kruppel-type zinc-finger (ZNF)-containing genes are present within the genomes of mammals. One-third or more of these genes contain a second, highly conserved element termed the Kruppel-associated box (KRAB). In a recent study, several partial cDNA clones encoding distinct KRAB elements were mapped in mouse. One of these sequences, clone KRAB10, was assigned to mouse Chromosome (Chr) 9. We have isolated the complete coding portion of the KRAB10-containing gene and demonstrate that it is identical to Zfp54, one of several related ZNF genes that are located on mouse Chr 17 in the interval that is deleted in the tw18 mutation. Sequence analysis has shown that the KRAB A domain encoded by Zfp54 is highly similar to the comparable motif encoded by its nearest known neighbor, Zfp51. However, other portions of the related proteins, including their ZNF domains, are noticeably different in structure. Studies of Zfp54 expression revealed the presence of transcript in several adult tissues and in embryos throughout development; however, elevated levels of transcript were detected only in adult testis and in 7-day-old embryos. These data suggest that Zfp54 gene expression is under spatial and temporal control and may, therefore, play important roles in male germ cell and embryonic development.
Immune response to two hours of rowing in elite female rowers.
The influence of carbohydrate (C) versus placebo (P) beverage consumption on the immune and hormonal responses to normal rowing training sessions was measured in 15 elite female rowers residing at the U.S. Olympic Training Center. In a randomized, counterbalanced design, the athletes received C or P beverages (double-blind) before, during, and after two 2-hour bouts of rowing (one day apart). Blood samples were collected before, and 5-10 minutes and 1.5 hours after rowing. Metabolic measures indicated that training was performed at moderate intensities, with some high intensity intervals interspersed throughout the sessions (mean oxygen uptake of 2,307+/-169 m x min(-1), 57% of VO2max). Glucose and insulin were significantly lower after two hours of rowing with ingestion of P compared to C. The patterns of change in cortisol, growth hormone, epinephrine, and norepinephrine did not differ between C and P rowing trials. Blood neutrophil cell counts and the neutrophililymphocyte ratio were significantly higher following P versus C rowing sessions. The patterns of change in blood lymphocyte and lymphocyte subset counts, and lymphocyte proliferative responses did not differ between P and C trials, except for a slight difference in NK cell counts and activity. In summary, minimal changes in blood hormonal and immune measures were found following two-hour bouts of training in elite female rowers. Carbohydrate compared to placebo ingestion attenuated the moderate rise in blood neutrophil counts, but had slight or no effects on other immune parameters.
Therapeutics and toxicology.
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Reactive airways dysfunction and systemic complaints after mass exposure to bromine.
Occasionally children are the victims of mass poisoning from an environmental contaminant that occurs due to an unexpected common point source of exposure. In many cases the contaminant is a widely used chemical generally considered to be safe. In the following case, members of a sports team visiting a community for an athletic event were exposed to chemicals while staying at a local motel. Bromine-based sanitizing agents and other chemicals such as hydrochloric acid, which were used in excess in the motel's swimming pool, may have accounted for symptoms experienced by the boy reported here and at least 16 other adolescents. Samples of pool water contained excess bromine (8.2 microg/mL; ideal pool bromine concentration is 2-4 microg/mL). Symptoms and signs attributable to bromine toxicity included irritative skin rashes; eye, nose, and throat irritation; bronchospasm; reduced exercise tolerance; fatigue; headache; gastrointestinal disturbances; and myalgias. While most of the victims recovered within a few days, the index case and several other adolescents had persistent or recurrent symptoms lasting weeks to months after the exposure.
Monkeybar injuries: complications of play.
BACKGROUND: Playground equipment resulted in >200 000 injuries from 1990 to 1994, according to the Consumer Product Safety Commission; 88% were attributable to climbers (monkeybars/jungle gyms [MB/JGs]), swings, and slides. Equipment-specific injury requiring emergency department (ED) evaluation has not been reported previously. OBJECTIVE: To describe the spectrum of significant MB/JG-related injuries. METHODS: A 2-year retrospective chart review was performed using the computerized charting system at a large urban Children's Hospital/Regional Pediatric Trauma Center with 50 000 ED visits per year. A telephone survey also was conducted after the chart review to obtain additional information concerning the injury location, the surface type below the equipment, and the presence of adult supervision. RESULTS: A total of 204 patients were identified. Mean age was 6.2 years (range, 20 months to 12 years); 114 (56%) were male. A seasonal variation was noted with June to August accounting for 43% of visits. Injuries included fractures in 124 (61%), contusions in 20 (10%), neck and back strains in 17 (8%), lacerations in 16 (8%), closed head injuries in 10 (5%), abdominal trauma in 5 (3%), genitourinary injuries in 5 (3%), and miscellaneous injuries in the remainder. Among fractures, 90% were fractures of the upper extremity; 48 (40%) were supracondylar fractures. One child sustained a C7 compression fracture. Abdominal injuries included 1 child who sustained a splenic laceration. All genitourinary injuries (2 vaginal hematomas, 1 vaginal contusion, 1 penile laceration, and 1 urethral injury) were from straddle-type injuries. Fifty-one (25%) patients were admitted to the hospital. Of these, 47 (92%) required an operative procedure (orthopedic reduction or vaginal examination under anesthesia). Analysis of the telephone data revealed that the surface did not influence the injury type. Of the 79 fractures, 30 occurred on "soft surfaces." Injury type was associated significantly with chronologic age. Younger children (1 to 4 years of age) sustained more long-bone fractures than did older children. The presence of adult (at least 18 years of age) supervision, did not influence the occurrence of fractures. CONCLUSIONS: These data suggest that 1) a significant proportion (25%) of MB/JG-related injuries that are evaluated in the ED require hospitalization; 2) most of the injuries resulting in admission will require operative intervention (92%); 3) the surface below the equipment has no influence on the type or severity of the injury; 4) younger children are more likely to sustain long-bone fractures than are older children; and 5) adult supervision does not influence the injury pattern. These data identify the need for additional investigation of means of making MB/JGs safer for child use.